Asymmetric synthesis of a selective endothelin A receptor antagonist

Abstract

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. A highly substituted pyridine intermediate 11a was efficiently prepared via a mono-amination of inexpensive 2,6-dichloropyridine followed by a Vilsmeier formylation. Asymmetric conjugate addition of aryl lithium 14 to the chiral oxazoline 13 followed by hydrolysis afforded 15 in 90% ee. Pd(OAc)2/dppf catalyzed carbonylation followed by chemoselective addition of aryl lithium 18 gave ketone 19. Diastereoselective reduction of the ketone with LS-Selectride® followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 21. Deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 10% overall yield from 11a. © 2002 Elsevier Science Ltd. All rights reserved.