Claisen Condensation Research Articles

A convenient total synthesis of indolo[2,3‐b]carbazole‐6,12‐dione

AbstractIndolo[2,3‐b]carbazole‐6,12‐dione is exceptionally attractive due to its efficient antitumor activity. Synthesis of biologically potent symmetric indolo[2,3‐b]carbazole‐6,12‐dione and its N‐alkylated derivatives has been achieved by exploring the keto group of easily accessible 2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐one with remarkable yields just in five steps, utilizing the two classical reactions—Japp‐Klingemann procedure followed by Fischer Indole Cyclisation as key steps. The required formylation of N‐alkylated 2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐one has been effectively accomplished through Cross Claisen Condensation.

Emerging diversity in polyketide synthase

There are three well-known types of polyketide synthase (PKS) that synthesize polyketides through decarboxylative Claisen condensation. Here, we review three recently reported PKSs whose biosynthesis is novel and representative, providing new insights into the mechanistic and structural diversity of PKSs.

Diesters Compound Intramolecular Condensation and Its Applications

Abstract: Diesters are important synthetic tools for many biologically active compounds. Dieckmann condensation is an important organic reaction. This reaction is generally used in the formation of larger molecules and form new carbon -carbon bond. Condensation reaction is important for the formation of biological molecules. Dieckmann condensation reaction is named after a German chemist Walter Dieckmann. Dieckmann condensation reaction is intramolecular organic reactions of diesters with base and give β-keto esters. Dieckmann condensation is equivalent to intramolecular claisen condensation reaction. In this project we will discuss about the mechanism and applications of dieckmann condensation.

Development of an Efficient New Route to PPARδ Agonist Fonadelpar: Formation of the C–C Bond by Claisen Condensation

Development of an Efficient New Route to PPARδ Agonist Fonadelpar: Formation of the C–C Bond by Claisen Condensation

Biosynthesis of the Unusual Carbon Skeleton of Nocuolin A.

Nocuolin A is a cytotoxic cyanobacterial metabolite that is proposed to be produced by enzymes of the noc biosynthetic gene cluster. Nocuolin A features a 1,2,3-oxadiazine moiety, a structural feature unique among natural products and, so far, inaccessible through organic synthesis, suggesting that novel enzymatic chemistry might be involved in its biosynthesis. This heterocycle is substituted with two alkyl chains and a 3-hydroxypropanoyl moiety. We report here our efforts to elucidate the origin of the carbon skeleton of nocuolin A. Supplementation of cyanobacterial cultures with stable isotope-labeled fatty acids revealed that the central C13 chain is assembled from two medium-chain fatty acids, hexanoic and octanoic acids. Using biochemical assays, we show that a fatty acyl-AMP ligase, NocH, activates both fatty acids as acyl adenylates, which are loaded onto an acyl carrier protein domain and undergo a nondecarboxylative Claisen condensation catalyzed by the ketosynthase NocG. This enzyme is part of a phylogenetically well-defined clade within similar genomic contexts. NocG presents a unique combination of characteristics found in other ketosynthases, namely in terms of substrate specificity and reactivity. Further supplementation experiments indicate that the 3-hydroxypropanoyl moiety of 1 originates from methionine, through an as-yet-uncharacterized mechanism. This work provides ample biochemical evidence connecting the putative noc biosynthetic gene cluster to nocuolin A and identifies the origin of all its carbon atoms, setting the stage for elucidation of its unusual biosynthetic chemistry.

Intrinsic Ability of the β-Oxidation Pathway To Produce Bioactive Styrylpyrones.

Naturally occurring α‐pyrones with biological activities are mostly synthesised by polyketide synthases (PKSs) via iterative decarboxylative Claisen condensation steps. Remarkably, we found that some enzymes related to the fatty acid β‐oxidation pathway in Escherichia coli, namely the CoA ligase FadD and the thiolases FadA and FadI, can synthesise styrylpyrones with phenylpropionic acids in vivo. The two thiolases directly utilise acetyl‐CoA as an extender unit for carbon‐chain elongation through a non‐decarboxylative Claisen condensation, thus making the overall reaction more efficient in terms of carbon and energy consumption. Moreover, using a cell‐free approach, different styrylpyrones were synthesised in vitro. Finally, targeted feeding experiments led to the detection of styrylpyrones in other species, demonstrating that the intrinsic ability of the β‐oxidation pathway allows for the synthesis of such molecules in bacteria, revealing an important biological feature hitherto neglected.

Intrinsic Ability of the β‐Oxidation Pathway To Produce Bioactive Styrylpyrones

AbstractNaturally occurring α‐pyrones with biological activities are mostly synthesised by polyketide synthases (PKSs) via iterative decarboxylative Claisen condensation steps. Remarkably, we found that some enzymes related to the fatty acid β‐oxidation pathway in Escherichia coli, namely the CoA ligase FadD and the thiolases FadA and FadI, can synthesise styrylpyrones with phenylpropionic acids in vivo. The two thiolases directly utilise acetyl‐CoA as an extender unit for carbon‐chain elongation through a non‐decarboxylative Claisen condensation, thus making the overall reaction more efficient in terms of carbon and energy consumption. Moreover, using a cell‐free approach, different styrylpyrones were synthesised in vitro. Finally, targeted feeding experiments led to the detection of styrylpyrones in other species, demonstrating that the intrinsic ability of the β‐oxidation pathway allows for the synthesis of such molecules in bacteria, revealing an important biological feature hitherto neglected.

Novel Zn(II) and Cd(II) coordination polymers derived from 1,2,3-triazole-1,3-diketone ligand. Syntheses and structural, thermal, computational, and luminescent studies

This article discloses the syntheses of two novel coordination polymers of Zn(II) and Cd(II) using a donor-functionalized 1,2,3-triazole-β-diketonato ligand, obtained by Claisen's condensation with ethyl 5-methyl-1-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxylate and 4-methoxyacetophenone. All compounds were characterized by spectroscopic solid-state techniques in solid-state, such as FT-IR, Single-crystal and powder X-Ray diffraction, luminescence, Thermal analyses (TGA/DSC), and, in the case of the precursor and donor ligand multinuclear NMR analyses. The syntheses of both coordination polymers were carried out under crystallization and bulk method, showing the same results in both methods according to the powder X-ray analyses. Thermal and luminescent properties allow us to conclude that these compounds are good candidates for UV – blue light emitters.

The synergistic effect of diketone and its chelate enables macroscale superlubricity for a steel/steel contact

In this article, the Claisen condensation method was used to synthesize 1-(4-ethylphenyl)-nonane-1,3-dione. The tribological properties of diketone, chelate and PAO6 were investigated. Among them, when the ratio of diketone to chelate in the mixed solution was 4:6, the optimal macroscale superlubricity can be obtained, the friction coefficient, wear scar diameter and contact pressure were 0.006, 210 µm and 105.2 MPa, respectively. Surface analysis showed that diketone can be adsorbed on the surface of the metal friction pair through tribochemical reactions. Characterization of the cross-section of the friction pair confirmed that a 2.7 nm thick film was indeed formed on the surface. The excellent lubrication performance of the mixed solution was due to the synergistic effect between diketone and chelate.

Synthesis of Heterocyclic Compounds Via 1,3-Diketones

Heterocyclic compounds acquire a unique place in medicinal chemistry as many of the pharmaceuticals, agrochemical industries use heterocyclic moieties in different kinds of drugs. Moreover, many of these compounds are naturally occurring and are known for their antibacterial properties from ancient times. These compounds like thiazole, pyrazole, imidazole, coumarin etc. are synthesized via 1,3-dicarbonyls as an intermediate. Essentially β-dicarbonyls are considered as promising scaffolds for the synthesis of heterocyclic compounds. Especially, due to keto-enol tautomerism, β-diketones show very distinct chemical properties. They could be made by combining an adequate methyl ketone with an acceptable ethyl ester in a Claisen reaction, which allows for a large range of potential combinations. In this review, we will discuss various synthetic approaches for the preparation of five and six membered heterocyclic compounds via 1,3-dicarbonyls.

Claisen Condensation Reaction Mediated Pimelate Biosynthesis via the Reverse Adipate-Degradation Pathway and Its Isoenzymes.

Pimelic acid is an important seven-carbon dicarboxylic acid, which is broadly applied in various fields. The industrial production of pimelic acid is mainly through a chemical method, which is complicated and environmentally unfriendly. Herein, we found that pimelic acid could be biosynthesized by the reverse adipate-degradation pathway (RADP), a typical Claisen condensation reaction that could be applied to the arrangement of C-C bond. In order to strengthen the supply of glutaryl-CoA precursor, PA5530 protein was used to transport glutaric acid. Subsequently, we discovered that the enzymes in the BIOZ pathway are isoenzyme of the RADP pathway enzymes. By combining the isoenzymes of the two pathways, the titer of pimelic acid reached 36.7 mg ⋅ L-1 under the optimal combination, which was increased by 382.9 % compared with the control strain B-3. It was also the highest titer of pimelic acid biosynthesized by Claisen condensation reaction, laying the foundation for the production of pimelic acid and its derivatives.

ᵧ.ᵧ-Disubstituted Itaconic Acids. Part Vll.1 The Stobbe Condensation of Benzyl-, p-Chlorobenzyl-, and p-Methoxybenzylphenyl Ketones with Diethyl Succinate

ᵧ.ᵧ-Disubstituted Itaconic Acids. Part Vll.1 The Stobbe Condensation of Benzyl-, p-Chlorobenzyl-, and p-Methoxybenzylphenyl Ketones with Diethyl Succinate

Integration of C-Acylation in the Solid-Phase Synthesis of Peptides and Peptidomimetics Employing Meldrum’s Acid, Phosphorus, and Sulfur Ylides

AbstractThe modification of native peptides to peptidomimetics is an important goal in medicinal chemistry and requires, in many cases, the integration of C-acylation steps involving amino acids with classical peptide synthesis. Many classical C-acylation protocols involving Claisen condensations and the use of ylides are not compatible with peptide synthesis, mostly due to the requirements for strong bases leading to epimerization or deprotection of peptides. Meldrum’s acid as well as several specific phosphorus and sulfur ylides, however, are acidic enough to provide reactive C-nucleophiles under mildly basic conditions tolerated during peptide synthesis. This review provides an overview of peptide-compatible C-acylations using Meldrum’s acid and phosphorus and sulfur ylides, and their application in the medicinal chemistry of peptides.1 Introduction2 C-Acylation of Meldrum’s Acid2.1 C-Acylation of Meldrum’s Acid on Solid Phase3 Ylides as Substrates for C-Acylation3.1 C-Acylation of Phosphorus Ylides in Solution Phase3.2 C-Acylation of Solid-Supported Phosphorus Ylides3.3 C-Acylation of Sulfur Ylides3.4 C-Acylation of Solid-Supported Sulfur Ylides4 Miscellaneous Ylides as Acyl Anion Equivalents5 Summary

A Valuable Method for the Synthesis of 2‐Benzylchromones: A Comparative Evaluation of Both Conventional and Microwave‐Assisted Synthesis

AbstractChromones (4H‐chromen‐4‐ones) contemplate a naturally occurring class of compounds widely distributed in Nature, particularly in plants. This singular ring system has emerged as a privileged scaffold in medicinal chemistry, mainly due to its unique structural features, diverse biological activities, and pharmacological properties. Throughout the past few years, our efforts have been focused on synthesizing a series of 2‐benzylchromones through a Claisen condensation, using 2’‐hydroxyacetophenones and ethyl 2‐phenylacetates. However, the extended periods of reaction necessary for the synthesis of 2‐benzylchromones led to the search for an alternative. Thus, microwave irradiation emerged as a suitable approach to obtain these chromones in shorter reaction times and with similar or even improved synthetic yields. Our work demonstrates that it is possible to synthesize 2‐benzylchromones through both conventional and microwave‐assisted synthesis, favoring the use of microwave irradiation.

Crystal structure of Pseudomonas aeruginosa FabB C161A, a template for structure-based design for new antibiotics

Background: FabB (3-oxoacyl-[acyl-carrier-protein] synthase 1) is part of the fatty acid synthesis II pathway found in bacteria and a potential target for antibiotics. The enzyme catalyses the Claisen condensation of malonyl-ACP (acyl carrier protein) with acyl-ACP via an acyl-enzyme intermediate. Here, we report the crystal structure of the intermediate-mimicking Pseudomonas aeruginosa FabB (PaFabB) C161A variant. Methods: His-tagged PaFabB C161A was expressed in E. coli Rosetta DE3 pLysS cells, cleaved by TEV protease and purified using affinity and size exclusion chromatography. Commercial screens were used to identify suitable crystallization conditions which were subsequently improved to obtain well diffracting crystals. Results: We developed a robust and efficient system for recombinant expression of PaFabB C161A. Conditions to obtain well diffracting crystals were established. The crystal structure of PaFabB C161A was solved by molecular replacement at 1.3 Å resolution. Binding site comparison between PaFabB and PaFabF revealed a conserved malonyl binding site but differences in the fatty acid binding channel. Conclusions: The PaFabB C161A crystal structure can be used as a template to facilitate the design of FabB inhibitors.

Iterative synthesis of nitrogen-containing polyketide via oxime intermediates.

Typical polyketides consist of C, H, and O atoms, whereas several types of N-containing polyketides are known to show intriguing properties. Because conventional synthetic approaches for such compounds focus on only specific structures, a more general method is desirable. Here, we have developed an iterative synthesis of nitrogen-containing polyketide. Chain elongation of carboxylic acid via decarboxylative Claisen condensation with malonic acid half thioester was iteratively performed to construct carbon frameworks. β-Keto groups formed by the chain elongation were appropriately converted to O-methyl oximes for incorporation of nitrogen atoms. Cyclization of the resulting oxime intermediates followed by reductive N–O cleavage afforded structurally diverse nitrogen-containing polyketides such as 2-pyridone, 4-aminopyrone, and 4-aminosalicylate. This method was finally applied to the synthesis of (R)-6-aminomellein, which is a nitrogen-substituted derivative of bioactive compound, (R)-6-methoxymellein. The versatility of the present method would enable the synthesis of diverse polyketides with nitrogen functional groups, which can be potentially utilized for the development of novel bioactive compounds.

Crystal structure of Pseudomonas aeruginosa FabB C161A, a template for structure-based design for new antibiotics

Background: FabB (3-oxoacyl-[acyl-carrier-protein] synthase 1) is part of the fatty acid synthesis II pathway found in bacteria and a potential target for antibiotics. The enzyme catalyses the Claisen condensation of malonyl-ACP (acyl carrier protein) with acyl-ACP via an acyl-enzyme intermediate. Here, we report the crystal structure of the intermediate-mimicking Pseudomonas aeruginosa FabB ( PaFabB) C161A variant. Methods: His-tagged PaFabB C161A was expressed in E. coli Rosetta DE3 pLysS cells, cleaved by TEV protease and purified using affinity and size exclusion chromatography. Commercial screens were used to identify suitable crystallization conditions which were subsequently improved to obtain well diffracting crystals. Results: We developed a robust and efficient system for recombinant expression of PaFabB C161A. Conditions to obtain well diffracting crystals were established. The crystal structure of PaFabB C161A was solved by molecular replacement at 1.3 Å resolution. Binding site comparison between PaFabB and PaFabF revealed a conserved malonyl binding site but differences in the fatty acid binding channel. Conclusions: The PaFabB C161A crystal structure can be used as a template to facilitate the design of FabB inhibitors.

Difluoroboron complexes of peripheral β-diketonates in cyclopheophorbides: Their syntheses and optical properties

Cyclopheophorbide-a prepared from intramolecular mixed Claisen condensation of methyl pyropheophorbide-a (one of the chlorophyll-a derivatives) was complexed with a difluoroboron species at the β-diketonate moiety on the exo-five-membered ring fusing the core cyclic tetrapyrrole π-skeleton. Its 3-substituted chlorin analogs and the related bacteriochlorin were also synthesized by difluoroboronation of the corresponding (bacterio)chlorins possessing a peripheral diketonate group. In solution, all the synthetic complexes showed broad Qy and redmost Soret absorption bands and an intense bluemost Soret band. Their maxima were dependent on the 3-substitution and the 7,8-dihydrogenation. The boron complexes were non-fluorescent, which was comparable to the boron-free counterparts.

Influence of aldol condensation processes on the formation of surface films during friction in ester lubricants

The boundary lubrication mode is usually implemented in conditions of low sliding speeds and high loads. The formation of strong boundary lubricating films under this friction mode determines the operability and durability of the friction units. It is believed that the formation of surface boundary films during friction includes the stages of the lubricant oxidation, and the aldol condensation reaction of oxidized molecules. As a result, high-molecular substances called “friction polymers” are formed. The paper studies the formation of surface films in the presence of substances with different reactivity in the aldol condensation and Claisen condensation reactions. Sunflower oil, bis (2-ethylhexyl) sebacate (DEHS), triisodecyl benzene-1,2,4-tricarboxylate (TC) were used as lubricants. It is shown by ATR IR-spectroscopy of that the common thing for the studied oils is that the C=O and C-O groups participate in the formation of boundary films in these oils. The addition of substances, active in aldol condensation reactions, into lubricants does not accelerate the formation of boundary films. Additives that can chemically interact with iron contribute to the dissolution of the surface oxide film and accelerate the formation of boundary layers. The formation of “friction polymers” occurs when the lubricant molecules interact with the metal surface.

Synthesis of oleic-based primary glycol with high molecular weight for bio-based waterborne polyurethane

Oleic acid, as a renewable resource, exists in almost every vegetable oil, especially olive and camellia oils, which has promising prospects for the preparation of bio-based polymers. In this study, a novel oleic-based primary glycol (OPG) was synthesized from methyl oleate (MO, derived from vegetable oil) via Claisen condensation and thiol-ene photo-click reactions and used as an alternative to petroleum-based glycol for the preparation of bio-based waterborne polyurethane (BWPU), and the differences in reactivity between the OPG and petroleum-based polypropylene glycol (PPG) and properties between BWPU and petroleum-based waterborne polyurethane (PWPU) were investigated. The yield of OPG was approximately 90%, the degree of functionality was 2.0, the hydroxyl value was about 155 mg KOH g−1 and the molecular weight (Mw) varied from 296 g mol−1 to 560 g mol−1 and 716 g mol−1 after the chain extension of Claisen condensation and thiol-ene photo-click reactions. In comparison with PPG, OPG exhibited lower activation energy towards IPDI, and the values showed an order of OPG (Ea/Eo=71.25/74.20 kJ mol−1) < PPG600 (Ea/Eo=106.83/108.03 kJ mol−1) < PPG1000 (Ea/Eo=129.20/129.37 kJ mol−1). Correspondingly, the end point of pre-polymerization appeared in 80 min for OPG and 420 min, 840 min for PPG600 and PPG1000 at 80 °C without catalyst, demonstrating that OPG had higher reactivity. Because of the difference in hydrophobicity, the minimum amount of hydrophilic extender used to obtain stable WPU emulsions was 7 wt% for OPG and 3.5 wt% for PPG respectively. The resulting BWPU films possessed good mechanical properties, including higher tensile strength (19.78 MPa) and Young’s modulus (206.61 MPa). But the thermal stability (Td5% ≤ 250 ℃) and low temperature resistance (Tg ≥ 28 ℃) of BWPU films were inferior to that of PWPU films.