Structure: Warfarin, Molecule of the Month for February 2011, by John Maher

The structure of Warfarin

Warfarin is optically active, and from the time of it's discovery it was recognised that the two enantiomers were clinically different in their effect as a drug. So establishing the absolute configuration of the two isomers was a priority.

R-Warfarin

R-warfarin 2D

S-Warfarin

S-warfarin 2D

Hemiketal Ring Formation

RR-Warfarin

RR-warfarin 2D

SS-Warfarin

SS-warfarin 2D

RS-Warfarin

RS-warfarin 2D

SR-Warfarin

SR-warfarin 2D

Assignment of stereochemistry

The stereochemical assignment of (−)-(S)-warfarin was initially achieved by relating it to (−)-(R)-beta-phenylcaproic acid through a series of reactions not involving the asymmetric center {B.D.West, S.Preis, C.H.Schroder, & K.P.Link, J.Amer.Chem.Soc., 1961,83, 2676}. This assignment was confirmed by a determination of the crystal and molecular structure, and using the anomalous scattering of oxygen, and absolute configuration of (−)-(S)-Warfarin was measured {E.J.Valente, W.F.Trager and L.H.Jensen, Acta Cryst. 1975. B31, 954}.

The Hemiketal

The primary feature of the structure of (−)-warfarin is the hemiketal ring formed by cyclization of the side-chain keto function and the phenolic hydroxyl in the 4 position of the coumarin ring system. The crystal structure of racemic warfarin has the same feature. In solution n.m.r. spectra shows that the hemiketal is present in acetone solution.

Bond Lengths

The hemiketal bonding is rather weak. Thus the bond lengths within the hemiketal show that the atoms retain some of the characteristic of an open side chain keto group.

The Absolute Configuration

In the open chain keto form warfarin has two isomers, R and S, however the hemiketal introduces a second assymmetric center, so that we can have RR, SS, RS, and SR forms. The crystal structure determination favoured the SS enantiomer in the crystal studied.

Enantiomers & Biochemical Function

The S-isomer is very much more potent than the R isomer in both rats and humans.The S-isomer is stereoselectively oxidized to the inactive 7-hydroxywarfarin, and the keto-group of the R-isomer is stereospecifically reduced to the slightly active R,S-alcohol. Both isomers are oxidized to the inactive 6-hydroxywarfarin.

It is evident that we are dealing with a very complex system indeed; the presence of the hemiketal adds four more enantiomers to the complexity pot. Recent work has unravelled some more of the mechanisms behind the Vitamin K1 antagonism of Warfarin.