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NATURE CHEMISTRY
Volume -, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41557-023-01295-x
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Transition metal catalysis plays a crucial role in activating unreactive C-H bonds. However, selectively activating distal aliphatic C-H bonds without directing templates is highly challenging. In this study, we demonstrated the activation of a methylene C-H bond in the presence of methyl C-H bonds to form unsaturated bicyclic lactones. This method enables the reversal of general selectivity in aliphatic C-H bond activation and simplifies the synthesis of important bicyclic lactones found in natural products and pharmaceuticals.
Transition 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 beta-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C-O cyclization, and subsequent beta-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.
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