Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer

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• 作者：Xiao-zhong Wang ; Xia Wang ; Ying-qi Chen…
• 关键词：Asymmetric synthesis ; Diastereoisomer ; Hydroxyl protection group ; D ; plenylglycinol ; 哌啶酮
生物碱 不对称合成 D ; 苯甘氨醇 ; 醇羟基保护基 ; TQ463
• 刊名：Journal of Zhejiang University - Science A
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：17
• 期：2
• 页码：163-170
• 全文大小：673 KB
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• 作者单位：Xiao-zhong Wang (1)
  Xia Wang (1)
  Ying-qi Chen (1)
  Li-yan Dai (1)
  Xing-cong Li (2)
  
  1. College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China
  2. National Centers for Natural Products Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, Mississippi, 38677, USA
  
• 刊物类别：Engineering
• 刊物主题：Physics
  Mechanics, Fluids and Thermodynamics
  Chinese Library of Science
  
• 出版者：Zhejiang University Press, co-published with Springer
• ISSN：1862-1775

文摘

This paper reports the asymmetric synthesis of an important pharmaceutical intermediate (3S)-1-[(1R)-2-hydroxy-1-phenylethyl]-3-methylpiperidin-2-one (compound 1) from commercially available D-plenylglycinol and delta-valerolactone. During the alkylation process, the hydroxyl group can be protected or unprotected, resulting in a different consumption of s-BuLi, and leading to a different diastereomeric excess (de) of compound 1. When 1-[(1R)-2-hydroxy-1-phenylethyl]-piperidin-2-one (compound 2) was alkylated with 2.5 eq. of s-BuLi, compound 1 was obtained as a single isomer detected by chiral high performance liquid chromatography (HPLC) columns with an overall yield of 91%. With the hydroxyl group protected, (R)-1-(2-[(tert-butyldimethylsil) oxy]-1-phenylethyl) piperidine-2-one (compound 6) could be alkylated with 1.5 eq. of s-BuLi, giving compound 1 and its diastereoisomer 8 in a ratio of 1:2.5 and a yield of methylation of 90%. Compounds 1 and 8 could be separated completely and easily by flash chromatography. The absolute configuration of compound 8 was determined by singlecrystal X-ray analysis. The mechanism of the alkylation process is discussed based on experimental results. Keywords Asymmetric synthesis Diastereoisomer Hydroxyl protection group D-plenylglycinol