Asymmetric synthesis of a selective endothelin A receptor antagonist

An asymmetric synthesis of a selective endothelin A receptor antagonist is described. A highly substituted pyridine intermediate was efficiently prepared via a mono-amination of inexpensive 2,6-dichloropyridine followed by a Vilsmeier formylation. Asymmetric conjugate addition of aryl lithium to the chiral oxazoline followed by hydrolysis afforded in 90% ee. Pd(OAc)2/dppf catalyzed carbonylation followed by chemoselective addition of aryl lithium gave ketone . Diastereoselective reduction of the ketone with LS-Selectride® followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate . Deprotection and purification by crystallization furnished the enantiomerically pure target molecule in 10% overall yield from .