1H and 13C NMR chemical shift assignments and conformational analysis for the two diastereomers of the vitamin K epoxide reductase inhibitor brodifacoum

Abstract

Proton and 13C NMR chemical shifts and 1H- 1H scalar couplings for the two diastereomers of the potent vitamin K epoxide reductase (VKOR) inhibitor brodifacoum have been determined at 293 K from acetone solutions containing both diastereomers. To facilitate difficult assignments, homo- and heteronuclear correlation spectra were acquired at 750 and 900 MHz over 268-303 K temperature range. Conformations of both diastereomers inferred from the scalar couplings and 1-D NOE measurements reveal that one diastereomer (SS/RR) adopts a strained geometry in the cyclohexene ring system of the tetralin group. The NMR spectra also show evidence of line broadening due to conformational exchange at room temperature for the SR/RS diastereomer. These assignments and conformational analyses may be useful in studies of biomolecular interactions of brodifacoum with target proteins such as VKOR and in source determination of brodifacoum. © 2009 John Wiley & Sons, Ltd.