Christian Roussel

Systematic evaluation of new chiral stationary phases for supercritical fluid chromatography using a standard racemate library.

A systematic approach to the evaluation of new chiral stationary phases (CSPs) for supercritical fluid chromatography (SFC) using a standard library of racemic analytes is described. A standard library of racemic analytes representing a variety of functional group classes was assembled from a mixture of proprietary and commercial compounds. The library is dispensed and stored in a convenient 96-well microplate format to facilitate ease of use, and to minimize the amount of analyte required for analysis. Automated SFC screening was performed on both established CSPs in common use, as well as a group of six recently commercialized CSPs. Screening results were archived in a structure-searchable database that allows convenient comparison of performance data to determine which CSPs shows the best performance.

Cationic β-cyclodextrin: a new versatile chiral additive for separation of drug enantiomers by high-performance liquid chromatography

Abstract The chromatographic separations of the enantiomers of a series of eight phenylhydantoin and methylhydantoin derivatives of amino acids are described, using reversed-phase HPLC with a chiral additive in the mobile phase: native β-cycodextrin (β-CD), carboxymethylated β-CD and a cationic β-CD derivative. Retentions time and selectivities obtained with these three chiral additives are compared. As the cationic β-CD gave promising results, its usefulness in the resolution of several drugs of particular interest (chlorthalidone, terbutaline, mephobarbital and hexobarbital) is demonstrated.

The Quantitative Analysis of Steric Effects in Heteroaromatics

Publisher Summary This chapter describes the quantitative analysis of steric effects in heteroaromatics. This chapter illustrates that, important progress in the quantitative analysis of steric effects in heteroaromatics has been made recently by linear free energy relationships (LFER), geometrical, and theoretical methods. Heterocycles have been used to propose and exemplify new concepts and new parameters in physical organic chemistry. This chapter is concerned with the importance of steric effects in rationalizing the reactivity and dynamic stereochemistry of heteroaromatics and with recent attempts to bridge the gap between them. There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. Heteroaromatics have features in common with aromatic hydrocarbons. However, the variety of geometrical situations, the number of heteroatoms and their associated reactivity, and the ease of monitoring stereochemistry often associated with the presence of heteroatoms all have made, and continues to make, heterocycles exceptional probes for better understanding of reactivity, structures, and the relations between them.

Example of the concentration dependence of elution order in the resolution of enantiomers on microcrystalline triacetylcellulose chiral stationary phase

Abstract The resolution of 3-(2-propylphenyl)-4-methyl-4-thiazolin-2-one atropisomers by liquid chromatography on microcrystalline triacetylcellulose shows an unprecedented inversion of the capacity factors with increasing amount of sample injected. The two enantiomers behave independently on the chiral stationary phase. The occurrence of such different isotherms for the two enantiomers is related to the presence of a propyl group and provides experimental proof of the intervention of different sites for chiral recognition in the supramolecular structure of microcrystalline triacetylcellulose.

Enantioselective correlation between retention factor and lipophilicity index in chiral separation on cellulose and amylose tris(3,5-dimethylphenylcarbamate) CSPs in reversed mode: A case study.

For a series of alkyl substituted N-arylthiazoline-2-(thi)one atropisomers 1-14, lipophilicity indexes log kw obtained by polycratic RP-HPLC were compared to ln k(+)-S and ln k(-)-R obtained on CHIRALCEL OD-R(R) (reversed mode) and CHIRALPAK AD-RH(R) (reversed mode). Linear correlations were obtained in most cases. It appears that the correlation lines for R and S enantiomers may be parallel, convergent, or divergent, accounting for the observed alpha variation in going from methyl to tert-butyl series. Some tentative hypothesis are given as future investigation routes. Copyright 2000 Wiley-Liss, Inc.

Part III: Supercritical Fluid Chromatographic Separations

The enantioseparation of 123 clinically used racemic drugs by supercritical fluid chromatography (SFC) on commercial chiral stationary phases (CSPs) available in 2006 is reviewed. The CSPs were briefly described in Part I of this work. The mobile phase compositions, with organic modifier and additives, are listed. The data was extracted and compiled from the ChirBase database (Marseille, France). All the drugs included are listed according to the thirteen therapeutic classes of the Anatomical Therapeutic Chemical (ATC) classification. It is evident that the nature of the SF mobile phase precludes the use of several classes of CSPs such as the crown ethers, ligand‐exchange or protein‐based CSPs. The polysaccharide based CSPs were responsible for two third of the enantiomer separation listed.

New route to 3-alkylthiazolo[3,2-a]benzimidazole derivatives.

3-Alkyl-thiazolo[3,2-a]benzimidazole derivatives are obtained in high yields via the corresponding 4-alkyl-N-3-(2-aminophenyl)-thiazoline-2-thiones which are easily prepared from 1,2-diaminobenzene, CS2 and halogenoketones. This new route compares advantageously with the classical mercaptobenzimidazole routes in term of simplicity, isolated yields and availability of the starting materials.

Atropisomerization in N-aryl-2(1H)-pyrimidin-(thi)ones: A Ring-Opening/Rotation/Ring-Closure Process in Place of a Classical Rotation around the Pivot Bond

Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less distorted transition states account for the experimental barrier to atropenantiomerization. In 1988, one of us hypothesized that, in N-aryl-2(1H)-pyrimidin-(thi)ones, a ring-opening/ring-closure process was contributing to the observed racemization process accounting for the lower barriers in the sulfur analogues than in oxygen analogues. Now, a series of six novel 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 5a-5f and two 6-amino-5-cyano-4-p-tolyl-1-substituted-2(1H)-pyrimidinethiones 6a and 6b were synthesized and characterized through spectroscopic and X-ray diffraction studies. Semipreparative HPLC chiral separation was achieved, and enantiomerization barriers were obtained by thermal racemization. The rotational barriers of 6-amino-5-cyano-1-o-tolyl-4-p-tolyl-2(1H)-pyrimidinone (5b) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-p-tolyl-2(1H)-pyrimidinone (5e) were found to be 120.4 and 125.1 kJ·mol(-1) (n-BuOH, 117 °C), respectively, and those of the corresponding thiones were 116.8 and 109.6 kJ·mol(-1) (EtOH, 78 °C), respectively. DFT calculations of the rotational barriers clearly ruled out the classical rotation around the pivotal bond with distorted transition states in the case of the sulfur derivatives. Instead, the ranking of the experimental barriers (sulfur versus oxygen, and o-tolyl versus 1-naphthyl in both series) was nicely reproduced by calculations when the rotation occurred via a ring-opened form in N-aryl-2(1H)-pyrimidinethiones.

Use of steric effects in determining the position of the transition state for the SN2 reaction between methyl iodide and Δ4-thiazoline-2-thiones

The quantitative nucleophilic reactivity of some 3-alkyl-Δ4-thiazoline-2-thiones (1) towards methyl iodide is described. Bulky alkyl groups increase the rate of S-alkylation and this unexpected behaviour is explained by strain release in the transition state. It is shown that the rate acceleration is closely related to the conformational state of the 3-alkyl group. Using steric effects to examine the transition state, we have shown that it is, in regard to the heterocyclic ring, 65% along the reaction co-ordinate from the initial state.

Synthesis, chiral separation, and absolute configuration of bis-(N-aryl) atropisomeric triads: 1,2-bis-[4-methyl-2-(thi)oxo-2,3-dihydrothiazol-3-yl]-benzene.

In this work, a series of 1,2-bis-[4-methyl-2-(thi)oxo-2,3-dihydrothiazol-3-yl]-benzene has been prepared. These atropisomeric molecular triads were exclusively found to exist in the anti-form. They were separated into enantiomers by liquid chromatography on a chiral support. The absolute configurations of the enantiomers were determined using a chemical correlation method together with chiral chromatography. The barriers to interconversion of the enantiomers were determined.