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Thin films derived by the deposition of charged microdroplets generated in the ESI source of a mass spectrometer act as highly concentrated reaction vessels in which the final products of an ion-molecule reaction can be isolated by their precipitation onto a solid surface under ambient conditions. In this study, the ESI Z-spray source supplied to a Q-TOF Ultima mass spectrometer was used to investigate the d-fructose acid-catalyzed reactions by microdroplets deposition onto a stainless-steel target surface. High conversion ratios of d-fructose into 5-hydroxymethylfuraldehyde (5-HMF), 5-methoxymethylfuraldehyde (5-MMF), and difructrose anhydrides (DFAs) were obtained with HCl and KHSO

Dibenzocycloctynes have emerged as a promising scaffold for bioorthogonal ligation. An important structural aspect that has not been addressed so far is connected with their chirality. Herein, we explore by theoretical and experimental methods this structural aspect that has been so far neglected. First, a computational analysis is conducted and results are used as a guideline for experimental investigation. Next, an array of different experiments (HPLC on chiral columns, chiroptical spectroscopy, X-ray diffraction) for structure elucidation are scrutinized in concert. Finally, this work demonstrates the chirality and the stereodynamic behavior of dibenzocycloctynes and of their triazole adducts with simple azides and uncover their conformational behavior.

Helicenes combine two central themes in chemistry: extended π-conjugation and chirality. Heteroatom doping preserves both characteristics and allows to modulate the electronic structure of a helicene. Herein, we report the (BO)2-doped tetrathia[7]helicene 1, which was prepared from 2-methoxy-3,3'-bithiophene via four steps. 1 is formally derived by substituting two (Mes)B-O moieties in place of (H)C=C(H) fragments in two benzene rings of parent tetrathia[7]helicene. X-ray crystallography revealed a dihedral angle of 50.26(9)° between the two terminal thiophene rings. (P)-/(M)-1 enantiomers were separated by chiral-HPLC and are configurationally stable at room temperature. The experimentally determined enantiomerization barrier of 27.4 ± 0.1 kcal mol-1 is lower than that of tetrathia[7]helicene (39.4 ± 0.1 kcal mol-1). Circular dichroism spectra of (P)- and (M)-1 show a perfect mirror-image relationship. 1 is a blue emitter (λem = 411 nm) with a photoluminescence quantum efficiency of ΦPL = 6% (cf. tetrathia[7]helicene: λem ≈ 405 nm, ΦPL = 5%).

The chiral Ni(II) and Pd(II) complexes of [6]helicene thioethyl porphyrazine have been synthesized and their spectroscopic, electrochemical, and chiroptical properties have been investigated by experimental and computational analyses. In these compounds, the tetrapyrrole macrocycle is β-substituted with an inherently chiral extended aromatic moiety potentially suitable to establish attractive π-π interactions with nanocarbons and endowed with helical chirality, both features providing interesting properties for optoelectronic applications. Experimental and density functional theory computational analyses highlight the presence of HOMO-LUMO charge-transfer transitions between the helicene moiety and the porphyrazine macrocycle. These compounds behave as mono-substituted push-pull systems without any typical electron-withdrawing or electron-donating groups and thus appear promising for optoelectronics. The enantiomers of the Ni(II) complex have been separated by chiral HPLC and their absolute configuration has been established by density functional theory computational analysis of electronic circular dichroism spectra. The magnetic circular dichroism spectrum of this complex has also been recorded providing better insight into its electronic structure.

The field of organocatalysis is expanding at a fast pace. Its growth is sustained by major stimuli, such as the effort toward an understanding of the mechanisms of reaction and catalytic processes in general, the elucidation of basic properties leading to stereocontrol and the search for broad applicability and scalability of the synthetic methodology. This paper reports a thorough study based on ESI-MS spectrometry of amino-organocatalyzed model reactions under different experimental conditions. Off-line reaction monitoring of mixtures containing different catalytic systems, by ESI-MSn showed the presence of several putative intermediate species, either in their protonated or sodiated forms. In addition, enantioselective chromatography of crude reactions provides the stereochemical outcome of asymmetric reactions. The bulk of the data collected offers a clue of the intricate pathways occurring in solution for the studied reactions.

We aimed to investigate salivary caffeine content, caffeine absorption and metabolism in Parkinson’s disease (PD) and verify whether salivary caffeine can be used as a biomarker of PD. We enrolled 98 PD patients and 92 healthy subjects. Caffeine and its major metabolite, paraxanthine, were measured in saliva samples collected before and 4 h after the oral intake of caffeine (100 mg). We measured caffeine absorption as the normalized increase in caffeine levels, and caffeine metabolism as the paraxanthine/caffeine ratio. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the Hoehn & Yahr, the presence of motor complications, and levodopa equivalent dose (LED) were assessed and correlated with caffeine levels, absorption, and metabolism. The effects of demographic and environmental features possibly influencing caffeine levels were also investigated. Caffeine levels were decreased in patients with moderate/advanced PD, while caffeine levels were normal in patients with early and de-novo PD, unrelated to caffeine intake. Caffeine absorption and metabolism were normal in PD. Decreased salivary caffeine levels in PD were associated with higher disease severity, longer duration, and the presence of motor complications, no significant association was found with LED. Salivary caffeine decrease correlates with PD progression.

Conformational chirality is a feature that may arise from the presence of a hindered rotation around a single bond that corresponds to a stereogenic axis. Atropisomers that feature such an element show interesting characteristics suitable for developing chiral systems with applicability in asymmetric synthesis, catalysis and materials chemistry. Here, we report the investigation of the stereochemical and chiroptical properties of a series of axially chiral intermediates useful in the synthesis of helicenes. Racemates of the four studied atropisomeric bisbenzodithiophenes were resolved by enantioselective HPLC and the single enantiomers were investigated by HPLC, ECD, VCD and CPL. Configurational stability was successfully established by dynamic HPLC or by monitoring thermal racemization, allowing the measurement of the free activation energy values for the stereomutation process. Moreover, the absolute configuration was assigned, thanks to a combination of TD-DFT and DFT calculations and experimental data derived by ECD and VCD, and the emissive chiral properties were measured by recording the CPL spectrum. Attention was paid to the importance of considering also aliphatic pendant groups in order to obtain a good calculation–experiment correspondence for both the ECD and VCD spectra. Considering the significant interest for axially chiral biaryl derivatives, this novel class of bisbenzodithiophenes are expected to have broad applications, not only in asymmetric synthesis, but also as potential chiral ligands or CPL emitters.

A direct enantio-, diastereo-, and chemo-selective high-performance liquid chromatographic method was developed for determining the content, enantiomeric purity, and related substances of the chiral antidepressant drug sertraline HCl in a single chromatographic run. The separation was achieved on a chiral stationary phase based on amylose tris(3-chloro-5-methylphenylcarbamate) under reversed-phase conditions. The method was optimized by evaluating the influence of the temperature and mobile phase composition on the retention and selectivity. The application of the single-run approach allowed to baseline resolve all investigated species in less than 15 min, without using buffers or tandem-coupled columns. The chromatographic method was validated according to the guidelines of the Official Medicines Control Laboratory and applied to control the content of sertraline HCl and related chiral substances in a generic antidepressant formulation., Graphical abstract Image 1, Highlights • Sertraline displays two stereogenic centers but only the (1S,4S) form is clinically useful. • A direct method was developed for evaluating assay and impurities in a single HPLC run. • The single-run RP method allowed resolving all species within 15 min, without using buffers. • Amylose tris(3-chloro-5-methylphenylcarbamate)-based CSP was used as a chiral support. • The method is selective, precise and accurate and it meets the requirements of the EP guidelines.

The use of the tetrabutylammonium additive was investigated in the ultra-high performance reversed-phase liquid chromatographic elution of basic molecules of pharmaceutical interest. When added to the mobile phase at low pH, the hydrophobic tetrabutylammonium cation interacts with the octadecyl chains and with the residual silanols, thus imparting a positive charge to the stationary phase, modulating retention and improving peak shape of protonated basic solutes. Two sources of additive were tested: a mixture of tetrabutylammonium hydroxide/trifluoroacetic acid and tetrabutylammonium hydrogen sulfate. Retention and peak shape of 11 basic pharmaceutical compounds were evaluated on commercially available ultra-fast columns packed with octadecyl stationary phases (Ascentis Express C18 2.0 µm, Acquity BEH C18 1.7 µm, Titan C18 1.9 µm). All columns benefit from the use of additive, especially tetrabutylammonium hydrogen sulfate, providing very symmetric peaks with reasonable retention times. Focusing on the probe compounds amitriptyline and sertraline, efficiency and asymmetry values were investigated at increasing retention factor. The trend is very different to that obtained in reversed-phase conditions and the effect lies in the complex molecular interaction mechanisms based on hydrophobic and ion exchange interactions as well as electrostatic repulsion.

We report on the synthesis of a novel class of functionalized thia[6]helicenes and a thia[5]helicene, containing a benzothiophene unit and a second heteroatom embedded in the helix (i.e., nitrogen and oxygen) or a pyrene or a spirobifluorene moiety. These systems are obtained through straightforward and general procedures that involve: (i) palladium-catalyzed annulation of iodo-atropoisomers with internal alkynes and (ii) Suzuki coupling of iodo-atropoisomers with phenyl boronic acid followed by a Mallory-type reaction. Both experimental and theoretical studies on the configurational stability of some selected thia[6]helicenes confirmed their stability toward racemization at room temperature, while the pyrene-based thia[5]helicene was found to be unstable. Moreover, the configuration assignment for one representative thiahelicene was established through the comparison between experimental and theoretical circular dichroism (CD) spectra. A systematic study of the photophysical properties of both thiahelicenes and the corresponding atropoisomers has been carried out to provide a complete overview on the new molecules proposed in this work. The obtained data showed regular trends in all the thiahelicene series with spectroscopic traits in line with those previously observed for similar heterohelicenes.

A mild and efficient synthesis of a broad scope of substituted naphtho[1,2-a]pyrene derivatives was accomplished in good yields using an InCl3/AgNTf2-mediated two-fold alkyne benzannulation reaction. HPLC enantiomeric separation was achieved and the interconversion barriers have been determined. The ECD spectra of two derivatives were recorded and interpreted through TD-DFT calculations. Raman spectra were also recorded and predicted through DFT calculations.

Two chiral triptycene derivatives were analyzed on the Chiralpak IB-U column packed with cellulose tris(3,5-dimethylphenylcarbamate)-based sub-2-μm diameter particles. Under normal-phase conditions, sub-minute baseline enantioseparations were obtained. Differences in structural elements and chromatographic behavior of the investigated compounds were evaluated to identify the interactions that drive the chiral discrimination process. From the evaluation of the experimental chromatographic data, it was found that hydrogen bond formation is essential for the separation of enantiomers.

The synthesis of pyreno[a]pyrene-based helicene hybrids was achieved in good yield via a four-fold alkyne benzannulation reaction that was promoted by Bronsted acid. The molecules are configuration...

The assignment of the absolute configuration (AC) of two conformational flexible organic molecules by means of TD-DFT simulation of the electronic circular dichroism (ECD) spectra is presented. The factors leading to a reliable assignment were evaluated in the various steps of the process. The effects of different functionals and basis sets in the geometry optimization step is very limited in terms of the resulting optimized geometries, whereas the inclusion of the solvent in the calculations has a much larger effect on the correct evaluation of the conformational ratio. B3LYP and M06-2x were found to be the most accurate functionals for geometry optimization. CAM-B3LYP and ωB97X-D provided the best results in the TD-DFT simulations.

Many efforts have been made to separate basic compounds, which are challenging to resolve in reversed phase liquid chromatography. In this process, they are strongly retained and the peak shape undergoes significant distortion. The principal origin of this has been identified with the non-negligible interaction with residual deprotonated silanols. Consequently, all solutions that efficiently shield silanols are being sought. This review is an upgrade on the use of the electrostatic repulsion reversed phase (ERRP) approach: retention of bases, in protonated form, can be achieved by modulating the charge repulsion caused by the presence of positive charges in the chromatographic system. This study successfully (i) introduced fixed positive charges in the structure of stationary phases, (ii) used cationic and hydrophobic additives in the mobile phase, and (iii) used the ERRP-like approach employed at the preparative level for peptide purification.

The couple of chiral sulfur compounds α-lipoic acid (ALA)/α-dihydrolipoic acid (DHALA) has attracted considerable attention in recent years owing to its remarkable anti-inflammatory and antioxidant properties. It is well known that the chirality of the C6 plays a key role in determining the biological activity of ALA. The natural occurring (R)-ALA enantiomer is an essential cofactor for key oxidative metabolism enzyme complexes and, after oral administration of the racemic mixture, it shows higher plasma concentration than (S)-ALA. Differently, the in vivo enantioselective action difference between the enantiomers of DHALA has not yet been studied. This lacking is perhaps due to the unavailability of analytical methods capable of determining the enantiomeric composition of biological samples during pharmacokinetic and pharmacodynamic events. In the present work, the direct and baseline enantioresolution of both chiral acids by HPLC on two amylose-derived chiral stationary phases is presented. The proposed chiral enantioselective protocol, therefore, does not require pre- or on-column derivatization. The performance of the coated Chiralpak AS-H CSP and the new immobilized Chiralpak IH-3 CSP, which have the same chiral selector amylose tris-[(S)-α-methylbenzylcarbamate], were compared using conventional normal-phase mobile phases containing ethanol or 2-propanol as alcoholic solvents and a fixed percentage of trifluoroacetic acid. Nonconventional eluents containing dichloromethane, ethyl acetate, and 2-methyltetrahydrofuran as organic cosolvents were applied in the separation of the enantiomers of two carboxylic acids on the immobilized Chiralpak IH-3 CSP. The effect of the column temperature was carefully evaluated in order to improve enantioselectivity. Adequate amounts of enantiomers were isolated by an analytical-size Chiralpak IH-3 column and submitted to chiroptical measurements. The absolute configuration assignment of the isolated enantiomers was determined by a multidisciplinary procedure based on the comparison of the experimental and calculated chiroptical properties.

The toolbox of medicinal chemists includes the 1,4-benzodiazepine scaffold as a “privileged scaffold” in drug discovery. Several biologically active small molecules containing a 1,4-benzodiazepine scaffold have been approved by the FDA for the treatment of various diseases, with most of them being used for their psychotropic effects. The therapeutic potential of 1,4-benzodiazepines has stimulated the interest of synthetic chemists in developing new synthetic strategies to a range of substituted analogues for biological evaluation. A structural variation of the classical benzodiazepine skeleton is observed e.g. in alprazolam, midazolam, and related benzodiazepines, which contain a 1,2,4-triazole or an imidazole ring fused to the benzodiazepine core. Irrespective of the presence of the fused heterocyclic ring, the seven-membered diazepine ring is far from planar, and its shape resembles a twist chair. Then, the unsymmetrical substitution pattern around the seven membered cycle renders these molecules chiral, as they lack any reflection-type symmetry element. However, chirality of this molecules is labile at room temperature, becausea simple ring flipping process converts one enantiomer into the other, and 1,4-benzodiazepines exist as a mixture of rapidly interconverting conformational enantiomers in solution at or near room temperature. Physical separation of the interconverting enantiomers of diazepam and of other related 1,4-benzodiazepin-2-ones can be accomplished by low temperature HPLC on chiral stationary phases (CSPs). If the HPLC column is cooled down to temperatures where the interconversion rate is sufficiently low, compared to the chromatographic separation rate, distinct separated peaks can be observed, provided the CSP is sufficiently enantioselctive. The apparent rate constants for the on-column enantiomerization and the corresponding free energy activation barriers were obtained by simulation of exchange-deformed HPLC profiles using a computer program based on the stochastic model. Here we report on the dynamic HPLC investigations carried out on a set of fused imidazo and triazolo-benzodiazepines (alprazolam, midazolam, triazolam and estazolam) The experimental dynamic chromatograms and the corresponding interconversion barriers reported in this paper show that the third fused heterocyclic ring increase the energy barrier by 2 kcal/mol.

2,2'-Bis[2-(5,2'-bithienyl)]-3,3'-bithianaphthene (1) is the progenitor of a class of C2 symmetric thiophene-based electroactive monomers that, when electrooxidized in the enantiomerically pure form, produce inherently chiral films endowed with outstanding electrochemical enantiorecognition properties. The enantioselective high-performance liquid chromatography (HPLC) is the only approach used so far to resolve the racemic form of 1 into enantiomers. In this work, an improved HPLC method for multimilligram enantiomer production is presented. Key factors controlling the enantioseparation, such as mobile phase composition and column temperature, were identified using a 100 × 4.6 mm i.d. Chiralpak IB-3 column and subsequently scaled up to a 250 × 10.0 mm i.d. Chiralpak IB column. In the optimized semipreparative conditions, about 34 mg of pure (P) and (M) enantiomers per hour could be produced.

During a screening of cyclodextrins (CDs) as chiral selectors for the separation of daclatasvir (DCV) and its enantiomer by capillary electrophoresis (CE), an unusual phenomenon for CDs was observed, that is two peaks with a plateau in between using γ-CD as chiral selector. The same result was encountered when enantiopure DCV was injected or when analyzing a sample containing enantiopure DCV and γ-CD in a CD-free background electrolyte. Peak coalescence was observed at 45°C and at a pH above 3.5. Two peaks with a plateau were also observed for DCV stereoisomers as well as a structural analog. However, only a single peak was detected if one or both amino acid moieties of DCV were lacking. Nuclear magnetic resonance (NMR) experiments including Nuclear Overhauser effect-based methods showed that in solution DCV adopted a folded conformation in which the isopropyl side chain of the valine residues pointed toward the aromatic rings of DCV. Moreover, NMR unequivocally demonstrated the simultaneous formation of DCV-γ-CD inclusion complexes with 1:1 and 2:1 stoichiometry, which was corroborated by mass spectrometry. In both complexes, DCV also adopted a folded structure. The RSSR-diastereomer of DCV as well as an analog lacking one of the amino acid moieties also formed 1:1 and 2:1 complexes with γ-CD although a plateau was only observed in the case of the RSSR-diastereomer. As shown by CE-MS, both DCV-γ-CD complexes surprisingly comigrated as the first peak, while the second migrating peak represents non-complexed DCV.

International audience; A straightforward approach to the synthesis of two different series of cationic [5]helicenes has been achieved including, in dioxa series, the possibility to introduce aromatic functional groups at the periphery of the helical structure. While photophysical study highlights that the introduction of aryl substituents at position 23 of the helical moieties has a negligible impact on the optical properties, styryl substituents allow a welcoming extension of the conjugation pathways. Finally, a red shift of the optical properties was evidenced upon introduction of nitrogen atoms in the helicene scaffold, leading to particularly good fluorescence efficiencies in the red domain for a helicenic dye. Detailed information on racemization kinetics was collected for the most stable species upon direct high-performance liquid chromatography (HPLC) resolution or, when configurational lability was too high, through VT-HPLC analysis on the chiral stationary phase (ΔG‡ values ranging from 85.0 to 137.1 kJ·mol–1 and above).

In this study, 31 racemates of N α-FMOC (fluorenylmethoxycarbonyl) amino acids (AAs) with different chemico-physical characteristics (neutral nonpolar, neutral polar, acidic and basic) have been success- fully resolved in fast enantioselective chromatography on recently-developed zwitterionic-teicoplanin chi- ral stationary phases (CSPs). The CSPs were prepared by covalently bonding the teicoplanin selector on fully-porous particles of narrow dispersion particle-size distribution (particle diameter 1.9 μm) and superficially-porous particles (2.0 μm). Both the zwitterionic-teicoplanin CSPs have proved to be ideal media for the separation of this important class of compounds. In particular, the zwitterionic CSP pre- pared on superficially-porous particles exhibited superior enantioselectivity and resolution, compared to that made of fully porous particles, in virtue of more favorable thermodynamics. The zwitterionic na- ture of these CSPs allowed avoiding the annoying effect of Donnan’s exclusion of enantiomers from the stationary phase. This effect, on the opposite, was frequently observed on a commercial teicoplanin CSP (Teicoshell) employed for comparative purposes. Noticeably, on the zwitterionic-teicoplanin CSPs, by us- ing either acetonitrile- or methanol-rich mobile phases (MPs), it was possible to favor speed over enan- tioresolution and vice versa. This work gives further replies to the request for rapid determination of enantiomeric excess of N α-FMOC proteinogenic (and non–proteinogenic) AAs, typically used as preferred chiral synthons in the solid-phase synthesis of therapeutic peptides.

A simple and green high-performance liquid chromatography method for the separation of paroxetine from its enantiomeric and diastereomeric impurities has been developed. The simultaneous chromatographic resolution was carried out on the amylose-based Chiralpak IA-3 chiral stationary phase using the mixture ethanol-water-diethylamine 80:20:0.1 (v/v/v) as a mobile phase. The effects of substitution of ethanol with methanol or acetonitrile and changes in column temperature on selectivity have been carefully investigated. The optimized single-run HPLC protocol allows the baseline separation of the enantiomers of paroxetine without suffering from interference from five other chiral and achiral impurities reported in the monograph of the European Pharmacopoeia.

Highly hydrophilic and biocompatible nanocarriers based on polysaccharide hydrogels (nanohydrogels, NHs) were shown to be promising systems for drug delivery applications. Following the idea of these emerging drug carriers, the aim of the present work was to develop self-assembled hydrogel nanoparticles based on amphiphilic derivatives of hyaluronic acid (HA) and riboflavin (Rfv), synthesized by "click" Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) reaction. The obtained amphiphilic product (HA-c-Rfv) was able to form nanohydrogels in aqueous environments, in particular by applying an innovative autoclave-based method. HA of different molecular weights (Mw) and degrees of substitution (DS) were prepared and the effect of these parameters on the NHs formation was assessed. The derivative HA220-c-Rfv 40/40 was chosen as the most interesting system, capable to form NHs in the range of 150-200nm and with a negative ζ-potential. NHs were very stable in water solutions and, by adding dextrose as cryoprotectant, it was also possible to freeze-dry the NHs formulation. The developed system is proposed for the delivery of hydrophobic drugs; for this purpose, dexamethasone, piroxicam and paclitaxel were used as model drugs; these molecules were loaded into NHs with high efficiency by film-hydration technique. Furthermore, a HA-c-Rfv derivative bearing an excess of propargylic portions was capable to react with other N3-derivatized molecules, opening the route to a wide spectrum of functionalization opportunities: in this direction, PEG-N3 has been tested as a model molecule for the preparation of PEGylated NHs.

The synthesis of pyreno[

The VCD spectra of several chiral compounds containing the CF

The VCD spectra of several chiral compounds containing the CF3 group are reviewed and analyzed. The list of compounds contains pharmaceutically relevant molecules as well as simple model molecules, having the value of case studies. In particular we point out the importance of the sign of the VCD band relative to some stretching normal mode of CF3 in the region 1110–1150 cm−1, as diagnostic of the configuration of stereogenic carbons C* to which the CF3 group is bound: the correspondence (−) ↔ (R) and (+) ↔ (S) holds for 100% of 1-aryl-2,2,2-trifluoroethanols. DFT calculations confirm these conclusions, but for the rule established here they serve just as a check. This rule is tested on two new compounds, namely N-tert-butanesulfinyl-1-(quinoline-4-yl)-2,2,2-trifluoroethylamine, 8, and 4-[2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, 10, both containing two stereogenic elements, one of them being an asymmetric carbon C* of unknown configuration binding a CF3 group. Discussion of the general validity of the rule is provided and some further tests are run on compounds in well-established drugs.