Facile Access to Polysubstituted Seven‐Membered Lactones via Relay Visible‐Light/Pd‐Catalyzed [3+2+2] Cycloaddition

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Comprehensive Summary A highly chemoselective palladium‐catalyzed formal [3+2+2] cycloaddition between ketenes and trimethylenemethane (TMM) synthons has been successfully established, which efficiently overrides the thermodynamically intrinsically favorable competing [3+2] cyclization pathway to form five‐membered carbocyclic byproducts. This modular three‐component annulation delivers a broad library of densely functionalized seven‐membered ( Z )‐enol ε‐lactone scaffolds in excellent isolated yields reaching up to 98%, alongside exceptional chemo‐, regio‐, and exclusive Z ‐stereoselectivity. To expand the practical synthetic scope of this transformation, a complementary relay catalytic protocol was further constructed, wherein readily accessible α‐diazoketones serve as bench‐stable ketene precursors via visible‐light‐mediated Wolff rearrangement. The synergistic combination of photochemical activation and palladium catalysis seamlessly couples in situ ‐generated ketenes with TMM to furnish identical seven‐membered lactone products with maintained high efficiency and selectivity. Furthermore, a catalytic asymmetric version of this unprecedented cycloaddition has been realized by introducing a chiral diphosphine ligand, which is a promising tool for the asymmetric synthesis of chiral medium‐ring lactone frameworks. Comprehensive mechanistic studies combining control experiments and DFT theoretical calculations elucidate the origin of the chemoselectivity. Although the [3+2] cyclization products possess more favorable thermodynamic free energies, the multi‐step [3+2+2] annulation manifold bears drastically lower kinetic energy barriers and thus dominates the overall reaction pathway. Beyond synthetic methodology development, preliminary biological evaluation of the obtained ε‐lactone derivatives uncovers their promising bioactivity, highlighting their great potential as lead antimicrobial agrochemical candidates for crop disease protection in agricultural applications.

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