Rapid Synthesis of 3-Methyleneisoindolin-1-ones via Metal-Free Tandem Reactions of Ester-Functionalized Aziridines.

We have disclosed a novel metal-free tandem cyclization reaction for the synthesis of 3-methyleneisoindolin-1-ones starting from ester-functionalized aziridines. This strategy can be effectively promoted by DBU and carboxylic acids. Mechanistically, it involves sequential ring opening of aziridines with carboxylic acids, lactamization, and elimination of carboxylic acids.

Two cases report of febuxostat-induced acute liver injury: acute heart failure as a probable risk factor?

Drug induced liver injury, as a sub-type of hepatotoxicity, is rare but practical problem, producing challenges for clinicians. Within the recent two months, two patients with heart failure develop febuxostat-induced acute liver injury during hospital stay. To the best of our knowledge, very few cases of febuxostat-induced hepatotoxicity have been reported up to now. In this paper, two unusual cases of febuxostat-induced acute liver injury are herein described. The medical history, drug treatment, clinical symptoms, liver function tests, diagnosis and prognosis are fully given in this paper. It should be noticed that, two liver injury happen in patients of heart failure with reduced ejection fraction. Whether heart failure is a risk factor of febuxostat related liver injury, deserves further research. This paper reminds the clinicians that more attention should be paid to the acute liver injury caused by febuxostat, and liver function tests are suggested especially for patients of heart failure.

Palladium-catalyzed Heck-carbonylation of alkene-tethered carbamoyl chlorides with aryl formates.

We report a palladium-catalyzed Heck-carbonylation of alkene-tethered carbamoyl chlorides by utilizing aryl formates as convenient CO surrogates. One C-O and two C-C bonds are constructed to give diversiform esterified oxindoles/γ-lactams bearing an all-carbon quaternary stereocenter under gas-free conditions. This transformation features a wide substrate scope and good functional group tolerance and can be easily applied to late-stage functionalization.

pH-Triggered Transition from Micellar Aggregation to a Host-Guest Complex Accompanied by a Color Change.

A pH-triggered transition from micellar aggregation to a host-guest complex was achieved based on the supramolecular interactions between calixpyridinium and pyrroloquinoline quinone disodium salt (PQQ-2Na) accompanied by a color change. Our design has the following three advantages: (1) a regular spherical micellar assembly is fabricated by the supramolecular interactions between calixpyridinium and PQQ-2Na at pH 6 in an aqueous solution, (2) increasing the pH can lead to a transition from micellar aggregation to a host-guest complex due to the deprotonation of calixpyridinium, and at the same time (3) increasing the pH can lead to a color change owing to the deprotonation of calixpyridinium and the complexation of deprotonated calixpyridinium with PQQ-2Na. Benefitting from the low toxicity of calixpyridinium and PQQ-2Na, this pH-induced transition from micellar aggregation to a host-guest complex was further studied as a controllable-release model.

Construction of Bridged Aza- and Oxa-[n.2.1] Skeletons via an Intramolecular Formal [3+2] Cycloaddition of Aziridines and Epoxides with Electron-Deficient Alkenes.

An intramolecular formal [3+2] cycloaddition of activated aziridines and epoxides with electron-deficient alkene has been developed for the general and efficient construction of bridged aza- and oxa-[n.2.1] (n = 3 or 4) skeletons. This strategy can be efficiently promoted by lithium iodide. To demonstrate its potential, the intramolecular formal [3+2] cycloaddition was used to access the important intermediate of homoepiboxidine.

Rhodium(iii)-catalyzed switchable C-H acylmethylation and annulation of 2,2'-bipyridine derivatives with sulfoxonium ylides.

A novel protocol for Rh(iii)-catalyzed switchable C-H acylmethylation and annulation of 2,2'-bipyridine derivatives with sulfoxonium ylides is reported. This protocol provides a facile approach to synthesize structurally diverse acylmethylated 2,2'-bipyridine derivatives and acyl pyrido[2,3-a]indolizines with a broad range of functional group tolerance.

UV Accelerated Assemblies Constructed Using Calixpyridinium in Aqueous Solution.

In this work, an irregular calixpyridinium-suramin sodium supramolecular assembly was constructed by the strong host-guest electrostatic interactions. More interestingly, a novel regular spherical supramolecular assembly was also fabricated by the hydrogen bonding interactions between suramin sodium and the UV accelerated addition product of deprotonated calixpyridinium in water. The same principle was also applied to construct a UV accelerated regular spherical self-assembly by the addition product of deprotonated calixpyridinium in water. Compared with the complicated and irreversible covalent connection of the light-responsive groups to the building block, which is one of the common means of obtaining light-responsive supramolecular systems, this finding not only provides a smart, facile, and universally applicable method to construct deprotonated calixpyridinium-based light-responsive host-guest systems but also provides a new idea for the development of other novel light-responsive building blocks.

Synthesis of bis-BN-Naphthalene-Fused Oxepins and Their Photoluminescence Including White-Light Emission.

A series of novel bis-BN-naphthalene-fused oxepin derivatives were synthesized via a Pd-catalyzed tandem reaction from brominated 2,1-borazaronaphthalenes and cis-bis(boryl)alkenes. X-ray crystallographic analysis revealed that bis-BN-naphthalene-fused oxepins feature a planar framework. The electronic and photophysical properties of the novel BN-naphthalene-fused oxepins were investigated by UV-vis and fluorescence spectroscopies and density functional theory (DFT) calculations, which disclosed the distinct electronic and photophysical properties of the analogous hydrocarbon system. Interestingly, dual-fluorescent emissions were observed upon dissolving N-substituted derivatives 10-14 in dimethyl sulfoxide. Tunable emission colors especially for white-light emissions can be achieved by controlling the ratio of solvents, concentration, or temperature using only a single-molecule compound.

Supramolecular Amphiphilic Assembly Formed by the Complexation of Calixpyridinium with Alimta.

In this work, the host-guest interaction between calixpyridinium and anionic anticancer drug Alimta was studied in aqueous media. Spherical supramolecular amphiphilic assembly rather than simple complex was accidentally fabricated by the complexation of calixpyridinium with Alimta. It is the third kind of anionic guest to be discovered to form the higher-order assembly by the complexation of calixpyridinium besides polyanionic guest and anionic gemini surfactant guest. The finding of this assembly approach supplies a new idea to construct various self-assembly architectures in water via the complexation of calixpyridinium with anionic drugs. The resulting calixpyridinium-drug assemblies may also have the potential to adjust the effects of drugs.

DNase I-Responsive Calixpyridinium-Mediated DNA Aggregation.

In this work, cationic macrocyclic calixpyridinium was employed as a new strategy to condense DNA. Moreover, the degradation of DNA by DNase I could lead to the calixpyridinium-DNA supramolecular aggregates being dissipated. Therefore, the present system is potentially applicable as the targeted drug delivery model at DNase I-overexpressed sites.

Diastereoselective Construction of 2-Aminoindanones via an In(OTf)3-Catalyzed Domino Reaction.

An In(OTf)3-catalyzed domino reaction involving sequential oxidative ring opening of aziridines by using the solvent dimethyl sulfoxide and intramolecular Michael addition has been developed for the modular synthesis of 2-aminoindanone compounds by the formation of one new C═O bond and one new C-C bond. The notable feature of this strategy includes broad substrate scope, excellent trans-diastereoselectivities, highly functionalized products, and mild conditions. The catalyst In(OTf)3 plays an important role in the formation of the indanone ring.

Rhodium(iii)-catalyzed unreactive C(sp3)-H alkenylation of N-alkyl-1H-pyrazoles with alkynes.

The first example of pyrazole-directed rhodium(iii)-catalyzed unreactive C(sp3)-H alkenylation with alkynes has been described, which showed a relatively broad substrate scope with good functional group compatibility. Moreover, we demonstrated that the transitive coordinating center pyrazole could be easily removed under mild conditions.

Palladium-catalyzed cascade reactions of alkene-tethered carbamoyl chlorides with N-tosyl hydrazones: synthesis of alkene-functionalized oxindoles.

A palladium-catalyzed cascade reaction of alkene-tethered carbamoyl chlorides with N-tosyl hydrazones is described. It provided a new way to synthesize various alkene-functionalized oxindoles bearing an all-carbon quaternary center. The olefin moieties could serve as versatile handles for further elaboration. This transformation was highly efficient and showed good functional group tolerance.

A novel fluoro-chromogenic Cu2+ probe for living-cell imaging based on rhodamine 6G-pyridine conjugation.

A novel fluoro-chromogenic rhodamine spirolactam probe (RP) has been prepared through the condensation of rhodamine hydrazine and 2-acetylpyridine, which displayed the detection of Cu2+ with high selectivity over a large number of other common metal ions. It shows a "turn-on" response to paramagnetic Cu2+ with an about 12-fold enhancement, and a color change from colorless to red that is observable by the naked eye. These changes are ascribed to the ring-opening of the spirolactam in RP, and subsequent host-guest coordination. The 2:1 binding stoichiometry of RP to Cu2+ was confirmed by Job's and B-H plots. The resulting fluorescence enhancement can be used to detect Cu2+ at concentrations from 2.0 to 20.0 µM with a limit of detection of 0.21 µM, which was lower than the maximum allowable Cu2+ level set by the WHO. Finally, RP has been utilized to monitor Cu2+ in living cells and natural water. Graphical abstract.

Enantioselective separation of twelve pairs of enantiomers on polysaccharide-based chiral stationary phases and thermodynamic analysis of separation mechanism.

The enantioseparation of twelve pairs of structurally related 1-aryl-1-indanone derivatives was studied in the normal-phase mode using three different polysaccharide-type chiral stationary phases, namely Chiralpak IB, Chiralpak IC, and Chiralpak ID. n-Hexane/2-propanol and n-hexane/ethanol were employed as mobile phases. Among all the investigated chiral columns, Chiralpak IC exhibited the most universal and the best enantioseparation ability toward all the racemates, particularly with the mobile phase composed of n-hexane/2-propanol (90/10, v/v). Then the effects of column temperature on retention and enantioselectivity were examined in the range of 25-40°C. Satisfactory enantioseparation was obtained at ambient temperature. The natural logarithm of retention and separation factors (ln k and ln α) versus the reciprocal of absolute temperature (1/T) (Van't Hoff plots) were found to be linear for all racemates, indicating that the retention and separation mechanisms were independent of temperature in the range investigated. Then, the thermodynamic parameters (ΔΔH°, ΔΔS°, and ΔΔG°) were calculated from Van't Hoff plots. These values indicated that the solute transfer from the mobile to stationary phase was enthalpically favorable, and the process of enantioseparation was mainly enthalpy controlled. At last, the impact of small changes in molecular structures of the tested 1-indanone derivatives on enantioseparation was also discussed.

Comparative studies of immobilized chiral stationary phases based on polysaccharide derivatives for enantiomeric separation of 15 azole compounds.

Immobilized polysaccharide-based columns showed excellent enantioselectivity in normal phase separation mode. In this work, enantioseparation abilities of four immobilized polysaccharide-derived chiral stationary phases (Chiralpak IA, Chiralpak IB, Chiralpak IC, and Chiralpak ID) toward 15 azole compounds were evaluated. Separation was carried out using n-hexane as mobile phase with ethanol, 1-propanol, 1-butanol, and 2-propanol as modifiers. And twelve compounds have achieved baseline separation with the resolutions ranging between 2.05 and 21.73. The enantioseparation on the four polysaccharide-based chiral columns using different alcohol modifiers was compared. In general, the best separation performance was identified as Chiralpak IC, which was able to resolve 11 compounds to baseline and two partially under the screening conditions. Separation on Chiralpak IB was not satisfactory, because only four compounds were baseline separated.

Facile and practical synthesis of ß-carbolinium salts and γ-carbolinium salts via rhodium-catalyzed three-component reactions.

A facile and practical [Cp*RhCl2]2-catalyzed three-component reaction between indolyl aldehydes, amines and alkynes involving C-H activation and cyclization has been developed. A series of ß-carbolinium salts and γ-carbolinium salts are successfully afforded in good to quantitative yields under mild conditions. This efficient and convergent strategy provides a good choice for constructing the libraries of ß-carbolinium salts and γ-carbolinium salts.

Study on the HPLC-based separation of some ezetimibe stereoisomers and the underlying stereorecognition process.

The enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different chiral stationary phases, ie, 3 polysaccharide-based chiral columns, was studied. It was observed that cellulose-based Chiralpak IC column exhibited the best resolving ability. After the optimization of mobile phase compositions in both normal and reversed phase modes, satisfactory separation could be obtained on Chiralpak IC column, especially in normal phase mode. The use of prohibited solvents as nonstandard mobile phase gave rise to better resolution than that of standard mobile phases (n-hexane/alcohol system). In addition, the presence of ethanol in nonstandard mobile phase has played an important role in enhancing chromatographic efficiency and resolution between ezetimibe stereoisomers. Various attempts were made to comprehensively compare the chiral recognition capabilities of immobilized versus coated polysaccharide-based chiral columns, amylose-based versus cellulose-based chiral stationary phases, reversed versus normal phase modes, and standard versus nonstandard mobile phases. Moreover, possible solute-mobile phase-stationary phase interactions were derived to explain how stationary and mobile phases affected the separation. Then the method validation with respect to selectivity, linearity, precision, accuracy, and robustness was carried out, which was demonstrated to be suitable and accurate for the quantitative determination of (RRS)-ezetimibe impurity in ezetimibe bulk drug.

Enantioseparation of nine indanone and tetralone derivatives by HPLC using carboxymethyl-ß-cyclodextrin as the mobile phase additive.

High-performance liquid chromatography (HPLC) is a powerful method in the area of chiral separation. In this study, a method of HPLC using carboxymethyl-ß-cyclodextrin (CM-ß-CD) as chiral selector was developed for enantioseparation of nine indanone and tetralone derivatives. The separation was performed on a conventional C18 column. The optimal mobile phase was a mixture of methanol and 0.05 mol/L phosphate buffer at pH 1.8 (55:45, v/v) containing 22.9 mmol/L CM-ß-CD. Under such conditions, the resolutions of all analytes were over 1.8 except for Compound F. The results of the study indicate the presence of a complex with 1:1 stoichiometry of the inclusion complex. In addition, it can be inferred from thermodynamic analysis that the behavior of formation of the inclusion complex and enantioseparation occurred simultaneously, while they were driven by different forces. The effect of analyte structure is also discussed.

Use of various ß-cyclodextrin derivatives as chiral selectors for the enantiomeric separation of ofloxacin and its five related substances by capillary electrophoresis.

A capillary electrophoretic method for the enantioseparation of ofloxacin and its five related substances (potential impurities, indicated as impurities B-F) was developed using ß-cyclodextrin derivatives as chiral selectors. To our knowledge, there are no previous studies about using capillary electrophoresis for the separation of impurities B-D. Six ß-cyclodextrin derivatives including cationic (piperidine- and cyclohexylamine-), neutral (dimethyl- and hydroxypropyl-), and anionic (carboxymethyl- and sulfated-) ß-cyclodextrin derivatives were tested and operational parameters such as buffer pH and concentration of ß-cyclodextrin derivatives were investigated. The best resolutions were all obtained with anionic ß-cyclodextrin derivatives: ofloxacin, impurities C-F could be best resolved with carboxymethyl-ß-cyclodextrin at satisfactory resolutions of 8.27, 9.98, 5.92, 8.49 and 6.78, respectively, while for impurity B, a particularly impressive resolution value, up to 21.38, was observed using sulfated-ß-cyclodextrin. The enhancement of enantioseparation observed for the tested analytes using anionic ß-cyclodextrin derivatives might be due to some favorable interaction between selectors and analytes. Given the fact that the selection of chiral selector depends on the structures of analytes, with the help of structural similarities and differences of the analytes, the structure-separation relationship was further discussed.