Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
Medicinal Chemistry Department, Neuroscience Discovery Research, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
Nat Chem. 2022 Sep;14(9):1068-1077. doi: 10.1038/s41557-022-00979-0. Epub 2022 Jul 21.
Strained bicyclic substructures are increasingly relevant in medicinal chemistry discovery research because of their role as bioisosteres. Over the last decade, the successful use of bicyclo[1.1.1]pentane (BCP) as a para-disubstituted benzene replacement has made it a highly valuable pharmacophore. However, various challenges, including limited and lengthy access to useful BCP building blocks, are hampering early discovery research. Here we report a single-step transition-metal-free multi-component approach to synthetically versatile BCP boronates. Radicals derived from commonly available carboxylic acids and organohalides perform additions onto [1.1.1]propellane to afford BCP radicals, which then engage in polarity-matched borylation. A wide array of alkyl-, aryl- and alkenyl-functionalized BCP boronates were easily prepared. Late-stage functionalization performed on natural products and approved drugs proceeded with good efficiency to generate the corresponding BCP conjugates. Various photoredox transformations forging C-C and C-N bonds were demonstrated by taking advantage of BCP trifluoroborate salts derived from the BCP boronates.
张力环双环结构在药物化学发现研究中越来越重要，因为它们是生物等排体。在过去十年中，双环[1.1.1]戊烷（BCP）作为对位二取代苯的替代品得到了成功应用，使其成为一种极具价值的药效团。然而，各种挑战，包括有限且冗长的获得有用的 BCP 构建块的途径，阻碍了早期的发现研究。在这里，我们报告了一种单步过渡金属免费多组分方法，用于合成多功能 BCP 硼酸酯。通常可获得的羧酸和有机卤化物衍生的自由基对[1.1.1]丙二烯进行加成，得到 BCP 自由基，然后进行极性匹配的硼化反应。很容易制备各种烷基、芳基和烯基官能化的 BCP 硼酸酯。在天然产物和已批准药物上进行的后期官能化反应，效率良好，生成相应的 BCP 缀合物。通过利用从 BCP 硼酸酯衍生的 BCP 三氟硼酸盐盐，展示了各种用于形成 C-C 和 C-N 键的光氧化还原转化。
