Asymmetric Synthesis of an Endothelin Receptor Antagonist.

Abstract

Two distinct synthetic approaches to the biologically active and structurally unique endothelin antagonist J-104132 (1) have been developed Each synthesis 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 desired product, with the former ultimately developed to pilot scale readiness.Several novel reactions have been developed throughout the course of our studies. These involve a mild bromination of a pyridone to form a bromopyridine, a mild and efficient TEMPO catalyzed oxidation of an alcohol to give a carboxylic acid, as well as a novel stereoselective samarium iodide mediated deoxygenation reaction. These reactions have proved to be quite general and have been applied to a wide variety of substrates.

Asymmetric Synthesis of a Selective Endothelin A Receptor Antagonist.

“…Earlier work on the synthesis of 1a showed that both are viable approaches. 6,7) We have recently disclosed a practical asymmetric synthesis of 1b utilizing the "bottom to top" approach A. 8) We have also disclosed an alternative asymmetric synthesis of 1b starting from amino substituted pyridine utilizing the "top to bottom" approach B.…”

“…With the intermediate 21 in hand, methoxycarbonylation of 21 15) was accomplished with CO (1 kg/cm 2 ) in methanol in the presence of NaHCO 3 and a catalytic amount of Pd(OAc) 2 and 1,1Ј-bis(diphenylphosphino)ferrocene (DPPF) in 97% yield. From the readily accessible 4-bromo-3-hydroxymethylanisole, 6,7) the bottom aryl bromide 23 was prepared by introduction of the PMB ( p-methoxybenzyl) protecting group to the hydroxymethyl group under standard conditions. Chemoselective addition of aryllithium from 23 to the methyl ester of 22 at low temperature afforded ketone 24 in 88% yield (Chart 4).…”