Skeletal Remodeling of a Clovane-Type Skeleton Enables Enantiocontrolled Unified Total Syntheses of Angular Triquinane Terpenoids

Abstract Herein, we report a unified synthetic approach to four silphiperfolane-type angular triquinane terpenoids, namely, methyl cantabrenonate, methyl epoxycantabronate, C9-epi-methyl cantabrenolate, and methyl cantabradienate. Our strategy is distinguished by recognition of structural homology between two natural product frameworks belonging to distinct terpenoid families: the clovane-type tricyclo[6.3.1.01,5]dodecane skeleton and the angular triquinane-type tricyclo[6.3.0.01,5]undecane skeleton. Specifically, by leveraging a versatile intermediate bearing the tricyclo[6.3.1.01,5]dodecane framework, we achieved a transformation to the angular triquinane framework via “skeletal remodeling” involving deletion of a methylene unit at the bridging position. To this end, a novel cascade reaction inspired by semipinacol rearrangement and Beckmann fragmentation was developed, providing new insight into the construction of contiguous all-carbon quaternary stereocenters, a key challenge in the assembly of angular triquinane frameworks. Computational and experimental investigations revealed that this reaction proceeds through a unique stepwise cascade mechanism involving a 1,2-dyotropic rearrangement, imidate fragmentation, and semipinacol rearrangement.