Additives promote Noyori-type reductions of a β-keto-γ-lactam: asymmetric syntheses of serotonin norepinephrine reuptake inhibitors

J Org Chem. 2013 Jun 7;78(11):5768-74. doi: 10.1021/jo400589j. Epub 2013 May 20.

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.

MeSH terms

  • Lactams / chemistry*
  • Molecular Structure
  • Oxidation-Reduction
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis*
  • Selective Serotonin Reuptake Inhibitors / chemistry

Substances

  • Lactams
  • Serotonin Uptake Inhibitors