Cyclen-based bismacrocycles for biological anion recognition. A potentiometric and NMR study of AMP, ADP and ATP nucleotide complexation

The behaviour of two cyclen-based bismacrocycles linked by aromatic spacers as receptors of adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP) anions is explored. The two bismacrocycles differ from one another by the nature of their spacers, which are respectively 1,3-dimethylbenzene (BMC), or 2,6-dimethylpyridine (BPyC). Potentiometric investigations supported by (1)H and (31)P NMR measurements were performed over a wide pH range to characterize and understand the driving forces implicated in the supramolecular assemblies. A comparison is also carried out with the results presented in this work and those obtained previously with these two ligands and inorganic phosphates. The comparison exhibits the importance of pi-stacking capability of the organic anions in the binding and hydrogen-bonding network. For BPyC, NMR studies highlight two coordination schemes depending on the protonation of the nitrogen atom of the pyridinyl spacer, which acts in acidic media as a supplementary anchoring point.     

Reactions of silyl-stabilised sulfur ylides with organoboranes: enantioselectivity, mechanism, and understanding

The reaction of trimethylsilyl-substituted sulfonium ylides with organoboranes (Ph(3)B, Et(3)B) has been studied and although homologated products were obtained in good yield (after oxidation to the corresponding alcohols), the enantiomeric excesses were low with our camphor-based chiral sulfide (up to 40% ee, cf. corresponding phenyl-substituted sulfonium ylides gave >95% ee). Cross-over experiments were conducted to ascertain the nature of this difference in selectivity. Thus, aryl- and silyl-substituted sulfonium ylides (1 equiv.) were (separately) reacted with Et(3)B (1.5 equiv.) followed by Ph(3)B (1.5 equiv.) The experiments were repeated changing the order of addition of the two boranes. It was found that the aryl-substituted sulfonium ylide only trapped the first borane that was added indicating that ate complex formation was non-reversible and so was the selectivity determining step. In contrast the silyl-substituted sulfonium ylide only trapped Ph(3)B (it is more reactive than Et(3)B) indicating that ate complex formation was reversible and so 1,2-migration was now the selectivity determining step. The reactions have been studied computationally and the experimental observations have been reproduced. They have further revealed that the cause of reversibility in the case of the silyl-substituted sulfonium ylides results from ate complex formation being less exothermic and a higher barrier to 1,2-migration.     

Palladium-catalyzed C-allylation of benzoins and an NHC-catalyzed three component coupling derived thereof: compatibility of NHC- and Pd-catalysts

A large range of benzoins was successfully applied as C-nucleophiles in the palladium-catalyzed allylic alkylation with several allyl acetates, resulting in functionalized tertiary homoallylic alcohols. A number of unsymmetrical benzoins can be coupled with high levels of regio- and chemoselectivity. Finally, the challenging compatibility of free N-heterocyclic carbenes with a palladium catalyst has been utilized in a number of metal- and organocatalyzed three-component coupling reactions.     

Chiral analysis of milnacipran by a nonchiral HPLC--circular dichroism: improvement of the linearity of dichroic response by temperature control

The determination of the enantiomeric excess (e.e.) of a basic drug has been investigated in LC using a nonchiral stationary phase and a circular dichroism (CD) detector in order to avoid expensive chiral columns. The CD detector records both dichroic (Deltaepsilon) and UV (epsilon) signals at the same wavelength and calculates the anisotropy factor (g=Deltaepsilon/epsilon), which is linearly related to the e.e. The enantiomeric and chemical composition of a chiral drug can be simultaneously determined on a nonchiral HPLC support. However, the g factor from the CD signal is temperature dependent. Indeed, the temperature has an influence on the stability of the CD signal and the linear regression between g factor and the e.e. of 1R,2S-enantiomer. So, a decrease in temperature gives rise to an improvement of the above-mentioned linearity correlation. After optimization of chromatographic parameters (porous graphitic carbon-based column, methanol/ phosphate buffer as mobile phase) and selection of CD wavelength, a linear regression of g factor versus e.e. of 1R,2S-enantiomer was obtained at temperature-controlled CD detection and an LOQ of 94% was found. The enantiomeric composition of milnacipran was determined with good accuracy.     

Biomimetic synthesis of pyrone-derived natural products: exploring chemical pathways from a unique polyketide precursor

Our biomimetic hypothesis proposes that families of diverse natural products with complex core structures such as 9,10-deoxytridachione, photodeoxytridachione and ocellapyrone A are derived in nature from a linear and conformationally strained all-( E) tetraene-pyrone precursor. We therefore synthesized such a precursor and investigated its biomimetic transformation under a variety of reaction conditions, both to the above natural products as well as to diverse isomers which we propose to be natural products "yet to be discovered". We also report herein the first synthesis of the natural product iso-9,10-deoxytridachione.     

Determination of synthetic polypeptide conformations and molecular geometrical parameters by nonaqueous CE

The aim of this work was to study changes in homopolypeptide chain conformation as a function of the number of residues by the modeling of the electrophoretic mobility. For this purpose, the frictional coefficients of poly(N(epsilon)-trifluoroacetyl-L-lysine) with different number of residues (up to 11) were determined from the absolute ionic mobilities and modeled by the hydrodynamic frictional coefficient of an equivalent cylinder. This approach allowed determination of geometrical parameters of the polypeptide chain in a liquid phase (nonaqueous solution of the BGE). The fact that the BGE and analyte are dissolved in mixed (methanol-ACN) organic solvent implied to take into account different effects and corrections that are generally not considered in aqueous solvent: namely, the effect of ion-pairs between constituents of the BGE for the calculation of the ionic strength, the effect of ion-pairs between the solutes and the electrolyte counterions and the correction due to the dielectric friction (Hubbard-Onsager equations). In addition, the influence of the ionic strength on the electrophoretic mobility was corrected using the Pitts equation, and the effect of lateral charges due to a slight deprotonation of the -NH- group in the lateral chain was also considered. From this modeling, molecular geometrical parameters relative to the linear and helico?dal conformations were obtained with very good correlation coefficients. Interestingly, this work also points out that the use of ionic mobility modeling for extracting molecular geometrical parameters can also be applied to end-charged polypeptides with slightly charged lateral chains (3% of elementary charge per residue).     

Quantification of very low enantiomeric impurity of efaroxan using a dual cyclodextrin system by capillary electrophoresis

A rapid method for the enantiomeric purity determination of efaroxan has been developed by capillary electrophoresis (CE) using a dual cyclodextrin (CD) system. The influence of the nature and the concentration of CDs on separation parameters has been studied. High resolution (R_s = 7) and peak efficiency (104 000-121 000 theoretical plates) values were obtained for efaroxan enantiomers by adding two cyclodextrins, one neutral (7.5 mM DM-β-CD) and the other negatively charged (3 mM CM-β-CD) to the running buffer composed of 100 mM phosphoric acid-triethanolamine (pH 3). These resolution and peak efficiencies values allowed the quantitation of the (S)-enantiomer of efaroxan at very low enantiomeric excess even if the minor component migrates after the major one. This method was fully validated for the enantiomeric impurity determination of the (S)-form of efaroxan at the 0.05% level. Calibration curve, expressed by the peak areas ratio versus the enantiomeric purity was linear over the 0.05-1% enantiomeric impurity range (r² = 0.9996). Limits of detection (LOD) and quantification (LOQ), expressed in term of (S)-enantiomer impurity were 0.02% and 0.05%, respectively. The accuracy of the method at 0.12%, 0.50% and 0.80% enantiomeric impurity levels for the (S)-form were determined. Recoveries were in 94-102% range for each quality control sample and were determined with good precision (intra-day R.S.D. = 3.54%, inter-day R.S.D. = 5.33%).     

Antimony-121 Mössbauer spectral study of alpha-Zn4Sb3

The M?ssbauer spectra of alpha-Zn4Sb3, a compound that is best formulated as alpha-Zn13Sb10 or (Zn2+)13(Sb3-)6(Sb24-)2, have been measured between 5 and 120 K. The resulting six spectra have been simultaneously fit with two components in the ratio of 3:2 corresponding to the Sb3- and Sb2- ions identified in this valence semiconductor. The fits yield temperature independent isomer shifts of -8.17(2) and -9.73(2) mm/s and quadrupole interactions of -4.9(2) and 0 mm/s for the Sb3- and Sb2- ions, respectively; the corresponding M?ssbauer temperatures are 197(5) and 207(5) K, temperatures that are lower than the Debye temperature of beta-Zn4Sb3. The isomer shifts correspond to electronic configurations between 5s25p6 and 5s1.755p4.01 for the Sb3- ions and between 5s25p5 and 5s1.805p3.38 for the Sb2- ions, configurations that are in good agreement with the expected configurations for this valence semiconductor and with the results of band structure calculations.