The replacement of aryl rings with C(sp<sup>3</sup>)-rich structures has garnered increasing interest in drug discovery due to the often-improved pharmacokinetic properties upon substitution. In particular, bicyclo[1.1.1]pentanes (BCPs) have been extensively shown to be valuable replacements for 1,4-<i>para</i>-substituted arene rings. To this end, a litany of methods exist to synthesize these 1,3-substituted BCPs from [1.1.1]propellane, via strain-release opening of the internal C–C bond by radicals or anionic metal complexes. However, general and rapid syntheses of 1,2- or 1,2,3-substituted BCPs, which could be valuable replacements for 1,2- or 1,3-substituted arene rings, remain elusive. As such, the development of a protocol to rapidly access a common precursor to diverse 1,2- or 1,2,3-substituted BCPs would be of high interest to the medicinal chemistry community. Herein, we leverage a photoredox approach to access a diverse array of 2-substituted BCPs, including BCP analogues of known pharmaceuticals.

Synthesis of strained polycyclic scaffolds by photoredox catalysis

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ACS Fall 2022

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