Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes

Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, -butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.0 ]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/ -butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.