A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; application to an enantioselective synthesis of atorvastatin

A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides. The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency over the previously developed catalyst comprising [Cu(CH(3)CN)(4)]PF(6)/Ph-BPE/LiOAr (first-generation catalyst), which required a tedious catalyst preparation process. In the reaction with the second-generation catalyst, the intermediate Cu-aldolate functioned as a Bronsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated ill a concise asymmetric synthesis of atorvastatin (Lipitor (R): atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol. (C) 2011 Elsevier Ltd. All rights reserved.