Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines

Abstract

In the present work, we illustrate the ability of high-performance liquid chromatography (HPLC) analysis to assist the synthesis of chiral imidazolines within our medicinal chemistry programs. In particular, a Chiralpak® IB® column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 μm silica gel was used for the enantioselective HPLC analysis of chiral imidazolines synthesized in the frame of hit-to-lead explorations and designed for exploring the effect of diverse amide substitutions. Very profitably, reversed-phase (RP) conditions succeeded in resolving the enantiomers in nine out of the 10 investigated enantiomeric pairs, with α values always higher than 1.10 and RS values up to 2.31. All compounds were analysed with 50% (v) water while varying the content of the two organic modifiers acetonitrile and methanol. All the employed eluent systems were buffered with 40 mM ammonium acetate while the apparent pH was fixed at 7.5. Based on the experimental results, the prominent role of π-π stacking interactions between the substituted electron-rich phenyl groups outside of the polymeric selector and the complementary aromatic region in defining analyte retention and stereodiscrimination was identified. The importance of compound polarity in explaining the retention behaviour with the employed RP system was readily evident when a quantitative structure-property relationship study was performed on the retention factor values (k) of the 10 compounds, as computed with a 30% (v) methanol containing mobile phase. Indeed, good Pearson correlation coefficients of retention factors (r - log k1st = −0.93; r - log k2nd = −0.94) were obtained with a water solubility descriptor (Ali-logS). Interestingly, a n-hexane/chloroform/ethanol (88:10:2, v/v/v)-based non-standard mobile phase allowed the almost base-line enantioseparation (α = 1.06; RS = 1.26) of the unique compound undiscriminated under RP conditions.

Synthesis, enantioseparation, and absolute configuration assignment of iminoflavans by chiral high‐performance liquid chromatography combined with online chiroptical detection

“…For iminoflavans 2 and 5, the elution order between the iminoflavan enantiomers was inverted, namely (R)-configuration for the first-eluting enantiomer. The inversion of elution order of enantiomers of 3 and 4 on Chiralcel R OD-H column must be attributed to the influence of the different aromatic substituents at the nitrogen, as it has been observed previously in other similar instances [32].…”

Polysaccharide- and β-Cyclodextrin-Based Chiral Selectors for Enantiomer Resolution: Recent Developments and Applications

“…Polysaccharide derivatives as CSPs efficiently supported the synthesis and isolation of new chemicals in terms of ES, thus shortening the timelines of chiral drug discovery and development, as suggested by Cerra et al [ 33 ]. A commercial chiral column, Chiralpak ® IB (250 × 4.6 mm, i.d., 5 µM silica gel, Table 1 ), was used to assist the isolation of chiral imidazolines ( Supplementary Materials Figure S9 ) by HPLC.…”