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 th...

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Bibliographic Details
Published in:Journal of organic chemistry 2013-06, Vol.78 (11), p.5768-5774
Main Authors: Magnus, Nicholas A, Astleford, Bret A, Laird, Dana L. T, Maloney, Todd D, McFarland, Adam D, Rizzo, John R, Ruble, J. Craig, Stephenson, Gregory A, Wepsiec, James P
Format: Article
Language:English
Subjects:
Lactams - chemistry
Molecular Structure
Oxidation-Reduction
Serotonin Uptake Inhibitors - chemical synthesis
Serotonin Uptake Inhibitors - chemistry
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Summary: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.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo400589j