Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines
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<sup>®</sup> IB<sup>®</sup> column cont...
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doaj-35ebf727cabf4c338062ba69c68d1d892020-11-25T02:05:53ZengMDPI AGMolecules1420-30492020-02-0125364010.3390/molecules25030640molecules25030640Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral ImidazolinesBruno Cerra0Antonio Macchiarulo1Andrea Carotti2Emidio Camaioni3Ina Varfaj4Roccaldo Sardella5Antimo Gioiello6Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, ItalyIn 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<sup>®</sup> IB<sup>®</sup> 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 R<sub>S</sub> 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 k<sub>1st</sub> = −0.93; r - log k<sub>2nd</sub> = −0.94) were obtained with a water solubility descriptor (Ali-logS). Interestingly, a <i>n</i>-hexane/chloroform/ethanol (88:10:2, <i>v</i>/<i>v</i>/<i>v</i>)-based non-standard mobile phase allowed the almost base-line enantioseparation (α = 1.06; R<sub>S</sub> = 1.26) of the unique compound undiscriminated under RP conditions.https://www.mdpi.com/1420-3049/25/3/640cellulose-based chiral stationary phasechiral imidazolinesenantiorecognition mechanismhit-to-lead chemical explorationreversed-phase conditions |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bruno Cerra Antonio Macchiarulo Andrea Carotti Emidio Camaioni Ina Varfaj Roccaldo Sardella Antimo Gioiello |
spellingShingle |
Bruno Cerra Antonio Macchiarulo Andrea Carotti Emidio Camaioni Ina Varfaj Roccaldo Sardella Antimo Gioiello Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines Molecules cellulose-based chiral stationary phase chiral imidazolines enantiorecognition mechanism hit-to-lead chemical exploration reversed-phase conditions |
author_facet |
Bruno Cerra Antonio Macchiarulo Andrea Carotti Emidio Camaioni Ina Varfaj Roccaldo Sardella Antimo Gioiello |
author_sort |
Bruno Cerra |
title |
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines |
title_short |
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines |
title_full |
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines |
title_fullStr |
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines |
title_full_unstemmed |
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines |
title_sort |
enantioselective hplc analysis to assist the chemical exploration of chiral imidazolines |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2020-02-01 |
description |
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<sup>®</sup> IB<sup>®</sup> 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 R<sub>S</sub> 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 k<sub>1st</sub> = −0.93; r - log k<sub>2nd</sub> = −0.94) were obtained with a water solubility descriptor (Ali-logS). Interestingly, a <i>n</i>-hexane/chloroform/ethanol (88:10:2, <i>v</i>/<i>v</i>/<i>v</i>)-based non-standard mobile phase allowed the almost base-line enantioseparation (α = 1.06; R<sub>S</sub> = 1.26) of the unique compound undiscriminated under RP conditions. |
topic |
cellulose-based chiral stationary phase chiral imidazolines enantiorecognition mechanism hit-to-lead chemical exploration reversed-phase conditions |
url |
https://www.mdpi.com/1420-3049/25/3/640 |
work_keys_str_mv |
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