Effects of mobile phase composition and temperature on the supercritical fluid chromatography enantioseparation of chiral fluoro-oxoindole-type compounds with chlorinated polysaccharide stationary phases.

The indole ring is present in many pharmaceutically active compounds, as in MaxiPost™ (or BMS-204352), an active pharmaceutical ingredient for post-stroke neuroprotection. Two different fluoro-oxindole-type chiral solutes derived from MaxiPost were prepared. The structural modification was placed on the NH indole function, which is probably taking part in the bioactivity, but also probably in the chromatographic enantiomer separation. Baseline resolution of the enantiomers of MaxiPost and the two derivatives was achieved on two commercial chlorinated polysaccharide stationary phases: cellulose tris-(3-chloro-4-methylphenylcarbamate) and amylose tris-(5-chloro-2-methylphenylcarbamate) (Lux Cellulose-2 and Lux-Amylose-2 from Phenomenex) in supercritical fluid chromatography (SFC). The effects of molecular structure on SFC retention and enantioresolution are studied. The effect of temperature, modifier nature (methanol or ethanol) and proportion were investigated in order to select the best conditions for preparative purposes. A temperature study led to Van't Hoff plots that were strongly dependent on the mobile phase composition. From linear portions of the plots for separation, thermodynamic parameters of the separation could be calculated. Incidentally, particular adsorption-desorption effects were observed. Semi-preparative resolution was then achieved, allowing retrieving about 10mg purified enantiomers for bioactivity testing.

Chiral separation of phosphine-containing alpha-amino acid derivatives using two complementary cellulosic stationary phases in supercritical fluid chromatography.

Enantiomeric separations of six amino-acid derivatives have been studied using packed-column supercritical fluid chromatography with two polysaccharide-based enantioselective stationary phases: cellulose tris(3,5-dimethylphenylcarbamate) and cellulose tris(3-chloro-4-methylphenylcarbamate) (Lux Cellulose-1 and -2). The effect of analyte structure on retention and separation was studied. Varied mobile phase compositions were investigated: alcohol modifier percentage was increased from 3 to 40% but smaller amounts were most effective in separating these compounds. Besides, ethanol was preferred to methanol or isopropanol as it proved to be a good compromise to achieve sufficient resolution in a reasonable analysis time. Moreover, a carbon dioxide-ethanol mixture allows performing analyses in safe and green conditions. The effect of temperature at constant mobile phase composition was explored between 10 and 40 degrees C. In most cases, increasing the temperature improved the chiral separation, up to an optimum temperature. The results are discussed in line with the structure variation of the racemic derivatives analyzed and the two columns are compared. The two columns were shown to provide complementary selectivities for the investigated solutes: whereas Lux 1 provided separation for five of the six racemates, Lux 2 could resolve the last racemic mixture. Finally, optimized conditions of separation are defined.

Self-adaptable catalysts: substrate-dependent ligand configuration.

Pd(II) allyl and Pd(0) olefin complexes containing the configurationally labile ligand 1,2-bis-[4,5-dihydro-3H-dibenzo[c-e]azepino]ethane were studied as models for intermediates in Pd-catalyzed allylic alkylations. According to NMR and DFT studies, the ligand prefers C(s) conformation in both eta3-1,3-diphenylpropenyl and eta3-cyclohexenyl Pd(II) complexes, whereas in Pd(0) olefin complexes it adopts different conformations in complexes derived from the two types of allyl systems in both solution and, as verified by X-ray crystallography, in the solid state. These results demonstrate that the Pd complex is capable of adapting its structure to the reacting substrate. The different structural preferences also provide an explanation for the behavior of 1,3-diphenyl-2-propenyl acetate and 2-cyclohexenyl acetate in Pd-catalyzed allylic alkylations using pseudo-C2 and pseudo-C(s) symmetric ligands.

Preparation of new axially chiral bridged 2,2'-bipyridines and pyridyl monooxazolines (pymox). Evaluation in copper(I)-catalyzed enantioselective cyclopropanation.

This work reports the synthesis of new axially chiral bridged 2,2'-bipyridines 1 and pyridylmonooxazolines (pymox) 2. The potential of these new axially chiral N,N-ligands was evaluated in asymmetric catalytic cyclopropanation of styrene derivatives 22a-c with diazoesters 21a,b. While 2,2'-bipyridines 1a-c afforded the corresponding cyclopropanes 23a-f in up to 65% ee, pymoxs 2a-e gave somewhat lower enantioselectivities (up to 53% ee). Both classes of ligands produced trans-cyclopropanes 23a-f as the major isomer, although with modest diasteroselectivities (56 : 44 to 78 : 22). A structure-stereoselectivity relationship study of ligands 1 and 2 identified the chiral biaryl axis as being mostly responsible for the enantioselective performances of these ligands.

Amine capture strategy for peptide bond formation by means of quinolinium thioester salts.

A new and unprecedented exploitation of quinolinium thioester salts 2 in peptide bond formation is reported. These synthetic tools were assessed during the preparation of a number of dipeptides 3a-f obtained in good yields with complete stereochemical integrity. A sequential mechanism related to a prior amine capture strategy is well-established. Additionally, a tripeptide 3g was prepared according to a "safety-catch" approach, thus demonstrating the important potential of these new synthetic tools in the design of new safety-catch linkers exploitable in Solid-Phase Peptide Synthesis (SPPS).