異喹啉衍生物的不對稱氫化研究

周永貴 時磊 葉智識

摘 要：該研究針對異喹啉的結構特點及其氫化中存在的難點，設計了采用芐溴衍生物活化異喹啉成鹽的策略。這一策略的設計主要是基于以下幾點考慮：（1）芐溴衍生物與吡啶反應成鹽可以有效地消除吡啶的強配位能力對催化劑的毒化作用，同時，吡啶成鹽后芳香性被破壞，提高了其反應活性。（2）芐基吡啶鹽的氫化過程中原位生成的溴化氫可有效地抑制產物哌啶與催化劑的配位作用。（3）氫化產物中的芐基保護基可以通過氫解方便的去除。經過詳細的條件篩選，采用手性銥催化劑成功實現了異喹啉鹽的不對稱氫化，該反應能獲得優異的轉化率和對映選擇性，氫化產物的對映體過量值最高可達96%。此外，采用該反應作為關鍵步驟，以85%的總收率完成了手性藥物索利那新（+）-Solifenacin的全合成。

關鍵詞：異喹啉 不對稱氫化 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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