Tetronic Acid Research Articles

ChemInform Abstract: An Organocatalytic Domino Michael‐Alkylation Reaction: Highly Enantioselective Construction of Spiro‐Cyclopentanoneoxindoles and Tetronic Acid Scaffolds.

AbstractThe title reaction of methyleneindolinones with ketoester (II) results in the formation of various spiro‐cyclopentanoneoxindoles which are obtained in high yields, good diastereoselectivities and excellent enantioselectivities via α‐alkylation.

Abyssomicin 2 reactivates latent HIV-1 by a PKC- and HDAC-independent mechanism.

Screening of a marine natural products library afforded three new analogues of the tetronic acid containing polyketide abyssomicin family and identified abyssomicin 2 as a selective reactivator of latent HIV virus. Examination of the mode of action of this new latent HIV reactivating agent demonstrated that it functions via a distinct mechanism compared to that of existing reactivating agents and is effective at reactivating latent virus in a subset of primary patient cell lines.

Unexpected Facile Synthesis of Tetronic Acid During the Research on Stereospecific Total Synthesis of (+)-Biotin Starting from D-Erythorbic Acid as Chiral Pool

Unexpected Facile Synthesis of Tetronic Acid During the Research on Stereospecific Total Synthesis of (+)-Biotin Starting from D-Erythorbic Acid as Chiral Pool

Stereocontrolled construction of 3H-furo[3,4-b]chromen-1(9H)-one scaffolds via organocatalyzed Michael addition and the following intramolecular dehydration

Stereocontrolled construction of 3H-furo[3,4-b]chromen-1(9H)-one scaffolds has been realized via chiral squaramide catalyzed asymmetric Michael addition of tetronic acid to 2-((E)-2-nitrovinyl)phenols and the subsequent intramolecular dehydration.

Support vector machine (SVM) classification model based rational design of novel tetronic acid derivatives as potent insecticidal and acaricidal agents

A novel SVM classification model was constructed and applied in the development of novel tetronic acid derivatives as potent insecticidal and acaricidal agents.

An organocatalytic domino Michael-alkylation reaction: highly enantioselective construction of spiro-cyclopentanoneoxindoles and tetronic acid scaffolds.

A new organocatalytic asymmetric domino Michael-alkylation reaction of methyleneindolinones and γ-halogenated-β-ketoesters is described. A variety of spiro-cyclopentanoneoxindoles were obtained in high yields (up to 96%), good diastereoselectivities (up to 12 : 1 dr) and excellent enantioselectivities (up to >99% ee) via α-alkylation. Interestingly, O-alkylated products with tetronic acid motifs could be obtained by tuning the N-protecting groups on methyleneindolinones with excellent enantioselectivities (up to >99% ee).

A three-component domino reaction for efficient synthesis of functionalized pyrazolo[3,4-f]quinolines under catalyst-free conditions

A three-component domino reaction of aromatic aldehyde, 1H-indazol-6-amine, and tetronic acid or 4-hydroxy-2H-chromen-2-one is described, giving pyrazolo[3,4-f]quinoline derivatives in high yields under catalyst-free conditions.

Synthesis, characterization, antifungal evaluation and 3D-QSAR study of phenylhydrazine substituted tetronic acid derivatives

A series of 3-(1-(2-(substituted phenyl)hydrazinyl)alkylidene)furan-2,4(3H,5H)-diones were designed and prepared using two synthetic routes. Their structures were confirmed by FT-IR, 1H NMR, 13C NMR, MS, elemental analysis and single-crystal X-ray diffraction. Their bioactivity was evaluated against Botrytis cinerea in vitro. Most target compounds exhibited remarkable antifungal activity. Two compounds 7f and 7h were highly effective and their EC50 values were 0.241μg/mL and 0.167μg/mL, respectively, close to that of the control drug procymidone. 3D-QSAR studies of CoMFA and CoMSIA were carried out. Models with good predictive ability were generated with the cross validated q2 values for CoMFA and CoMSIA being 0.565 and 0.823. Conventional r2 values were 0.983 and 0.945, respectively. The results provided a practical tool for guiding the design and synthesis of novel and more potent tetronic acid derivatives containing substituted phenylhydrazine moiety.

2+2] Photocycloaddition Studies on Complex Tetronic Acid Esters Related to the Synthesis of Cembranoid Diterpenes

Twelve different tetronic acid esters bearing two potentially reactive olefinic groups were prepared and subjected to [2+2] photocycloaddition reactions by irradiation at λ = 254 nm in tert-butanol (5 mM). The diastereoselectivity and regioselectivity of the reaction was studied with regard to the synthesis of cembranoid diterpenes. When the tetronic acid core carried an alk-3-enyl substituent in the γ-position and an alk-3-enyloxy substituent in the β-position, the undesired γ-products prevailed and were formed in 48–81% yield. Altering the γ-alk-3-enyl substituent into an alk-3-ynyl or alk-2-ynyl substituent, resulted in formation of the desired β-photocycloaddition products. The latter products were obtained in yields of 56–88%, with two out of three products exhibiting very high regio- and diastereoselectivity.

Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors

A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a–t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01–0.5μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed.

RE12 derivatives displaying Vaccinia H1-related phosphatase (VHR) inhibition in the presence of detergent and their anti-proliferative activity against HeLa cells

New derivatives of Vaccinia H1-related phosphatase (VHR) inhibitor RE12 (5) were designed by replacing the long straight alkyl chain with other hydrophobic functionalities containing two aromatic rings, with the aim of obtaining potent, cell-active inhibitors. We established a direct coupling reaction between tetronic acid derivative and thioimidate to prepare the RE derivatives 6a–6i efficiently. These compounds all showed VHR-inhibitory activity in the presence of 0.001% NP-40, whereas RE12 (5) was inactive under this condition, even at 100μM. Further structure–activity studies focused on terminal substitution afforded trifluoromethyl derivative 6k (RE176) and nitro derivative 6l (RE177). The IC50 value of 6l in the presence of NP-40 was almost equivalent to that of RE12 (5) in its absence. Compound 6k (RE176) potently inhibited proliferation of HeLa cells.

Targeting Staphylococcus aureus Quorum Sensing with Nonpeptidic Small Molecule Inhibitors

A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

ChemInform Abstract: Synthesis of Diaminomethylidene Derivatives of Tetronic Acid

Abstractvia ketene aminal (III) as key intermediate

ChemInform Abstract: Synthesis of a New Class of Tetronic Acid Derivatives: A One‐Pot Three‐Component Condensation Reaction Between Isoquinoline or Pyridine and Dialkyl Acetylenedicarboxylate with Tetronic Acid.

AbstractTetronic acid derivatives [(IV) and (VI)] are smoothly synthesized via 1:1:1 addition reaction.

Mechanistic investigation and implications of a sacrificial aniline for the tandem cascade synthesis of 4-aza-podophyllotoxin analogues

Mechanistic investigations were pursued to determine a plausible mechanism in the cascade reaction involving tetronic acid with aldehydes and anilines to generate the 4-aza-2,3-dehydropodophyllotoxin core structure. The mechanistic driven hypothesis paved the way for a new reaction design using for the first time a sacrificial electron deficient aniline leading to an optimized cascade protocol (up to threefold yield improvement) for the synthesis of novel 4-aza-2,3-dehydropodophyllotoxin analogues.

ChemInform Abstract: Diverse Transformations of Chiral Propargylic Alcohols Generated by BINOL‐Catalyzed Alkyne Addition to Aldehydes

AbstractReview: 35 refs.

Biosynthesis of tetronate antibiotics: A growing family of natural products with broad biological activities

Tetronate antibiotics, a growing family of natural products featuring a characteristic tetronic acid moiety, are of importance and of particular interest for their typical structures, especially the spirotetronate structure, and corresponding versatile biological activities. Considerable efforts have persistently performed since the first tetronate was isolated, to elucidate the biosynthesis of natural tetronate products, by isotope-labeled feeding experiments, genetical characterization of biosynthetic gene clusters, and biochemical reconstitution of key enzymatic catalyzed reactions. Accordingly, the biosynthesis of spirotetronates has been gradually determined, including biosynthesis of a polyketide-derived backbone for spirotetronate aglycone, incorporation of a glycerol-derived three-carbon unit into tetronic acid moiety, formation of mature aglycone via Diels-Alder-like reaction, and decorations of aglycone with various deoxysugar moieties. In this paper, the biosynthetic investigations of natural tetronates are well documented and a common biosynthetic route for this group of natural products is summarized accordingly.

Dissipation, residues, and risk assessment of spirodiclofen in citrus

The dissipation, residues, and distribution of spirodiclofen, a new type of insecticide and acaricide that belongs to the class of ketoenols or tetronic acids, in citrus were investigated in this study. Risk assessment of sprodiclofen was also conducted based on those data. The open-field experiments were conducted in Guangdong, Fujian, and Guangxi of China. Results showed that the half-lives in citrus ranged from 6.5 to 13.6 days at three sites. The terminal residues of spirodiclofen were all below the FAO/WHO maximum residue limit of 0.5 mg/kg in citrus, when they were determined 14 days after final application. Distribution of spirodiclofen in peel and flesh was analyzed, and residues were found to be concentrated on peel. Risk assessment was performed by calculation of risk quotient, which showed that the use of spirodiclofen is comparably safe for humans.

Biomimetic Total Synthesis of ent-Penilactone A and Penilactone B

The total synthesis of ent-penilactone A and penilactone B has been achieved via biomimetic Michael reactions between tetronic acids and o-quinone methides. A five-component cascade reaction between a tetronic acid, formaldehyde, and a resorcinol derivative that generates four carbon-carbon bonds, one carbon-oxygen bond, and two stereocenters in a one-pot synthesis of penilactone A is also reported.

A Facile and Expeditious Microwave-Assisted Synthesis of Furo[3,4-b]indeno[2,1-f]quinolin-1-one DerivativesviaMulticomponent Reaction

A series of furo[3,4-b]indeno[2,1-f]quinolin-1-one derivatives were synthesized by the condensation of an aromatic aldehyde with tetronic acid and 9H-fluoren-2-amine in solvent of glacial acetic acid under microwave irradiation. This procedure offers several advantages including operational simplicity, clean reaction, and increased safety for small-scale high-speed synthesis.