Access to unsaturated bicyclic lactones by overriding conventional C(sp3)–H site selectivity

Abstract

AbstractTransition metal catalysis plays a pivotal role in transforming unreactive C–H bonds. However, regioselective activation of distal aliphatic C–H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C–H bond in the presence of methyl C–H is underexplored. Here we show activation of a methylene C–H bond in the presence of methyl C–H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C–H bond activation. Computational studies suggest that reversible C–H activation is followed by β-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C–O cyclization, and subsequent β-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C–H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.