Search Results (35)

Herein, we report a one-pot palladium- and ligand-free tandem Sonogashira coupling/regioselective 6-endo-dig oxacyclization reaction of 2,4-diiodo-1-methyl-imidazole-5-carboxylic acid with terminal alkynes mediated by Copper(I). This impressive approach offers a straightforward, practical, and efficient tandem procedure for accessing 2-alkynylated pyrano[4,3-d]imidazol-4-one in moderate to good yields with an exclusive 6-endo-dig oxacyclization. Notably, this cost-effective methodology demonstrates broad substrate compatibility with various commercially available aliphatic and (hetero)aromatic terminal alkynes. Furthermore, DFT studies were performed to elucidate the origin of this regioselective 6-endo-dig oxacyclization reaction. Full article

Glycosylation is a critical enzymatic modification that involves the attachment of sugar moieties to target compounds, considerably influencing their physicochemical and biological characteristics. This review explored the role of two primary enzyme classes—glycosyltransferases (GTs) and glycoside hydrolases (GHs, glycosidases)—in catalyzing the glycosylation of natural products, with a specific focus on Ganoderma triterpenoids. While GTs typically use activated sugar donors, such as uridine diphosphate glucose, certain GHs can leverage more economical sugar sources, such as sucrose and starch, through transglycosylation. This paper also reviewed strategies for producing novel terpenoid glycosides, particularly recently isolated bacterial GTs and GHs capable of glycosylating terpenoids and flavonoids. It summarized the newly synthesized glycosides’ structures and biotransformation mechanisms, enhanced aqueous solubility, and potential applications. The regioselectivity and substrate specificity of GTs and GHs in catalyzing O-glycosylation (glucosylation) at distinct hydroxyl and carboxyl groups were compared. Furthermore, a special case in which the novel glycosylation reactions were mediated by GHs, including the formation of unique glycoside anomers, was included. The advantages and specific capabilities of GT/GH enzymes were evaluated for their potential in biotechnological applications and future research directions. Novel fungal triterpenoid glycosides produced through various glycosidases and sugars is expected to expand their potential applications in the future. Full article

The use of CO₂ as a C1 carbon source for the synthesis of valuable chemicals through biotechnology methods represents an effective strategy to fix carbon dioxide. Phenolic acid decarboxylases possess the capability to introduce a carboxyl group into para-hydroxystyrenes for the regionally selective synthesis of (E)-para-hydroxycinnamic acids, utilizing bicarbonate as a CO₂ source. It is difficult to achieve this reaction with traditional chemical methods, and only a few enzymes have been isolated and characterized. Here, we mined which low amino acid sequence shared its identity with those of related decarboxylases and which heterologously expressed phenolic acid decarboxylase PAD_Cs from Clostridium sp. DSM 8431 in E. coli. The recombinant PAD_Cs displayed maximum activity at 50 °C, and pH 5.0. PAD_Cs showed distinct carboxylation ability. The carboxylated substrates have a wide range of substitution modes on aromatic systems, including alkyl and alkoxy groups as well as halogens. Furthermore, the carboxylation conversion rates were impressive: para-hydroxystyrene exceeded 20% and 2-methoxy-4-vinylphenol surpassed 26%. This study indicated that PAD_Cs might serve as a potential enzyme source in biotechnological CO₂ fixation. Full article

The Thymus vulgaris and Origanum vulgare essential oils (contained thymol and carvacrol in a range of 35–80%) are used in various products in the fields of medicine, cosmetics, and foods. Molecular hybridization between benzothiazole (BT) and phenolic monoterpenoids is a promising method for the development of biologically active compounds. New benzothiazole–monoterpenoid hybrids were synthesized through a regioselective α-amidoalkylation reaction of thymol and carvacrol with high yields (70–96%). This approach is both simple and cost-effective, employing easily accessible and inexpensive reagents to produce target molecules. The structure of the synthesized compounds was characterized spectrally using ¹H-, ¹³C-NMR, FT-IR, and HRMS data. The newly obtained compounds are structural analogues of the UVB filter PBSA, which is used in cosmetics. The spectral properties of the aromatic products thymol hybrid (2-(4-hydroxy-5-isopropyl-2-methylphenyl)benzo[d]thiazole) and carvacrol hybrid (2-(4-hydroxy-2-isopropyl-5-methylphenyl)benzo[d]thiazole) were successfully examined, using a validated spectrophotometric method. SPF values varied from 31 to 36, compared to the PBSA (30), and were observed at concentrations of 1–0.25 mM. 2-Hydroxyphenylbenzothiazoles are known antimicrobial and antioxidant agents that have potential applications in the food industry and cosmetics as preservatives and antioxidants. In this context, antimicrobial activity of the hybrid compounds was evaluated using the agar diffusion method against E. coli, S. aureus, P. aeruginosa, and C. albicans. Compounds of methyl-2-(4-hydroxy-2-isopropyl-5-methylphenyl)benzo[d]thiazole-3(2H)-carboxylate containing carvacrol fragments showed high activity against Staphylococcus aureus ATCC 25923 (with 0.044 μmol content). The radical scavenging activity was determined using ABTS and DPPH assays, the highest activity was exhibited by the thymol hybrids ethyl-2-(4-hydroxy-5-isopropyl-2-methylphenyl)benzo[d]thiazole-3(2H)-carboxylate (IC₅₀—133.70 ± 10 µM) and methyl-2-(4-hydroxy-5-isopropyl-2-methylphenyl)benzo[d]thiazole-3(2H)-carboxylate (IC₅₀—157.50 ± 10 µM), defined by ABTS. The aromatic benzothiazole–monoterpenoid hybrids are classified using in silico analyses as non-mutagenic, with low toxicity, and they are non-irritating to the skin. These compounds were identified as new hit scaffolds for multifunctional molecules in cosmetics. Full article

Natural ectoine, (+)-(4S)-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid, is an extremely important small biomolecule belonging to the class of osmolytic/osmoprotective compounds. It stabilizes biomacromolecules such as DNA and proteins and protects them from denaturation by heat, dehydration, and UV radiation. The rapidly growing interest in this compound resulted in currently exclusive biotechnological production, while a chemical process along with enantioseparation as an alternative has not yet been established. An improved chemical synthesis of racemic ectoine starting from γ-butyrolactone in very good yield is described. Regioselective monoacetylation is achieved by the complexation of a copper(II)-ion with two molecules of 2,4-diamonobutyric acid in the key synthetic step. The racemic ectoine was synthesized with the aim of being successfully enantioseparated for the first time by high-performance liquid chromatography (HPLC) using a teicoplanin-based Chiral-T column in different solvent systems. The presence of (+)-ectoine was determined and quantified using an HPLC protocol on the Synergy Polar-RP column in fermentation broths inoculated with different strains of Streptomyces sp. bacteria isolated from the Adriatic Sea and grown on different NaCl concentrations. Full article

A simple protocol for the preparation of O-acylated enol form (R/S)-ethyl-2-acetoxy-4-phenyl-4H-chromene-3-carboxylate 5 was presented. The compound was characterized by ¹H-, ¹³C-and DEPT135 NMR spectra, including {¹H,¹H} COSY, {¹H,¹³C} HSQC, {¹H,¹³C} HMBC, and 2D-NOESY spectra. The preferred regioselectivity for O-acylation of 3,4-dihydrocoumarin 5 in the presence of substituent in the 4th position in the chroman ring and accounting for the steric hindrance of the ester group in the 3rd place was confirmed. Full article

The investigation of cycloaddition reactions involving acridine-based dipolarophiles revealed distinct regioselectivity patterns influenced mainly by the electronic factor. Specifically, the reactions of methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate and 4-[(1E)-2-phenylethenyl]acridine with unstable benzonitrile N-oxides were studied. For methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate, the formation of two regioisomers favoured the 5-(acridin-4-yl)-4,5-dihydro-1,2-oxazole-4-carboxylates, with remarkable exclusivity in the case of 4-methoxybenzonitrile oxide. Conversely, 4-[(1E)-2-phenylethenyl]acridine displayed reversed regioselectivity, favouring products 4-[3-(substituted phenyl)-5-phenyl-4,5-dihydro-1,2-oxazol-4-yl]acridine. Subsequent hydrolysis of isolated methyl 5-(acridin-4-yl)-3-phenyl-4,5-dihydro-1,2-oxazole-4-carboxylates resulted in the production of carboxylic acids, with nearly complete conversion. During NMR measurements of carboxylic acids in CDCl₃, decarboxylation was observed, indicating the formation of a new prochiral carbon centre C-4, further confirmed by a noticeable colour change. Overall, this investigation provides valuable insights into regioselectivity in cycloaddition reactions and subsequent transformations, suggesting potential applications across diverse scientific domains. Full article

Regioselective C6 and C2,C3 carboxylated cellulose nanofibrils (CNFs) have been robustly generated from dissolving pulp, a readily available source of unmodified cellulose, via stoichiometrically optimized 2,2,6,6-tetramethylpyperidine-1-oxyl (TEMPO)-mediated and sequential sodium periodate-sodium chlorite (PC) oxidation coupled with high-speed blending. Both regioselectively optimized carboxylated CNF series possess the widest ranges of comparable charges (0.72–1.48 mmol/g for T-CNFs vs. 0.72–1.10 mmol/g for PC-CNFs), but similar ranges of thickness (1.3–2.4 nm for T-CNF, 1.8–2.7 nm PC-CNF), widths (4.6–6.6 nm T-CNF, 5.5–5.9 nm PC-CNF), and lengths (254–481 nm T-CNF, 247–442 nm PC-CNF). TEMPO-mediated oxidation is milder and one-pot, thus more time and process efficient, whereas the sequential periodate–chlorite oxidation produces C2,C3 dialdehyde intermediates that are amenable to further chemical functionalization or post-reactions. These two well-characterized regioselectively carboxylated CNF series represent coherent cellulose nanomaterial models from a single woody source and have served as references for their safety study toward the development of a safer-by-design substance evaluation tool. Full article

We disclose a direct approach to the diastereoselective synthesis of phosphorus substituted N-acylaziridines based on a one-pot ZnCl₂-catalyzed Joullié–Ugi three-component reaction of phosphorylated 2H-azirines, carboxylic acids and isocyanides. Hence, this robust protocol offers rapid access to an array of N-acylaziridines in moderate-to-good yields and up to 98:2 dr for substrates over a wide scope. The relevance of this synthetic methodology was achieved via a gram-scale reaction and the further derivatization of the nitrogen-containing three-membered heterocycle. The diastereo- and regioselective ring expansion of the obtained N-acylaziridines to oxazole derivatives was accomplished in the presence of BF₃·OEt₂ as an efficient Lewid acid catalyst. Full article

An efficient regioselective approach to novel functionalized bis(isoxazoles) with a variety of aromatic and aliphatic linkers was elaborated, based on the heterocyclization reaction of electrophilic alkenes under the treatment with tetranitromethane-triethylamine complex affording 3-EWG-5-nitroisoxazoles. The subsequent S_NAr reactions of 5-nitroisoxazoles with various O,O-, N,N- and S,S-bis(nucleophiles) provide a wide range of bis(isoxazole) derivatives in good isolated yields. Employing an elaborated method, a series of novel bis(3-EWG-isoxazoles) as the promising allosteric modulators of AMPA receptors were designed and synthesized. The effect of the compounds on the kainate-induced currents was studied in the patch clamp experiments, revealing modulator properties for several of them. The best positive modulator potency was found for dimethyl 5,5′-(ethane-1,2-diylbis(sulfanediyl))bis(isoxazole-3-carboxylate), which potentiated the kainate-induced currents in a wide concentration range (10⁻¹²–10⁻⁶ M) with maximum potentiation of 77% at 10⁻¹⁰ M. The results were rationalized using molecular docking and molecular dynamics simulations of modulator complexes with the dimeric ligand-binding domain of the GluA2 AMPA receptor. The predicted physicochemical, ADMET, and PAINS properties confirmed that the AMPA receptor modulators based on the bis(isoxazole) scaffold may serve as potential lead compounds for the development of neuroprotective drugs. Full article

Details of the structural elucidation of the clinically useful photodynamic therapy sensitizer NPe6 (15) are presented. NPe6, also designated as Laserphyrin, Talaporfin, and LS-11, is a second-generation photosensitizer derived from chlorophyll-a, currently used in Japan for the treatment of human lung, esophageal, and brain cancers. After the initial misidentification of the structure of this chlorin-e₆ aspartic acid conjugate as (13), NMR and other synthetic procedures described herein arrived at the correct structure (15), confirmed using single crystal X-ray crystallography. Interesting new features of chlorin-e₆ chemistry (including the intramolecular formation of an anhydride (24)) are reported, allowing chemists to regioselectively conjugate amino acids to each available carboxylic acid on positions 13¹ (formic), 15² (acetic), and 17³ (propionic) of chlorin e₆ (14). Cellular investigations of several amino acid conjugates of chlorin-e₆ revealed that the 13¹-aspartylchlorin-e₆ derivative is more phototoxic than its 15²- and 17³-regioisomers, in part due to its nearly linear molecular conformation. Full article

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles. Full article

The catalytic activity and selectivity of two different water-soluble palladium nanoparticles capped with 5-(trimethylammonio)pentanethiolate and 6-(carboxylate)hexanethiolate ligands are investigated using the catalytic reaction of allyl benzene. The results show that the regioselective transformation of allyl benzene to 3-phenylpropanal occurs at room temperature and under atmospheric pressure in neat water via a Tsuji–Wacker type oxidation. Conventionally, the Tsuji–Wacker oxidation promotes the Markovnikov oxidation of terminal alkenes to their respective ketones in the presence of dioxygen. Water-soluble Pd nanoparticles, however, catalyze the anti-Markovnikov oxidation of allyl benzene to 3-phenylpropanal in up to 83% yields. Catalytic results of other aromatic alkenes suggest that the presence of benzylic hydrogen is a key to the formation of a p-allyl Pd intermediate and the anti-Markovnikov addition of H₂O. The subsequent b-H elimination and tautomerization contribute to the formation of aldehyde products. Water-soluble Pd nanoparticles are characterized using nuclear magnetic resonance (NMR), UV–vis spectroscopy, thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). Catalysis results are examined using ¹H NMR and/or GC-MS analyses of isolated reaction mixtures. Full article

Herein, we report the preparation of methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate 2, obtained by the regioselective oxidative dehydrogenation of the dihydropyrimidine derivative 1 in the presence of cerium ammonium nitrate. The structure of compound 2 was investigated by single-crystal X-ray diffraction (SC-XRD), which allowed the determination of its tautomeric form. Moreover, the presence of non-covalent interactions and their impact on the crystal structure were analyzed. To better characterize the intermolecular contacts, the Hirshfeld surface and enrichment ratio analyses were performed. Furthermore, the antimycotic activity of compounds 1 and 2 was investigated against Candida albicans, Aspergillus flavus, and Aspergillus niger, and their efficacy was compared to that of fluconazole. Computational investigations on the putative target of the compounds provided insights to explain the better activity of 2 with respect to its synthetic precursor. Full article

A general approach towards the synthesis of tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-a]indol-1-one and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1H-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation—yielding target pyrazolo[1,5-a][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1H-indole- and ethyl 1H-benzo[d]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by ¹H, ¹³C, and ¹⁵N-NMR spectroscopy and HRMS investigation. Full article