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.
