Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

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/bleachcatalyzed oxidation by sodium chlorite (NaClO 2 ) or chromium oxide catalyzed oxidation by periodic acid. The overall process has been run successfully to make multikilograms of the drug in high purity.

Asymmetric Conjugate Addition of Ketones to β‐Nitrostyrenes by Means of 1,2‐Amino‐Alcohol‐Derived Prolinamides as Bifunctional Catalysts

“…Catalysts 21 were prepared in good to excellent yields from Cbz-or Fmoc-Lproline or Cbz-4-hydroxy-L-proline and the corresponding commercially available chiral amines and β-amino alcohols through the reaction sequence shown in Scheme 3. β-Amino alcohols employed in the preparation of catalysts 21i [35] and 21n [36] were synthesized according to literature procedures from (1S,2R)-cis-1-amino-2-indanol and (1R,E)-camphorquinone-3-oxime, respectively. Very recently, Córdova has demonstrated that simple amides derived from primary amino acids such as alanine (see 10 in Scheme 1) efficiently catalyze the direct enantioselective addition of ketones to nitrostyrenes.…”

Asymmetric Conjugate Addition of Ketones to β‐Nitrostyrenes by Means of 1,2‐Amino‐Alcohol‐Derived Prolinamides as Bifunctional Catalysts.

“…Catalysts 21 were prepared in good to excellent yields from Cbz-or Fmoc-Lproline or Cbz-4-hydroxy-L-proline and the corresponding commercially available chiral amines and β-amino alcohols through the reaction sequence shown in Scheme 3. β-Amino alcohols employed in the preparation of catalysts 21i [35] and 21n [36] were synthesized according to literature procedures from (1S,2R)-cis-1-amino-2-indanol and (1R,E)-camphorquinone-3-oxime, respectively. Very recently, Córdova has demonstrated that simple amides derived from primary amino acids such as alanine (see nitrostyrenes.…”

Synthesis and antioxidant evaluation of some new pyridines

“…Many naturally occurring as well as synthetic compounds containing the pyridine scaffold exhibit interesting pharmacological properties [6][7][8][9][10]. Furthermore, pyridine is one of the most popular N-heteroaromatics incorporated into the structure of many pharmaceuticals.…”