Application of 2D EXSY and qNMR Spectroscopy for Diastereomeric Excess Determination Following Chiral Resolution of β‐Lactams

Abstract

Abstract 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, 1H 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

• chiral resolution
• chirality
• NMR spectroscopy
• liquid chromatography
• structure elucidation