Practical asymmetric synthesis of an endothelin receptor antagonist

Zhiguo J. Song, Mangzhu Zhao, Richard Desmond, Paul Devine, David M. Tschaen, Richard Tillyer, Lisa Frey, Richard Heid, Feng Xu, Bruce Foster, Jing Li, Robert Reamer, Ralph Volante, Edward J.J. Grabowski, Ulf H. Dolling, Paul J. Reider, Shigemitsu Okada, Yoshiaki Kato, Eiichi Mano

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

An efficient, practical, asymmetric synthesis of the endothelin receptor antagonist 1 is reported. The key pyridine-fused cyclopentane ring bearing three consecutive chiral centers was constructed by first an auxiliary induced asymmetric conjugate addition of the bottom aryllithium from 19 to an unsaturated ester 21 in high diastereoselectivity. After a highly diastereoselective addition of the top aryl Grignard reagent to the aldehyde 22, the alcohol product then underwent a stereospecific intramolecular alkylation of the ester 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 from cis-1-amino-2-indanol-derived chiral auxiliaries, one in the conjugate addition reaction, the other in setting the chiral center of the bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcohol 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 process has been run successfully to make multikilograms of the drug in high purity.

Original languageEnglish (US)
Pages (from-to)9658-9667
Number of pages10
JournalJournal of Organic Chemistry
Volume64
Issue number26
DOIs
StatePublished - Dec 24 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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