Stopped-flow enantioselective HPLC-CD analysis and TD-DFT stereochemical characterization of methyl trans-3-(3,4-dimethoxyphenyl)glycidate

This is the peer reviewed version of the article which has been published in final form on Chirality 27:914–918 (2015), available at https://doi.org/10.1002/chir.22539. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self Archived Versions.
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ABSTRACT

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 anti-cancer 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 off-line 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 on-line 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 (2S,3R)-3 as the first eluted enantiomeric fraction on the Lux Cellulose-2 column, therefore achieving a full stereochemical characterization of the chiral oxirane under investigation.