Practical asymmetric synthesis of an endothelin receptor antagonist

An efficient, practical, asymmetric synthesis of the endothelin receptor an tagonist 1 is reported. The key pyridine-fused cyclopentane ring bearing th ree consecutive chiral centers was constructed by first an auxiliary induce d asymmetric conjugate addition of the bottom aryllithium from 19 to an uns aturated ester 21 in high diastereoselectivity. After a highly diastereosel ective addition of the top aryl Grignard reagent to the aldehyde 22, the al cohol product then underwent a stereospecific intramolecular alkylation of the eater enolate by the phosphate of the alcohol, resulting in the desired trans-trans relative stereochemistry on the cyclopentane ring. The two key chiral centers that set the chirality of the molecule were both induced fr om cis-1-amino-2-indanol-derived chiral auxiliaries, one in the conjugate a ddition reaction, the other in setting the chiral center of the bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcoho l to the carboxylic acid in the bottom side chain was carried out with the newly developed TEMPO/bleach-catalyzed oxidation by sodium chlorite (NaClO2 ) or chromium oxide catalyzed oxidation by periodic acid. The overall proce ss has been run successfully to make multikilograms of the drug in high pur ity.