Palladium-Catalyzed [7 + 5] and Higher-Order Annulations of Oxa-1,n-dipoles: Synthesis of 12- to 15-Membered Lactones

Macrolactones are commonly found in natural products and pharmaceuticals. Herein, we present Pd-catalyzed [7 + 5] and higher-order annulations between unprecedented oxa-1,n-dipoles (n = 7-9) with active enol lactones. This protocol enables the rapid synthesis of complex 12 to 15-membered lactones bearing internal <i>E</i>-alkenes. Density functional theory calculations have revealed the favorable reaction pathway and identified coordination interactions between active enol lactones and palladium centers of π-allyl dipole species as key factors in manipulating these dipoles in annulations.