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CLC number: TQ463

On-line Access: 2016-02-02

Received: 2015-01-04

Revision Accepted: 2015-05-30

Crosschecked: 2016-01-25

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Xia Wang

http://orcid.org/0000-0001-8025-1309

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Journal of Zhejiang University SCIENCE A 2016 Vol.17 No.2 P.163-170

http://doi.org/10.1631/jzus.A1500008


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


Author(s):  Xiao-zhong Wang, Xia Wang, Ying-qi Chen, Li-yan Dai, Xing-cong Li

Affiliation(s):  College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China; more

Corresponding email(s):   dailiyan@zju.edu.cn, xcli7@olemiss.edu

Key Words:  Asymmetric synthesis, Diastereoisomer, Hydroxyl protection group, D-plenylglycinol


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Xiao-zhong Wang, Xia Wang, Ying-qi Chen, Li-yan Dai, Xing-cong Li. Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer[J]. Journal of Zhejiang University Science A, 2016, 17(2): 163-170.

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publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.A1500008"
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%T Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer
%A Xiao-zhong Wang
%A Xia Wang
%A Ying-qi Chen
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%A Xing-cong Li
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T1 - Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer
A1 - Xiao-zhong Wang
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A1 - Xing-cong Li
J0 - Journal of Zhejiang University Science A
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Abstract: 
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 single-crystal X-ray analysis. The mechanism of the alkylation process is discussed based on experimental results.

This article describes the use of a chiral auxiliary for the asymmetric synthesis of 3-methylpiperidin-2-one. Key the success of this approach is the discovery of a highly diastereoselective alkylation of lithium elongate dianions of N-hydroxy phenethyl substituted piperidin-2-one.

(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮的合成

目的:探索合成(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮的新方法。
创新点:以常规化工原料D-苯苷氨醇为主要原料,在比较温和的条件下合成重要的药物中间体(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮及其同系物。该方法中的甲基化步骤较常规甲基化步骤减少1当量s-BuLi的用量,更环保和安全。
方法:利用D-苯苷氨醇的空间位阻作用,在六元环内酰胺中引入具有特定光学纯度的手性甲基。在甲基化过程中,用叔丁基二甲基氯硅烷对羟基进行保护,以减少仲丁基锂的用量。
结论:以工业易得的δ-戊内酯及D-苯苷氨醇为初始原料,探索合成3-甲基-2-哌啶酮类物质的新方法。新方法中对仲丁基锂的消耗量与常规方法有所不同。当羟基受保护时,甲基化1当量六元环内酰胺(化合物7)消耗1.5当量而非2.5 当量仲丁基锂,甲基化产物脱掉醇羟基保护基,得到(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮(化合物1)及其非对映异构体(3R)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮(化合物8),二者摩尔比为1:2.5。通过重结晶或柱层析的方法可对二者进行完全分离。

关键词:哌啶酮;生物碱;不对称合成;D-苯甘氨醇;醇羟基保护基

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