Studies in the synthesis of the thromboxane receptor antagonist EP 092 and its enantiomers

An improved synthesis of EP 092 was developed. Resolution of an early intermediate was achieved by using butane-2(R), 3(R)-diol ketals. Both enantiomers of EP 092 were found to possess platelet aggregation inhibition activity, but the l enantiomer was much more potent. A new synthesis was devised for the enantiomers starting from known enantiomerically pure chiral intermediates. It was found that the symmetry of these starting materials permitted the facile inversion of one enantiomer into the other via the Wharton reaction. Molecular mechanics studies provided a basis for explaining partial kinetic resolution during ketal formation as well as differences in the ease of Baeyer-Villiger oxidation of epimeric α-methyl ketones