jo400589j_si_002.pdf (3 MB)

Additives Promote Noyori-type Reductions of a β‑Keto-γ-lactam: Asymmetric Syntheses of Serotonin Norepinephrine Reuptake Inhibitors

Download (3 MB)
journal contribution
posted on 07.06.2013 by Nicholas A. Magnus, Bret A. Astleford, Dana L. T. Laird, Todd D. Maloney, Adam D. McFarland, John R. Rizzo, J. Craig Ruble, Gregory A. Stephenson, James P. Wepsiec
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.