Enantioselective Complexation of Xylopinine: A Cyclodextrin-Assisted CE and NMR Study

Várnagy, Erzsébet and Tóth, Gergő and Hosztafi, Sándor and Malango, Milo and Fejős, Ida and Béni, Szabolcs (2025) Enantioselective Complexation of Xylopinine: A Cyclodextrin-Assisted CE and NMR Study. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 26. No. 9405. ISSN 1661-6596

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Abstract

Tetrahydroprotoberberine alkaloids (THPBs) are bioactive natural products bearing stereogenic centers that frequently exhibit enantiomer-specific pharmacological effects. Xylopinine (XPN), a representative THPB, shows cytotoxic, antimicrobial, and antimalarial activity in vitro, and displays pronounced stereoselectivity in vivo, with the naturally occurring (S)-enantiomer emphasizing the need for reliable enantioselective analysis. In this study, we present the synthesis of racemic XPN from norlaudanosine, and its first comprehensive cyclodextrin-assisted capillary electrophoresis screening dedicated to the enantioseparation of XPN. Sulfated- and sulfobutyl-ether-β-cyclodextrin (S-β-CyD, SBE-β-CyD) provided efficient resolution (Rs > 3), while heptakis-(6-deoxy-6-(2-carboxyethyl)thio)-β-CyD (subetadex, SBX) yielded outstanding separation (Rs > 9). The enantiomer migration order was consistently R,S, except when using SBE-β-CyD, which showed the inverse sequence. Chiral HPLC using a Chiralpak AD column in polar organic mode with methanol modified with 0.1% diethylamine as mobile phase enabled the semi-preparative isolation of XPN enantiomers, with the (S)-enantiomer exceeding 95% purity. The absolute configuration was confirmed by circular dichroism spectroscopy. 1H NMR titration and 2D rotating-frame nuclear Overhauser effect correlation spectroscopy (ROESY) consistently revealed multi-site recognition of XPN by SBX, supporting the inclusion of both aromatic rings (A and D).

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