Claisen Condensation Research Articles

Domino reactions of diazodicarbonyl compounds with α,β-unsaturated δ-amino esters: a convenient way towards 2-oxopiperidines, dihydropyridinones and isoquinolinediones.

Thermal decomposition of a series of diazodicarbonyl compounds in the presence of α,β-unsaturated δ-amino esters and sodium hydride gives rise to a variety of nitrogenous heterocycles. The direction of these processes is highly dependent on the structure of the initial reagents giving rise to the formation of multi-functionalized 2-oxopiperidines, 5,6-dihydropyridin-2(1H)-ones or tetrahydroisoquinoline-1,6(2H,8aH)-diones. The reactions occur in domino processes involving the Wolff rearrangement of diazocarbonyl compounds, NaH-catalyzed anti-stereoselective intramolecular Michael addition to the α,β-unsaturated system of amino esters, and in some cases also cycloelimination and intramolecular Claisen condensation of the initial products formed.

Functional characterization of a chalcone synthase from the liverwort Plagiochasma appendiculatum.

A chalcone synthase gene ( PaCHS ) was isolated and functionally characterized from liverwort. The ectopic expression of PaCHS in Marchantia paleacea callus raised the flavonoids content. Chalcone synthase (CHS; EC 2.3.1.74) is pivotal for the biosynthesis of flavonoid and anthocyanin pigments in plants. It produces naringenin chalcone by condensing one p-coumaroyl- and three malonyl-coenzyme A thioesters through a polyketide intermediate that is cyclized by intramolecular Claisen condensation. Although CHSs of higher plants have been extensively studied, enzyme properties of the CHSs in liverworts have been scarcely characterized. In this study, we report the cloning and characterization of CHS (designated as PaCHS) from the liverwort Plagiochasma appendiculatum. The gene product was 60-70 % identical with chalcone synthases from other species, and contained the characteristic conserved Cys-His-Asn catalytic triad. The recombinant PaCHS was able to catalyze p-coumaroyl-CoA and malonyl-CoA to generate naringenin in vitro. Heterologously expressed PaCHS protein showed similar kinetic properties to those of higher plant CHS. The ectopic expression of PaCHS in Marchantia paleacea callus raised the content of the total flavonoids. These results suggested that PaCHS played a key role in the flavonoids biosynthesis in liverworts. Furthermore, when the thallus of P. appendiculatum was treated with abiotic stress inducers methyl jasmonate, salicylic acid and abscisic acid, PaCHS expression was enhanced. This is the first time that a CHS in liverworts has been functionally characterized.

Enol phosphates of phosphorylated derivatives of furylacetic aldehyde and furylpiruvic acid

Phosphorylated derivatives of isomeric furylacetic aldehydes and furylpiruvic acids have been synthesized via formylation and oxalylation of dialkyl (ethoxycarbonylfuryl)methanephosphonates under conditions of the Claisen reaction. 1H, 13C, and 31P NMR spectroscopy studies have shown that the products exist as equilibrium mixtures of the carbonyl compounds and its E- and Z-enol forms in chloroform solutions. Acylation of these substances with diethyl chlorophosphate has yielded the corresponding enol phosphates. Influence of the substituents location in the furan ring on predominance of cis- or trans-configuration has been demonstrated.

Ligand-dependent active-site closure revealed in the crystal structure of Mycobacterium tuberculosis MenB complexed with product analogues.

1,4-Dihydroxy-2-naphthoyl coenzyme A (DHNA-CoA) synthase catalyzes an essential intramolecular Claisen condensation in menaquinone biosynthesis and is an important target for the development of new antibiotics. This enzyme in Mycobacterium tuberculosis is cofactor-free and is classified as a type II DHNA-CoA synthase, differing from type I enzymes, which rely on exogenous bicarbonate for catalysis. Its crystal structures in complex with product analogues have been determined at high resolution to reveal ligand-dependent structural changes, which include the ordering of a 27-residue active-site loop (amino acids 107-133) and the reorientation of the carboxy-terminal helix (amino acids 289-301) that forms part of the active site from the opposing subunit across the trimer-trimer interface. These structural changes result in closure of the active site to the bulk solution, which is likely to take place through an induced-fit mechanism, similar to that observed for type I DHNA-CoA synthases. These findings demonstrate that the ligand-dependent conformational changes are a conserved feature of all DHNA-CoA synthases, providing new insights into the catalytic mechanism of this essential tubercular enzyme.

Operon for biosynthesis of lipstatin, the Beta-lactone inhibitor of human pancreatic lipase.

Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-β-lactone structure with an N-formyl-l-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the α-branched 3,5-dihydroxy fatty acid β-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two β-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the α-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the α-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3β-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the β-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique β-lactone ring.

Structural Study of Thioesterase Domains in Complex with Covalent Inhibitors

Polyketide synthases (PKS) are large multifunctional enzymes that are responsible for the biosynthesis of a wide array of secondary metabolites that are of great interest for medical applications. PKS catalyze carbon-carbon bond formations by successive Claisen condensations of small thioesters. All PKS are organized in modules where each module is composed of catalytic domains that add a single ketide unit to the growing chain and optionally reduce the beta-keto function. The Thioesterase (TE) domain is responsible for the released of the final polyketide chain. Two ways are used by the TE domains: hydrolysis to form a linear chain or cyclization to form a macrolide. The molecular mechanism which controls the cyclization versus hydrolysis decision is not fully understood and a better understanding of this mechanism could be a great interest for generating new pharmaceutical compounds. To answer this question, we are studying the structure and function of PKS TE domains in collaboration with the group of Dr. Boddy (University of Ottawa). Recent results about the biochemical study in complex with inhibitors, crystallization and structures of one of these TE domains will be presented.

Novel synthesis of benzo[b]carbazoles

A new method was adopted for the synthesis of benzo[b]carbazoles by Claisen condensation followed by Fischer indole cyclization. Newly synthesized benzo[b]carbazoles were treated with ethanol amine in the presence of polyphosphoric acid which leads to the formation of pyrazino carbazoles. All the synthesized compounds were characterized by all spectral means.

ChemInform Abstract: Synthesis of 3,4‐Dibenzyltetrahydrofuran Lignans (9,9′‐Epoxylignanes)

AbstractReview: 51 refs.

Total Synthesis and Configurational Validation of (+)‐Violapyrone C

AbstractGold(I)‐catalyzed intramolecular 6‐endo‐dig cyclization of tert‐butyl ynoates afforded α‐pyrone cores of violapyrones. Moreover, this reaction was successfully applied to the stereospecific syntheses of (+)‐ and (–)‐violapyrone C, which allowed the absolute configuration of natural (+)‐violapyrone C to be assigned by comparison of the optical rotations. This first total synthesis, which proceeded in 22 % yield over 10 steps from (S)‐(–)‐2‐methylbutanol, features silver(I) oxide promoted monobenzylation of 1,4‐butanediol, Wittig olefination, Claisen condensation, Corey–Fuchs reaction, and gold(I)‐catalyzed α‐pyrone synthesis.

Correction to “Synthesis of Trifluoromethyl Ketones via Tandem Claisen Condensation and Retro-Claisen C–C Bond Cleavage Reaction”

Correction to “Synthesis of Trifluoromethyl Ketones via Tandem Claisen Condensation and Retro-Claisen C–C Bond Cleavage Reaction”

Highly selective trifluoroacetic ester/ketone metathesis: an efficient approach to trifluoromethyl ketones and esters

A highly selective and atom efficient ‘trifluoroacetic ester/ketone metathesis’ has been sincerely witnessed. Enolizable alkyl (at least two non-hydrogen atoms) aryl ketones were found to react readily with ethyl trifluoroacetate under the promotion of NaH to afford trifluoroacetic ester/ketone exchange products, trifluoromethyl ketones (TFMKs), and aromatic acid esters, which were quite different from the general Claisen condensation products, 1,3-diketones. The outcome of the reaction between ketone and ethyl trifluoroacetate is strongly related to the structures of substrates, the steric congestion caused by alkyl group is in favor of the C–C bond cleavage. DFT investigation further disclosed that the metathesis reaction was a kinetically favored pathway. Using only a slight excess of cheap trifluoromethylation reagent, simple operation and mild conditions make it a practical method for preparation of TFMKs on large scale, as well as a new choice of converting aryl alkyl ketones to aromatic acid esters.

ChemInform Abstract: Regioselective Oxidative Dehydrogenation under Nonenzymatic Conditions: A Synthetic Route to Gossypol.

A practical and scalable route was developed for the total synthesis of gossypol to allow for the construction of dozens of gossypol derivatives. tBuO2Ac was found to be a highly efficient oxidant for the polymerization of hemigossypol through a biosynthetic process under nonenzymatic conditions to give gossypol. Hemigossypol was synthesized on a gram scale by starting from commercially available carvacrol and dimethyl succinate and using a Stobbe condensation, an electrophilic cyclization, and the Michael addition of ortho-quinone methide as key steps.

Synthesis and spectroscopic properties of some new difluoroboron bis-β-diketonate derivatives

Six new bis-β-diketones (RCOCH2CO-C7H7N-COCH2COR) were synthesized from 3,5-diacetyl-2,6-dimethylpyridine via Claisen condensation with the corresponding esters, and then reacted with boron trifluoride etherate to afford difluoroboron bis-β-diketonate derivatives. Their spectroscopic properties were investigated by UV–vis, FTIR, 1H NMR and fluorescence spectroscopic techniques. It was found that these boron complexes exhibited violet or blue fluorescence emission at 422–445nm and possessed high extinction coefficients. The results indicate that the extending π-conjugation can increase the fluorescence intensity and quantum yield for these boron complexes. Especially, the compound 2b displayed the stronger fluorescence intensity and the highest fluorescence quantum yield (Φu=0.94) in these boron compounds. However, compounds 2c and 2d had the lower fluorescence intensity and quantum yield as a result of the heavy atom effect of the chlorine atom in the molecules.

An efficient synthesis of furano analogs of duocarmycin C1 and C2: seco-iso-cyclopropylfurano[e]indoline-trimethoxyindole and seco-cyclopropylfurano[f]quinoline-trimethoxyindole

seco-Iso-cyclopropylfurano[e]indoline-trimethoxyindole 1 and seco-cyclopropylfurano[f]quinoline-trimethoxyindole 2 are potent cytotoxic agents. Previous synthesis of these compounds was inefficient and the approach required separation of a mixture containing the isomeric indoline and quinoline intermediates 11 and 12, formed from radical cyclization of allylic bromide 10. Reported herein is an efficient and selective synthesis of either intermediate 11 or 12, thus product 1 or 2, as needed. The conditions of the Stobbe condensation, bromination, 5-exo-trig radical cyclization, amine-carboxylic acid coupling, and debenzylation were optimized for multi gram scale. As a result, the reaction times were shortened, the products were readily isolated, and the yields and purity improved.

Anisyl and ferrocenyl adducts of methylenepyran-containing β-diketone: Synthesis, spectral, structural, and redox properties

Wittig reaction between the in situ generated [2,6-diphenyl-4H-pyran-4-yl phosphorane and methyl 4-formylbenzoate afforded the methyl 4-[(2,6-diphenyl-4H-pyran-4-ylidene)methyl]benzoate precursor 2 in 75% yield. The anisyl and ferrocenyl adducts of methylenepyran-containing β-diketones 3 and 4, respectively, were prepared from the base-catalyzed Claisen condensation reaction between precursor 2 and 4-methoxyacetophenone or acetylferrocene, using t-BuO−K+ as basic initiator. Both β-diketones 3 and 4 were isolated as an orange and dark-red crystalline solids in 50% yield, respectively. The acetyl derivative 6, 1-acetyl-1′-methylenepyranyl-ferrocene, was synthesized following a classical Friedel–Crafts acylation reaction of the parent ferrocenylmethylenepyran 5, and isolated in 61% yield as a red microcrystalline powder. The condensation reaction between the electron-rich acetyl complex 6 and acetyl acetate, using lithium diisopropylamide as the active base initiator, provided the ferrocenylmethylenepyran-containing β-diketone, 1-(1,3-dioxobutyl)-1′-[(2,6-diphenyl-4H-pyran-4-ylidene)methyl] ferrocene 7, isolated in 20% yield as an orange powder. The composition and identity of the new compounds 2–4, 6 and 7 are supported by elemental analysis, FT-IR, one- and two-dimensional 1H and 13C NMR spectral data and mass spectrometry. Additionally, the molecular structures of compounds 2, 4 and 6 were ascertained by single-crystal X-ray diffraction study. FT-IR and NMR spectral data indicate that both β-diketones 3 and 4 do solely exist as their keto–enol tautomeric form in solution and in the solid state, whereas a mixture of keto–enol and β-diketone tautomers in a 73:27 spectroscopic ratio was observed for 7. In the three cases, enolization takes place exclusively away from the anisyl or ferrocenyl group with formation of a six-membered pseudo-aromatic keto–enol ring, confirmed by the crystal structure of 4. Cyclic voltammetric measurements revealed that all the compounds undergo a single one-electron oxidation, localized presumably at the methylenepyran unit. This first oxidation generates a radical cation that undergoes an intermolecular C–C bond coupling to form the corresponding dimer. Anodically shifted to the first oxidation, cyclovoltammogram of 4 exhibits one reversible two-electron oxidation while that of 6 and 7 present two successive reversible one-electron oxidations, attributed in the three cases to the ferrocenyl fragment of the dimer.

Phylogenetic relationships and classification of thiolases and thiolase-like proteins of Mycobacterium tuberculosis and Mycobacterium smegmatis

Thiolases are enzymes involved in lipid metabolism. Thiolases remove the acetyl-CoA moiety from 3-ketoacyl-CoAs in the degradative reaction. They can also catalyze the reverse Claisen condensation reaction, which is the first step of biosynthetic processes such as the biosynthesis of sterols and ketone bodies. In human, six distinct thiolases have been identified. Each of these thiolases is different from the other with respect to sequence, oligomeric state, substrate specificity and subcellular localization. Four sequence fingerprints, identifying catalytic loops of thiolases, have been described. In this study genome searches of two mycobacterial species (Mycobacterium tuberculosis and Mycobacterium smegmatis), were carried out, using the six human thiolase sequences as queries. Eight and thirteen different thiolase sequences were identified in M.tuberculosis and M.smegmatis, respectively. In addition, thiolase-like proteins (one encoded in the Mtb and two in the Msm genome) were found. The purpose of this study is to classify these mostly uncharacterized thiolases and thiolase-like proteins. Several other sequences obtained by searches of genome databases of bacteria, mammals and the parasitic protist family of the Trypanosomatidae were included in the analysis. Thiolase-like proteins were also found in the trypanosomatid genomes, but not in those of mammals. In order to study the phylogenetic relationships at a high confidence level, additional thiolase sequences were included such that a total of 130 thiolases and thiolase-like protein sequences were used for the multiple sequence alignment. The resulting phylogenetic tree identifies 12 classes of sequences, each possessing a characteristic set of sequence fingerprints for the catalytic loops. From this analysis it is now possible to assign the mycobacterial thiolases to corresponding homologues in other kingdoms of life. The results of this bioinformatics analysis also show interesting differences between the distributions of M.tuberculosis and M.smegmatis thiolases over the 12 different classes.

An Efficient One‐pot Synthesis of Aryl‐substituted 1‐(Thiazol‐2‐yl)‐1H‐pyrazole‐3‐carboxylates via a Hantzsch Synthesis‐Knorr Reaction Sequence

AbstractThe treatment of α‐bromoalkyl aryl ketones and 2‐(propan‐2‐ylidene)hydrazine carbothioamide afforded 4‐aryl‐2‐(2‐(propan‐2‐ylidene)hydrazinyl)thiazoles via a Hantzsch‐thiazole synthesis, which reacted with 4‐aryl‐2,4‐diketoesters via a sequential Knorr‐pyrazole reaction to deliver a variety of aryl‐substituted ethyl 1‐(thiazol‐2‐yl)‐1H‐pyrazole‐3‐carboxylates in a one‐pot fashion with moderate to high yields. The key intermediates 4‐aryl‐2,4‐diketoesters, existing as its enolic lithium salt, were synthesized in situ by a high‐yield tert‐BuOLi‐mediated Claisen condensation of alkylphenones and diethyl oxalate. This class of elegant molecule comprises aryl groups on the two different heterocyclic cores, and the configurations of two representative molecules were determined by single crystal X‐ray crystallography.

Tricyclic Pyrazoles: Synthesis, Characterization, Antimicrobial, Antituberculosis, and Antitumor Activity of N,1-Diphenyl-1,4-dihydrothiochro-meno[4,3-c]pyrazole-3-carboxamide-5,5-dioxide Derivatives

Aims: A series of N,1-diphenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxamide 5,5-dioxide derivatives (6a-m) were synthesized and evaluated for anticancer, antibacterial, and antifungal activity.Methodology: Reaction of 2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide 2 with diethyl oxalate in ethanol in the presence of a base afforded the Claisen condensation product 3. Subsequent reaction of 3 with phenylhydrazine hydrochloride at reflux in ethanol afforded ethyl 1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (4). Alkaline hydrolysis of 4 furnished the corresponding 1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide 5. The pyrazole acid 5 was converted into the corresponding acid chloride followed by treatment with an excess of the appropriate amine to give 6a-m.Results: Compound 6k showed better activity than chloroamphenicol against Klebsiella pneumoniae and Escherichia coli and equipotent to clotrimazole in inhibiting the growth of Candida albicans (MIC 3.125 µg/mL). All compounds were screened for their cytotoxic activity against two tumor cell lines, namely, human colon tumor cell line (HCT116) and human cervical cancer cell line (HeLa) using the colorimetric MTT assay. Most of the tested compounds exhibited potent antitumor activity. Particularly, compound 6k displayed the highest activity among the tested compounds with IC50 equal to 17 µM (HeLa) and 15 µM (HCT116) respectively. Among the tested compounds, 6k was found to be more active against M. tuberculosis, (H37Rv) with minimum inhibitory concentration (7.8 µM).Conclusion: The chloro- (6b and 6c), 2-aminobenzothiazole- (6l), and 4-aminoantipyrine- (6k) linkages exhibited better antimicrobial activity than their counterparts. Compound 6k was found to possess comparatively more antimicrobial, antituberculosis, and antitumor activity against the other derivatives.

Facile Synthesis of β‐Diketone Alcohols for Combined Functionality: Initiation, Catalysis, and Luminescence

Primary alcohol-functionalized β-diketones (bdks) are successfully synthesized via facile one-step Claisen condensation between aromatic monoketones and ε-caprolactone (ε-CL). To demonstrate application potentials, these bdk alcohols are used to chelate with various Lewis acids, including Tb (III), Eu (III), and B (III). It is discovered that the resulting Tb (III) and Eu (III) diketonate complexes can serve as both catalysts and initiators for ring-opening polymerization (ROP) under solvent-free conditions, using lactide monomer as an example. The polylactides (PLAs) thus obtained exhibit luminescence properties characteristic of Tb (III) and Eu (III), respectively. On the other hand, boron-chelated diketone can initiate ROP of lactide in the presence of Sn(oct)2 , and affords a PLA material with dual-emission, i.e., fluorescence and room temperature phosphorescence. The synthesis described here represents a shortcut for the preparation of bdk-based macroligands and subsequent functional materials.

Carbene variations of some classical reactions

Carbene variations of a series of fundamental reactions, the features of their course in comparison with classical analogues have been first summarized and analyzed in the review. A number of carbene transformations described in the literature relates to classical name reactions being substantially their carbene variations acquiring the characteristics with the participation of carbenes. The attention in the review is drawn to such important analogies. Besides the carbene mechanism, they differ from the classical versions of the reactions because they mostly proceed under milder, sometimes considerably milder conditions. They always lead to specific products, the structure of which is conditioned by the nature of carbenes as ambiphilic reagents, and it affects certain stages and the final result of the reaction. In the above terms, such reactions are considered for the cases when carbenes are stoichiometrical components (carbene variations of Bodger, Michaelis-Arbuzov, Leuckart-Wallach reactions, Claisen condensation, Hoffman elimination), as well as for the cases when they are catalytic components (transesterification, Stetter reactions, benzoin condensation, nucleophilic aromatic substitution). At the present stage carbene variations of the classical reactions have become promising in the synthesis of some pharmaceutical substances, as well as in diesel fuel obtaining from vegetable oils. The review is intended to initiate further searches and deepening of such analogies.