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有机化学
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有机化学 ›› 2010, Vol. 30 ›› Issue (03): 401-408. 上一篇    下一篇

研究论文

手性药物催化β-酮酸酯不对称α-羟基化反应研究

宫斌，孟庆伟*，苏田，高占先   

  1. (大连理工大学精细化工国家重点实验室 大连 116012)
  • 收稿日期:2009-07-17 修回日期:2009-09-02 发布日期:2010-03-28
  • 通讯作者: 孟庆伟 E-mail:mengqw@chem.dlut.edu.cn

Chiral Drug-Catalyzed Asymmetric α-Hydroxylation of β-Keto Esters

Gong Bin,Meng Qingwei*,Su Tian,Gao Zhanxian   

  1. (State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012)
  • Received:2009-07-17 Revised:2009-09-02 Published:2010-03-28

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以商业化易得的具有碱性氮原子的手性药物为有机催化剂, 用于催化β-酮酸酯不对称α-羟基化反应, 发现以噻吗洛尔或普萘洛尔为催化剂, 反应对映选择性分别可达32%和18%. 对噻吗洛尔和普萘洛尔进行结构修饰, 合成了12个洛尔药物类似物, 并考察了其催化效果, 发现在优化的反应条件下, 以30 mol% (R)-1-叔丁胺基-3-(2-萘氧基)-2-丙醇(7f)为催化剂, 20 mol% β-环糊精为助催化剂, 叔丁基过氧化氢为氧化剂, 正己烷为溶剂, 反应对映选择性最高可达57%, 收率92%. 不对称α-羟基化产物(S)-5-氯-2-羟基-1-茚酮-2-甲酸甲酯(2a)在乙酸乙酯中一次重结晶后, 对映体光学纯度可达99%, 收率68%.

关键词: 不对称α-羟基化, β-酮酸酯, 有机催化, 手性药物, 噻吗洛尔, 普萘洛尔, β-环糊精

Using commercially available, basic nitrogen atom containing chiral drugs as the organocatalysts for asymmetric α-hydroxylation of β-keto esters, it was found that the enantioselectivity reached 32% and 18% when using timolol and propranolol as the organocatalyst, respectively. The structures of timolol and propranolol were then modified and twelve analogs were synthesized to investigate the catalysis performance. It was found that under the optimized reaction conditions, using 30 mol% of (R)-1-(tert-butylamino)-3- (naphthalen-2-yloxy)propan-2-ol (7f) as the organocatalyst, 20 mol% of β-cyclod- extrin as the cocatalyst, tert-butyl hydroperoxide as oxidant and n-hexane as solvent, the enantioselectivity reached up to 57% with the yield of 92%. The ee value of (S)-methyl-5-chloro-2-hydroxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2a) reached up to 99% with the yield of 68% after a single recrystallization from ethyl acetate.

Key words: asymmetric α-hydroxylation, β-keto ester, organocatalysis, chiral drug, timolol, propranolol, β-cyclodextrin