Department of Chemistry, National University of Singapore, Singapore, Singapore.
School of Chemistry and Chemical Engineering, Chongqing Key Laboratory of Theoretical and Computational Chemistry, Chongqing University, Chongqing, China.
Nat Chem. 2020 Sep;12(9):860-868. doi: 10.1038/s41557-020-0503-7. Epub 2020 Jul 27.
Medium-sized rings, including those embedded in bridged and fused bicyclic scaffolds, are common core structures of myriad bioactive molecules. Among various synthetic strategies towards their synthesis, intermolecular higher-order cycloaddition provides great potential to build complex medium-sized rings from simple building blocks. Unfortunately, such transformations are often plagued with competitive reaction pathways and low levels of site- and stereoselectivity. Herein, we report catalyst-controlled divergent access to three classes of medium-sized bicyclic compounds in high efficiency and stereoselectivity, by palladium-catalysed cycloadditions of tropones with γ-methylidene-δ-valerolactones. Mechanistic studies and density functional theory calculations disclosed that the divergent reactions stem from the different reaction profiles of the diastereomeric intermediates. While one undergoes either O- or C-allylation to provide [5.5.0] or [4.4.1] bicyclic compounds, the unique conformation of the other diastereomer allows an unconventional alkene isomerization to deliver bridgehead alkene-containing bicyclo[4.4.1] compounds. The conversion of these products to diverse complex polycyclic scaffolds has also been demonstrated.
中等大小的环，包括那些嵌入桥环和稠合双环支架中的环，是无数生物活性分子的常见核心结构。在合成这些环的各种方法中，分子间的高阶环加成反应为从简单的构建块构建复杂的中等大小的环提供了巨大的潜力。然而，这种转化通常受到竞争反应途径和低的位点和立体选择性的困扰。在此，我们报告了钯催化的螺环酮与γ-亚甲基-δ-戊内酯的环加成反应，以高效和立体选择性地控制不同的方法得到三类中等大小的双环化合物。通过机理研究和密度泛函理论计算揭示，不同的反应途径源于非对映异构体中间体的不同反应轮廓。其中一个中间体经历 O-或 C-烯丙基化反应，提供[5.5.0]或[4.4.1]双环化合物，而另一个非对映异构体的独特构象允许非常规的烯烃异构化，从而得到桥环烯基含有的双环[4.4.1]化合物。还证明了这些产物可以转化为各种复杂的多环支架。
