Stereoselective Synthesis of cis-3,4-Disubstituted Piperidines through Ring Transformation of 2-(2-Mesyloxyethyl)azetidines

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• 作者：Karen Mollet ; Saron Catak ; Michel Waroquier ; Veronique Van Speybroeck ; Matthias D鈥檋ooghe ; Norbert De Kimpe
• 刊名：Journal of Organic Chemistry
• 出版年：2011
• 出版时间：October 21, 2011
• 年：2011
• 卷：76
• 期：20
• 页码：8364-8375
• 全文大小：1062K
• 年卷期：v.76,no.20(October 21, 2011)
• ISSN：1520-6904

文摘

The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding 尾-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an S_N2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.