Claisen Condensation Reaction Research Articles

Fast Claisen condensation reaction optimization in a continuous flow reactor

In our previous study, we described the batch synthesis of CPL304110, an innovative pan-FGFR inhibitor. Herein, we transferred the Claisen condensation reaction, one of the synthesis steps to a continuous flow reactor. A simple solvent switch from ethanol to tetrahydrofuran shortened the original reaction time from 20 h to 10 min. With the use of the design of experiment method and program Statistica®, we optimized reaction parameters and increased the reaction yields from 73 to 84% with greatly shortened reaction times (20 h vs. 2 min), improved productivity (74.4 g h−1), and increased space–time yield (3720 kg h−1 m−3).Graphical abstract

Thiolase: A Versatile Biocatalyst Employing CoA-Thioester Chemistry for Making and Breaking C-C Bonds.

Thiolases are CoA-dependent enzymes that catalyze the thiolytic cleavage of 3-ketoacyl-CoA, as well as its reverse reaction, which is the thioester-dependent Claisen condensation reaction. Thiolases are dimers or tetramers (dimers of dimers). All thiolases have two reactive cysteines: (a) a nucleophilic cysteine, which forms a covalent intermediate, and (b) an acid/base cysteine. The best characterized thiolase is the Zoogloea ramigera thiolase, which is a bacterial biosynthetic thiolase belonging to the CT-thiolase subfamily. The thiolase active site is also characterized by two oxyanion holes, two active site waters, and four catalytic loops with characteristic amino acid sequence fingerprints. Three thiolase subfamilies can be identified, each characterized by a unique sequence fingerprint for one of their catalytic loops, which causes unique active site properties. Recent insights concerning the thiolase reaction mechanism, as obtained from recent structural studies, as well as from classical and recent enzymological studies, are addressed, and open questions are discussed. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

A Computational Study on the Antioxidant Activity of Certain Random Copolyesters Containing Bis(arylidene) Cycloalkanone Moiety in the Main Chain

A series of five random copolyesters was synthesized by polycondensation of different arylidene diols with curcumin as a common diol and a common diacid chloride in the ratio of 1:1:2, respectively. The five arylidene diols were synthesized by an acid-catalyzed Claisen condensation reaction. The repeating units present in these five random copolyesters and also the backbone was identified by FT-IR, 1H-NMR, and 13C-NMR spectroscopic techniques. The curcumin based copolyester exhibited good antioxidant activity, confirmed by various antioxidant activity determinations. Structural analysis such as HOMO and LUMO energies and the HOMO-LUMO energies gap of the molecule has been calculated using the B3LYP/6-311+G (d, p) level of theory. The antioxidant property of the molecule can be explained by the hydrogen atom transfer by theoretical study.

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.

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.

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.

P-Nitrophenyl esters provide new insights and applications for the thiolase enzyme OleA.

The OleA enzyme is distinct amongst thiolase enzymes in binding two long (≥C8) acyl chains into structurally-opposed hydrophobic channels, denoted A and B, to carry out a non-decarboxylative Claisen condensation reaction and initiate the biosynthesis of membrane hydrocarbons and β-lactone natural products. OleA has now been identified in hundreds of diverse bacteria via bioinformatics and high-throughput screening using p-nitrophenyl alkanoate esters as surrogate substrates. In the present study, p-nitrophenyl esters were used to probe the reaction mechanism of OleA and shown to be incorporated into Claisen condensation products for the first time. p-Nitrophenyl alkanoate substrates alone were shown not to undergo Claisen condensation, but co-incubation of p-nitrophenyl esters and CoA thioesters produced mixed Claisen products. Mixed product reactions were shown to initiate via acyl group transfer from a p-nitrophenyl carrier to the enzyme active site cysteine, C143. Acyl chains esterified to p-nitrophenol were synthesized and shown to undergo Claisen condensation with an acyl-CoA substrate, showing potential to greatly expand the range of possible Claisen products. Using p-nitrophenyl 1-13C-decanoate, the Channel A bound thioester chain was shown to act as the Claisen nucleophile, representing the first direct evidence for the directionality of the Claisen reaction in any OleA enzyme. These results both provide new insights into OleA catalysis and open a path for making unnatural hydrocarbon and β-lactone natural products for biotechnological applications using cheap and easily synthesized p-nitrophenyl esters.

The 3-ketoacyl-CoA thiolase: an engineered enzyme for carbon chain elongation of chemical compounds.

Because of their function of catalyzing the rearrangement of the carbon chains, thiolases have attracted increasing attentions over the past decades. The 3-ketoacyl-CoA thiolase (KAT) is a member of the thiolase, which is capable of catalyzing the Claisen condensation reaction between the two acyl-CoAs, thereby achieving carbon chain elongation. In this way, diverse value-added compounds might be synthesized starting from simple small CoA thioesters. However, most KATs are hampered by low stability and poor substrate specificity, which has hindered the development of large-scale biosynthesis. In this review, the common characteristics in the three-dimensional structure of KATs from different sources are summarized. Moreover, structure-guided rational engineering is discussed as a strategy for enhancing the performance of KATs. Finally, we reviewed the metabolic engineering applications of KATs for producing various energy-storage molecules, such as n-butanol, fatty acids, dicarboxylic acids, and polyhydroxyalkanoates. KEY POINTS: • Summarize the structural characteristics and catalyzation mechanisms of KATs. • Review on the rational engineering to enhance the performance of KATs. • Discuss the applications of KATs for producing energy-storage molecules.

Systematic approach to the chemical synthesis of arabidopyrones, the unique α-pyrones of Arabidopsis metabolites

Total synthesis of two arabidopyrones, iso-arabidopyl alcohol (1) and iso-arabidopic acid (2) isolated from Arabidopsis thaliana was achieved for the first time using Claisen condensation and Wittig reaction as the key steps. In addition, arabidopic acid (4) was synthesized from the methyl ester of arabidopyl alcohol (3). Thus, chemical synthesis of the unique natural α-pyrones 1–4 was accomplished with a short synthetic route by a systematic approach from readily available substances.

Application of N‐Acylimidazoles in the Claisen Condensation Reaction

AbstractThe Claisen condensation reaction is a classical method used for the formation of C−C bonds. Homo‐ and cross‐Claisen condensation reactions are usually carried out using a Ti(IV)‐based reagent at ultra‐low‐temperatures. In this report, intermediate β‐keto acyl imidazoles were synthesised using a sodium imidazolide‐catalysed homo‐ and cross‐condensation reaction of N‐acyl imidazoles performed under mild conditions and subsequently used to prepare a range of β‐keto esters and ketones via alcoholysis or hydrolysis. This method is particularly suitable for the synthesis of isotopically‐labelled acetylacetic ester compounds. N‐acyl imidazole compounds are useful reactants for the Claisen condensation reaction.

Nickel-Catalyzed Claisen Condensation Reaction between Two Different Amides.

A nickel-catalyzed Claisen condensation reaction between two amides, where one possesses an α-proton, for the synthesis of β-ketoamides was developed. Ni(glyme)Cl2 and terpyridine serve as the active catalysts in the presence of Mn and LiCl. N,N-Methylphenyl and N,N-diphenyl benzamide derivatives react with cyclic and noncyclic amides to give their corresponding β-ketoamides in moderate to good yields. In addition, a DFT calculation suggests that reductive elimination is the rate-determining step.

Regioselective synthesis and evaluation of novel sulfonamide 1,2,3-triazole derivatives as antitumor agents

A novel series of 1,2,3-triazole containing sulfonamide moiety was synthesized. Treatment of 4-acetyl 1,2,3-triazole 3 with different aldehydes gave α,β-unsaturated ketones 4a–c. Condensation of 3 with dimethylformamide dimethylacetal (DMF-DMA) gave formimidamide 5. Chalcone 7 was achieved via two ways from the reaction of 5 with benzaldehyde or from treatment of 4a with DMF-DMA. Reaction of 7 with hydrazine hydrate afforded pyrazoline 8. 5-Methyl pyrazole 12 was synthesized from Claisen condensation reaction of 3 or 5 with ethyl acetate to give 1,3-diketone adduct 9 or 10, respectively, followed by treatment with hydrazine hydrate. 5-Aminopyrazole 17 was synthesized from the reaction of ester 13 or formimidamide ester 13a with acetonitrile to afford cyanoacetyl derivatives 14 or 15, respectively, followed by treatment with hydrazine hydrate. The new compounds were screened for their in vitro antitumor activity. The results of this investigation revealed that compounds 12, 7, and 17 had a significant anticancer activity against MCF-7 cancer cell line with IC50 values 12.4, 19.8, and 23.4 µM, respectively, in relation to the standard drug, doxorubicin.

Synthesis and Biological Activity of 4-(Pyridin-3-yl)-2-hydroxy-4-oxobut-2-enoic Acid Derivatives

Claisen condensation reaction of diethyl oxalate with 1-[4-(furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]ethan-1-one afforded (Z)-4-[4-(furan-2-yl)-2-methyl-5-nitro-6-phenylpyridin-3-yl]-2-hydroxy-4-oxobut-2-enoic acid. The latter reacted with various binucleo­philes to form the corresponding 3,4-dihydroquinoxaline-2(1H)-one, 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one, and 1H-pyrazole derivatives. Biological screening of the obtained compounds revealed analgesic and antibacterial activity.

Concise synthesis of 23-hydroxylated vitamin D3 metabolites

Three 23-hydroxylated vitamin D3 derivatives, which are metabolites of 25-hydroxyvitamin D3 produced by CYP24A1 and a related diastereomer, were efficiently synthesized. Each C23 hydroxy unit was constructed by the Claisen condensation reaction with ethyl acetate or the Grignard reaction with 2-methylallymagnesium chloride. Stereochemistry at the C23 position was determined by a modified Mosher’s method. The triene structures were constructed by the Wittig-Horner reaction utilizing the A-ring phosphine oxide moiety.

The chejuenolide biosynthetic gene cluster harboring an iterative trans-AT PKS system in Hahella chejuensis strain MB-1084

Hahella chejuensis MB-1084 is a Gram-negative marine bacterial strain that produces unusual 17-membered carbocyclic tetraenes, chejuenolide A and B. Two fosmid clones responsible for chejuenolide production were identified from the genomic DNA library of the MB-1084 strain. Systematic inactivation of the open reading frames (ORFs) in the sequenced region defines the boundaries of the chejuenolide (che) biosynthetic gene cluster (24.9 kbp) that encodes one non-ribosomal peptide synthase (NRPS)-polyketide synthase (PKS) hybrid protein, three modular PKSs, two PKS domains, and an amine oxidase homolog. Based on the results, we found that the che PKSs have non-canonical features such as trans-AT system and insufficient number of KS domains (five KS domains) for chejuenolide production (requires eight rounds of Claisen condensation reaction). Heterologous expression of the che PKSs in the E. coli BAP1 strain provides strong evidence of the iterative characteristic of the modular PKSs. Additionally, the phylogenetic relatedness of the KS domains of che PKSs and other trans-AT PKSs was analyzed to propose a possible pathway for chejuenolide biosynthesis.

Engineering Erg10 Thiolase from Saccharomyces cerevisiae as a Synthetic Toolkit for the Production of Branched-Chain Alcohols.

Thiolases catalyze the condensation of acyl-CoA thioesters through the Claisen condensation reaction. The best described enzymes usually yield linear condensation products. Using a combined computational/experimental approach, and guided by structural information, we have studied the potential of thiolases to synthesize branched compounds. We have identified a bulky residue located at the active site that blocks proper accommodation of substrates longer than acetyl-CoA. Amino acid replacements at such a position exert effects on the activity and product selectivity of the enzymes that are highly dependent on a protein scaffold. Among the set of five thiolases studied, Erg10 thiolase from Saccharomyces cerevisiae showed no acetyl-CoA/butyryl-CoA branched condensation activity, but variants at position F293 resulted the most active and selective biocatalysts for this reaction. This is the first time that a thiolase has been engineered to synthesize branched compounds. These novel enzymes enrich the toolbox of combinatorial (bio)chemistry, paving the way for manufacturing a variety of α-substituted synthons. As a proof of concept, we have engineered Clostridium's 1-butanol pathway to obtain 2-ethyl-1-butanol, an alcohol that is interesting as a branched model compound.

Crystal structure of cytoplasmic acetoacetyl-CoA thiolase from Saccharomyces cerevisiae.

Thiolases are vital enzymes which participate in both degradative and biosynthetic pathways. Biosynthetic thiolases catalyze carbon-carbon bond formation by a Claisen condensation reaction. The cytoplasmic acetoacetyl-CoA thiolase from Saccharomyces cerevisiae, ERG10, catalyses carbon-carbon bond formation in the mevalonate pathway. The structure of a S. cerevisiae biosynthetic thiolase has not previously been reported. Here, crystal structures of apo ERG10 and its Cys91Ala variant were solved at resolutions of 2.2 and 1.95 Å, respectively. The structure determined shows that ERG10 shares the characteristic thiolase superfamily fold, with a similar active-site architecture to those of type II thiolases and a similar binding pocket, apart from Ala159 at the entrance to the pantetheine-binding cavity, which appears to be a determinant of the poor binding ability of the substrate. Moreover, comparative binding-pocket analysis of molecule B in the asymmetric unit of the apo structure with that of the CoA-bound complex of human mitochondrial acetoacetyl-CoA thiolase indicates the canonical binding mode of CoA. Furthermore, the steric hindrance revealed in a structural comparison of molecule A with the CoA-bound form raise the possibility of conformational changes that are associated with substrate binding.

Synthesis, photoluminescent and electrochemical properties of diacetoxyboron derivatives for bis-β-diketone linked thienothiophene

Six novel diacetoxyboron complexes of bis-β-diketones linked thienothiophene moiety were synthesized from acetoacetone by cyclization, Claisen condensation and chelation reaction. The obtained complexes were confirmed by means of 1H NMR, FTIR, MS and elemental analysis and their electrochemical and photoluminescent properties were investigated by cyclic voltammetry, UV–vis absorption and fluorescence spectroscopy. The results showed that these diacetoxyboron complexes yielded a blue emission in DMF solution and emitted a greenish-yellow emission in powders and PMMA films. Especially, diacetoxyboron bis-β-diketonate with tert-butylphenyl thienothiophene exhibited the most intense photoluminescent intensity, highest quantum efficiency (Φu = 0.95) in solution and longest lifetime value (τ = 38.42 μs) in PMMA film among these complexes. In addition, these diacetoxyboron complexes showed the low-lying LUMO energy levels (2.71–2.75 eV), which was suitable for electron transfer.

Photoluminescence by Intercalation of a Fluorescent β-Diketone Dye into a Layered Silicate.

A β-diketone dye was packed into the two-dimensional nanospace of a synthetic smectite (Sumecton SA), which is a cation-exchangeable layered silicate, to induce strong emission owing to molecular packing of the dye. An emissive dye, 1-(4-methoxyphenyl)-3-(4-pyridyl)-1,3-propandione, was prepared through a Claisen condensation reaction; the dye exhibited aggregation-induced emission, which is enhanced emission owing to clustering of molecules to form aggregates in poor solvents or in the solid state. The dye was nonemissive in solution. However, strong green emission was observed because of the restriction of molecular motion when the protonated dye was accommodated into the interlayer nanospace of the silicate layers through cation-exchange reactions. The restricted motion was confirmed by the smaller nonradiative relaxation rate constant obtained by time-resolved luminescence and quantum yield measurements. A moderate dye packing (0.11 mmol/g) in the interlayer space is important to obtain enhanced emission, whereas the intercalation of a large amount of dye (0.27 mmol/g) resulted in concentration quenching. Therefore, the interlayer space of the layered silicate used here was responsible for the strong emission because of moderate packing of the accommodated β-diketones.