Catalytic Highly Enantioselective Alkylation of Aldehydes with Deactivated Grignard Reagents and Synthesis of Bioactive Intermediate Secondary Arylpropanols

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• 作者：Yi Liu ; Chao-Shan Da ; Sheng-Li Yu ; Xiao-Gang Yin ; Jun-Rui Wang ; Xin-Yuan Fan ; Wei-Ping Li ; Rui Wang
• 刊名：Journal of Organic Chemistry
• 出版年：2010
• 出版时间：October 15, 2010
• 年：2010
• 卷：75
• 期：20
• 页码：6869-6878
• 全文大小：922K
• 年卷期：v.75,no.20(October 15, 2010)
• ISSN：1520-6904

文摘

Because of the high reactivity of Grignard reagents, a direct, highly enantioselective Grignard reaction with aldehydes has rarely been disclosed. In this report, Grignard reagents were introduced with bis[2-(N,N′-dimethylamino)ethyl] ether (BDMAEE) to effectively deactivate their reactivity; thus, a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(OⁱPr)₂. It is thought that BDMAEE chelates the in situ generated salts MgBr₂ from a Schlenk equilibrium of RMgBr and Mg(OⁱPr)Br from transmetalation of RMgBr with Ti(OⁱPr)₄. The Mg salts can actively promote the undesired background reaction to give the racemate. The chelation definitely inhibits the catalytic activity of the Mg salts, suppresses the unwanted background reaction, and enables the highly enantioselective addition catalyzed by (S)-BINOL-Ti(OⁱPr)₂. Consequently, the Mg salt byproducts were not removed, less Ti(OⁱPr)₄ than RMgBr was used, and extremely low temperature was avoided in this catalytic asymmetric reaction in comparison with the research disclosed before. Various alkyl Grignard reagents were investigated in the asymmetric addition, and ⁱBuMgBr resulted in the highest enantioselectivity, >99%. Furthermore, important intermediate secondary arylpropanols for chiral drug synthesis were effectively synthesized with high enantioselectivity, up to 97%, in one step.