Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (-)-morphine
Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (-)-morphine
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全碳四元立构中心顺式氢苯并呋喃的对映选择性合成及其在(-)-吗啡全合成中的应用
DOI：
10.1038/s41467-019-10398-4
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发表时间：
2019-06-07
影响因子：
16.6
通讯作者：
Tu, Yong-Qiang
中科院分区：
文献类型：
--
作者：
Zhang, Qing;Zhang, Fu-Min;Tu, Yong-Qiang
（-）-吗啡被世界卫生组织列为基本药物，广泛应用于疼痛相关疾病的治疗。由于其具有合成挑战性的分子结构和重要的临床作用，已经进行了广泛的吗啡型生物碱的合成研究。然而，催化不对称全合成（-）-吗啡仍然是一个长期的挑战。在这里，我们公开了一种有效的对映选择性全合成（-）-吗啡在最长的线性序列的16个步骤。关键的转化具有高度对映选择性的罗宾逊环化，使我们的螺-吡咯烷催化剂，以快速构建密集官能化的顺式-氢二苯并呋喃框架含有邻位立体中心与全碳季中心。这种不对称合成方法为合成（-）-吗啡及其类似物提供了一种新的合成方法。
(-)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (-)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (-)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (-)-morphine and its analogues.