Claisen Condensation Research Articles

Noncanonical Functions of Ketosynthase Domains in Type I Polyketide Synthases.

Modular type I polyketide synthases (PKSs) are remarkable molecular machines that can synthesize structurally complex polyketide natural products with a wide range of biological activities. In these molecular machines, ketosynthase (KS) domains play a central role, typically by catalyzing decarboxylative Claisen condensation for polyketide chain extension. Noncanonical KS domains with catalytic functions rather than Claisen condensation have increasingly been evidenced, further demonstrating the capability of type I PKSs for structural diversity. This review provides an overview of the reactions involving unusual KS activities, including PKS priming, acyl transfer, Dickmann condensation, Michael addition, aldol-lactonization bicyclization, C-N bond formation and decarbonylation. Insights into these reactions can deepen the understanding of PKS-based assembly line chemistry and guide the efforts for rational engineering of polyketide-related molecules.

Synthesis, structure, and biological activity of sodium, zinc, and magnesium mono- and bis-1-alkoxy-4-(2′-naphthyl)-1,4-dioxo-2-buten-2-olates

The search for new biologically active compounds is a key area of chemical science. Therefore, the synthesis of compounds with a potentially bactericidal effect seems relevant. In order to extend the range of biologically active substances, the synthesis of sodium 4-(2’-naphthyl)-1,4-dioxo-1-ethoxy-2-buten-2-olate and sodium 1-butoxy-4-(2´-naphthyl)-1,4-dioxo-2-buten-2-olate was carried out by Claisen condensation of equimolar amounts of 2-acetonaphtone and dialkyloxalates in a non-polar medium in the presence of sodium as a condensing agent. Bidentate mononuclear metal chelates were obtained by the metal exchange reaction of sodium oxoenolates with Zn(II) and Mg(II) salts. The structure of the synthesized compounds was confirmed by infrared spectroscopy, (1Н, 13С) nuclear magnetic resonance spectroscopy, and mass spectrometry. The infrared spectra of solid samples of sodium oxoenolates and metal complexes contain bands of stretching vibrations of ester carbonyl groups, skeletal vibrations of aromatic rings, as well as “ether” bands due to vibrations of C–O–C bonds. The 1Н and 13С nuclear magnetic resonance spectra recorded in CDCl3 and Dimethyl sulfoxide-d6 are characterized by a complete set of all expected signals with chemical shift values that are well comparable with the reference data. In the mass spectra of the analyzed compounds, recorded in an acetonitrile solution in the electrospray mode, signals of [M+H]+ and [M+Na]+ protonated and cationized molecules are observed. The bactericidal action of the synthesized preparations was assessed using the agar well diffusion method in combination with the serial dilution method. The biological activity of sodium 4-(2’-naphthyl)-1,4-dioxo-1-ethoxy-2-buten-2-olate against Pseudomonas Aeruginosa and Staphylococcus Aureus, as well as sodium 1-butoxy-4-(2’-naphthyl)-1,4-dioxo-2-buten-2-olate against Pseudomonas Aeruginosa, was revealed. Pronounced resistance of Salmonella spp. to the studied compounds was established.

Accessing the Cloke-Wilson Rearrangement via Conjugate Addition of Phosphoranes to Michael Acceptors: A Route to Cyclopropanes and 5-Membered Ring Heterocycles Investigated by Density Functional and Ab Initio Theory.

Conjugate addition of unstabilized Wittig-type phosphonium ylides to 1,1-diacceptor- and 1-acceptor-substituted alkenes is investigated by density functional theory and high-level ab initio (DLPNO-CCSD(T)) calculations. The results indicate that the initial conjugate addition step should be facile with barriers predicted to be between 0 and 21 kcal mol-1. Potential intramolecular follow-up reactions include the formation of acceptor-substituted cyclopropanes as well as the formation of dihydrofuran derivatives via intramolecular SN2-type transition state structures. The barriers calculated for these potentially valuable cyclization reactions are substantial with Gibbs free energies of activation between 19 and 40 kcal mol-1. Competing reaction channels include Wittig olefination (for ketones and aldehydes), as well as Claisen condensation reactions. The reaction offers an alternative entry point to the nucleophile-catalyzed Cloke-Wilson rearrangement.

Co‐Catalyzed Dehydrogenation Claisen Condensation of Secondary Alcohols with Esters†

Comprehensive SummaryCatalytic dehydrogenation, with its exceptional atom economy and chemoselectivity, offers a highly desirable yet challenging approach for converting multiple environmentally friendly alcohols into crucial molecules. Furthermore, the utilization of catalysts based on abundant elements found on Earth for alcohol dehydrogenation to produce acryl ketone holds significant promise as a versatile strategy in synthesizing key building blocks for numerous pharmaceutical applications. The present study describes a practical Co‐catalyzed cascade dehydrogenative Claisen condensation of secondary alcohols with esters, facilitating the synthesis of a wide range of 3‐hydroxy‐prop‐2‐en‐1‐ones. We introduce a catalytic system based on novel and scalable indazole NNP‐ligands coordinated to cobalt for efficient dehydrogenations of secondary alcohols, and propose a plausible reaction mechanism supported by control experiments and labeling studies. Notably, it allows for the streamlined synthesis of multiple pharmaceuticals in one‐pot.

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.

Synthesis, in vitro cytotoxic activity and molecular docking study of androstene and estrone derivatives

The development and discovery of steroidal drugs to cure cervical cancer is of the most important. The Claisen condensation of androstene and estrone with aromatic aldehydes was catalyzed by potassium tert. butoxide in tert. butanol to give the corresponding 2-arylidene and 16-arylidene estrone. Subsequently, the 16-arylidene estrone reacted with acid chloride in presence of quaternary amine in halogenated solvent resulting in the steroidal arylidene derivatives. Synthesis, Characterization and in vitro cytotoxic activity of arylidenes are rationalized. Fifteen compounds are synthesized and six of them were evaluated for cytotoxic activity against cervical cancer cell line. HT-3 cell line examination revealed a considerable growth inhibition. Compounds 4a, 4b, 6b, 8c, and 8d, which are estrone-based arylidenes, are the most potent of the series, with IC50 value of 7.15, 10.76, 6.37, 3.56, and 1.55 µM/ml against HT-3 cell line. In addition, molecular docking studies were performed for the steroidal arylidenes to elucidate the binding interactions. Compound 4a, 4b, 6b, 8c and 8d showed excellent binding energy. Docking studies agreed well with in vitro studies. The end result offers an alternative approach to develop steroidal arylidenes that are more effective and are based on estrone, leading to the development of novel anticancer agents.

Novel thioxoimidazolidinone derivatives as dual EGFR and CDK2 inhibitors: Design, synthesis, anticancer evaluation with in silico study

Fifteen thioxoimidazolidinone derivatives were designed as dual EGFR and CDK2 inhibitors and synthesized following Claisen and Knoevenagel condensation. Derivative 12 showed the best EGFR and CDK2 IC50 giving 0.098 μM and 0.087 μM, respectively, followed by 13 with IC50 0.108 μM and 0.144 μM, respectively. Both derivatives showed better cancerous cell line growth inhibition than erlotinib over HCT-116, MCF-7, and HepG-2. Furthermore, the colorectal HCT-116 was the most responsive to treatment with IC50 of 1.87 μM and 2.70 μM for 12 and 13, respectively in comparison to 15.40 μM of erlotinib. Moreover, the molecular docking simulation of 12 and 13 explained their astonishing kinase inhibition at the molecular level, where both exhibited better EGFR binding energy than its co-crystallized ligand consolidated with the crucial amino acid interactions. Similarly, derivative 12 showed comparable binding energy to CDK2 to its co-crystallized ligand and demonstrated the characteristic interactions with CDK2 binding site and gatekeeper residues.

Rational Design of the Substrate Tunnel of β-Ketothiolase Reveals a Local Cationic Domain Modulated Rule that Improves the Efficiency of Claisen Condensation

Formation of carbon–carbon bonds via Claisen condensation catalyzed by thiolase generates a diverse range of carbon frameworks in biosynthetic chemistry. During catalysis, the substrate tunnel of thiolases plays an important role in the binding and condensation of substrates, directly affecting enzyme activity. Therefore, rational engineering of the substrate tunnel is a promising approach for enhancing enzyme performance. However, the lack of a general engineering rule hinders rational engineering of the substrate tunnel. In this study, we reported the crystal structure of Tfu_0875, a thermostable β-ketothiolase from Thermobifida fusca belonging to the thiolase superfamily. The enzyme had a Cys–His–Cys catalytic triad and a narrow substrate tunnel mainly built from the cationic domain, the adenine-binding pocket, and the pantetheine loop. Focusing on the substrate tunnel, mutant candidates with increased kcat were predicted by the deep learning approach. The best mutation in the cationic domain (L163H) exhibited a 313% increase in enzyme activity compared with the wild-type enzyme. Molecular dynamics simulations revealed a local cationic domain modulated rule (LCDMR): mutating the nonconserved residue at the junction between the loop region and the α5 region in the sandwich topology to histidine significantly improved enzyme activity by increasing the reaction space and interaction with the substrate or unstable intermediate. The LCDMR has general applicability in rational engineering of the substrate tunnel to enhance the enzyme activity of other β-ketothiolases.

Synthesis and spectroscopic study of complex compounds of some 3D metals with the condensation product of 1-ferrocenylbutanedione-1,3 and succinic acid dihydrozide

We obtained by Claisen condensation β-diketone-1-ferrocenylbutanedione-1,3. The dicarboxylic acid dihydrazone of 1-ferrocenylbutanedione-1,3 (H4L) was synthesized by reacting succinic acid dihydrazide with ferrocenylacetone in a ratio of 2:1. Based on them, homobinuclear complex compounds with copper(II), zinc(II)and nickel(II) ions were obtained. The IR-, UV- and NMR spectra of the synthesized organic compounds were studied. The results of the studies showed that the H4L ligand in solution exists as a tautomeric mixture: diketone (A), keto-enol (B) and in dienol(C) forms. According to the results of spectroscopic studies, the complexes were assigned a square planar structure, where the four times deprotonated ligand residue is coordinated by each metal atom through two oxygen atoms and a nitrogen atom of the hydrazone fragment. The fourth position in the planar square of the trans-N2O2 coordination site is occupied by the ammonia molecule. Planar five- and six-membered metal cycles of synthesizers are practically coplanar with each other.

Synthesis and optical properties of some 3D metal complexes based on β-dicarbonyl ferrocene derivatives

We obtained β-diketone – 1-ferrocenylbutanedione-1,3 by Claisen condensation. Ligands - hydrazones of monocarboxylic acids 1-ferrocenylbutanedione-1,3 (H2L) were synthesized by the interaction of carboxylic acid hydrazides with ferrocenoylacetone. The optical properties of all compounds synthesized in the work have been studied; based on the absorption spectra data, the values of the optical band gap were determined; it was shown that all the synthesized compounds are d-π type chromophores and have a band gap of 1,39–2,26 eV, i.e. they belong to narrow-gap semiconductors.

Characterization of an Unusual α-Oxoamine Synthase Off-Loading Domain from a Cyanobacterial Type I Fatty Acid Synthase.

Type I fatty acid synthases (FASs) are known from higher eukaryotes and fungi. We report the discovery of FasT, a rare type I FAS from the cyanobacterium Chlorogloea sp. CCALA695. FasT possesses an unusual off-loading domain, which was heterologously expressed in E. coli and found to act as an α-oxoamine synthase (AOS) in vitro. Similar to serine palmitoyltransferases from sphingolipid biosynthesis, the AOS off-loading domain catalyzes a decarboxylative Claisen condensation between l-serine and a fatty acyl thioester. While the AOS domain was strictly specific for l-serine, thioesters with saturated fatty acyl chains of six carbon atoms and longer were tolerated, with the highest activity observed for stearoyl-coenzyme A (C18 ). Our findings suggest a novel route to α-amino ketones via the direct condensation of iteratively produced long-chain fatty acids with l-serine by a FAS with a cis-acting AOS off-loading domain.

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.

ATP‐Independent and Cell‐Free Biosynthesis of β‐Hydroxy Acids Using Vinyl Esters as Smart Substrates

AbstractIn vitro biosynthetic pathways that condense and reduce molecules through coenzyme A (CoASH) activation demand energy and redox power in the form of ATP and NAD(P)H, respectively. These coenzymes must be orthogonally recycled by ancillary reactions that consume chemicals, electricity, or light, impacting the atom economy and/or the energy consumption of the biosystem. In this work, we have exploited vinyl esters as dual acyl and electron donor substrates to synthesize β‐hydroxy acids through a non‐decarboxylating Claisen condensation, reduction and hydrolysis stepwise cascade, including a NADH recycling step, catalyzed by a total of 4 enzymes. Herein, the chemical energy to activate the acyl group with CoASH and the redox power for the reduction are embedded into the vinyl esters. Upon optimization, this self‐sustaining cascade reached a titer of (S)‐3‐hydroxy butyrate of 24 mM without requiring ATP and simultaneously recycling CoASH and NADH. This work illustrates the potential of in vitro biocatalysis to transform simple molecules into multi‐functional ones.

ATP-Independent and Cell-Free Biosynthesis of β-Hydroxy Acids Using Vinyl Esters as Smart Substrates.

In vitro biosynthetic pathways that condense and reduce molecules through coenzyme A (CoASH) activation demand energy and redox power in the form of ATP and NAD(P)H, respectively. These coenzymes must be orthogonally recycled by ancillary reactions that consume chemicals, electricity, or light, impacting the atom economy and/or the energy consumption of the biosystem. In this work, we have exploited vinyl esters as dual acyl and electron donor substrates to synthesize β-hydroxy acids through a non-decarboxylating Claisen condensation, reduction and hydrolysis stepwise cascade, including a NADH recycling step, catalyzed by a total of 4 enzymes. Herein, the chemical energy to activate the acyl group with CoASH and the redox power for the reduction are embedded into the vinyl esters. Upon optimization, this self-sustaining cascade reached a titer of (S)-3-hydroxy butyrate of 24 mM without requiring ATP and simultaneously recycling CoASH and NADH. This work illustrates the potential of in vitro biocatalysis to transform simple molecules into multi-functional ones.

New Method for the Synthesis of Ferrocenylperfluoroalkyl 1,3-Diketones and Different Heterocycles on their Base

The Claisen condensation of acetylferrocene with perfluoroalkylcarboxylic acid esters in hexane in the presence of potassium tert-butoxide leads to the formation of potassium salts of ferrocenylperfluoroalkyl diketones. The resulting diketones are used as convenient precursors for the synthesis of various heterocyclic derivatives which have been isolated in high yields. It is shown that the [3+2]-dipolar cycloaddition with substituted azides as well as the reactions of the diketones with bidentate nucleophiles proceed regioselectively.

Decarboxylative Claisen Condensations with Substituted Malonic Acid Half Oxyesters

AbstractA decarboxylative Claisen condensation involving substituted malonic acid half oxyesters (SMAHOs) as pronucleophiles has been developed. The addition of their magnesium enolates to various acyl donors allows the synthesis of functionalized α-substituted β-keto esters in moderate to excellent yields (13–96%). In addition to acyl chlorides and acid anhydrides, these conditions proved efficient for the use of carboxylic acids as acylating agents, thus allowing to greatly extend the scope of this transformation (32 examples overall).

Elodexanthones A—J, Isoprenylated Xanthone Derivatives with Diverse Skeletons and Bioactivities from Hypericum elodeoides

Comprehensive SummaryElodexanthones A—J (1—10), two pairs of rearranged isoprenylated xanthone enantiomers with an unprecedent 6/6/5/6 tetracyclic core (1—2) along with seven new isoprenylated xanthones (3—9) and a pair of phenylpropanoid xanthones (10), were purified and enantio‐separated from the whole plant of Hypericum elodeoides. Their structures including absolute configurations were characterized by the comprehensive analysis of NMR, HRESIMS, NMR calculations, and ECD calculations. Through Bayer‐Villiger oxidation, Claisen condensation and electrophilic addition, the rearranged skeletons of elodexanthones A—B (1—2) were generated from isoprenylated xanthone precursors. The bioactivities evaluation exhibited that compounds 3, 5, 8—10 showed anti‐inflammatory activity with the IC50 values in the range of 9.53—34.39 μmol/L, and compounds 3—7, and 9 showed notable α‐glucosidase inhibitory activity (IC50: 6.02—257.11 μmol/L).

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.