Oxazoline Ring Research Articles

Pulsed plasma-polymerized 2-isopropenyl-2-oxazoline coatings: Chemical characterization and reactivity studies

Thin coatings were deposited by means of low pressure plasma polymerization of 2-isopropenyl-2-oxazoline (2-IOX). Depositions were performed in the pulsed mode, exploiting the carbon-carbon double bond of the monomer, in order to maximize the retention of oxazoline rings in the coatings. The wettability of the thin films was assessed by water contact angle measurements, while their stability was investigated by immersion in different aqueous environments (Phosphate Buffer Saline (PBS) at 37°C and aqueous solutions with different pH) and was found to be dependent on the deposition conditions. Chemical characterization of the coatings was performed by means of Attenuated Total Reflectance Fourier Transform Infrared (FTIR/ATR) spectroscopy, Nuclear Magnetic Resonance (1H NMR) spectroscopy and Gel Permeation Chromatography (GPC). All these techniques allowed to assess the retention of oxazoline ring, which can be exploited through reaction of the plasma deposited coatings with carboxylic acid groups. To this end, reactions with poly(acrylic acid) in different conditions (temperature, reaction time) were investigated.

Conformational properties of ascydiacyclamide analogues with cyclic α-amino acids instead of oxazoline residues

Ascidiacyclamide [ASC, cyclo(-Ile-oxazoline-d-Val-thiazole-)2] is a cyclic octapeptide isolated from tunicates. We designed ASC analogues [cyclo(-Ile-Xxx-d-Val-thiazole-)2] in which Pro or a homologue was substituted for oxazoline: [Pro]ASC (Xxx: proline), [Aze]ASC (Xxx: (S)-Azetidine-2-carboxylic acid), [Pip]ASC (Xxx: (S)-Piperidine-2-carboxylic acid) and [ΔPro]ASC (Xxx: (S)-3-pyrroline-2-carboxylic acid) to explore their potential to serve as substitutes for the oxazoline ring. The conformations of these analogues were examined using X-ray diffraction, 1H NMR and CD spectroscopy. In both the crystal and solution states, the conformations of [Pro]ASC, [Aze]ASC and [ΔPro]ASC were novel square structures having two trans imide bonds and stabilized by two intramolecular hydrogen bonds. The crystal structure of [Pip]ASC was a folded conformation with cis and trans imide bonds. Three isomers (cc, ct and tt) were present in a solution of [Pip]ASC. From crystal structures, the degree of puckering in the side chains of Pro and its homologues was estimated to be in the order Pip > Pro > Aze > ΔPro. [Pro]ASC and [Pip]ASC showed strong cytotoxicity, but [Aze]ASC and [ΔPro]ASC showed no cytotoxicity. Among the four analogues, there is consistency between the prolyl ring puckering and cytotoxicity, but not between the peptide backbone structure and cytotoxicity.

Synthesis and antitumor activity of alkylated bile acids and oxazolines

Bile acid derivatives with a free carboxylic group or an oxazoline ring in the side chain and with different lengths of alkyl chains on steroid skeleton were synthetized and their antitumor activity against six human cancer cell lines was investigated. Methyl, ethyl, butyl or octyl chains were introduced stereoselectively by Grignard reaction at C-7 of acid and oxazoline, and at C-12 of oxazoline. Carbonyl group at C-12 of acid compound gave addition product only with methyl Grignard reagent, and complex mixture of products with other used reagents. Due to enolization, the C-3 carbonyl group did not participate in the Grignard reaction. Steric reasons are a main cause of this chemical behavior. Compounds with a butyl chain at the C-7 position showed very good antitumor activity with IC50 < 5 μM.

Manganese-Catalyzed Asymmetric Hydrosilylation of Aryl Ketones.

We disclose the synthesis of a series of manganese complexes of chiral iminopyridine oxazoline ligands and their application in the first manganese-catalyzed asymmetric ketone hydrosilylations. The most sterically hindered manganese catalyst bearing two CH(Ph)2 groups at the 2,6-ortho positions of the imino aryl ring and a tBu group on the oxazoline ring furnishes the secondary alcohols in high enantioselectivities and yields.

Synthesis and biological evaluation of oxoapratoxin E and its C30 epimer

30R- and 30S-oxazoline analogues of apratoxin E have been prepared with late-stage formation of an oxazoline ring. These two compounds have a potent inhibitory effect on HCT-116 cell proliferation with IC50 values of 345 and 638nM, respectively. These results suggest that apratoxin E oxazoline bioisosteres are approximately 6-fold less potent than their thiazoline parent compounds. A positive impact of the 30R conformation on antiproliferative activity was also observed, with approximately 2-fold enhancement when compared to the 30S epimer.

Electrochemical Reduction of CO2 Catalyzed by Re(pyridine-oxazoline)(CO)3Cl Complexes.

A series of rhenium tricarbonyl complexes coordinated by asymmetric diimine ligands containing a pyridine moiety bound to an oxazoline ring were synthesized, structurally and electrochemically characterized, and screened for CO2 reduction ability. The reported complexes are of the type Re(N-N)(CO)3Cl, with N-N = 2-(pyridin-2-yl)-4,5-dihydrooxazole (1), 5-methyl-2-(pyridin-2-yl)-4,5-dihydrooxazole (2), and 5-phenyl-2-(pyridin-2-yl)-4,5-dihydrooxazole (3). The electrocatalytic reduction of CO2 by these complexes was observed in a variety of solvents and proceeds more quickly in acetonitrile than in dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The analysis of the catalytic cycle for electrochemical CO2 reduction by 1 in acetonitrile using density functional theory (DFT) supports the C-O bond cleavage step being the rate-determining step (RDS) (ΔG⧧ = 27.2 kcal mol-1). The dependency of the turnover frequencies (TOFs) on the donor number (DN) of the solvent also supports that C-O bond cleavage is the rate-determining step. Moreover, the calculations using explicit solvent molecules indicate that the solvent dependence likely arises from a protonation-first mechanism. Unlike other complexes derived from fac-Re(bpy)(CO)3Cl (I; bpy = 2,2'-bipyridine), in which one of the pyridyl moieties in the bpy ligand is replaced by another imine, no catalytic enhancement occurs during the first reduction potential. Remarkably, catalysts 1 and 2 display relative turnover frequencies, (icat/ip)2, up to 7 times larger than that of I.

Taxodikaloids A and B, Two Dimeric Abietane-Type Diterpenoids from Taxodium ascendens Possessing an Oxazoline Ring Linkage.

Two dimeric diterpenoids, taxodikaloids A (1) and B (2), have been identified from the seeds of Taxodium ascendens. The diterpenoid structures were established on the basis of comprehensive spectroscopic analysis, and the absolute configuration of taxodikaloid A (1) was further confirmed by single-crystal X-ray diffraction. Both structures feature an unprecedented oxazoline ring linkage connecting two abietane diterpenoid monomers. A plausible biosynthetic pathway for compounds 1 and 2 is proposed. Both compounds show potential neuroprotective activity against Aβ25-35-induced damage in SH-SY5Y cells.

An Efficient Strategy for the Synthesis of 1-(Trifluoromethylsulfonamido)propan-2-yl Esters and the Evaluation of Their Cytotoxic Activity.

An efficient method for the synthesis of 1-(trifluoromethylsulfonamido)propan-2-yl benzoates is described, the products of the reaction were characterized by heteronuclear single quantum coherence spectroscopy (HSQC), heteronuclear multiple bond correlation (HMBC) and NMR experiments. The overall process began with the activation of the oxazoline ring by triflic anhydride, followed by the opening of the five-membered ring in the 5-methyl-2-phenyl-4,5-dihydrooxazole system. The cytotoxic activity of the new trifluoromethyl sulfonamides was evaluated with six cancer cell lines and human gingival fibroblasts, posteriorly analyzing the influence on cytotoxicity exerted by the withdrawing and donor substituents at the para-position of the phenyl ring. Compounds 3b-e showed cytotoxic activity, with IC50 values ranging from 17-17.44 µM for the cell lines tested, finding the highest effect for compound 3e.

Structural and mutational analysis of the nonribosomal peptide synthetase heterocyclization domain provides insight into catalysis

Nonribosomal peptide synthetases (NRPSs) are a family of multidomain, multimodule enzymes that synthesize structurally and functionally diverse peptides, many of which are of great therapeutic or commercial value. The central chemical step of peptide synthesis is amide bond formation, which is typically catalyzed by the condensation (C) domain. In many NRPS modules, the C domain is replaced by the heterocyclization (Cy) domain, a homologous domain that performs two consecutive reactions by using hitherto unknown catalytic mechanisms. It first catalyzes amide bond formation, and then the intramolecular cyclodehydration between a Cys, Ser, or Thr side chain and the backbone carbonyl carbon to form a thiazoline, oxazoline, or methyloxazoline ring. The rings are important for the form and function of the peptide product. We present the crystal structure of an NRPS Cy domain, Cy2 of bacillamide synthetase, at a resolution of 2.3 Å. Despite sharing the same fold, the active sites of C and Cy domains have important differences. The structure allowed us to probe the roles of active-site residues by using mutational analyses in a peptide synthesis assay with intact bacillamide synthetase. The drastically different effects of these mutants, interpreted by using our structural and bioinformatic results, provide insight into the catalytic mechanisms of the Cy domain and implicate a previously unexamined Asp-Thr dyad in catalysis of the cyclodehydration reaction.

Non-enzymatic reaction of glycosyl oxazoline with peptides

Recently, a number of chemoenzymatic strategies have been explored for achieving preparation of homogeneous glycopeptides and glycoproteins, especially by using endoglycanases and glycosyl oxazolines. However, concomitant occurrence of non-enzymatic reactions has been reported, but no further characterization of the byproducts was conducted. In this work, we made an attempt to identify the side product by using model substrates. Analysis of the product allowed us to propose that the oxazoline ring was attacked by the amino group of lysine, leading to the formation of disubstituted acetamidine.

New bis(oxazoline)–vanadyl complexes, supported by electrostatic interaction in Laponite clay, as heterogeneous catalysts for asymmetric oxidation of methyl phenyl sulfide

Chiral bis(oxazoline) ligands are used for the first time to promote the enantioselective vanadium-catalyzed oxidation of sulfides with alkyl hydroperoxides. Several bis(oxazoline)-VO complexes have been prepared and supported by cation exchange in Laponite clay. The substituent in the oxazoline ring, and the type of hydroperoxide are relevant parameters that control the activity and selectivity of the resulting catalysts. Tert-butyl hydroperoxide is more reactive but less enantioselective than cumenehydroperoxide, both with the neat and supported VO-bis(oxazoline) complexes. Activities and enantioselectivities obtained with the heterogeneous catalysts are always lower than in solution, and in general better and more consistent results are obtained with box(iPr) ligand which seems to be also the best chiral auxiliary in homogeneous phase, leading to a modest but significant enantioselectivity of 20% ee in heterogeneous phase and of 28% in homogeneous phase. The recovered of the best catalyst shows a decrease in the catalytic activity and in the enantioselectivity, in agreement with some decomplexation of the chiral ligand, whereas the supported vanadium species remain stable and recoverable.

Ligand-Controlled Stereodivergent, Enantioselective Conjugate Addition of 2-Oxazoline- and 2-Thiazoline-4-carboxylate to Nitroalkene Catalyzed by Chiral Copper Complexes.

The copper-catalyzed asymmetric conjugate addition of 2-oxazoline- and 2-thiazoline-4-carboxylate to a nitroalkene proceeded to give either the syn or anti adduct selectively in high enantiomeric excess when an appropriate chiral ligand was used. Subsequent reduction of the nitro group followed by hydrolysis of the oxazoline ring yielded an optically active γ-lactam of protected α-quaternary serine derivative.

Synthesis, crystal structures and catalytic activities of new palladium(II)–bis(oxazoline) complexes

Palladium–bis(oxazoline) complexes (Pd-BOX-A and Pd-BOX-B) were synthesized and characterized by 1H, 13C NMR, IR and elemental analysis. The molecular structures of the complexes were confirmed by single-crystal X-ray analysis. In both cases, the palladium center is coordinated by the nitrogen atoms of the two oxazoline rings and two chloride ligands in a distorted square planar geometry. Despite the fact that the bis(oxazoline) ligand is achiral, the asymmetrical substitution on the phenyl spacer and the rigid backbone of the complex Pd-BOX-A induce inherent chirality and the compound crystallizes as a racemic mixture. Both complexes were found to be highly effective catalysts for Suzuki–Miyaura, Mizoroki–Heck and Sonogashira cross-coupling reactions. They also show excellent catalytic activities toward carbonylative coupling reactions.

Plasma polymerized 2-ethyl-2-oxazoline: Chemical characterization and study of the reactivity towards different chemical groups

Poly(2-ethyl-2-oxazoline) thin coatings were deposited on different substrates by means of low pressure plasma polymerization. The stability of the thin films was evaluated by immersion in different aqueous environments (Phosphate Buffer Saline (PBS) at 37°C, sodium dodecyl sulfate (SDS) solutions, aqueous solutions with different pH) and was found to be dependent on the deposition conditions. Chemical characterization of the coatings deposited with different process parameters was performed by means of Attenuated Total Reflectance Fourier Transform Infrared (FTIR/ATR) spectroscopy and Nuclear Magnetic Resonance (NMR) spectroscopy. Partial retention of the oxazoline ring was assessed also for the stable coatings. Noteworthy, the coatings displayed an intrinsic fluorescence with an emission maximum around 534–542nm. The reactivity of the plasma deposited coatings towards carboxylic, amino- and hydroxyl groups was investigated through selected reactions with poly(acrylic acid), amino-terminated polyethylene glycol and zonyl FSO-100 fluorosurfactant. Results indicate strong reactivity with COOH groups, probably as a consequence of the partial retention of the oxazoline ring. As a result, it is suggested that stable coatings can be exploited for the covalent immobilization of COOH-containing proteins or biomolecules, opening a wide range of potential applications.

Synthesis, NMR, and X-ray Studies of Iridium Dihydride C,N and N,P Ligand Complexes

The iridium(III) dihydride complexes [Ir(H)2(L1)(6,6′-bi-2-picoline)]BArF (5; L1 = (S)-1-[2-(2-adamantan-2-yl-4,5-dihydrooxazol-4-yl)-ethyl]-3-(2,6-diisopropylphenyl)-1,2-dihydroimidazol-2-ylidene, BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) and [Ir(H)2(L2)(6,6′-bi-2-picoline)]BArF (6; L2 = (R)-2-((di-tert-butylphosphanyl)methyl)-4-phenyl-4,5-dihydrooxazole) were prepared from the corresponding [Ir(COD)(L)]BArF precursors by treatment with 6,6′-bi-2-picoline under H2 and characterized by 2D NMR spectroscopy and X-ray diffraction. In solution, the N,P complex 6 exists as two isomeric dihydride species (6a and 6b) that are in rapid equilibrium at room temperature. Furthermore, the X-ray structures for [Ir(COD)(L1)]BArF (1) and [Ir(COD)(L2)]BArF (2) are reported. The structural comparison of the solid-state structures of the iridium(I) precursor 1 and the iridium(III) dihydride complex 5 revealed a significant change in the backbone geometry of the C,N ligand. The original U-shaped conformation of the ligand switches to an S-shaped conformation, and therefore, the substituent in the oxazoline ring occupies different quadrants in the iridium coordination sphere. Notable in this context is the finding that a similar switch in the ligand backbone was observed for the C,N iridium(III) dihydride olefin species 3 ([Ir(H)2[(E)-1-methyl-4-(1-phenylprop-1-en-2-yl)benzene-D5](L1)]BArF), which represents a catalytically competent intermediate.

Electronic structure and reactivity of nickel(i) pincer complexes: their aerobic transformation to peroxo species and site selective C-H oxygenation.

The study is aimed at a deeper understanding of the electronic structure of the T-shaped nickel(i) complex [LigiPr(iso)Ni] (1b), bearing the iso-PyrrMeBox (bis(oxazolinylmethylidene)pyrrolidinido) pincer ligand, and its CO adduct [LigiPr(iso)Ni(CO)] (2b) as well as to provide insight into the mechanism of autoxidation of the different nickel peroxo species of this ligand type. CO was found to react reversibly with complex 1b resulting in the corresponding CO adduct 2b. The EPR data as well as the results of DFT modeling revealed significant differences in the electronic structure of 1b and 2b. Reaction of [LigPh(iso)Ni] and [LigiPr(iso)Ni] (1a and b) with dioxygen yielded the 1,2-μ-peroxo complexes [Lig(iso)NiO]23a and b which reacted with hydrogen peroxide to give the hydroperoxo complexes [Lig(iso)NiOOH] 5a and b. Thermal aerobic decomposition of the peroxo species 3a and 5a in the presence of O2 led to a C-H activation of the ligand at the benzylic position of the oxazoline ring forming diastereomeric cyclic peroxo complexes 6 and 6'. For the 1,2-μ-peroxo complex 3b the autoxidation of the pincer in the absence of O2 occurred at the tertiary C-H bond of the iPr-group and led to a selective formation of the terminal hydroxo complex [LigiPr(iso)NiOH] 7b and the cyclic alkoxy complex 8 in equimolar quantities, while the corresponding cyclic peroxo species 9 was formed along with 7b in the presence of oxygen. Whether or not O-O bond cleavage occurred in the generation of 9 was established upon performing labeling experiments which indicate that the transformation does not involve an initial O-O bond cleaving step. Based on these observations and a series of stoichiometric transformations a tentative proposal for the processes involved in the anaerobic and aerobic decomposition of 3b has been put forward. Finally, the nickel(ii) methyl complex [LigPh(iso)NiMe] 14 reacted with O2 to give the methylperoxo complex [LigPh(iso)NiOOMe] 15 which slowly converted to a mixture of near equal amounts of the formato and the hydroxo complexes, [LigPh(iso)NiOOCH] 16 and [LigPh(iso)NiOH] 7a, along with half an equivalent of methanol. The formato complex 16 itself decomposed at elevated temperatures to CO2, dihydrogen as well as the nickel(i) species 1a.

Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel-Crafts Alkylations.

A series of eight novel bis(oxazoline) ligands incorporating gem-disubstitution on one of the oxazoline rings were prepared from (S)-valine. These ligands are designed as a cost-effective alternative to similar ligands possessing an oxazolinyl C(5)-tert-butyl group derived from expensive (S)-tert-leucine. Four of the ligands possess a C(4)-gem-dimethyl group and four a C(4)-gem-diphenyl group adjacent to the C(5)-isopropyl substituent. Zinc complexes of ligands 11a-h, along with non-C(4)-gem-disubstituted analogues 1a-g, were effective in the Friedel-Crafts alkylation of both indole (up to 74% ee) and 2-methoxyfuran (up to 95% ee) with a series of nitroalkenes. Three of the ligands (11a-c), an iron dichloride complex of ligand 11d and two zinc dichloride complexes, were characterized by X-ray crystallography, one with ligand 11d and the second a bis-tert-butyl-substituted N-methylamine ligand. A direct comparison of the latter structures clearly illustrates the gem-dimethyl effect.

Platinum(II) Monomer and Dimer Complexes with a Bis(oxazolinyl)phenyl Pincer Ligand.

A series of platinum(II) complexes with the formulas Pt(phebox)(L)(+) (phebox(-) = 1,3-bis(4,4'-dimethyl-2'-oxazolinyl)phenyl anion; L = pyridine (py), 4-phenylpyridine, quinoline, acridine) and Pt2(phebox)2(μ-L')(2+) (L' = pyrazine, 4,4'-bipyridine, 1,2-bis(4-pyridyl)ethane) was prepared. Crystallographic data establish that the metal center is bonded to the tridentate phebox(-) and monodentate pyridyl ligands. The five-membered oxazoline rings favor a CH2-CMe2 twist conformation. Pt(phebox)Cl and Pt(phebox)(py)(+) undergo a ligand-based chemically reversible redox reaction, whereas the electrochemistry of the other complexes is chemically and electrochemically less reversible. In contrast to complexes with the 1,3-bis(piperdylmethyl)phenyl anion ligand (pip2NCN(-)) or related pincer ligands, each of the phebox(-) complexes described here exhibits intense emission in room-temperature methylene chloride solution, which is assigned as originating from a lowest, predominantly phebox(-) ligand-centered excited state. In acetonitrile, the complexes undergo solvolysis resulting in displacement of the pyridyl ligands. The accumulated data demonstrate that subtle variations in the nature of the NCN and ancillary ligands of platinum(II) complexes provide access to at least five orbitally distinct emissive excited states.

Effect of Metals in Biomimetic Dimetal Complexes on Affinity and Gas-Phase Protection of Phosphate Esters.

Although the biomimetic dimetal complex [LGa2(OH)2(H2O)2](3+) [L = 2,6-bis((N,N'-bis(2-picolyl)amino)methyl)-4-tertbutylphenolate] provides efficient protection against phosphate loss in phosphopeptides upon collision-induced dissociation tandem mass spectrometry (CID MS/MS), the underlying mechanism remains unknown. Here, we explored the mechanism in detail and investigated the selective binding to phosphate groups in solution. Dimetal complexes containing combinations of Ga(3+), In(3+), Fe(3+), Co(3+), Zn(2+), Cu(2+), and V(2+) were reacted with HPO4(2-), phosphoserine, and a phosphopeptide (FQpSEEQQQTEDELQDK, abbreviated "βcas") and studied with isothermal titration calorimetry (ITC), CID MS/MS, and density functional theory (DFT). Ka for HPO4(2-) binding scaled with the metal charge and was 35-fold larger for [LGa2(OH)2(H2O)2](3+) (3.08 ± 0.31 × 10(6) M(-1)) than for [LZn2(HCOO)2](+). CID MS/MS of [LGa2(βcas)](n+) revealed protection against phosphate detachment (<3% of the total ion intensity). Phosphate detachment from βcas was 22-40% and increased to 42-71% when bound to dimetal complexes of lower charge than {LGa2}(5+). CID data suggests that facile metal-phosphate dissociation is associated with proton transfer from the intermediate oxazoline ring formed in the phosphopeptide to the metal-phosphate complex. The observed phosphate stabilization was attributed to a significant reduction in the gas-phase basicity (GB) of the phosphate group when bound to {LGa2}(5+)/{LIn2}(5+) complex cores. Absence of proton transfer results in formation of an ion-zwitterion intermediate with a greater dissociation threshold. This hypothesis is supported by DFT calculations for [LGa2(PO4)](2+), [LGaZn(PO4)](+), [LZn2(PO4)], and 2,4-dimethyl-3-oxazoline showing that [LGa2(PO4)](2+) is the only compound with a substantial lower GB (321 kJ/mol less) than 2,4-dimethyl-3-oxazoline.

Preparation of a C70 Bis-heterocyclic Derivative with High Chemio- and Regioselectivity.

C70 bis-heterocyclic derivative (1) bearing one oxazoline ring and one imidazoline ring with the 2 o'clock configuration is obtained with high chemio- and regioselectivity via the reaction of C70 with hydroxide and benzonitrile quenched with I2. Further study with benzylation experiment and theoretical calculations indicate that the oxazoline ring is the one first formed on the C70 cage, while the imidazoline ring is the one formed after the addition of I2 via a radical coupling reaction mechanism.