HPLC Enantioseparation of Rigid Chiral Probes with Central, Axial, Helical, and Planar Stereogenicity on an Amylose (3,5-Dimethylphenylcarbamate) Chiral Stationary Phase.

The chiral resolving ability of the commercially available amylose (3,5-dimethylphenylcarbamate)-based chiral stationary phase (CSP) toward four chiral probes representative of four kinds of stereogenicity (central, axial, helical, and planar) was investigated. Besides chirality, the evident structural feature of selectands is an extremely limited conformational freedom. The chiral rigid analytes were analyzed by using pure short alcohols as mobile phases at different column temperatures. The enantioselectivity was found to be suitable for all compounds investigated. This evidence confirms that the use of the amylose-based CSP in HPLC is an effective strategy for obtaining the resolution of chiral compounds containing any kind of stereogenic element. In addition, the experimental retention and enantioselectivity behavior, as well as the established enantiomer elution order of the investigated chiral analytes, may be used as key information to track essential details on the enantiorecognition mechanism of the amylose-based chiral stationary phase.

Helicity: A Non-Conventional Stereogenic Element for Designing Inherently Chiral Ionic Liquids for Electrochemical Enantiodifferentiation.

Configurationally stable 5-aza[6]helicene (1) was envisaged as a promising scaffold for non-conventional ionic liquids (IL)s. It was prepared, purified, and separated into enantiomers by preparative HPLC on a chiral stationary phase. Enantiomerically pure quaternary salts of 1 with appropriate counterions were prepared and fully characterized. N-octyl-5-aza[6]helicenium bis triflimidate (2) was tested in very small quantities as a selector in achiral IL media to perform preliminary electrochemical enantiodifferentiation experiments on the antipodes of two different chiral probes. The new organic salt exhibited outstanding enantioselection performance with respect to these probes, thus opening the way to applications in the enantioselective electroanalysis of relevant bioactive molecules.

Establishment and Preliminary Characterization of Three Astrocytic Cells Lines Obtained from Primary Rat Astrocytes by Sub-Cloning.

Gliomas are complex and heterogeneous tumors that originate from the glial cells of the brain. The malignant cells undergo deep modifications of their metabolism, and acquire the capacity to invade the brain parenchyma and to induce epigenetic modifications in the other brain cell types. In spite of the efforts made to define the pathology at the molecular level, and to set novel approaches to reach the infiltrating cells, gliomas are still fatal. In order to gain a better knowledge of the cellular events that accompany astrocyte transformation, we developed three increasingly transformed astrocyte cell lines, starting from primary rat cortical astrocytes, and analyzed them at the cytogenetic and epigenetic level. In parallel, we also studied the expression of the differentiation-related H1.0 linker histone variant to evaluate its possible modification in relation with transformation. We found that the most modified astrocytes (A-FC6) have epigenetic and chromosomal alterations typical of cancer, and that the other two clones (A-GS1 and A-VV5) have intermediate properties. Surprisingly, the differentiation-specific somatic histone H1.0 steadily increases from the normal astrocytes to the most transformed ones. As a whole, our results suggest that these three cell lines, together with the starting primary cells, constitute a potential model for studying glioma development.

"Inherently Chiral" Ionic-Liquid Media: Effective Chiral Electroanalysis on Achiral Electrodes.

To achieve enantioselective electroanalysis either chiral electrodes or chiral media are needed. High enantiodiscrimination properties can be granted by the "inherent chirality" strategy of developing molecular materials in which the stereogenic element responsible for chirality coincides with the molecular portion responsible for their specific properties, an approach recently yielding outstanding performances as electrode surfaces. Inherently chiral ionic liquids (ICILs) have now been prepared starting from atropisomeric 3,3'-bicollidine, synthesized from inexpensive reagents, resolved into antipodes without need of chiral HPLC and converted into long-chain dialkyl salts with melting points below room temperature. Both the new ICILs and shorter family terms, solid at room temperature, employed as low-concentration additives in achiral ILs, afford impressive enantioselection for the enantiomers of different probes on achiral electrodes, regularly increasing with additive concentration.

Determination of the Enantiomerization Barrier of the Residual Enantiomers of C3 -Symmetric Tris[3-(1-Methyl-2-Alkyl)Indolyl]Phosphane Oxides: Case Study of a Multitasking HPLC Investigation Based on an Immobilized Polysaccharide Stationary Phase.

The residual enantiomers of three tris-(3-indolyl)-phosphane oxides bearing different alkyl groups (methyl, ethyl or i-propyl) in position 2 of the indole rings constituting the blades were separated on the immobilized type Chiralpak IC column in polar organic and reversed-phase modes. The good enantioselectivity and versatility of the IC CSP allowed easy isolation of the enantiomerically highly enriched samples suitable for configurational stability studies. The enantiomerization barriers of residual phosphane oxides were evaluated both by off-column techniques (CD signal and enantiomeric purity decay kinetics) and by dynamic enantioselective high-performance liquid chromatography (HPLC).

Inherently chiral macrocyclic oligothiophenes: easily accessible electrosensitive cavities with outstanding enantioselection performances.

Linear conjugated oligothiophenes of variable length and different substitution pattern are ubiquitous in technologically advanced optoelectronic devices, though limitations in application derive from insolubility, scarce processability and chain-end effects. This study describes an easy access to chiral cyclic oligothiophenes constituted by 12 and 18 fully conjugated thiophene units. Chemical oxidation of an "inherently chiral" sexithiophene monomer, synthesized in two steps from commercially available materials, induces the formation of an elliptical dimer and a triangular trimer endowed with electrosensitive cavities of different tunable sizes. Combination of chirality with electroactivity makes these molecules unique in the current oligothiophenes literature. These macrocycles, which are stable and soluble in most organic solvents, show outstanding chiroptical properties, high circularly polarized luminescence effects and an exceptional enantiorecognition ability.

Influence of the nature of alkyl substituents on the high-performance liquid chromatography enantioseparation and retention of new atropisomeric 1,1'-bibenzimidazole derivatives on amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase.

Six new atropisomeric heteroarenes were synthesized by connecting two 2-alkylbenzimidazole fragments via N-N junction. They differ by the substituent nature (methyl, ethyl, propyl, butyl, pentyl and hexyl) of the aliphatic function. The novel atropisomeric compounds were used as chiral probes to study the chromatographic behavior of the amylose tris(3,5-dimethylphenyl carbamate) (Chiralpak AD-3) chiral stationary phase (CSP) under normal phase mode. The pivotal role of the length and flexibility of the 2,2'-alkyl groups on retention, enantioselectivity and enantiomer elution order was demonstrated by enantioselective HPLC analysis. Additional information on the chiral recognition mechanism was obtained from the evaluation of the correlated thermodynamic data.

Chirality in the absence of rigid stereogenic elements: steric and electronic effects on the configurational stability of C3 symmetric residual tris-aryl phosphanes.

Residual stereoisomers result whenever closed subsets of appropriately substituted interconverting isomers (the residual stereoisomers) are generated from a full set of stereoisomers under the operation of a favored stereomerization mechanism. In the case of the three-bladed propellers, differentiation of the edges of the blades and strict correlation in the motion of the rings are the prerequisites for the existence of residual stereoisomers. In these systems, the two-ring flip mechanism is the lowest energy process. It does not interconvert all possible conformational stereoisomers generated by helicity and the three-blade-hub rotors. In the case of C3 symmetric systems, two noninterconverting subgroups (the residual stereoisomers) are generated, each one constituted of quickly interconverting diastereoisomers. A series of tris-aryl phosphanes, structurally designed for existing as residual enantiomers or diastereoisomers, bearing substituents differing in size and electronic properties on the aryl rings, were synthesized and characterized. The configurational stability of residual phosphanes, evaluated by dynamic (1) H- and (31) P-NMR analysis and by dynamic enantioselective high-performance liquid chromatography (HPLC), was found 10 kcal mol(-1) lower than that shown by the corresponding phosphane-oxides. In accordance with the calculations, an unexpectedly low barrier for phosphorus pyramidal inversion was invoked as responsible for the scarce configurational stability of the residual tris-arylphosphanes.

Potential-driven chirality manifestations and impressive enantioselectivity by inherently chiral electroactive organic films.

The typical design of chiral electroactive materials involves attaching chiral pendants to an electroactive polyconjugated backbone and generally results in modest chirality manifestations. Discussed herein are electroactive chiral poly-heterocycles, where chirality is not external to the electroactive backbone but inherent to it, and results from a torsion generated by the periodic presence of atropisomeric, conjugatively active biheteroaromatic scaffolds, (3,3'-bithianaphthene). As the stereogenic element coincides with the electroactive one, films of impressive chiroptical activity and outstanding enantiodiscrimination properties are obtained. Moreover, chirality manifestations can be finely and reversibly tuned by the electric potential, as progressive injection of holes forces the two thianaphthene rings to co-planarize to favor delocalization. Such deformations, revealed by CD spectroelectrochemistry, are elastic and reversible, thus suggesting a breathing system.

Steric and electronic effects on the configurational stability of residual chiral phosphorus-centered three-bladed propellers: tris-aryl phosphane oxides.

A series of tris-aryl phosphane oxides existing as residual enantiomers or diastereoisomers with substituents on the aryl rings differing in size and electronic properties were synthesized and characterized. Their electronic properties were evaluated on the basis of their electrochemical oxidation and reduction potentials together with those of the corresponding "blade bromides" (i.e., the naphthalene derivatives displaying the same substitution pattern of the tris-naphthyl phosphane oxide blades, with a bromo substituent where the phosphorus atom is located) determined by CV. The residual stereoisomeric phosphane oxides were isolated in a stereochemically pure state and were found to be highly configurationally stable at room temperature (stereoisomerization barriers of about 27 kcal mol(-1)). The chiroptical properties of the residual stereoisomers and the assignments of absolute configuration are discussed. The configurational stability of residual tris-aryl phosphane oxides was found to be scarcely influenced by the electronic properties of the substituents present on the aromatic rings constituting the blades, while steric effects play the most relevant role. Detailed theoretical calculations are in agreement with the experimental results and also contribute to a rational interpretation of the stereodynamics of these systems.

Steric and electronic effects on the configurational stability of residual chiral phosphorus-centered three-bladed propellers: tris-aryl phosphanes.

A series of tris-aryl phosphanes, structurally designed to exist as residual enantiomers or diastereoisomers, bearing substituents differing in size and electronic properties on the aryl rings, were synthesized and characterized. Their electronic properties were evaluated on the basis of their electrochemical oxidation potential determined by voltammetry. The configurational stability of residual phosphanes, evaluated by dynamic HPLC on a chiral stationary phase or/and by dynamic (1)H and (31)P NMR spectroscopy, was found to be rather modest (barriers of about 18-20 kcal mol(-1)), much lower than that shown by the corresponding phosphane oxides (barriers of about 25-29 kcal mol(-1)). For the first time, the residual antipodes of a tris-aryl phosphane were isolated in enantiopure state and the absolute configuration assigned to them by single-crystal anomalous X-ray diffraction analysis. In this case, the racemization barrier could be calculated also by CD signal decay kinetics. A detailed computational investigation was carried out to clarify the helix reversal mechanism. Calculations indicated that the low configurational stability of tris-aryl phosphanes can be attributed to an unexpectedly easy phosphorus pyramidal inversion which, depending upon the substituents present on the blades, can occur even on the most stable of the four conformers constituting a single residual stereoisomer.

Towards molecular design rationalization in branched multi-thiophene semiconductors: the 2-thienyl-persubstituted alpha-oligothiophenes.

The introduction of branching in multi-thiophene semiconductors, although granting the required solubility for processing, results in an increased molecular fluxionality and a higher level of distortion, thus hampering pi conjugation. Accordingly, branched oligothiophenes require rationalization of their structure-reactivity relationships for target-oriented design and optimization of the synthetic effort. Our current research on spiderlike oligothiophenes affords deep insight into the subject, and introduces new, easily accessible molecules with attractive functional properties. In particular, a regular series, T'X(Y), of five new multi-thiophene systems, T'5(3), T'8(4), T'11(5), T'14(6), and T'17(7), constituted by five, eight, 11, 14, and 17 thiophene units, respectively, their longest alpha-conjugated chain consisting of tri-, tetra-, penta-, hexa-, and heptathiophene moieties, respectively, has been synthesized and fully characterized from the structural, spectroscopic, and electrochemical point of view. The electronic properties of the monomers and their electropolymerization ability are discussed and rationalized as a function of their molecular structure, particularly in comparison with the series of 5-(2,2'-dithiophene)yl-persubstituted alpha-oligothiophenes (TX(Y)) previously reported by us. These oligothiophenes are easily accessible materials, with promising properties for applications as active layers in multifunctional organic devices including solar cells.

Chirality in the absence of rigid stereogenic elements: the absolute configuration of residual enantiomers of C3-symmetric propellers.

Two new tris(aryl)phosphane oxides existing as configurationally stable residual enantiomers have been synthesised and their racemates resolved by semipreparative HPLC on a chiral stationary phase (CSP HPLC). One of them, recognised as a conglomerate, could be resolved by fractional crystallisation at a preparative scale level. In this case, the absolute configuration of the propeller-shaped molecule was determined by anomalous X-ray scattering. The problem of the correlative assignment of the absolute configuration to all known C(3)-symmetric three-bladed propeller-shaped molecules existing as stable residual enantiomers is discussed. The configurational stability of the new chiral phosphane oxides and of the corresponding phosphanes was evaluated by CD signal decay kinetics and dynamic (1)H NMR spectroscopy. The racemisation barriers in phosphanes were found about 10 kcal mol(-1) lower than those found for the corresponding oxides, though geometry and inter-ring gearing would be very similar in the two series. Configurational stability of residual tris(aryl)phosphanes was found to be influenced by the electronic availability of the phosphorus centre, as evaluated by electrochemical CV experiments.

Chirality in the absence of rigid stereogenic elements: the design of configurationally stable C3-symmetric propellers.

Residual stereoisomerism is a form of stereoisomerism scarcely considered so far for applicative purposes, though extremely interesting, since the production of stereoisomers does not involve classical rigid stereogenic elements. In three-bladed propeller-shaped molecules, a preferred stereomerization mechanism, related to the correlated rotation of the rings, allows the free interconversion of stereoisomers inside separated sets (the residual stereoisomers) that can interconvert through higher energy pathways. In light of possible future applications as chiral ligands for transition metals in stereoselective processes, some C(3)-symmetric phosphorus-centered propellers, which could exist as residual enantiomers, are synthesized and the possibility of resolving their racemates into residual antipodes is explored. While the tris(aryl)methanes are configurationally stable at room temperature, only selected tris(aryl)phosphane oxides display a configurational stability high enough to allow resolution by HPLC on a chiral stationary phase (CSP HPLC) at a semipreparative level at room temperature. Stability was evaluated through different techniques (circular dichroism (CD) signal decay, dynamic CSP HPLC (CSP DHPLC), dynamic NMR analysis (DNMR)) and the results compared and discussed. Phosphanes were found much less stable than the corresponding phosphane oxides, for which preliminary calculations suggest that the three-ring-flip enantiomerization mechanism (M(0)) would be easier than phosphorus pyramidal inversion. The parameters affecting the configurational stability of the residual enantiomers of C(3)-symmetric propellers are discussed.

Steric and electronic tuning of chiral bis(oxazoline) ligands with 3,3'-bithiophene backbone.

[structure: see text] The role played by the electronic properties and the steric features of bis(oxazoline) ligands in the Cu(I)-catalyzed cyclopropanation of styrene effected with ethyl diazoacetate was investigated. Two pairs of new bis(oxazolines) displaying flexible and atropisomeric 3,3'-bithiophene backbones were synthesized and structurally and electronically characterized. For the first time, the electrochemical oxidative potential was used as a reliable index of the electronic density on the nitrogen atom of the chelating groups of new and, for comparative purposes, of already known bis(oxazolines). The Cu(I) complexes of the new ligands were prepared, and their enantioselection ability and catalytic efficiency were tested. This investigation suggests that steric factors and catalyst geometrical features are clearly more important than any consideration of the electronic properties of the chiral ligands.

2,5-Dimethyl-3,4-bis[(2R,5R)-2,5-dimethylphospholano]thiophene: first member of the hetero-DuPHOS family.

[reaction: see text] The 2,5-dimethyl-3,4-bis[(2R,5R)-2,5-dimethylphospholano]thiophene (UlluPHOS), a new thiophene-based analogue of (R,R)-1,2-bis(phospholano)benzene (Me-DuPHOS), was synthesized, geometrically and electronically characterized, and employed as ligand of Rh and Ru in some standard hydrogenation reactions of prostereogenic functionalized carbon-carbon and carbon-oxygen double bonds. The synthesis of UlluPHOS is much easier than that provided for Me-DuPHOS. UlluPHOS and Me-DuPHOS display very similar geometries, while the electronic availability of the former is higher than that exhibited by the latter. The Rh and Ru complexes of UlluPHOS produced excellent enantiomeric excesses (98.9-99.5%) in the hydrogenation of N-acetyl-alpha-enamino acids and reaction rates higher than those found when employing the analogous complexes of Me-DuPHOS.