Advantages of electronic circular dichroism detection for the stereochemical analysis and characterization of drugs and natural products by liquid chromatography

Bertucci, Carlo; Tedesco, Daniele

doi:10.1016/j.chroma.2012.09.046

Cited by 30 publications

(22 citation statements)

References 150 publications

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“…Often the only possibility is to study isolated enantiomers deeply by means of independent methods, i.e. X‐ray diffraction, NMR, optical rotation and circular dichroism measurement and their combinations . These methods are commonly used in combination with liquid phase separation .…”

Section: Resultsmentioning

confidence: 99%

Analytical and semipreparative chiral separation ofcis-itraconazole on cellulose stationary phases by high-performance liquid chromatography

2016

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cis-Itraconazole is a chiral antifungal drug administered as a racemate. The knowledge of properties of individual cis-itraconazole stereoisomers is vital information for medicine and biosciences as different stereoisomers of cis-itraconazole may possess different affinity to certain biological pathways in the human body. For this purpose, either chiral synthesis of enantiomers or chiral separation of racemate can be used. This paper presents a two-step high-performance liquid chromatography approach for the semipreparative isolation of four stereoisomers (two enantiomeric pairs) of itraconazole using polysaccharide stationary phases and volatile organic mobile phases without additives in isocratic mode. The approach used involves the separation of the racemate into three fractions (i.e. two pure stereoisomers and one mixed fraction containing the remaining two stereoisomers) in the first run and consequent separation of the collected mixed fraction in the second one. For this purpose, combination of cellulose tris-(4-methylbenzoate) and cellulose tris-(3,5-dimehylphenylcarbamate) columns with complementary selectivity for cis-itraconazole provided full separation of all four stereoisomers (with purity of each isomer > 97%). The stereoisomers were collected, their optical rotation determined and their identity confirmed based on the results of a previously published study. Pure separated stereoisomers are subjected to further biological studies.

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Section: Resultsmentioning

confidence: 99%

Analytical and semipreparative chiral separation ofcis-itraconazole on cellulose stationary phases by high-performance liquid chromatography

2016

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“…The other is to measure the enantiomeric excess (ee) with a circular dichroism (CD) detector . The combination of achiral high‐performance liquid chromatography (HPLC) separation and CD detection has shown advantages in chiral analysis . For instance, an achiral HPLC‐CD system can be used for ee measurements without chiral separation and thus shortens the time required for analysis.…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11] The combination of achiral high-performance liquid chromatography (HPLC) separation and CD detection has shown advantages in chiral analysis. 12 For instance, an achiral HPLC-CD system can be used for ee measurements without chiral separation and thus shortens the time required for analysis. Additionally, an HPLC-CD system makes it possible to simultaneously determine the ee values for many chiral compounds in a complex sample.…”

Section: Introductionmentioning

confidence: 99%

Deviations from Beer's law in electronic absorption and circular dichroism: Detection for enantiomeric excess analysis

et al. 2019

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The electronic absorption (UV) to circular dichroism (CD) signal ratio can be used for enantiomeric excess (ee) analysis within linear range. However, CD detection often requires a high sample concentration where deviations from Beer's law may occur. Individual enantiomers of four chiral compounds were separated from commercial racemates by semipreparative high‐performance liquid chromatography (HPLC) with chiral columns. They were used to trace possible deviations in both UV and CD detection on achiral HPLC with a photodiode array detector and a CD detector. The CD/UV ratios for samples with the same ee value decreased by up to 7.8 to 52% when the injection volume increased, indicating that the linear standard curve of ee versus CD/UV is only valid within a narrow range. To extend the sample amount to a wider range, a data‐processing method was developed based on two second‐order polynomial functions, which were constructed to fit the relationship between the intensities of the UV and CD signals for two enantiomers. Moreover, a more simplified method based on a third‐order polynomial function was established to calculate the ee values. The variations between the predicted and experimental ee values were within ±0.08 for both methods. To our knowledge, this is the first study that the deviations from Beer's law are considered in both UV and CD detection for ee analysis.

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“…If a chiral compound is not obtained as a pure enantiomer through synthesis, as in the case of trans ‐ 3 , separation techniques such as enantioselective high‐performance liquid chromatography (HPLC) can be employed in combination with chiroptical spectroscopies, such as electronic circular dichroism (ECD), in order to assign the correct absolute configuration to its enantiomers. Two possible strategies can be used for this purpose: 1) isolation of the enantiomers by preparative enantioselective HPLC followed by offline ECD spectroscopic analysis on the purified enantiomeric fractions; 2) hyphenation of HPLC with an ECD detection system (labeled HPLC‐CD to avoid confusion with electrochemical detection) and online determination of the ECD spectra of enantiomers during the enantioselective HPLC separation by means of stopped‐flow measurements . The preparative HPLC approach is useful beyond the purposes of stereochemical characterization, allowing the preparation of highly pure enantiomeric samples in the absence of enantioselective synthetic procedures .…”

mentioning

confidence: 99%

“…Two possible strategies can be used for this purpose: 1) isolation of the enantiomers by preparative enantioselective HPLC followed by offline ECD spectroscopic analysis on the purified enantiomeric fractions; 2) hyphenation of HPLC with an ECD detection system (labeled HPLC-CD to avoid confusion with electrochemical detection) and online determination of the ECD spectra of enantiomers during the enantioselective HPLC separation by means of stopped-flow measurements. 12,13 The preparative HPLC approach is useful beyond the purposes of stereochemical characterization, allowing the preparation of highly pure enantiomeric samples in the absence of enantioselective synthetic procedures. 14 The HPLC-CD approach, on the other hand, provides a valuable analytical tool to avoid the time-consuming collection of pure enantiomers; moreover, the risk of contamination and degradation of collected samples, arising by the necessary step of solvent evaporation, is completely avoided.…”

mentioning

confidence: 99%

Stopped‐Flow Enantioselective HPLC‐CD Analysis and TD‐DFT Stereochemical Characterization of Methyl Trans‐3‐(3,4‐Dimethoxyphenyl)Glycidate

et al. 2015

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Caffeic acid-derived polyethers are a class of natural products isolated from the root extracts of comfrey and bugloss, which are endowed with intriguing pharmacological properties as anticancer agents. The synthesis of new polyether derivatives is achieved through ring-opening polymerization of chiral 2,3-disubstituted oxiranes, whose absolute configurations define the overall stereochemistry of the produced polymer. The absolute stereochemistry of one of these building blocks, methyl trans-3-(3,4-dimethoxy-phenyl)glycidate (3), was therefore characterized by the combination of enantioselective high-performance liquid chromatography (HPLC), electronic circular dichroism (ECD) spectroscopy, and time-dependent density functional theory (TD-DFT) calculations. Initial efforts aiming at the isolation of enantiomers by means of a standard preparative HPLC protocol followed by offline ECD analysis failed due to unexpected degradation of the samples after collection. The stopped-flow HPLC-CD approach, by which the ECD spectra of enantiomers are measured online with the HPLC system, was applied to overcome this issue and allowed a fast, reliable, and chemical-saving analysis, while avoiding the risks of sample degradation during the collection and processing of enantiomeric fractions. Subsequent TD-DFT calculations identified ( as the first eluted enantiomeric fraction on the Lux Cellulose-2 column, therefore achieving a full stereochemical characterization of the chiral oxirane under investigation.

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Advantages of electronic circular dichroism detection for the stereochemical analysis and characterization of drugs and natural products by liquid chromatography

Cited by 30 publications

References 150 publications

Analytical and semipreparative chiral separation ofcis-itraconazole on cellulose stationary phases by high-performance liquid chromatography

Analytical and semipreparative chiral separation ofcis-itraconazole on cellulose stationary phases by high-performance liquid chromatography

Deviations from Beer's law in electronic absorption and circular dichroism: Detection for enantiomeric excess analysis

Stopped‐Flow Enantioselective HPLC‐CD Analysis and TD‐DFT Stereochemical Characterization of Methyl Trans‐3‐(3,4‐Dimethoxyphenyl)Glycidate

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