A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres

C(sp(3))-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes, 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 emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Therefore, a general synthetic route to BCHs is needed if their potential as bioisosteres is to be realized. Here we describe a broadly applicable catalytic approach that delivers substituted BCHs by intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2-catalysed process works for a wide range of electron-deficient alkenes and substituted BCB ketones, operates with SmI2 loadings as low as 5 mol% and is underpinned by a radical relay mechanism that is supported by density functional theory 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.

Automated summary

A general synthetic route to substituted bicyclo[2.1.1]hexanes (BCHs) has been developed through intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2-catalysed process can be applied to a wide range of electron-deficient alkenes and substituted BCB ketones, with low loadings of SmI2. The resulting BCH ketones have been shown to be versatile synthetic intermediates and can be used for selective downstream manipulation and the expedient synthesis of a saturated hydrocarbon analogue of the broad-spectrum antimicrobial, phthalylsulfathiazole.