Asymmetric synthesis of an endothelin receptor antagonist

Two distinct synthetic approaches to the biologically active and structural ly unique endothelin antagonist J-104132 (1) have been developed Each synth esis involves a highly selective intramolecular cyclization of a late stage intermediate (bottom to top vs top to bottom) produced from a common early intermediate. Both routes initially yielded multi-gram quantities of the d esired product, with the former ultimately developed to pilot scale readine ss. Several never reactions have been developed throughout the course of ou r studies. These involve a mild bromination of a pyridone to form a bromopy ridine, a mild and efficient TEMPO catalyzed oxidation of an alcohol to giv e a carboxylic acid, as well as a novel stereoselective samarium iodide med iated deoxygenation reaction. These reactions have proved to be quite gener al and have been applied to a wide variety of substrates.