Copper-Mediated Synthesis of Drug-like Bicyclopentanes

Multicomponent reactions (MCRs) have become a mainstay in both academic and industrial synthetic organic chemistry due to their step- and atom-economy advantages over traditional synthetic sequences(1). Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of benzene rings, and, in particular, 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements(2). Often these structures are generated from [1.1.1]propellane via opening of the internal C─C bond, either through the addition of radicals or metal-based nucleophiles (3-13). The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective to date, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Herein we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short time scales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has substantially different pharmacokinetic properties to those of its commercial progenitor.