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

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.