Tang Si-Yuan, Wang Zhan-Jie, Wu Jin-Jiao, Xing Zhi-Xi, Du Ze-Yi, Huang Huan-Ming
School of Physical Science and Technology, ShanghaiTech University Shanghai 201210 China
Department of Medicinal Chemistry, School of Pharmacy, Fudan University No. 826 Zhangheng Road Shanghai 201203 China.
Chem Sci. 2025 May 26. doi: 10.1039/d5sc02836a.
Development of new synthetic strategies to prepare C(sp)-rich arene bioisosteres, especially their heteroatom incorporating analogs, is less explored, but highly in demand. Here we report a photocatalytic [2π + 2σ] cycloaddition reaction between bicyclo[1.1.0]butanes and aldehydes enabled by cobalt under visible light irradiation. The key step is that bicyclo[1.1.0]butanes could be oxidized to generate radical cation intermediates which could be promoted by cobalt, facilitating a nucleophilic addition to the aldehydes. This unprecedented strategy exhibits broad functional group tolerance and efficiently constructs complex molecular architectures and derivatives of natural products with good to excellent yields. Detailed mechanistic studies and product manipulation have demonstrated the viability of this open-shell approach. The desired 2-oxa-BCH motif demonstrated excellent acidity tolerance and significantly enhanced lipophilicity potentially leading to enhanced metabolic properties and bioactivities compared to its parent phenyl-type bioisostere.
开发用于制备富含C(sp)的芳烃生物电子等排体的新合成策略，特别是其含杂原子的类似物，目前研究较少，但需求很大。在此，我们报道了在可见光照射下，钴催化双环[1.1.0]丁烷与醛之间的光催化[2π + 2σ]环加成反应。关键步骤是双环[1.1.0]丁烷可以被氧化生成自由基阳离子中间体，该中间体可以被钴促进，从而促进对醛的亲核加成。这种前所未有的策略具有广泛的官能团耐受性，能够高效构建复杂的分子结构和天然产物衍生物，产率良好至优异。详细的机理研究和产物操作证明了这种开壳方法的可行性。与母体苯基型生物电子等排体相比，所需的2-氧杂-BCH基序表现出优异的耐酸性和显著增强的亲脂性，这可能导致代谢性质和生物活性增强。
