Bicyclo[1.1.0]butane: A Flexible Template for Strain-release Functionalization in Cyclobutane Synthesis

Abstract Bicyclo[1.1.0]butanes (BCBs) have emerged as powerful strain-release substrates that enable the transformation of inherently unreactive σ-bonds into versatile synthetic handles. High ring strain enables diverse functionalization reactions, providing access to densely functionalized cyclobutanes that are of interest in medicinal chemistry for their three-dimensionality, metabolic stability, and favorable pharmacokinetic behavior. These strategies offer precise control over regio-, diastereo-, and enantioselectivity while maintaining broad functional-group tolerance under mild conditions. Notably, modulation of syn- and anti-selectivity through distinct activation modes has further expanded the synthetic utility of these systems. This review summarizes recent advances in the functionalization of BCBs as strain-release precursors to functionalized cyclobutanes, with emphasis on reaction design, mechanistic understanding, and substrate scope across Lewis acid, metal-catalyzed, photocatalytic, dual photo/metal, and electrocatalytic approaches. Collectively, these developments highlight the growing importance of BCBs as key building blocks in strain-release chemistry and outline future opportunities for the development of unified catalytic strategies toward complex molecular architectures.