School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, 100084, China.
Nat Commun. 2024 Jan 31;15(1):941. doi: 10.1038/s41467-024-45140-2.
Stereoisomeric polycyclic natural products are important for drug discovery-based screening campaigns, due to the close correlation of stereochemistry with diversified bioactivities. Nature generates the stereoisomeric yohimbine alkaloids using bioavailable monoterpene secolaganin as the ten-carbon building block. In this work, we reset the stage by the development of a bioinspired coupling, in which the rapid construction of the entire pentacyclic skeleton and the complete control of all five stereogenic centers are achieved through enantioselective kinetic resolution of an achiral, easily accessible synthetic surrogate. The stereochemical diversification from a common intermediate allows for the divergent and collective synthesis of all four stereoisomeric subfamilies of yohimbine alkaloids through orchestrated tackling of thermodynamic and kinetic preference.
立体异构多环天然产物对于基于药物发现的筛选活动非常重要，因为立体化学与多样化的生物活性密切相关。自然界使用生物可利用的单萜 secologanin 作为十碳构建块来产生立体异构育亨宾生物碱。在这项工作中，我们通过开发一种受生物启发的偶联反应重新设定了舞台，通过对非手性、易于获得的合成替代物进行对映选择性动力学拆分，快速构建整个五环骨架并完全控制所有五个手性中心，从而实现了这一目标。从常见中间体进行的立体化学多样化允许通过协调解决热力学和动力学偏好，对育亨宾生物碱的所有四个立体异构亚家族进行发散和集体合成。
