Modular Synthesis of C2-Substituted Bicyclo[1.1.1]pentanes via Photocatalysis

Image SourceJ. Am. Chem. Soc. Abstract:Bicyclo[1.1.1]pentanes (BCPs) play a crucial role as saturated bioisosteres for planar phenyl rings. As strategic three-dimensional substitutes for ortho- or meta-substituted aromatics, C2-substituted BCPs provide an opportunity to access an underexplored chemical space. Finding efficient and broadly applicable synthetic routes for these scaffolds remains a significant challenge, primarily due to the unique topological features of the BCP core. Here, Professor Bin Tan from Southern University of Science and Technology presents a robust and modular strategy for the direct synthesis of C2-substituted BCPs from readily available bicyclo[1.1.0]butanes (BCBs) and diazo compounds. Utilizing the homolytic cleavage of the central bond in BCBs, a carbene insertion process initiated by triplet energy transfer occurs, forming 1,4-diboryl radical species, which are ultimately converted to the target BCPs through rapid radical recombination. This method establishes a modular platform for systematically generating C2-functionalized BCP structures, allowing for rapid diversification of the three-dimensional scaffolds. Its practicality has been further demonstrated by collectively replacing phenyl groups with bioisosteric BCPs in 15 bioactive molecules.Image SourceJ. Am. Chem. Soc. Image SourceJ. Am. Chem. Soc. Image SourceJ. Am. Chem. Soc. Image SourceJ. Am. Chem. Soc. Image SourceJ. Am. Chem. Soc. Image SourceJ. Am. Chem. Soc. Conclusion:

Professor Bin Tan from Southern University of Science and Technology has developed a modular approach to construct C2-substituted bicyclo[1.1.1]pentanes (BCPs) through an energy transfer (EnT) mediated intermolecular triplet carbene insertion reaction into BCBs. By decarboxylation functionalization of the resulting BCPs at the bridgehead and bridge positions, a diverse array of functionalized BCPs has been successfully prepared.

Importantly, the replacement of phenyl rings with three-dimensional bioisosteric BCPs has been successfully achieved in 15 drug molecules. This not only highlights the robustness and practicality of this method but also showcases its broad application prospects in the field of medicinal chemistry. Mechanistic studies indicate that triplet carbene addition, ring inversion, and 1,4-diboryl radical coupling are key steps in this reaction.

Crucially, this triplet reaction pathway does not produce diene byproducts, which distinctly differentiates it from the singlet dibromocarbene pathway, indicating that the radical coupling process is faster than the competing cleavage process. Achieving catalytic asymmetric control of this transformation via light-induced triplet carbene insertion remains an unresolved challenge. Ongoing research is currently underway.

References:

Triplet Carbene Insertion Enables Modular Access to C2-Substituted Bicyclo[1.1.1]pentanesJ. Am. Chem. Soc. 2025https://doi.org/10.1021/jacs.5c10649