Propellane-free access to bicyclo[1.1.1]pentanes

Bicyclo[1.1.1]pentane (BCP) has emerged over the past decade as a valuable three-dimensional bioisostere for benzene, attracting considerable interest in pharmaceutical research for its ability to improve drug-like properties. Although [1.1.1]propellane has traditionally served as the key precursor to mono- and 1,3- disubstituted BCPs, the growing demand for multisubstituted and bridge-functionalized BCP derivatives has spurred the development of alternative, propellane-free synthetic strategies. Recent advances toward these highly strained and sterically hindered ring systems can be broadly organized into three mechanistic categories: intramolecular diradical couplings, carbene-mediated ring expansions, and two-electron disconnections. This Perspective highlights these emerging methodologies, assesses their scope and limitations, and offers an outlook on remaining synthetic challenges and their implications for medicinal chemistry. Bicyclo[1.1.1]pentane (BCP) is a valuable three-dimensional bioisostere of benzene. This Perspective highlights emerging, propellane-free strategies to access multisubstituted and bridge-functionalized BCP derivatives, assesses their scope and limitations, and outlines remaining challenges.