C(sp3)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes (BCPs), play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop science. Substituted bicyclo[2.1.1]hexanes (BCHs) are new emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, which to date remain difficult to access. Therefore, a general synthetic route to BCHs is urgently needed, if their potential as bioisosteres is to be realized. Here, we describe a broadly applicable catalytic approach that delivers substituted BCHs by a highly atom-economical intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2–catalyzed process embraces a wide range of electron-deficient alkenes and substituted BCB ketones, operates with loadings of SmI2 as low as 5 mol%, and is underpinned by a radical-relay mechanism that is supported by DFT calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation, and the expedient synthesis of a saturated hydrocarbon analogue of the broad spectrum antimicrobial, phthalylsulfathiazole. Our findings have provided the first general catalytic approach to the substituted BCH scaffold, and serve as a launchpad for the widespread use of this largely unexplored family of bioisosteres in medicinal chemistry.
Supporting Information file (pdf). Experimental procedures, characterisation data, spectra, X-ray data, computational data.