Conformational Flexibility as a Tool for Enabling Site-Selective Functionalization of Unactivated sp3 C–O Bonds in Cyclic Acetals

A dual catalytic manifold that enables site-selective functionalization of unactivated sp³ C–O bonds in cyclic acetals with aryl and alkyl halides is reported. The reaction is triggered by an appropriate σ*–p orbital overlap prior to sp³ C–O cleavage, thus highlighting the importance of conformational flexibility in both reactivity and site selectivity. The protocol is characterized by its excellent chemoselectivity profile, thus offering new vistas for activating strong σ sp³ C–O linkages.