title: Additives promote Noyori-type reductions of a β-keto-γ-lactam: asymmetric syntheses of serotonin norepinephrine reuptake inhibitors.
abstract: Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on β-keto-γ-lactam 8 to afford β-hydroxy-γ-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(L)-tartaric acid diastereomeric salt 16 enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9, it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was reducing faster to 9 than the equilibration of the stereocenter of 8.
authors: Eli Lilly and Company, Small Molecule Design and Development Division, Indianapolis, Indiana 46285, United States. magnus_nicholas_a@lilly.com
authors: Nicholas A
authors: NA
authors: Magnus
authors: Bret A
authors: BA
authors: Astleford
authors: Dana L T
authors: DL
authors: Laird
authors: Todd D
authors: TD
authors: Maloney
authors: Adam D
authors: AD
authors: McFarland
authors: John R
authors: JR
authors: Rizzo
authors: J Craig
authors: JC
authors: Ruble
authors: Gregory A
authors: GA
authors: Stephenson
authors: James P
authors: JP
authors: Wepsiec
mesh_terms: D007769:Lactams / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D007769:Lactams; D017367:Selective Serotonin Reuptake Inhibitors