异喹啉衍生物的不对称氢化研究

周永贵 时磊 叶智识

摘 要：该研究针对异喹啉的结构特点及其氢化中存在的难点，设计了采用苄溴衍生物活化异喹啉成盐的策略。这一策略的设计主要是基于以下几点考虑：（1）苄溴衍生物与吡啶反应成盐可以有效地消除吡啶的强配位能力对催化剂的毒化作用，同时，吡啶成盐后芳香性被破坏，提高了其反应活性。（2）苄基吡啶盐的氢化过程中原位生成的溴化氢可有效地抑制产物哌啶与催化剂的配位作用。（3）氢化产物中的苄基保护基可以通过氢解方便的去除。经过详细的条件筛选，采用手性铱催化剂成功实现了异喹啉盐的不对称氢化，该反应能获得优异的转化率和对映选择性，氢化产物的对映体过量值最高可达96%。此外，采用该反应作为关键步骤，以85%的总收率完成了手性药物索利那新（+）-Solifenacin的全合成。

关键词：异喹啉 不对称氢化 索利那新

Asymmetric Hydrogenation of Isoqunolines

Zhou Yonggui Shi Lei Ye Zhishi

（Dalian Institute of Chemical Physics， Chinese Academy of Sciences）

Abstract：Asymmetric hydrogenation of isoquinolines is still one of the important challenges that remain unmet. In an activated N-benzyl isoquinolinium form， the isoqunolines substrates can be smoothly hydrogenated with excellent activity and enantioselectivity and the value of ee is up to 96%. This substrate activation not only destroys the aromaticity of isoquinoline to enhance the reactivity but also efficiently avoid the coordination between catalyst and substrates. Besides， the poison effect of amine product would be suppressed due to the formation of salt with the acid generated during the hydrogenation. Moreover， using asymmetric hydrogenation of N-benzyl isoquinolinium as the key step， a total synthesis of （+）-Solifenacin， a urinary antispasmodic drug， is completed in 85% overall yield.

Key Words：Isoquinoline；Asymmetric hydrogenation；Solifenacin

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