Oxazoline Ring Research Articles

New oligomeric terpenoids fused with an oxazoline ring linkage from cones of Taxodium ascendens and their biological activities

Taxodascaloids A-C (1–3), three uncommon oligomeric terpenoids featuring an oxazoline ring linkage, were purified from the cones of Taxodium ascendens. Compounds 1 and 2, a unique pair of stereoisomers, represented the first identified diterpenoid-monoterpenoid adducts linked by an oxazoline ring. Compound 3 was an uncommon dimeric diterpenoid and composed of a seco-abietane unit and an abietane unit, also containing an oxazoline ring. The planar structures and absolute configurations of these compounds were determined using extensive spectroscopic analysis and X-ray diffraction techniques. Compounds 1 and 2 demonstrated potent anticancer activity against human colon cancer HCT cells, with the IC50 values of 25.7 and 40.1 μM, respectively. Further research indicated that compound 1 could induce both ferroptosis and apoptosis in HCT-116 cells. Additionally, compound 3 showed notable α-glucosidase inhibitory activity in a mixed-type manner with an IC50 value of 2.9 μM.

Asymmetric 1,n‐Remote Aminoacetoxylation of Unactivated Internal Alkenes Enabled by Palladium Catalysis**

AbstractA palladium‐catalyzed asymmetric 1,n‐remote aminoacetoxylation of cis‐alkenes has been developed using PhI(OAc)2 as an oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine‐oxazoline (Pyox) L3 with a tert‐butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

Asymmetric 1,n-Remote Aminoacetoxylation of Unactivated Internal Alkenes Enabled by Palladium Catalysis.

A palladium-catalyzed asymmetric 1,n-remote aminoacetoxylation of cis-alkenes has been developed using PhI(OAc)2 as an oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine-oxazoline (Pyox) L3 with a tert-butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

5(S)-((3aR,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole

5(S)-((3aR,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-phenyl-4,5-dihydrooxazole was synthesized from isosorbide in a three-step sequence, with an overall yield of 46%. The first reaction step involves a single regioselective ring-opening reaction of isosorbide with Me3SiI in the presence of acetone followed by an intramolecular nucleophilic substitution to transform the iodoalcohol into its corresponding epoxide. The last reaction allows the formation of the oxazoline ring directly from the epoxide with benzonitrile in the presence of BF3·Et2O.

Crystal structure of a three-coordinate lithium complex with monodentate phenyloxazoline and hexamethyldisilylamide ligands

The reaction of lithium hexamethyldisilylamide, [Li{N(Si(CH3)3)2}] (LiHMDS), with 4,4-dimethyl-2-phenyl-2-oxazoline (Phox, C11H13NO) in hexane produced colourless crystals of bis(4,4-dimethyl-2-phenyl-2-oxazoline-κN)(hexamethyldisilylamido-κN)lithium, [Li(C6H18NSi2)(C11H13NO)2] or [Li{N(Si(CH3)3)2}(Phox)2] in high yield (89%). Despite the 1:1 proportion of the starting materials in the reaction mixture, the product formed with a 1:2 amide:oxazoline ratio. In the unit cell of the C2/c space group, the neutral molecules lie on twofold rotation axes coinciding with the Li—N(amide) bonds. The lithium(I) centre adopts a trigonal–planar coordination geometry with three nitrogen donor atoms, one from the HMDS anion and two from the oxazolines. All ligands are monodentate. In the phenyloxazoline units, the dihedral angle defined by the five-membered heterocyclic rings is 35.81 (5)°, while the phenyl substituents are approximately face-to-face, separated by 3.908 (5) Å. In the amide, the methyl groups assume a nearly eclipsed arrangement to minimize steric repulsion with the analogous substituents on the oxazoline rings. The non-covalent interactions in the solid-state structure of [Li{N(Si(CH3)3)2}(Phox)2] were assessed by Hirshfeld surface analysis and fingerprint plots. This new compound is attractive for catalysis due to its unique structural features.

Mid-IR and CH stretching vibrational circular dichroism spectroscopy to distinguish various sources of chirality: The case of quinophaneoxazoline based ruthenium(II) complexes.

Five diastereomers of ruthenium(II) complexes based on quinolinophaneoxazoline ligands were investigated by vibrational circular dichroism (VCD) in the mid-IR and CH stretching regions. Diastereomers differ in three sources of chirality: the planar chirality of the quinolinophane moiety, the central chirality of an asymmetric carbon atom of the oxazoline ring, and the chirality of the ruthenium atom. VCD, allied to DFT calculations, has been found to be effective in disentangling the various forms of chirality. In particular, a VCD band is identified in the CH stretching region directly connected to the chirality of the metal. The analysis of the calculated VCD spectra is carried out by partitioning the complexes into fragments. The anharmonic analysis is also performed with a recently proposed reduced-dimensionality approach: such treatment is particularly important when examining spectroscopic regions highly perturbed by resonances, like the CH stretching region.

Deciphering Deoxynybomycin Biosynthesis Reveals Fe(II)/α-Ketoglutarate-Dependent Dioxygenase-Catalyzed Oxazoline Ring Formation and Decomposition.

The antibacterial agents deoxynybomycin (DNM) and nybomycin (NM) have a unique tetracyclic structure featuring an angularly fused 4-oxazoline ring. Here, we report the identification of key enzymes responsible for forming the 4-oxazoline ring in Embleya hyalina NBRC 13850 by comparative bioinformatics analysis of the biosynthetic gene clusters encoding structurally similar natural products DNM, deoxynyboquinone (DNQ), and diazaquinomycins (DAQs). The N-methyltransferase DnmS plays a crucial role in catalyzing the N-dimethylation of a tricyclic precursor prenybomycin to generate NM D; subsequently, the Fe(II)/α-ketoglutarate-dependent dioxygenase (Fe/αKGD) DnmT catalyzes the formation of a 4-oxazoline ring from NM D to produce DNM; finally, a second Fe/αKGD DnmU catalyzes the C-12 hydroxylation of DNM to yield NM. Strikingly, DnmT is shown to display unexpected functions to also catalyze the decomposition of the 4-oxazoline ring and the N-demethylation, thereby converting DNM back to prenybomycin, to putatively serve as a manner to control the intracellular yield of DNM. Structure modeling, site-directed mutagenesis, and quantum mechanics calculations provide mechanistic insights into the DnmT-catalyzed reactions. This work expands our understanding of the functional diversity of Fe/αKGDs in natural product biosynthesis.

Antimicrobial property of polyethersulfone (PES) membrane by plasma copolymerization of TEOS and oxazoline for organic dyes filtration

Plasma-based surface modification has been regarded as a green method to avoid the usage of toxic solvents in order to introduce various functional groups on the filtration membrane. In this paper, we employ plasma polymerization on the polyethersulfone (PES) ultrafiltration membrane by using simultaneously Tetraethyl orthosilicate (TEOS) and Oxazoline precursor exhibiting superhydrophilic and antibacterial properties to be used for organic dyes filtration. The addition of nanoscale coatings produced by the proposed plasma copolymerization of TEOS and Oxazoline could enhance the overall performance of the membrane in terms of pure water flux and antimicrobial properties compared to untreated sample. We evaluate its chemical composition by using Attenuated Total Reflectance Fourier Transform Infrared (FTIR/ATR) and XPS spectroscopy to ensure the presence of Oxazoline ring and Silicate functional group. Thus, our proposed plasma-modified membrane could be promising to solve specific issues regarding antibiofouling and improve simultaneously its overall performance.

Electrochemical behavior of oxazoline‐based plasma polymers for biosensing applications

AbstractPlasma‐polymerized polyoxazoline (POx) thin films offer a fast, scalable, and solvent‐free method of electrode functionalization through the unique chemistry of the oxazoline ring. However, for POx to be a viable green alternative to existing surface modification approaches, the films should be able to withstand the processing steps involved in biosensing. Here, the effects that current exposure, extended incubation, and repeated electrode rinses have on the electrochemical and physical stability of polymethyloxazoline thin films are investigated. The films are observed to become more diffusive after incubation and rinse steps. While no significant changes in chemistry were observed, a marked change in nanotopography occurred after exposure to current, suggesting a change in the polymer film structure.

Steric evaluation of Pyox ligands for asymmetric intermolecular Heck-Matsuda reaction

A structure selectivity relationship was established by systematically increasing the steric of the ligands from phenyl substituent to mesityl on the pyridine ring of Pyox and isopropyl to tert-butyl group on the oxazoline ring. The ligand 6MesPyoxsBu bearing a sterically demanding mesityl group at position 6 of the pyridine ring showed optimum catalytic activity for Heck-Matsuda desymmetrization reaction of non-activated cyclopentene using Pd(tfa)2 as the catalyst. A wide range of arenediazonium salts bearing electronically distinct substituents was evaluated in Heck-Matsuda coupling, which resulted in good to excellent isolated yields (67–92 %), excellent enantio- and diastereoselectivity (up to 96 % ee, >20:1 dr).

Silver‐Catalyzed Asymmetric Aldol Reaction of Isocyanoacetic Acid Derivatives Enabled by Cooperative Participation of Classical and Nonclassical Hydrogen Bonds

AbstractThe silver‐catalyzed asymmetric aldol reaction of isocyanoacetic acid derivatives with aldehydes has been developed by employing a chiral prolinol‐phosphine as a hydrogen‐bond‐donating P,N,O ligand. DFT calculations indicated that the reaction proceeds in a stepwise manner, involving C−C bond forming carbonyl addition and subsequent enantioselectivity‐determining oxazoline ring formation. An O−H⋅⋅⋅O/sp3‐C−H⋅⋅⋅O two‐point hydrogen bond donated by the prolinol moiety of the ligand activates the aldehyde in the C−C bond formation step and facilitates the subsequent cyclization under stereocontrol by the catalyst. The calculations further suggest that additional nonclassical C−H⋅⋅⋅O hydrogen bonds as well as London dispersion interactions may also participate synergistically in the stereocontrol.magnified image

Protecting-group- and microwave-free synthesis of β-glycosyl esters and aryl β-glycosides of N-acetyl-d-glucosamine

A protecting-group-free method for synthesis of β-glycosyl esters and aryl β-glycosides was developed by using latent chemical reactivity of N-acetyl-d-glucosamine (GlcNAc) oxazoline. The GlcNAc oxazoline was spontaneously reacted with carboxylic acids and phenol derivatives via the oxazoline ring opening without the use of a catalyst or heating conditions (i.e., microwave irradiation), affording the desired products in moderate to excellent yields with β-selectivity. This simple protecting-group-free method exhibits a wide substrate scope and good functional group tolerance, and it allows the efficient production of a novel class of GlcNAc-conjugated biomaterials and prodrug candidates.

Design, synthesis, and fungicidal activities of novel ethylenediamine bridged thiazole derivatives containing oxime ether or oxime ester moieties

AbstractTo study the influence of changing the piperidine ring on the fungicidal activity, at the same time based on the successful experience of opening the oxazoline ring, a series of novel ethylenediamine bridged thiazole derivatives containing oxime ether and oxime ester moieties were designed, synthesized, and first evaluated for their fungicidal activities against phytophthora capsaicae in vitro. The bioassays results showed that the target compounds possessed moderate fungicidal activities against phytophtho‐ra capsaicae. Compound 28b showed 53.6% fungicidal activity at 50 μg/ml. Oxime ether and oxime ester derivatives showed the similar level of activities. However, the activities of these compounds were lower than that of oxathiapiprolin, suggesting the piperidine ring was essential to maintain the fungicidal activities of these compounds. For the oxime ether derivatives, 16b, 22a, 25b, and 28b, the substituents on ethylenediamine have certain influence on the activity. Increasing the chain length of substituents is beneficial to the fungicidal activity. Meanwhile, these compounds were tested their fungicidal activities against other 9 fungi, and these compounds showed broad spectrum fungicidal activities. Some compounds exhibited more than 70% fungicial activities against specific fungi.

Synthesis and structures of three new pyridine-containing oxazoline ligands of complexes for asymmetric catalysis.

Three new chiral pyridine-containing oxazoline derivatives with fluorine and perfluoromethyl groups, namely, 2-({2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C21H16F3N3O, 2-({5-fluoro-2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C18H17F4N3O, and 2-({2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C22H16F3N3O, as chiral ligands in metal-catalysed asymmetric reactions, were synthesized and characterized by spectral and X-ray diffraction methods. The conformation of the molecules is influenced by strong N-H...N hydrogen bonding and weak C-H...X (X= O and N) interactions. There are no intermolecular hydrogen bonds in the crystal structures of the analysed compounds. Hirshfeld surface analysis showed that the H...H contacts constitute a high percentage of the intermolecular interactions. The conformational analysis was performed by theoretical calculations using the density functional theory (DFT) method. The mechanism of complex formation in terms of the electron-withdrawing effect of the substituents on the oxazoline ring and the ligand conformation is discussed.

Aliphatic C–H hydroxylation activity and durability of a nickel complex catalyst according to the molecular structure of the bis(oxazoline) ligands

• Bis(oxazoline) complexes of nickel catalyze alkane hydroxylation with m-CPBA. • Structure of bis(oxazoline) ligands influences the catalytic performance. • Durability of catalysts toward O 2 depends on the structure of the bis(oxazoline) ligands. Applicability of the oxazoline-based compounds, bis(2-oxazolynyl)methane (BOX) and 2,6-bis(2-oxazolynyl)pyridine (PyBOX), as supporting ligands of nickel(II) complexes for the catalysis of aliphatic C H hydroxylation with m -CPBA ( meta -chloroperoxybenzoic acid) was explored. Substituent groups at the fourth and fifth positions of oxazoline rings and the bridgehead carbon atom of the BOX derivatives affected the catalytic performances toward cyclohexane hydroxylation. Presence of dioxygen led to a reduced catalytic performance of the nickel complexes, except in the case of a fully substituted BOX ligand complex.

Concise synthesis of the Taxol side chain and demethoxy-4-epi-cytoxazone via oxazoline formation through intramolecular benzylic substitution of a bis-trichloroacetimidate

A concise and efficient method for synthesizing the Taxol side chain via the corresponding oxazoline intermediate was developed. The oxazoline ring is formed via an SN1 mechanism to ensure that the trans-oxazoline stereochemistry is retained. This process was induced by intramolecular benzylic substitution of a 1,2-bis-trichloroacetimidate, which was obtained from a known, enantiomerically pure diol. Demethoxy-4-epi-cytoxazone was also obtained from the intermediary trans-oxazoline 3b.

Mechanism and selectivity of nickel-catalyzed [3 + 2] cycloaddition of cyclopropenones and α,β-unsaturated ketones: A computational study

Density functional theory calculations have been performed to investigate the nickel-catalyzed [3 + 2] cycloaddition of cyclopropenones and α,β-unsaturated ketones. The computations show that the overall catalytic cycle consists of four major steps, including: (1) C-C oxidative addition of the cyclopropenone to afford the four-membered nickelacycle, (2) isomerization, (3) migratory insertion via a 4,1-insertion fashion, and (4) C-C reductive elimination to deliver the [3 + 2] cycloaddition product. The enantioselectivity is mainly attributed to the π-π interaction between the diphenylcyclopropenone moiety and the phenyl substituent of the oxazoline ring of the ligand. The chemoselectivity of the C = O versus C = C insertion was rationalized in terms of the steric effect.

Chiral Imidazoline Ligands and Their Applications in Metal‐Catalyzed Asymmetric Synthesis†

AbstractAs a structural analog of oxazoline, imidazoline (4,5‐dihydroimidazole) has received much attention in the rational design of chiral ligands. The additional N‐substituent provides broader space for fine‐tuning of electronic and steric effects, and it offers a good handle for immobilizing onto solid supports. In the past decades, imidazoline ring has emerged as a powerful candidate for the design of chiral nitrogen‐containing ligands, as well as a significant alternative for oxazoline ring. Various chiral imidazoline ligands have been designed and utilized in asymmetric organic reactions. These new catalysts can not only be applied in classical reactions, but also be employed to develop new organic reactions with high enantioselectivities. This review provides an overview of chiral imidazoline ligands. Their applications in asymmetric synthesis are also summarized.

Synthesis of “Click BOX” ligands and preliminary results on their application in the asymmetric copper catalysed Henry reaction of o-methoxybenzaldehyde

Two new chiral “click BOX” ligands have been synthetised with high yields starting from commercially available dimethyl propargylmalonate and optically pure alkanolamines, followed by copper catalysed cycloaddition (CuAAC) and oxazoline ring formation. Catalytic activity of the new ligands has been tested in the copper mediated Henry addition. The model reaction between nitromethane and o-anisaldehyde affords the related 1-(2-methoxyphenyl)-2-nitroethanol in high yields (up to 92%) and moderate enantioselectivities (up to 67% e.e.) under straightforward experimental conditions.

Mechanistic Insights into the Hydrolysis of O-GlcNAcylation Catalyzed by Human O-GlcNAcase.

O-GlcNAc glycosylation occurs on specific serine/threonine residues of intracellular proteins, which is widely related to various diseases, including type II diabetes, cancer, and Alzheimer's disease. Human O-GlcNAcase (hOGA) is responsible for the removal of O-GlcNAc modification and thus serves as the main target for inhibitor design. In this work, we systematically investigated the mechanism catalyzed by hOGA using the quantum mechanical/molecular mechanical method. Based on calculated free energy profiles, two essential steps named cyclization (Cyc) step and ring opening step are required to generate the final hemiacetal product. The Cyc of the 2-acetamido group, the rate-limiting step, leads to the generation of the intermediate of a bicyclic oxazolinium ion (EI1). Next, the oxazoline ring could be broken via the nucleophilic attack of a water molecule at the C1 position, which generates the final product. Along with this, our simulations clearly suggest the existence of an oxazoline intermediate (EI2), which is produced via proton transfer (PT) from the 2-acetamido group (EI1) to D174. This PT step features a reversible process with a low energy barrier, which could be attributed to a low barrier hydrogen bond between the donor and acceptor. The stabilizing effect of the low barrier hydrogen bond on EI1 is proposed to be very important for accelerating the overall reaction. In fact, the site-directed mutagenesis simulations of D174A and D175A strongly indicate that the catalytic residues mainly affect the observed reaction rate by affecting the stability of the intermediate.