Trans-β-lactam isomers have garnered much attention as anti-cancer microtubule targeting agents. Currently available synthetic methods are available for the preparation of enantiopure β-lactams and favour isomeric cis/trans β-lactam mixtures. Indirect chiral resolution offers the opportunity for isolation of exclusively enantiopure trans-β-lactams. In this study, liquid chromatography chiral resolution of β-lactams derivatized as diastereomer mixtures with a panel of N-protected amino acids is explored, where N-(Boc)-L-proline served as the optimal chiral derivatising reagent. High-performance liquid chromatography failed to adequately determine diastereomeric excess (de) of resolved diastereomers. Variable temperature, 1 H NMR and 2D EXSY spectroscopic analyses of proline-derivatised diastereomers were successfully employed to characterise equilibrating rotamers of resolved diastereomers and determine their de. Integration of resolved resonances corresponding to H3 and H4 of the β-lactam ring served as a quantitative qNMR tool for the calculation of de following resolution.
Keywords: NMR spectroscopy; chiral resolution; chirality; liquid chromatography; structure elucidation.
© 2022 The Authors. Published by Wiley-VCH GmbH.