美国普林斯顿大学MacMillan, David W. C.团队报道作为苯生物异构体立方烷的通用制备方法。相关研究成果于2023年4月4日发表在国际顶尖学术期刊《自然》。

在候选药物中用sp3-杂交生物异构酶取代苯环通常可以改善药代动力学特性，同时保持生物活性。刚性应变框架，如双环[1.1.1]戊烷和立方烷，特别适合，因为环应变赋予其高键强度，从而赋予其C–H键代谢稳定性。立方烷是理想的生物异山梨醇，因为它提供了与苯最接近的几何匹配。然而，目前，药物设计中的所有立方烷，就像几乎所有的苯生物异山梨醇一样，都只能作为单取代或对取代苯环的替代品。这是由于难以获得1,3-和1,2-二取代的立方烷前体。由于竞争性金属催化的价异构，交叉偶联反应与立方烷支架的相容性较差，进一步阻碍了立方烷在药物设计中的应用。

该文中，研究人员分别报告了使用方便的环丁二烯前体和光解的C–H羧化反应制备1,3-和1,2-二取代立方烷构建块的有利途径。此外，利用铜的缓慢氧化添加和快速还原消除来开发C–N、C–C（sp3）、C–C（sp2）和C–CF3交叉偶联协议。该研究使所有立方烷异构体能够容易地制备成候选药物，从而实现邻位、间位和对位取代苯的理想生物同位替代。

附：英文原文

Title: General Access to Cubanes as Benzene Bioisosteres

Author: Wiesenfeldt, Mario P., Rossi-Ashton, James A., Perry, Ian B., Diesel, Johannes, Garry, Olivia L., Bartels, Florian, Coote, Susannah C., Ma, Xiaoshen, Yeung, Charles S., Bennett, David J., MacMillan, David W. C.

Issue&Volume: 2023-04-04

Abstract: The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity1–5. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well-suited since the ring strain imparts high bond strength and thus metabolic stability on its C–H bonds. Cubane is the ideal bioisostere since it provides the closest geometric match to benzene6,7. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings1–7. This is due to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the poor compatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalyzed valence isomerization8–11. Herein, we disclose expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C–H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C–N, C–C(sp3), C–C(sp2), and C–CF3 cross-coupling protocols12,13. Our research enables facile elaboration of all cubane isomers into drug candidates thus enabling ideal bioisosteric replacement of ortho-, meta-, and para-substituted benzenes.

DOI: 10.1038/s41586-023-06021-8

Source: https://www.nature.com/articles/s41586-023-06021-8