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

Abstract

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.