Bicyclo [1.1.1]pentanes (BCPs) are saturated phenyl bioisosteres that have been recently popularized within drug discovery (Scheme 1A). Over the past decade, there have been significant advances in synthetic methods for producing and functionalizing this ring system. Bicyclo [1.1.0]butanes (BCBs), despite being isolated and characterized many decades ago , are far less commonly represented in reported bioactive compounds. Reports of bioactive compounds containing BCBs include one biosynthesized fatty acid , but primarily include bridgehead-substituted BCBs in which the BCB serves as a pseudo-Michael acceptor for covalent modification by a biological target (Scheme 1B). Curiously, BCBs have less ring strain (64-66 kcal/mol) than BCPs (67-68 kcal/mol). Nevertheless, the high s-character of the bridgehead carbons allows BCBs to react with electrophiles, nucleophiles, carbenes, and radicals. BCBs are beginning to be employed more broadly in drug discovery as covalent modulators (Scheme 1B) and as building blocks for the construction of sp 3 -rich molecules. The increased chemical stability of disubstituted BCBs suggests they could be incorporated into final drug molecules. Much of the literature describing the synthesis of BCBs concerns intramolecular substitution reactions of cyclobutyl and cyclopropyl carbanions or intramolecular [2+1] reactions with carbenes. Synthetic routes to BCBs starting from commercial materials that do not require the preparation of [1.1.1]propellane would be most ideal.