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

Eavan C. McLoughlin*, John E. O'Brien, Cristina Trujillo, Mary J. Meegan, Niamh M. O'Boyle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalChemistryOpen
DOIs
Publication statusAccepted/In press - 2022

Keywords

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

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