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用于桥连多环优势骨架多组分构建的苯基降冰片基钯物种的操控

Manipulations of phenylnorbornyl palladium species for multicomponent construction of a bridged polycyclic privileged scaffold.

作者信息

Yin Lina, Guan Ting, Cheng Jie, Pan Dongchao, Lu Jinyang, Huang Jiahui, Wu Jiaqi, Chen Xiaoli, You Taiyun, Huo Xuting, He Yuting, Pang Jiayun, Hu Qingzhong

机构信息

School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Panyu, 510006, Guangzhou, People's Republic of China.

School of Science, Faculty of Engineering and Science, University of Greenwich Medway Campus, Central Avenue, Chatham Maritime, Chatham, ME4 3RL, UK.

出版信息

Commun Chem. 2022 Oct 29;5(1):140. doi: 10.1038/s42004-022-00759-4.

DOI:10.1038/s42004-022-00759-4
PMID:36697919
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9814782/
Abstract

Hexahydromethanocarbazole is a privileged scaffold in the discovery of new drugs and photoactive organic materials due to its good balance between structural complexity and minimized entropy penalty upon receptor binding. To address the difficulty of synthesizing this highly desirable bridged polycyclic scaffold, we designed a convenient multicomponent reaction cascade as intercepted Heck addition/C-H activation/C-palladacycle formation/electrophilic attack of ANP/N-palladacycle formation/Buchwald amination. A distinguishing feature of this sophisticated strategy is the successive generation of two key phenylnorbornyl palladium species to control the reaction flow towards desired products. DFT calculations further reveal the crucial roles of CsCO and 5,6-diester substitutions on the norbornene reactant in preventing multiple side-reactions. This innovative method exhibits a broad scope with good yields, and therefore will enable the construction of natural-product-like compound libraries based on hexahydromethanocarbazole.

摘要

由于六氢甲基咔唑在结构复杂性与受体结合时最小化的熵罚之间具有良好的平衡，它在新药和光活性有机材料的发现中是一种优势骨架。为了解决合成这种非常理想的桥连多环骨架的困难，我们设计了一种便捷的多组分反应串联，即截获的Heck加成/C-H活化/C-钯环形成/ANP的亲电攻击/N-钯环形成/Buchwald胺化。这种复杂策略的一个显著特征是连续生成两个关键的苯基降冰片基钯物种，以控制反应流向所需产物。密度泛函理论计算进一步揭示了碳酸铯和降冰片烯反应物上的5,6-二酯取代在防止多种副反应方面的关键作用。这种创新方法具有广泛的适用范围且产率良好，因此将能够构建基于六氢甲基咔唑的天然产物类化合物库。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2d9/9814782/252ed209352d/42004_2022_759_Fig9_HTML.jpg
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