Β-keto Acids Research Articles

Synthesis of β-Keto Acids and Methyl Ketones UsingBis(trimethylsilyl) Malonate and Triethylamine in the Presence of Lithium or Magnesium Halides

Abstract Bis(trimethylsilyl) malonate is acylated in good yields with acid chlorides and acyl carbonates using triethylamine and magnesium or lithium salts to give β-keto acids or methyl ketones. Compared to other procedures, which use strong bases, this method is inexpensive, safe and convenient; especially for large scale reactions.

Lipoic acid and diabetes II: Mode of action of lipoic acid

Intraperitoneal administration of lipoic acid (10 mg/100 g) does not effect changes in serum insulin levels in normal and alloxan diabetic rats, while normalising increased serum pyruvate, and impaired liver pyruvic dehydrogenase characteristic of the diabetic state. Dihydrolipoic acid has been shown to participate in activation of fatty acids with equal facility as coenzyme A. Fatty acyl dihydrolipoic acid however is sparsely thiolyzed to yield acetyl dihydrolipoic acid. Also acetyl dihydrolipoic acid does not activate pyruvate carboxylase unlike acetyl coenzyme A. The reduced thiolysis of Β-keto fatty acyl dihydrolipoic acid esters and the lack of activation of pyruvic carboxylase by acetyl dihydrolipoic acid could account for the antiketotic and antigluconeogenic effects of lipoic acid

ChemInform Abstract: REACTION OF FLUORINE‐CONTAINING β‐KETOESTERS WITH BIFUNCTIONAL N‐NUCLEOPHILES

AbstractWerden die Ketoester (I) mit Hydrazin, Hydrazinhydrat oder Phenylhydrazin (II) in siedendem Methanol umgesetzt, so entstehen die Pyrazolone (III).

Association and tautomeric equilibrium in β-keto acids

Examination of the concentration dependence of n.m.r. spectra of 3-oxo-3-phenylpropanoic acid and related compounds demonstrates that the tautomeric equilibrium constants in β-keto acids is dependent upon the state of association.

Reaction of fluorine-containing ?-ketoesters with bifunctional N-nucleophiles

1. Fluoroalkyl β-ketoesters with phenylhydrazine at 20‡C form phenylhydrazones of the β-ketoesters, which form hydroxypyrazoles on heating. 2. 4,4-Difluoroacetoacetic ester with ethylenediamine yields the 3,3′-(N,N′-ethylenediamine)-bis-4,4-difluoro-2-butenoate ester whereas on lengthening the fluoroalkyl substituent internal salts of the aminoethylamides of the β-keto acids are formed from the β-ketoesters. 3. Hydrazine and o-phenylenediamine react with fluorine-containing β-ketoesters with the formation of pyrazoles and benzodiazepinones respectively.

Synthesis of pyrazofurin and its analogues

Pyrazofurin and its analogues have been synthesized from ribosyl β-keto acid derivatives, which can be readily prepared by Wittig reaction of the protected D-ribose with phosphoranes.

Acylation of Trimethylsilyl Acetate. A Synthetic Route to β-Keto Acids and Methyl Ketones

Abstract β-Keto acids are important intermediates for the preparation of ketones1,2 and for the synthesis of a variety of natural products.3,4 These compounds have also been used extensively for studies of the mechanism of decarboxylation.5,6

Synthesis of 1,3-dioxin-4-one derivatives.

A facile and general synthesis of 2, 2-dimethyl-1, 3-dioxin-4-one derivatives (1) is reported. Treatment of β-keto acids with a mixture of acetone, acetic anhydride, and conc. sulfuric acid or with a mixture of isopropenyl acetate and conc. sulfuric acid gave 2, 2-dimethyl-1, 3-dioxin-4-ones (1). Similar treatment of tert-butyl esters of β-keto acids also gave 1.

SYNTHESIS AND USES OF β-KETO ACIDS. A BRIEF REVIEW

(1982). SYNTHESIS AND USES OF β-KETO ACIDS. A BRIEF REVIEW. Organic Preparations and Procedures International: Vol. 14, No. 4, pp. 249-264.

Evidence for the occurrence of a novel pathway of benzoic acid metabolism involving the addition of a two carbon fragment

The metabolism of benzoic acid has been investigated in the horse as part of a study on the fate of carboxylic acids in this species (1). The greater part of an orally administered dose of the acid is excreted in the urine in the form of the glycine conjugate, hippuric acid, together with small quantities of benzoyl glucuronide and the free acid. In addition to these the urine samples were found to contain a further metabolite, accounting for some 2% of the dose which exhibited a chromatographic mobility intermediate between that of the parent acid and hippuric acid. This communication provides evidence that this unknown metabolite arises from the addition of a two carbon fragment to the carboxyl group of benzoic acid, leading to the excretion of β-hydroxyphenylpropionic acid and the corresponding β-keto acid in the urine.

Crown ether catalysis of decarboxylation and decarbalkoxylation of β-keto acids and malonates: a synthetic application

The effect of 18-crown-6 ether on the decarboxylation rates of the sodium and potassium salts of 3-camphorcarboxylic acid 1 and of 1-carbomethoxy-1-carboxycyclohexane 2 was studied. For 2 the K-18C6 salt reacted ca. 104 times faster than the parent acid. This remarkable difference in reactivity was used in developing a one-pot, two-step procedure for decarbalkoxylation of malonic esters. This procedure was then applied to a range of malonates, β-keto esters, and an α-cyano ester. The effect of 15C5, other cations, and good nucleophiles was also studied.

ChemInform Abstract: THE CARBONYLATION OF α‐HALOACETOPHENONES AND BENZYL HALIDES BY DISODIUM TETRACARBONYLFERRATE

α-Haloacetophenones and benzyl chlorides can be converted into derivatives of β-keto acid and phenylacetic acid respectively by two succesive reactions, with Na2-Fe(CO)4 and then with nitrobenzenes or iodine-ethanol as the oxidizing reagents.

Metabolism of l-β-lysine in a Pseudomonas: Conversion of 6- N-acetyl- l-β-lysine to 3-keto-6-acetamidohexanoate and of 4-aminobutyrate to succinic semialdehyde by different transaminases

Some kinetic properties of two new species of transaminase found in extracts of a β-lysine-utilizing Pseudomonas are reported. Transaminase A catalyzes transamination between 6- N-acetyl- l-β-lysine (3-amino-6-acetamidohexanoate) and α-ketoglutarate to form 3-keto-6-acetamidohexanoate and glutamate. Transaminase B catalyzes a reaction between 4-aminobutyrate and pyruvate to form succinic semialdehyde and alanine. The formation of both transaminases is induced by growth of the bacteria on l-β-lysine, although transaminase B is also produced in the absence of this substrate. Transaminase A requires pyridoxal phosphate for activity. The β-keto acid formed from acetyl-β-lysine by transaminase A has been purified and characterized by decarboxylation, conversion to a formazan, reduction to a stable β-hydroxy acid, and conversion of the latter to its methyl ester. Transaminase B, unlike previously reported transaminases utilizing 4-aminobutyrate, cannot use α-ketoglutarate as an amino group acceptor. This enzyme is not stimulated by addition of pyridoxal phosphate, but is inhibited by hydroxylamine or cyanide. Both transaminases appear to function in the main pathway of β-lysine degradation.

The Carbonylation of α-Haloacetophenones and Benzyl Halides by Disodium Tetracarbonylferrate

Abstract α-Haloacetophenones and benzyl chlorides can be converted into derivatives of β-keto acid and phenylacetic acid respectively by two succesive reactions, with Na2-Fe(CO)4 and then with nitrobenzenes or iodine-ethanol as the oxidizing reagents.

Specificity in the formation of a seven-membered ring in the synthesis of dihydro-1.5-benzodiazepinones from aromatic diamines

It is shown that a mixture of 7- and 8-substituted 2,3-dihydro-1,5-benzodiazepinones is formed in the reaction of unsymmetrical aromatic diamines (4-chloro-,4-methyl-, and 4-methoxy-o-phenylenediamines) with acetoacetic and benzoylacetic esters under severe conditions. The corresponding anilide of benzoylacetic acid, the cyclization of which again leads to a mixture of isomeric dehydrobenzodiazepinones, can be isolated (in the case of benzoylacetic ester) when the concentrations of the reacting substances and the reaction time are decreased; this makes it possible to assume amidation of the Β-keto acids as one of the steps in the high-temperature synthesis of dihydrobenzodiazepinones. The quantitative ratio of the isomers formed in the reaction was determined by UV spectroscopy. The UV, IR, and PMR spectral data are presented.

Ammoniation of Aflatoxin B1: Isolation and Identification of the Major Reaction Product

Abstract The major product formed from reacting pure aflatoxin B1 with ammonium hydroxide at 100°C under pressure was isolated in crystalline form. The compound, molecular weight 286 (mass spectra), ultraviolet (UV) absorption, λMe0H 227, 324 nm (ε 15,920, 12,440), is nonfluorescent, exhibits phenolic properties, and lacks the lactone group characteristic of aflatoxin B1. Acidification of the compound did not regenerate aflatoxin B^ Calculations made from UV absorption spectra indicate that this molecular weight 286 compound comprises about 30% of the crude ammoniation product. It is postulated that the new product, C16H14O5, arises from opening the lactone ring of aflatoxin B1 during ammoniation, formation of the ammonium salt of the resultant hydroxy acid, and loss of carbon dioxide from this β-keto acid. Because this compound arises from decarboxylation, the trivial name aflatoxin D1 is proposed.

Studies on the ethanol-induced decrease of fatty acid oxidation in rat and human liver slices

In order to elucidate the mechanisms involved in the acute ethanol-induced liver triglyceride accumulation, the oxidation, esterification and β-keto acid formation have been studied in rat and human liver slices after incubation with albumin bound, long chain fatty acids (palmitic. oleic and linoleic acids). The addition of alcohol to rat and human liver slices depressed the formation of 14CO 2 from palmitic acid-1- 14C, oleic acid-1- 14C and linoleic acid-1- 14C. The esterification to triglycerides and phospholipids was increased and the formation of β-keto acids was decreased by alcohol. Addition of 4-methylpyrazole, an inhibitor of liver alcohol dehydrogenase, almost prevented the alcohol effect on the lipid metabolism of the liver slices. The oxidation of alcohol is thus obligatory for the decreased β-oxidation of fatty acids, the increased esterification and for the decreased formation of β-keto acids. The results suggest that ethanol oxidation inhibits β-oxidation of fatty acids and that this primary effect leads to accumulation of liver triglycerides by increased esterification of plasma free fatty acids.

Biosynthesis of mycolic acids formation of a C 32 β-keto ester from palmitic acid in a cell-free system of corynebacterium diphtheriae

By disrupting Corynebacterlum diphtheriae in a high EDTA (0.01 M) phosphate buffer, a cell-free extract was prepared which activated and condensed 2 moles of [1- 14C]palmitic acid by a Claisen-like process to form a derivative of 2-tetradecyl-3-keto-octadecanoic acid. The β-keto acid derivative formed in these cell-free extracts was chemically and quantitatively reduced by NaBH 4 to give a mixture of stereoisomers of corynomycolic acid. These hydroxyacids and palmitone formed by saponification of the β-keto derivative were characterized by radio gas chromatography. Pyrolysis and gas-liquid chromatography of the hydroxyacids showed that labeled palmitate was incorporated equally into the mero-aldehyde and carboxyl terminal moieties of the molecule. The condensation reaction was inhibited by avidin indicating the presence of a biotin enzyme in the reaction sequence.

Chemical and Enzymatic Evidence for the Participation of a 2-Carboxy-3-ketoribitol-1,5-diphosphate Intermediate in the Carboxylation of Ribulose 1,5-Diphosphate

Abstract The hypothesis that 2-carboxy-3-ketoribitol-1,5-diphosphate (3-keto-CRDP) is an intermediate in the enzymatic carboxylation of ribulose 1,5-diphosphate is supported by the finding that 2-carboxyribitol-1,5-diphosphate (CRDP), a structural analogue of 3-keto-CRDP, is a potent inhibitor of ribulose diphosphate carboxylase (Siegel, M. I., and Lane M. D., (1972) Biochem. Biophys. Res. Commun. 48, 508). The present investigation shows that 3-keto-CRDP, prepared chemically from CRDP, undergoes nonenzymatic, as well as enzymatic, cleavage to yield 2 molecules of 3-phosphoglycerate. Catalytic oxidation (100% oxygen, platinum on carbon catalyst, 0°) of 2-[14C]carboxyribitol-1,5-diphosphate in 10 mm MgCl2 gives rise to the predicted 3-keto and 4-keto derivatives which were characterized by reduction with [3H]NaBH4 and periodate degradation. Divalent magnesium ion which binds stoichiometrically to CRDP and alters its NMR spectrum is absolutely required for this catalytic oxidation at 0°. One of the oxidation products, 2-[14C]carboxy-3-ketoribitol-1,5-diphosphate—the proposed intermediate in the enzymatic carboxylation reaction—is an unstable β-keto acid and decarboxylates spontaneously to 14CO2 and a pentose diphosphate. Chemically synthesized 2-[14C]carboxy-3-ketoribitol-1,5-diphosphate also undergoes spontaneous hydrolytic cleavage at 25° and pH 9, giving rise to 1 molecule of d-3-phosphoglycerate and 1 molecule of l-3-phosphoglycerate, the unlabeled d isomer arising from carbon atoms 3, 4, and 5 and the 14C-labeled l-isomer from the carboxyl group and carbon atoms 1 and 2 of 2-[14C]carboxy-3-ketoribitol-1,5-diphosphate. The hypothesis that 3-keto-CRDP is an intermediate in the enzymatic carboxylation of d-ribulose 1,5-diphosphate is substantiated by the finding that chemically synthesized 3-keto-CRDP is cleaved by ribulose diphosphate carboxylase giving rise to 3-phosphoglycerate of unknown absolute configuration. Since enzymatic carboxylation leads to the formation of 2 molecules of d-3-phosphoglycerate, it is suggested that the carboxylase directs the stereochemistry of cleavage of 3-keto-CRDP.

Ketene bis(trialkylsilyl) acetals: synthesis, pyrolysis and spectral studies

Two hgh yield synthetic methods are described for the preparation of alkyl, dialkyl, aryl and diaryl ketene bis(trialkylsilyl)acetals. One is by reaction of αmetalated trimethylsilyl carboxylates with trimethylchlorosilane (TMCS) and the otehr is by inteaction of dianions of carboxylic acids and TMCS. The dianion of cyclopropane carboxylic acid and TMCS gave C-silated ester in 90% yield. Pyrolysis of diphenyl ketene bis(trialkylsilyl) acetals to diphenyl ketene and bis(trialkylsily) ethers has been shown by crossover experiments to proceed intermoleculary. Pyrolysis of monosubstituted and dialkyl ketene (trimethylsilyl) acetals gave ketene-ketene acetal addition products (III) which on solvolysis afforded β-keto acids in high yield. NMR and mass spectral data are given for many of the compounds.