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.
Kato, Y., Niiyama, K., Nemoto, T., Jona, H., Akao, A., Okada, S., … Mase, T. (2002). Asymmetric synthesis of a selective endothelin A receptor antagonist. Tetrahedron, 58(17), 3409–3415. https://doi.org/10.1016/S0040-4020(02)00280-6