title: Enantioselective nitrile anion cyclization to substituted pyrrolidines. A highly efficient synthesis of (3S,4R)-N-tert-butyl-4-arylpyrrolidine-3-carboxylic acid.
abstract: [reaction: see text] A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94-99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans-pyrrolidine carboxylic acid target compound in >99.9% chemical and optical purity. This chemistry was also shown to be applicable to both electronically neutral and rich substituted phenyl substrates.
authors.affiliation: Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. john_chung@merck.com
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chung
authors.forename: Raymond
authors.initials: R
authors.lastname: Cvetovich
authors.forename: Joseph
authors.initials: J
authors.lastname: Amato
authors.forename: J Christopher
authors.initials: JC
authors.lastname: McWilliams
authors.forename: Robert
authors.initials: R
authors.lastname: Reamer
authors.forename: Lisa
authors.initials: L
authors.lastname: DiMichele