Active Ester Research Articles

α-Branched amines through radical coupling with 2-azaallyl anions, redox active esters and alkenes.

α-Branched amines are fundamental building blocks in a variety of natural products and pharmaceuticals. Herein is reported a unique cascade reaction that enables the preparation of α-branched amines bearing aryl or alkyl groups at the β- or γ-positions. The cascade is initiated by reduction of redox active esters to alkyl radicals. The resulting alkyl radicals are trapped by styrene derivatives, leading to benzylic radicals. The persistent 2-azaallyl radicals and benzylic radicals are proposed to undergo a radical–radical coupling leading to functionalized amine products. Evidence is provided that the role of the nickel catalyst is to promote formation of the alkyl radical from the redox active ester and not promote the C–C bond formation. The synthetic method introduced herein tolerates a variety of imines and redox active esters, allowing for efficient construction of amine building blocks.

Acylation of m-cresol with acetic acid supported by in-situ ester formation on H-ZSM-5 zeolites

Friedel-Crafts acylation of phenolic compounds with carboxylic acids catalyzed by Brønsted-acid zeolites is an interesting reaction that could find application in the production of fuels and chemicals from renewable feedstocks. The mechanism of direct acylation of m-cresol with acetic acid over protonic zeolites and the role that the confining environment may have on reaction rate and product selectivity are topics of current interest. Here, we evaluate this reaction at varying conditions over H-ZSM-5 catalysts with different acid site densities. By decoupling the effect of parasitic phenomena – diffusion and catalyst deactivation – we have been able to evaluate the true kinetics of this reaction. We have found that, in the absence of a solvent, the reaction over H-ZSM-5 zeolites under commonly studied conditions (Si/Al = 40) at 250 °C is often influenced by the diffusion of reactants to active sites. By further decreasing active site density and operating under diffusion-free conditions, the true activation barrier for acetophenone (2-hydroxyl-4-methylacetophenone) formation obtained on H-ZSM-5 under surface-saturation conditions is relatively low (41 kJ/mol). This value is significantly lower than the barrier associated with the dehydration of the carboxylic acid to form surface acyl species when not assisted by the formation of intermediate ester species. Based on reaction kinetic analysis, it is proposed that the formation of acylium ion from adsorbed m-tolyl acetate is the rate-limiting step. However, feeding the intermediate ester – i.e., m-tolyl acetate – to act as acylating agent, results in reduced rates compared to those in which the acylating agent is acetic acid. This result reveals that diffusion of m-tolyl acetate is slow and that the kinetically relevant ester is formed within the confines of the zeolite pores. By co-feeding water with m-tolyl acetate, we reveal that the bulky ester is hydrolyzed to form smaller molecules that diffuse faster inside zeolite pores and subsequently enhance the reaction rate. Vapor phase acylation of m-cresol with acetic acid over low acid site density H-Beta zeolite confirms the role of the active intermediate ester in accelerating the rate of acylated product formation. Catalyst deactivation during reaction increases with the partial pressure of acetic acid, even under the zero-order kinetic regime, during which the partial pressure of produced gaseous ketene remains constant. This result would indicate that this usual coke precursor is not the main cause of deactivation, but rather bulkier compounds formed by subsequent esterification of acetic acid with the acylated product (e.g., 2-hydroxyl-4-methylacetophenone).

STUDY OF BIOLOGICAL ACTIVITY OF RACEMIC AND OPTICALLY ACTIVE ESTERS OF NAPHTHENIC AND FATTY ACIDS BASED ON UNSATURATED OXYESTERS

Petrochemical products based on petroleum naphthenic acids have special properties. Esters of naphthenic acids possess practically valuable organic compounds. The aim of this work is the development of effective methods for the preparation of aromatic esters based on naphthenic and individual fatty acids which is a very promising direction in the medicine practice. The synthesis of unsaturated racemic and chiral oxyethers was carried out on the basis of the interaction of chloromethylpropargyl (allyl) esters with carbonyl compounds with the participation of metallic zinc. Also, to study the biological activity, racemic and optically active esters were synthesized based on naphthenic acids and unsaturated racemic and chiral oxyesters. As test cultures used: gram-positive (Staphylo-coccus aureus-Staphylococcus aureus), gram-negative (Pseudomonas aeruginosa – Pseu-domonas aeruginosa, Escherichia coli) bacteria, as well as yeast-like fungi of the genus Candida - Candida albicans. Analysis of the biological activity of the synthesized compounds showed that optically active bicyclo [2.2.1] hept-5-ene-2-methylol monoesters have higher antimicrobial and antifungal activity compared to their racemic analogs and drugs used in medicine.

Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid.

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H37Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.

Rapid determination of 2,4-diaminopyrimidine residues through sample pretreatment using immunomagnetic bead purification along with HPLC–UV

To reduce matrix interference and realize simultaneous detection of multiple homologous compounds (trimethoprim (TMP), diaveridine (DVD), ormetoprim (OMP), baquiloprim (BQP), and aditoprim (ADP) in pig, cattle, chicken, and fish muscles), an immunomagnetic bead (IMB)-based sample purification pretreatment with HPLC–UV was developed. A broad-spectrum monoclonal antibody (mAb, named 14C6) was prepared and conjugated with carboxylic-acid-functionalized magnetic nanoparticles using the active ester method to obtain IMBs for sample purification. The extraction solvent was optimized based on the extraction efficiency. Good linearity was observed for all the five analytes (10–200 μg/kg) with the LOD and LOQ of 5 and 10 μg/kg, respectively. The mean recoveries ranged from 62.5% to 76.9%, while the coefficient of variation was <12.2%. The IMB method afforded greater sample purification and enrichment than those achieved with the SPE column-based conventional method. Hence, the IMB-based sample purification is a useful tool to determine 2,4-diaminopyrimidine residues in edible animal tissues.

A high-performance fluorescence immunoassay based on pyrophosphate-induced MOFs NH2-MIL-88B(Fe) hydrolysis for chloramphenicol detection

In this work, we firstly found and verified that pyrophosphate (PPi) can form a competitive coordination effect with the metal-organic frameworks (MOFs) NH2-MIL-88B(Fe), causing the MOFs structure to collapse and release diaminoterephthalic acid (NH2-BDC), and then weakening the ligand-metal charge transfer (LMCT) of the MOFs network structure, allowing the original fluorescence of NH2-BDC be recovered. Based on this new principle, synthesized high-stability MOFs NH2-MIL-88B(Fe) were employed as fluorescent signal sources to trace target recognition, and MOFs fluorescent immunoprobes were prepared by chemically coupling anti-chloramphenicol (CAP) monoclonal antibodies via the active ester method (EDC/Sulfo-NHS). A direct competitive fluorescence immunoassay was established for the detection of CAP residues in milk samples, in which the limit of detection (LOD) was 0.028 μg L−1, the linear range was 0.05–0.75 μg L−1, and the recovery rate was 91.8%–112.3%. This study employed a simple and time-saving one-step method for releasing fluorescent signals, which was also useful for the rapid and accurate detection of CAP residues.

Electroreductive Cross-Coupling of Trifluoromethyl Alkenes and Redox Active Esters for the Synthesis of Gem-Difluoroalkenes.

An electroreductive access to gem-difluoroalkenes has been developed through the decarboxylative/defluorinative coupling of N-hydroxyphtalimides esters and α-trifluoromethyl alkenes. The electrolysis is performed under very simple reaction conditions in an undivided cell using cheap carbon graphite electrodes. This metal-free transformation features broad scope with good to excellent yields. Tertiary, secondary as well as primary alkyl radicals could be easily introduced. α-aminoacids L-aspartic and L-glutamic acid-derived redox active esters were good reactive partners furnishing potentially relevant gem-difluoroalkenes. In addition, it has been demonstrated that our electrosynthetic approach toward the synthesis of gem-difluoroalkenes could use an easily prepared Kratitsky salt as alkyl radical precursor via a deaminative/defluorinative carbofunctionalization of trifluoromethylstyrene.

Synthesis of isoeugenol biobased epoxy polymer by forming α‐hydroxyl ester and degradation studies

AbstractThe synthesis of bio‐based monomers and polymers from renewable feedstock, such as plant biomass, is desirable because of the depletion of fossil fuel resources and the reliance of thermosetting epoxy resin on non‐renewable petrochemical monomers. Despite the excellent polymeric properties of bisphenol‐based epoxy resins, these negatively impact human health. Herein, the synthesis of self‐curable epoxy polymers from the bio‐based material isoeugenol by forming α‐hydroxyl esters is reported. The epoxides are named AB (single epoxide and ester groups) and A2B2 (double epoxide and ester groups), based on the number of active ester and epoxide groups. The materials derived from the bio‐based material, AB and A2B2, were initiated with and without the catalyst N,N′‐dimethylaminopyridine (DMAP) and curing agent diaminodiphenylmethane. Without the catalyst, AB and A2B2 self‐polymerized at 247 and 210°C, respectively. Notably, the polymerization temperatures for AB and A2B2 decreased after the addition of DMAP. The self‐cured epoxy resin without the catalyst showed the highest thermal stability and glass transition temperature (Tg = 156°C). Degradation and recovery studies suggested forward that 51% of the material could be recovered and 94% of the polymer could be degraded from the self‐cured A2B2 in 25 wt% NaOH solution.

A Ratiometric Fluorescent Conjugated Oligomer for Amyloid β Recognition, Aggregation Inhibition, and Detoxification.

The sensitive recognition and effective inhibition of toxic amyloid β protein (Aβ) aggregates play a critical role in early diagnosis and treatment of neurodegenerative diseases. In this work, a new conjugated oligo(fluorene-co-phenylene) (OFP) modified with 1,8-naphthalimide (NA) derivative OFP-NA-NO2 is designed and synthesized as a ratiometric fluorescence probe for sensing Aβ, inhibiting the assembly of Aβ, and detoxicating the cytotoxicity of Aβ aggregates. In the presence of Aβ, the active ester group on the side chain of OFP-NA-NO2 can covalently react with the amino group on Aβ, effectively inhibiting the formation of Aβ aggregates and degrading the preformed fibrils. In this case, the fluorescence intensity ratio of NA to OFP (INA /IOFP ) increases greatly. The detection limit is calculated to be 89.9nM, presenting the most sensitive ratiometric recognition of Aβ. Interestingly, OFP-NA-NO2 can dramatically recover the cell viability of PC-12 and restore the Aβ-clearing ability of microglia. Therefore, this ratiometric probe exhibits the targeted recognition of Aβ, effective inhibition of Aβ aggregates, and detox effect, which is potential for early diagnosis and treatment of neurodegenerative diseases.

In Situ Biomineralized Phosphorylated Poly(l-Glutamic Acid)/Sodium Alginate Injectable Hydrogels

Biomineralized hydrogels have attracted much attention as biomaterials for bone regeneration. In our research described here poly(L-glutamic acid) (PLGA) was activated by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysulfosuccinimide to prepare PLGA-NHS active ester, which was then reacted with adipic acid hydrazide (ADH) and phosphorylethanolamine (PA) to obtain phosphonic and hydrazide-modified poly(L-glutamic acid) (PLGA-ADH-PA). The Schiff base reaction between PLGA-ADH-PA and oxidized alginate (OALG) led to the formation of phosphorylated PLGA/ALG injectable hydrogels. The nano-hydroxyapatite (nHA)/PLGA/ALG composite hydrogels were obtained by in situ biomineralization of the phosphorylated PLGA/ALG hydrogels in simulated body fluid. The chemical structure and rheological properties of the hydrogels before and after mineralization, and the size and morphology of the nHA were studied. After biomineralization, the growth of HA with soaking time was detected at the surface and interior of the PLGA/ALG hydrogels. The average sizes of the nHA particles were 120 nm and 350 nm, respectively, at 12 h and 5 d. The amount of hydroxyapatite deposited increased with the increase of PA grafting degree. Compared with unmineralized hydrogels, the mechanical properties of the mineralized hydrogels were significantly improved.

Transferrin binding protein-B from Neisseria meningitidis C as a novel carrier protein in glycoconjugate preparation: an in silico approach

The linking of polysaccharide in glycoconjugate vaccine with carrier protein is an imperative step to develop a strong memory response. The excessive use of similar carrier protein known to result in bystander immunity warrants an urgent need for new carrier protein. The preparation of the glycoconjugate vaccine using cyanylation chemistry is to link the active cyanate ester site of polysaccharide with the carrier protein. In the present study, transferrin binding protein-B (Tbp-B) has been explored as a new carrier protein to develop in silico pneumococcal polysaccharide serotype-5 (PnPs-5) conjugate vaccine. The homology model of Tbp-B was constructed using the Prime module and stereochemically validated using ProSA, PDBsum and ProQ. The selected model revealed a Z-score of −5.6 within the X-ray region in ProSA analysis, LGscore: 9.776, and MaxSub: 0.8 in protein quality predictor suggesting its preferred use. Loop modeling and active site analysis followed by in silico PnPs-5 activation with cyanalyting agent CDAP was docked with Tbp-B using Glide module. The complex stability of cyanate esters with Tbp-B, analyzed by molecular dynamics (MD) simulation, revealed an average RMSD of 2.49 Å for its binding to the receptor. The RMSF values of cyanate ester-1, -2, and -3 were observed to be 1.06, 1.39 and 0.79 Å, respectively. The higher RMSF of 1.39 Å of cyanate ester-2 was further found unstable which corroborates its non-binding to the protein and also incurring conformational changes to a carrier protein. Molecular simulations revealed that cyanate ester-1 and cyanate ester-3 formed stable conjugates with carrier protein Tbp-B. Communicated by Ramaswamy H. Sarma

Modification of polyvinyl chloride membranes for mycotoxins detection

In this work, we investigated modification and characterizations of modified-Polyvinyl Chloride (PVC) membranes for mycotoxin detections. The modification of PVC is a successfully nucleophilic substitution of Chloride atoms on the PVC membranes. The chemical compositions and characteristics of modified-PVC were characterized by Raman Microscope, NMR, GPC, DSC and FE-SEM. Sulfo-N-hydroxysuccinimide (Sulfo-NHS) and Carbodiimide EDC were used as an active ester functionalities with amino groups of modified-PVC membranes for covalent bonding of antibody. The antibody and mycotoxin interactions can be transduced directly by measuring the Differential Pulse Voltammetry (DPV). It was found that the zearalenone (ZEN) detections can be accomplished with these performances: sensitivity 14.1 ± 3 μA/μg, linear range 10−2 - 10−5 μg/ml and linearity 0.999.

Development of a New Monoclonal Antibody against Brevetoxins in Oyster Samples Based on the Indirect Competitive Enzyme-Linked Immunosorbent Assay.

The consumption of shellfish contaminated with brevetoxins, a family of ladder-frame polyether toxins formed during blooms of the marine dinoflagellate Karenia brevis, can cause neurotoxic poisoning, leading to gastroenteritis and neurotoxic effects. To rapidly monitor brevetoxin levels in oysters, we generated a broad-spectrum antibody against brevetoxin 2 (PbTx-2), 1 (PbTx-1), and 3 (PbTx-3) and developed a rapid indirect competitive enzyme-linked immunosorbent assay (icELISA). PbTx-2 was reacted with carboxymethoxylamine hemihydrochloride (CMO) to generate a PbTx-2-CMO hapten and reacted with succinic anhydride (HS) to generate the PbTx-2-HS hapten. These haptens were conjugated to keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) to prepare immunogen and coating antigen reagents, respectively, using the active ester method. After immunization and cell fusion, a broad-spectrum monoclonal antibody (mAb) termed mAb 1D3 was prepared. The 50% inhibitory concentration (IC50) values of the icELISA for PbTx-2, PbTx-1, and PbTx-3 were 60.71, 52.61, and 51.83 μg/kg, respectively. Based on the broad-spectrum mAb 1D3, an icELISA was developed to determine brevetoxin levels. Using this approach, the limit of detection (LOD) for brevetoxin was 124.22 μg/kg and recoveries ranged between 89.08% and 115.00%, with a coefficient of variation below 4.25% in oyster samples. These results suggest that our icELISA is a useful tool for the rapid monitoring of brevetoxins in oyster samples.

Quantum dots‐based fluorescence immunoassay for detection of tiamulin in pork

AbstractTiamulin (TML) is a kind of diterpenoid veterinary antibiotic. If abused, it will cause residues in edible tissues of animals and endanger human health. Thus, a facile, sensitive, and accurate method is essential for TML detection. In this study, TML complete antigen was synthesized by oximation and active ester method, and monoclonal antibodies with high specificity and sensitivity were prepared. ZnCdSe/ZnS quantum dots (QDs) coupled with goat anti‐mouse IgG were used as a fluorescence detection probe to establish indirect competitive fluorescent immunosorbent assay (icFLISA) for the determination of TML in pork. The 50% inhibitory concentration (IC50) of the icFLISA was 0.069 ng/ml, and the limits of detection (LOD) were 0.309 pg/ml. The recovery of the spiked pork samples for the icFLISA ranged from 85.6 to 96.8%, and the coefficient of variation (CV) was less than 9.4%. The results showed that the icFLISA based on ZnCdSe/ZnS QDs was more sensitive than the traditional indirect competitive enzyme‐linked immunosorbent assay for the detection of TML in edible animal tissues.

Copper-Catalyzed Decarboxylative Propargylic Alkylation of Enol Carbonates: Stereoselective Synthesis of Quaternary α-Amino Acids

A copper-catalyzed asymmetric decarboxylative propargylic alkylation of enol carbonates has been realized, allowing for the highly stereoselective formation of acyclic vicinal tri- and tetrasubstituted stereocenters. With this strategy, a series of optically active quaternary α-amino acid esters with an adjunct chiral tertiary propargylic moiety have been prepared from propargyl azlactone-enol carbonates in high yields and with good to excellent diastereo- and enantioselectivities. The success of this reaction exemplifies the high potential of the decarboxylative strategy to resolve unmet challenges present in traditional catalytic propargylic alkylation.

A mechanical, electrical dual autonomous self-healing multifunctional composite hydrogel.

The versatile properties make hydrogels a potential multipurpose material that finds wide applications. However, the preparation of multipurpose hydrogels is very challenging. Here, we report a method based on free radical reaction and composite mechanisms to prepare mechanical and electrical self-healing multifunctional hydrogels. In this study, the introduction of imidazolium salt ionic liquids and glycerol in the hydrogel system endows the gels with good antibacterial, conductive, and adhesive properties and excellent antifreeze properties. The testing results show that the as-prepared hydrogel has stable mechanical and electrical properties even under the extremely cold condition of −50°C after self-healing. Moreover, the active esters formed in the dynamic radical reaction have better reducibility, thus further investing the as-prepared hydrogel with high antioxidant activity. The application results show that these comprehensive properties make such hydrogel system very useful in wound repair and wearable strain sensors.

Chiral Arylated Amines via C−N Coupling of Chiral Amines with Aryl Bromides Promoted by Light

AbstractThe Buchwald‐Hartwig C‐N coupling reaction has found widespread applications in organic synthesis. Over the past two decades or so, many improved catalysts have been introduced, allowing various amines and aryl electrophiles to be readily used nowadays. However, there lacks a protocol that could be used to couple a wide range of chiral amines and aryl halides, without erosion of the enantiomeric excess (ee). Reported in this article is a method based on molecular Ni catalysis driven by light, which enables stereoretentive C‐N coupling of optically active amines, amino alcohols, and amino acid esters with aryl bromides, with no need for any external photosensitizer. The method is effective for a wide variety of coupling partners, including those bearing functional groups sensitive to bases and nucleophiles, thus providing a viable alternative to accessing synthetically important chiral N‐aryl amines, amino alcohols, and amino acids esters. Its viability is demonstrated by 92 examples with up to 99 % ee.

Chiral Arylated Amines via C−N Coupling of Chiral Amines with Aryl Bromides Promoted by Light

The Buchwald-Hartwig C-N coupling reaction has found widespread applications in organic synthesis. Over the past two decades or so, many improved catalysts have been introduced, allowing various amines and aryl electrophiles to be readily used nowadays. However, there lacks a protocol that could be used to couple a wide range of chiral amines and aryl halides, without erosion of the enantiomeric excess (ee). Reported in this article is a method based on molecular Ni catalysis driven by light, which enables stereoretentive C-N coupling of optically active amines, amino alcohols, and amino acid esters with aryl bromides, with no need for any external photosensitizer. The method is effective for a wide variety of coupling partners, including those bearing functional groups sensitive to bases and nucleophiles, thus providing a viable alternative to accessing synthetically important chiral N-aryl amines, amino alcohols, and amino acids esters. Its viability is demonstrated by 92 examples with up to 99 % ee.

Studies on 2‐Formylphenylboronic Acid‐Based Ser/Thr Ligation and Cys/Pen Ligation†

Main observation and conclusionDeveloping an effective chemoselective ligation strategy for assembling unprotected peptide segments is important to peptide/protein synthesis. The ligation efficiency and selectivity depend on the chemistry between the C‐terminal active ester of the peptide (e.g., the thioester in Native Chemical Ligation or the salicylaldehyde ester in Ser/Thr Ligation and Cys/Pen Ligation) and N‐terminal functional groups of the second peptide (Cys or Ser/Thr). Increasing the reactivity of the ligation and decreasing the hydrolysis of the active ester are more like the opposite sites in balance. We investigated the potential application of the peptide acyl ester of 2‐formylphenylboronic acid (2‐FPBA) in the Ser/Thr ligation and Cys/Pen ligation. With the assistance of boronic acid group, the peptidyl FPBA ester showed remarkable stability in aqueous buffer and its reactivity towards Ser/Thr and Cys/Pen also improved. However, the strong coordination of the amine at the N‐terminus and boronic acid suppressed the acyl transfer process when the peptide acyl group was used. More effects should be made to enhance the ligation chemistry.

Ultrasound-assisted continuous-flow synthesis of PEGylated MIL-101(Cr) nanoparticles for hematopoietic radioprotection

Metal-organic frameworks (MOFs) are useful as drug delivery carriers with high loading capacity and excellent biocompatibility. We fabricated a new drug carrier based on MIL-101(Cr) environmentally and loaded it with 47.2 wt% WR-1065 (active metabolite of amifostine). Moreover, the permeability and stability of these nanoparticles increased after PEGylation by the N-hydroxysuccinimide active ester protocol. Then, a “green” continuous-flow system equipped with an ultrasound applicator was newly designed to prepare the nanoparticles under the effect of acoustic cavitation. Response surface methodology (RSM) was used to optimize the large-scale process conditions with Box-Behnken design to obtain high space-time yield (5785 kg m−3 day−1). These less toxic MOFs nanoparticles increased cell viability by scavenging the accumulated reactive oxygen species and resisting DNA damage after irradiation. They are capable of mitigating radiation injury, achieving a 30-d survival rate of 90% in mice after lethal total body irradiation (8.0 Gy). This countermeasure significantly improved the peripheral blood cell count, hematopoietic stem and progenitor cells frequency, and clonogenic function of hematopoietic progenitor cells. It probably prevents irradiation-induced hematopoietic damage through the p53-dependent apoptotic pathway. Therefore, ultrasound-assisted continuous-flow synthesis is a sustainable method to produce MOFs on a large scale for radioprotection.