Β-keto Acids Research Articles

Direct Carbon−Carbon Bond Formation via Chemoselective Soft Enolization of Thioesters: A Remarkably Simple and Versatile Crossed-Claisen Reaction Applied to the Synthesis of LY294002

Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr2 x OEt2 and i-Pr2NEt to give beta-keto thioesters. Prior enolate formation is not required, and the reaction is conducted using untreated CH2Cl2 open to the air. The coupled products are stable synthetic equivalents of beta-keto acids and can be converted directly into beta-keto esters, beta-keto amides, and beta-diketones under mild conditions. The utility of this carbon-carbon bond-forming method is shown through the synthesis of the PI3-K inhibitor LY294002.

In Vitro Synthesis of Curcuminoids by Type III Polyketide Synthase from Oryza sativa

Curcuminoids, major components of the spice turmeric, are used as a traditional Asian medicine and a food additive. Curcumin, a representative curcuminoid, has received a great deal of attention because of its anti-inflammatory, anticarcinogenic, and antitumor activities. Here we report a novel type III polyketide synthase named curcuminoid synthase from Oryza sativa, which synthesizes bisdemethoxycurcumin via a unique mechanism from two 4-coumaroyl-CoAs and one malonyl-CoA. The reaction begins with the thioesterification of the thiol moiety of Cys-174 by a starter molecule, 4-coumaroyl-CoA. Decarboxylative condensation of the first extender substrate, malonyl-CoA, onto the thioester of 4-coumarate results in the formation of a diketide-CoA intermediate. Subsequent hydrolysis of the intermediate yields a beta-keto acid, which in turn acts as the second extender substrate. The beta-keto acid is then joined to the Cys-174-bound 4-coumarate by decarboxylative condensation to form bisdemethoxycurcumin. This reaction violates the traditional head-to-tail model of polyketide assembly; the growing diketide intermediate is hydrolyzed to a beta-keto acid that subsequently serves as the second extender to form curcuminoids. Curcuminoid synthase appears to be capable of the synthesis of not only diarylheptanoids but also gingerol analogues, because it synthesized cinnamoyl(hexanoyl)methane, a putative intermediate of gingerol, from cinnamoyl-CoA and 3-oxo-octanoic acid.

A New Class of Labile Surfactants that Break Down to Non-surface Active Products upon Heating or after a Pre-set Time, without the Need for a pH Change

Abstract A new class of labile surfactants that break down at a controllable rate without the need for a change in pH will be presented. The invention has been patented by YKI Institute for Surface Chemistry, and is based on use of β-keto acids or their salts as surface-active compounds. These surfactants spontaneously break down through decarboxylation, to form an oil-like ketone and CO2/HCO3 −/CO3 2− depending on pH. The rate of breakdown can be controlled within a wide range by temperature or by certain additives, but, unlike most cleavable surfactants, a change in pH is not needed. Furthermore the surfactants can be conveniently activated from a stabile precursor just before use, and one (of many possible) precursors of this kind is already available on the industrial scale in the form of a well-known chemical that is FDA-approved in other, non-surfactant, applications. The compound in question, alkyl ketene dimer (AKD), is produced in large scale by a number of large chemical producers today, and used for hydrophobization of paper. The present article gives an overview of the surfactant chemistry, with focus on recent studies of the kinetics of activation of the surfactant precursor and breakdown kinetics of the labile surfactant at different conditions. Furthermore, possible industrial applications of the surfactant will be discussed, with one example taken from a recent feasibility study performed within the car washing area.

Mineralization of metanilic acid by Pseudomonas aeruginosa CLRI BL22.

Pseudomonas aeruginosa CLRI BL22 was able to degrade metanilic acid, a sulfonated aromatic amine upto a concentration of 1,500mgl(-1). The degradation of metanilic acid started when the organism reached its exponential growth phase. Chromatographic and spectrophotometric analyses confirmed the presence of aniline and β-keto adipic acid indicating the ortho pathway reaction. Further proof for this pathway was provided by dioxygenase activity of the strain grown in the medium containing metanilic acid and glucose.

Nocardia sp. vanillic acid decarboxylase

Vanillic acid is an abundant renewable chemical useful for the biocatalytic synthesis of aromatics. The bacterium, Nocardia sp. NRRL 5646 efficiently catalyzes the decarboxylation of vanillic acid to the phenolic product, guaiacol. For purification and characterization of vanillic acid decarboxylase (VAD), a simple, rapid enzyme assay was devised to couple the vanillic acid decarboxylase reaction with horseradish peroxidase/H 2O 2. Guaiacol formed in the decarboxylation reaction is oxidized by peroxidase to tetraguaiacol, a chromophoric substance, which is measurable at 470 nm. Soluble, VAD activity was inducible in cells grown with vanillic acid. VAD was purified 185-fold by a combination of DEAE cellulose, phenylsepharose and sephacryl S-200 chromatographies. SDS-PAGE gave an estimated molecular mass of 46 ± 0.8 kDa while active native VAD was 92 kDa by gel chromatography. VAD required no cofactors, displayed optima at pH 7.0 and 30 °C, and a K m of 0.8 mM for vanillic acid. The N-terminal amino acid sequence was determined to be AEYTLPDLDYDYSALEPHIS. 4-Hydroxybenzoic acid, vanillic acid, and syringic acid were excellent substrates, while VAD showed no activity for isovanillic acid, ferulic acid, p-coumaric acid, 2-hydroxybenzoic acid and 3-hydroxybenzoic acid. Purified VAD required a phenolic functional group para to the carboxylic acid moiety in the best substrates. The vanillic acid decarboxylation reaction is non-oxidative in nature. Conduct of the decarboxylation process in deuterium oxide results in incorporation of one deuterium atom para to the phenolic hydroxyl group of guaiacol. Vanillic acid decarboxylation likely involves enzymatic tautomerization to a vinylogous β-keto acid that spontaneously decarboxylates to guaiacol.

Kinetics and mechanism of picolinic acid promoted chromic acid oxidation of maleic acid in aqueous micellar media

The kinetics and mechanism of chromic acid oxidation of maleic acid in the presence and absence of picolinic acid (PA) in aqueous acid media have been studied under the conditions [maleic acid]≫[CrVI]T at different temperatures. Under the kinetic conditions, the monomeric species of CrVI has been found kinetically active in the absence of PA while in the PA-catalysed path, CrVI-PA complex has been suggested as the active oxidant. In the PA-catalysed path, CrVI-PA complex receives a nucleophilic attack by the substrate to form a ternary complex, which subsequently experiences a 2e-transfer redox decomposition leading to the epoxide and CrIV-PA complex at the rate determining step. Subsequently, the epoxide produces pyruvic acid through the decarboxylation of β-keto acid in a faster step. Then CrIV-PA complex participates further in the oxidation of maleic acid in faster steps and ultimately is converted into the inert CrIII-PA complex. In the uncatalysed path, CrVI-substrate ester experiences a redox decomposition through 2e-transfer at the rate determining step in the same way. The uncatalysed path shows a mixed order (i.e. first order+second order) dependence on [H+] while the PA-catalysed path shows a first order dependence on [H+]. Both the uncatalysed path and PA-catalysed path show the first order dependence on both [maleic acid]T and [CrVI]T. The PA-catalysed path is first order in [PA]T. In the presence of surfactants like N-cetylpyridinium chloride (CPC, a cationic surfactant) and sodium dodecyl sulfate (SDS, an anionic surfactant), the reaction orders remain unchanged. CPC has been found to retard both the uncatalysed and PA-catalysed paths but the patterns are different while SDS shows the rate accelerating effect for the both paths in the same pattern. The observed micellar effects have been explained by considering hydrophobic and electrostatic interactions between the reactants and surfactants in terms of the proposed mechanism.

Condensation of N-3-substituted 5-pyrazolones with esters of β-keto acids. Synthesis of pyrano[2,3-c]pyrazol-6-ones

N-Substituted 5-pryazolones undergo thermal condensation with esters of β-keto acids, losing water and alcohol molecules, to form N-substituted pyrano[2,3-c]pyrazol-6-ones. The pyran ring in these products is readily cleaved by the action of alkali to give the corresponding salts of unsaturated acids.

Electrochemical Carboxylation of Aliphatic Ketones: Synthesis of .BETA.-Keto Carboxylic Acids

A constant current electrolysis of saturated aliphatic ketones in a CH3CN or DMF solution containing 0.1 mol dm−3 Bu4NBF4 with a platinum cathode and a magnesium anode under an atmospheric pressure of CO2 resulted in an efficient fixation of CO2 at α-position of carbonyl group in the ketones to give the corresponding β-keto carboxylic acids in moderate to good yields.

Transition Metal Catalyzed Decarboxylative Additions of Enolates

AbstractFor Abstract see ChemInform Abstract in Full Text.

Biosynthetic Pathway of Pseudomonas aeruginosa 4-Hydroxy-2-Alkylquinolines

The role of intercellular communication in the regulation of bacterial multicellular behavior has received widespread attention, and a variety of signal molecules involved in bacterial communication have been discovered. In addition to the N-acyl-homoserine lactones, 4-hydroxy-2-alkylquinolines (HAQs), including the Pseudomonas quinolone signal, have been shown to function as signal molecules in Pseudomonas aeruginosa. In this study we unraveled the biosynthetic pathway of HAQs using feeding experiments with isotope-labeled precursors and analysis of extracted HAQs by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. Our results show that the biosynthesis of various HAQ metabolites is directed via a common metabolic pathway involving a "head-to-head" condensation of anthranilic acid and beta-keto fatty acids. Moreover, we provide evidence that the beta-keto-(do)decanoic acids, crucial for the biosynthesis of the heptyl and nonyl derivatives of the 4-hydroxyquinolines in P. aeruginosa, are at least in part derived from a common pool of beta-hydroxy(do)decanoic acids involved in rhamnolipid biosynthesis.

Enantioselective Reduction of β‐Keto Acids with Engineered Streptomyces coelicolor

Compelling evidence for the intermediacy of the free β-keto acid 1, rather than the corresponding enzyme-bound thiolate as previously proposed, in the biosynthesis of the antibiotic actinorhodin (2) was obtained from studies of the enantioselective reduction of a range of β-keto acids by the engineered strain of S. coelicolor CH999/pIJ5675. This excellent whole-cell biotransformation system gave the desired S β-hydroxy acids with >95 % ee.

Synthesis of an Analogue of the Marine Polypropionate Tridachiahydropyrone

[reaction: see text] A novel approach to the formation of the unusual pyrone-containing ring systems as found in polypropionate metabolites from the Tridachia family of marine molluscs has been developed. This approach includes an intramolecular cyclization of a beta-keto acid onto a cyclohexenone ring to afford a fused, bicyclic pyrone.

β‐Lactam Synthesis by Ugi Reaction of β‐Keto Acids in Aqueous Solution.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Condensation of 1‐Substituted 5‐Aminopyrazoles with β‐Dicarbonyl Compounds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Omega-Amino acid:pyruvate transaminase from Alcaligenes denitrificans Y2k-2: a new catalyst for kinetic resolution of beta-amino acids and amines.

Alcaligenes denitrificans Y2k-2 was obtained by selective enrichment followed by screening from soil samples, which showed omega-amino acid:pyruvate transaminase activity, to kinetically resolve aliphatic beta-amino acid, and the corresponding structural gene (aptA) was cloned. The gene was functionally expressed in Escherichia coli BL21 by using an isopropyl-beta-D-thiogalactopyranoside (IPTG)-inducible pET expression system (9.6 U/mg), and the recombinant AptA was purified to show a specific activity of 77.2 U/mg for L-beta-amino-n-butyric acid (L-beta-ABA). The enzyme converts various beta-amino acids and amines to the corresponding beta-keto acids and ketones by using pyruvate as an amine acceptor. The apparent K(m) and V(max) for L-beta-ABA were 56 mM and 500 U/mg, respectively, in the presence of 10 mM pyruvate. In the presence of 10 mM L-beta-ABA, the apparent K(m) and V(max) for pyruvate were 11 mM and 370 U/mg, respectively. The enzyme exhibits high stereoselectivity (E > 80) in the kinetic resolution of 50 mM D,L-beta-ABA, producing optically pure D-beta-ABA (99% enantiomeric excess) with 53% conversion.

Diastereoselectivity in the Carroll Rearrangement of β‐Keto Esters of Tertiary Allylic Alcohols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

β-Lactam Synthesis by Ugi Reaction of β-Keto Acids in Aqueous Solution

A novel protocol for accelerating Ugi reactions in aqueous solution enables the application of the reaction to β-keto acids. This process results in the preparation of even highly strained ring-fused β-lactams.

Diastereoselectivity in the Carroll rearrangement of β-keto esters of tertiary allylic alcohols

Carroll rearrangement of β-keto esters derived from tertiary allylic alcohols, for example, 7 , under basic conditions followed by decarboxylation of the resulting β-keto acids yielded the expected γ,δ-unsaturated methyl ketones 8 with a range of olefin geometries from 100:0 to 1:1.8 E/ Z, depending on the relative steric requirements of the two groups at the allylic center.

Condensation of 1-substituted 5-aminopyrazoles with β-dicarbonyl compounds

Condensation of N-substituted 5-aminopyrazoles with β-diketones occurs with the formation of pyrazolo[4,5-b]pyridines. Depending on the conditions, their reaction with β-keto acids can give either 6-oxo- or 4-oxopyrazolo[4,5-b]pyridines.

Novel Fungal Metabolites as Cell Wall Active Antifungals. Fermentation, Isolation, Physico-chemical Properties, Structure and Biological Activity.

Two novel antifungal compounds, 1 (SCH 466457), and 2 (SCH 466456), active in a "cell wall" assay, were isolated from the fermentation broth of an unidentified fungus. The active compounds were separated from the broth filtrate by adsorption on a macroreticular resin and were purified on reverse phase HPLC. Detailed mass spectrometric and NMR experiments and degradative studies helped in elucidating the structures of these compounds. The compounds were identified to be peptides containing amino acids such as alanine, aminoisobutyric acid, proline, leucine, valine, glycine and a previously identified beta-keto acid, 2-methyl 3-oxotetradecanoic acid. (5) Both compounds were active against Candida, dermatophytes and Aspergillus (Geometric Mean MIC's, 8.9, 20 and 16 microg/ml, and 64, 128 and 23 microg/ml, respectively for 1 and 2).