Asymmetric Synthesis of a Selective Endothelin A Receptor Antagonist

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conjugate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96% ee via purification as (S)-(−)-1-phenylethylamine salt. Pd(OAc)2/dppf (1,1′-bis(diphenylphosphino)ferrocene) catalyzed carbonylation followed by chemoselective addition of aryllithium derived from 23 which gave ketone 24. Diastereoselective reduction of the ketone with catecholborane followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 26. Introduction of amino moiety on the pyridine ring by imidoyl rearrangement followed by deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 8% overall yield from 16.