Asymmetric hydrogenation of β-amino ketones with the bimetallic complex RuPHOX-Ru as the chiral catalyst

Abstract

Asymmetric hydrogenations of a series of β-amino ketones were carried out with a bimetallic complex (RuPHOX-Ru) as the chiral catalyst. Almost all the reactions (performed in a mixed solvent system of toluene and H2O in the presence of KOH) gave quantitative conversions into their respective products with up to 99.9% ee. The RuPHOX-Ru catalyst is stable to both moisture and air. The procedure has the benefits of being inexpensive, environmentally friendly and highly efficient. Under a relatively low catalyst loading (TON = 2000), key intermediates of fluoxetine, tomoxetine and nisoxetine could be obtained in quantitative yield and in up to 99.9% ee. This methodology represents a promising alternative to the synthesis of the aforementioned drugs and their analogues.

Computational design of syntheses leading to compound libraries or isotopically labelled targets

“…Importantly, the entire scheme to prepare 12 different compounds requires only 18 individual reactions and takes advantages of several common intermediates including interconversions of some library members. We note that the proposed strategy comprising enantioselective reduction of appropriate b-aminoacetophenone [44][45][46] and Mitsunobu displacement with phenol 47,48 has already been used in several syntheses of structurally related compounds including our synthesis of hydroxyduloxetine. 18 We also emphasize that this "global" synthetic plan is different from the plans that Chematica produces for each target separatelyfor instance, if the program's task is to make des-triuoromethyl congener of uoxetine A1 (Fig.…”

ZnCl2‐Promoted Asymmetric Hydrogenation of β‐Secondary‐Amino Ketones Catalyzed by a P‐Chiral Rh–Bisphosphine Complex

“…Over the last several years, our research has focused on the asymmetric hydrogenation of several types of substrates 7. During our continuing research interest in the synthesis of the above‐mentioned drug molecules, we have made encouraging progress towards the asymmetric hydrogenation of β‐tertiary‐amino ketones, a route through which ( R )‐fluoxetine and ( R )‐atomoxetine could be synthesized with excellent enantioselectivities 7d. However, the application of this method to thienyl‐substituted substrates was unsuccessful, probably due in part to the additional coordination ability of the sulfur atom.…”

Yolk‐Shell‐Mesostructured Silica‐Supported Dual Molecular Catalyst for Enantioselective Tandem Reactions

“…Earlier works employed chiral Rh‐MCPPM complex (MCPPM: 4‐dicyclohexylphosphino‐2‐diphenylphosphinomethyl‐1‐( N ‐methylcarbamoyl)pyrrolidine) and chiral Rh‐Duanphos complex as catalysts converted β‐amino ketones into chiral γ‐secondary amino alcohols –. Recent reports utilized chiral Rh‐benzbisphosphine complex as a catalyst and ZnCl 2 as an activator via asymmetric hydrogenation– and chiral Ru‐diamine complexes via asymmetric transfer hydrogenation (ATH) [7h] to perform the highly efficient preparations of γ‐secondary amino alcohols. Despite of these well‐established asymmetric catalysis, the inherent drawbacks of homogeneous catalysis, such as expensive transition‐metal cost, environmentally unfriendly solvent and inevitable product contamination, still greatly hinder their applications.…”