Catalytic asymmetric synthesis of (S)-oxybutynin and a versatile intermediate for antimuscarinic agents

A practical synthesis of (S)-oxybutynin, a muscarinic receptor antagonist, using catalytic enantioselective cyanosilylation of cyclohexyl phenyl ketone (9a) as a key step is described. The key reaction proceeded with 94% ee using 1 mol% of Gd-1 catalyst, and was performed on a 100 g-scale. In addition, a short catalytic enantioselective synthesis of the versatile intermediate for Scios Nova analogues of antimuscarinic agents (7) is described. Application of the catalytic enantioselective cyanosilylation to ketones containing two sterically similar substituents on the carbonyl group is also discussed.     

Amide-based atropisomers in tachykinin NK1-receptor antagonists: synthesis and antagonistic activity of axially chiral N-benzylcarboxamide derivatives of 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one

A series of novel N-benzylcarboxamide derivatives of bicyclic compounds, 3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one and 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one, were synthesized by cyclization of N-benzyl-2-chloro-N-(2-hydroxyethyl)- [and -(3-hydroxypropyl)-] nicotinamides, respectively. Atropisomerism was observed in 5-[3,5-bis(trifluoromethyl)benzyl]-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-ones due to steric hindrance of the carboxamide moiety and restriction of its rotation. Cyclization of N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-[(2S)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenylnicotinamide gave (3S)-5-[3,5-bis(trifluoromethyl)benzyl]-3,8-dimethyl-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3b][1,5]oxazocin-6-one, which exists predominantly in the thermodynamically stable aR-conformer in CDCl₃. This compound showed excellent NK₁-antagonistic activity with IC₅₀ value (in vitro inhibition of [¹²⁵I]-Bolton-Hunter-substance P binding in human IM-9 cells) of 0.47 nM, which is ca. 200-fold more potent than that of its enantiomer, indicating that the atropisomer chirality affects NK₁-receptor recognition.     

A convenient preparation of (S)-(−)-4-hydroxy-2-methylcyclopent-2-en-1-one and its application as a chiral synthetic equivalent of 2-methylcyclopent-2-en-1-one in the terpenoid synthesis

A method for the preparation of (S)-4-hydroxy-2-methylcyclopent-2-en-1-one from 1-(2-furyl)ethanol using modified Piancatelli rearrangement and enzymatic kinetic resolution of the racemate was developed. An application of O-protected derivatives of 4-hydroxy-2-methylcyclopent-2-en-1-one to terpenoid synthesis through tandem conjugate addition of allyl-metal reagents, enolate trapping, and consecutive Mukaiyama–Michael addition was studied. An optically active azulene derivative useful for terpenoid synthesis was efficiently synthesized.