Synthetic approaches to 2-(4-hydroxy-7-chromanyl)benzoic acids as antagonists of leukotriene B4

Structural modification of 1 led to a series of 2-(4-hydroxy-7-chromanyl)benzoic acid LTB4 antagonists exemplified by 2 and 3. The use of an organostannane biaryl coupling, a non steroselective reduction and a chromatographic resolution limited the utility of this synthetic route. To address these issues, a new synthetic route was developed utilizing a palladium catalyzed coupling of aryl oxazolines in tandem with a stereospecific enone reduction as key synthetic steps. Resolution was achieved by fractional crystallization of a (S)-(-)-alpha-methylbenzylamine salt.