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化学学报
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化学学报 ›› 2009, Vol. 67 ›› Issue (22): 2635-2640. 上一篇    下一篇

研究论文

二元活性酯胺解法合成米格列奈及其区域选择性的探讨

曹小辉a，马 翼b,c，周小丽a，陈立功*,a   

  1. (a天津大学化工学院 天津 300072) (b南开大学元素有机化学国家重点实验室 天津 300071) (c南开大学元素有机化学研究所 天津 300071)
  • 投稿日期:2008-09-29 修回日期:2009-05-23 发布日期:2009-07-20
  • 通讯作者: 陈立功 E-mail:lgchen@tju.edu.cn
  • 基金资助:

    天津市应用基础研究计划（07JCYBJC00200）

Synthesis of KAD-1229 through Amidation of Bis-activated Esters and Discussion of Regioselectivity of the Reactions

Cao, Xiaohuia，Ma, Yi b,c，Zhou, Xiaolia，Chen, Ligong*,a   

  1. (a School of Chemical Engineering, Tianjin University, Tianjin 300072) (b National Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071) (c Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071)
  • Received:2008-09-29 Revised:2009-05-23 Published:2009-07-20

PDF

1474

被引次数

4

通过(S)-2-苄基丁二酸二元活性酯中间体选择性胺解的方法得到米格列奈, 实验中发现三个活性酯胺解反应中具有不同程度的区域选择性, 其中对硝基苯酚和N-羟基琥珀酰亚胺(HOSu)活性酯选择性非常高(100∶0, 98.9∶1.1), 而N-羟基苯并三氮唑(HOBt)活性酯的选择性则只有73.6∶26.4. 采用模拟退火方法得到了三个活性酯分子的低能构象, 并采用Hartree-Fock方法在6-31G*基组水平上对其进行全几何优化, 通过对构象的分析对产生区域选择性的因素进行了初步探讨, 发现分子一端的酯基团与侧链的苄基芳环之间存在着π-π堆积作用, 并导致了低能构象中相关原子对两端羰基形成不同程度的屏蔽, 并由此产生了反应的区域选择性.

关键词: 米格列奈, 二元活性酯, 区域选择性, 分子模拟, π-π堆积作用

KAD-1229 was obtained through regioselective amidation of bis-activated esters of (S)-2-benzylsuccinic acid. It was found that amidation of three different activated esters yielded different regioselectivities; amidations of p-nitrophenyl ester and N-hydroxysuccinimide ester gave high regioselectivity (100∶0 and 98.9∶1.1) while N-hydroxybenzotriazole (HOBt) ester produced lower regioselectivity (73.6∶26.4). By the way of simulated annealing, the stable conformations of the three activated esters were obtained. The structures have been fully optimized using a Hartree-Fock method at 6-31G* level. The regioselectivity of these reactions was studied via analysis of these stable conformations, finding that there exists the π-π stacking interaction between the ester group and the benzyl aromatic-ring in the molecule. The π-π stacking interaction resulted in somewhat shield on the carbonyl group from related atoms in the stable conformations, thus different regioselectivities of these reactions were obtained.

Key words: KAD-1229, bis-activated ester, regioselectivity, molecular modeling, π-π stacking interaction