A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; application to an enantioselective synthesis of atorvastatin |
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Authors: | Yuji Kawato Mitsutaka Iwata Ryo Yazaki Naoya Kumagai Masakatsu Shibasaki |
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Affiliation: | a Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan b Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan |
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Abstract: | 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(CH3CN)4]PF6/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 Brønsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise asymmetric synthesis of atorvastatin (Lipitor®: atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol. |
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Keywords: | Asymmetric catalysis Aldol reaction Thioamide Atorvastatin Mesitylcopper |
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