Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines
Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines
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DOI：
10.3390/molecules25030640
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发表时间：
2020-02-01
期刊：
影响因子：
4.6
通讯作者：
Gioiello, Antimo
中科院分区：
文献类型：
--
作者：
Cerra, Bruno;Macchiarulo, Antonio;Gioiello, Antimo
在目前的工作中，我们说明了高效液相分析在我们的药物化学项目中辅助合成手性咪唑类化合物的能力。特别地，Chiralpak((R))IB(R)色谱柱含有固定在5微米硅胶上的纤维素三(3，5-二甲基苯基氨基甲酸酯)，用于在Hit-to-Lead探索框架内合成的手性咪唑类化合物的对映选择性高效液相色谱分析，旨在探索不同的酰胺取代的影响。非常有利的是，反相(RP)条件成功地拆分了10个对映体中的9个对映体，α值始终高于1.10，R-S值高达2.31。所有化合物在50%(V)水中分析，同时改变两种有机改性剂乙腈和甲醇的含量。所有使用的洗脱系统都用40 mM醋酸铵缓冲，而表观pH固定在7.5。根据实验结果，确定了聚合物选择器外取代的富电子苯基和互补芳香区之间的pi-pi堆积作用在定义分析物保留和立体区分方面的显著作用。当对10种化合物的保留因子值(K)进行定量结构-性质关系研究时，化合物的极性在解释所采用的RP系统的保留行为中的重要性是显而易见的，这10种化合物的保留因数值(K)是用30%(V)含甲醇的流动相计算的。事实上，保留因子的皮尔逊相关系数(r-logk(1)=-0.93；r-logk(2)=-0.94)是通过水溶性描述符(ALI-LOGS)获得的。有趣的是，基于正己烷/氯仿/乙醇(88：10：2，v/v/v)的非标准流动相允许在RP条件下对唯一化合物进行几乎基线的对映体分离(α=1.06；R-S=1.26)。
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((R)) IB (R) column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 mu m 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 alpha values always higher than 1.10 and R-S 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 pi-pi 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(1st) = -0.93; r - log k(2nd) = -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 (alpha = 1.06; R-S = 1.26) of the unique compound undiscriminated under RP conditions.