Ligand-enabled distal desaturative lactonization of aliphatic acids

Transition-metal catalysis is a fundamental strategy for transforming inert C-H bonds into valuable functional motifs^1,2. However, achieving regioselective activation of remote C-H bonds remains challenging, particularly in unbiased hydrocarbon frameworks^2,3. In this context, distal C(sp³)-H bonds are especially difficult to functionalize, as conformational flexibility favours proximal C-H activation^3,4. In this study, we demonstrate a ligand-enabled strategy using designed O-allyl amido ester ligands for palladium-catalysed activation of γ-methylene and methine C-H sites in unbiased aliphatic carboxylic acids, derived from readily available fatty and cyclic acid feedstocks. This protocol enables direct transformation of aliphatic carboxylic acid substrates into distal desaturated γ-lactones and double-dehydrogenated γ-spirolactones. Mechanistic studies are consistent with a pathway involving Pd(II)-mediated γ-C(sp³)-H activation, followed by dehydrogenation and intramolecular cyclization. These lactones, with an unsaturated arm, serve as key intermediates for the formation of complex natural products and pharmaceuticals. For instance, muricatacin (from soursop/Laxman phal) and its analogue were rapidly assembled in three steps from margaric acid using this strategy and evaluated for anticancer activity, thereby demonstrating the potential of our approach for providing a rapid access to biologically relevant frameworks for traditional medicine. The introduced distal desaturation further opens up new avenues for remote functionalization, streamlining access to diverse bioactive molecules with improved step and atom economy.