Open-cyclic warfarin isomerism: 5-hydroxywarfarin

Abstract

Addition of a 5-hydroxy substituent to warfarin [3-(1-phenyl-3-oxobutyl)-4-hydroxycoumarin] shifts the solution equilibrium in chloroform to favor the open isomeric form over the two cyclic diastereomeric hemiketals. X-ray diffraction analysis reveals 5-hydroxywarfarin crystallizes as the open isomer in contrast to the more than 20 warfarin and analog structures which occur ascis ortrans hemiketal forms in the solid. The two peri hydroxyl groups in the structure of 3-(1-phenyl-3-oxobutyl)-4,5-dihydroxycoumarin are intramolecularly H-bonded. Methyl kctal derivatives of 5-hydroxywarfarin and a close analog effectively model the minor cyclic hemiketal forms in solution. Structures of bothcis andtrans cyclic methyl ketals of 3-(4-oxopent-2-yl)-4,5-dihydroxy-coumarin have been determined and the aryl hydroxyls H-bond to the dihydropyranyl ring oxygens of the cyclic ketals. Nuclear magnetic resonance studies suggest that these intramolecular H-bonds persist in chloroform solution. Infrared spectroscopy on the series of compounds in KBr pellets is consistent with the crystallographically determined structures and H-bonding schemes.