Fine-tuning the effect of π-π interactions on the stability of the NTB phase.

The synthesis and liquid-crystalline properties are reported for novel bent-shaped dimers in which a naphthyl group has been incorporated into the mesogenic cores. In addition to the nematic and twist-bend nematic phase, a new liquid-crystalline phase was observed. The combined experimental and computational study demonstrated how the interplay between the molecular geometry and π-π interactions affects the thermal stability of the twist-bend nematic and nematic phases. Correlation between mesomorphic properties and molecular geometry revealed that a greater conformational diversity leads to a broader distribution of bend-angles and destabilization of the NTB phase. Qualitative correlation between the thermal behaviour and electronic structure of the molecules of a similar geometry suggested that the transition temperatures of both nematic phases depend on the relative contribution of dispersion and electrostatic energies which determines the strength of the π-π interactions. These results provide an insight into how subtle changes in chemical structure can be exploited to tune the intermolecular interactions and influence the thermal stability of the liquid crystalline phase.

High-Efficiency Microflow and Nanoflow Negative Electrospray Ionization of Peptides Induced by Gas-Phase Proton Transfer Reactions.

Liquid chromatography coupled with electrospray ionization mass spectrometry (ESI-MS) is routinely used in proteomics research. Mass spectrometry-based peptide analysis is performed de facto in positive-ion mode, except for the analysis of some post-translationally modified peptides (e.g., phosphorylation and glycosylation). Collected mass spectrometry data after peptide negative ionization analysis is scarce, because of a lack of negatively charged amino acid side-chain residues that would enable efficient ionization (i.e., on average, every 10th amino acid residue is negatively charged). Also, several phenomena linked to negative ionization, such as corona discharge, arcing, and electrospray destabilization, because of the presence of polar mobile-phase solutions or acidic mobile-phase additives (e.g., formic or trifluoroacetic acid), reduce its use. Named phenomena influence microflow and nanoflow electrospray ionization (ESI) of peptides in a way that prevents the formation of negatively charged peptide ions. In this work, we have investigated the effects of post-column addition of isopropanol solutions of formaldehyde, 2,2-dimethylpropanal, ethyl methanoate, and 2-phenyl-2-oxoethanal as the negative-ion-mode mobile-phase modifiers for the analysis of peptides. According to the obtained data, all four modifiers exhibited significant enhancement of peptide negative ionization, while ethyl methanoate showed the best results. The proposed mechanism of action of the modifiers includes proton transfer reactions through oxonium ion formation. In this way, mobile phase protons are prevented from interfering with the process of negative ionization. To the best of our knowledge, this is the first study that describes the use and reaction mechanism of aforementioned modifiers for enhancement of peptide negative ionization.

Comparison between enhanced MALDI in-source decay by ammonium persulfate and N- or C-terminal derivatization methods for detailed peptide structure determination.

Amino acid sequencing and more detailed structure elucidation analysis of peptides and small proteins is a very difficult task even if state-of-the-art mass spectrometry (MS) is employed. To make this task easier, chemical derivatization methods of the N terminus with 4-sulfophenyl-isothiocyanate (SPITC) or the C terminus with 2-methoxy-4,5-dihydro-1H-imidazole (Lys-tag) can enhance peptide fragmentation or fragment ionizability, via proton mobility/localization mechanisms making tandem MS (MS(2)) spectra more informative and less demanding for structural interpretation. Observed disadvantages related to both derivatization methods are sample- and time-consuming procedures and the increased number of reaction byproducts. A novel, sulfate radical in-source formation method of matrix-assisted laser desorption ionization (MALDI) MS based on chemically enhanced in-source decay (ISD) can be accomplished by simple addition of ammonium persulfate (APS) in the matrix solution. This method enables effective decomposition of peptide ions already in the first stage of MS analysis where a large number of fragment ions are produced. The resultant MALDI-ISD mass spectra (MS after APS → MALDI-ISD MS) are almost equivalent to conventional, collision-induced dissociation (CID) MS(2) spectra. These fragment ions are further subjected to the second stage of the MS, and consequently, MS(3) spectra are produced, which makes the sequence analysis more informative and complete (CID MS(2) is thus equivalent to CID MS(3)). Multiply stage MS after APS addition showed enhanced sensitivity, resolution, and mass accuracy compared to peptide derivatization (SPITC and Lys-tag) or conventional MS and MS(2) analyses and offered more detailed insight into peptide structure.

Sulfur ylide promoted synthesis of N-protected aziridines: a combined experimental and computational approach.

A range of N-protected aziridines [N-Tosyl (N-Ts), N-2-trimethylsilylethanesulfonamide (N-SES), N-tert-butoxycarbonylamido (N-Boc), and N-o-nitrobenzenesulfonamide (oNs)] were prepared in moderate to good yield and with high enantiomeric excess of both isomers starting from N-protected imines, using a sulfonium salt derived from Eliel's oxathiane. The diastereoselectivities of the reactions are influenced by the imine N-protecting group, the imine substituent, and the sulfide structure. An unusual cis selectivity was observed in the formation of N-tosyl-2-phenyl-3-tert-butylaziridine and N-o-trimethylsilylethanesulfonamide-2-phenyl-3-tert-butylaziridine, which was explained by using computational models. The analysis suggests that betaine formation in the case of N-tosyl-tert-butylaldimine aziridination using oxathiane benzyl sulfonium ylide 1' is reversible and that the selectivity is determined at the rotation step, which is unusual for semistabilized ylide aziridination. We have shown herein that the steric bulk of an imine substituent, in combination with a sterically demanding sulfonium ylide, can also affect the reversibility of the reaction. This is the first example of this sort involving aziridinations using semistabilized ylides.

Synthesis, characterization and in vitro pharmacology of novel pregabalin derivatives.

A series of novel pregabalin derivatives were synthesized starting from N-protected pregabalin, different amino sugars, adamantylamine, serotonin and tryptamine. New compounds were spectroscopically characterized and in vitro tested on gabapentin receptor binding assay. The serotonin-pregabalin adduct showed significant binding effect and its IC50 value was determined.

Efficient chemoenzymatic dynamic kinetic resolution of 1-heteroaryl ethanols.

The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR) through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B (Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution (KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at 80 degrees C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the previously reported outer sphere mechanism. These results support the further understanding of the mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in comparison to reference substrates, as often referred to in the literature.

LC-NMR and LC-MS identification of an impurity in a novel antifungal drug icofungipen.

Successful use of LC-NMR and LC-MS for rapid identification of an impurity in a novel antifungal drug icofungipen has been demonstrated. Complementary information obtained from the two methods made it possible to determine the structure of A1 prior to its isolation and purification. Stop-flow LC-NMR ((1)H and DQFCOSY), LC-MS and LC-MS/MS spectra have shown that A1 is structurally related to icofungipen. It was later isolated and prepared synthetically and its structure was corroborated by high-resolution NMR spectroscopy.

Desymmetrization of cyclic anhydrides mediated by cinchona alkaloids: synthesis and olfactory properties of new fragrances based on (R)- and (S)-2-ethylhexanol.

A series of enantiomerically pure new fragrances, derived from 2-ethylhexanol, have been prepared and their olfactory properties evaluated. The key step of the synthesis is cinchona-alkaloid-catalyzed desymmetrization of cyclic meso-anhydrides with (R)- and (S)-2-ethylhexanol and proceeded in good to excellent diastereoselectivities (92:8-98:2 dr). Enantiomerically pure alcohols were prepared by lipase-catalyzed kinetic resolution of 2-ethylhexanol using vinyl laurate as acyl donor.

Determination of the absolute configuration of flexible molecules by ab initio ORD calculations: a case study with cytoxazones and isocytoxazones.

Ab initio calculations of the optical rotatory power of the natural cytokine modulator cytoxazone 1 and its trans-diastereomer 2, as well as the structural isomers cis-3 and trans-4 isocytoxazones, have been performed at four different wavelengths (589, 546, 435, and 405 nm) by Density Functional Theory. The calculation of ORD curves provides a reliable method for the assignment of absolute configuration of these conformationally flexible molecules. The absolute configurations of isocytoxazones has been established as (+)-(4R,5S)-cis-3 and (+)-(4S,5S)-trans-4.