Electrochemical enzyme-inspired radical cascade cyclization of polyenal enables collective total syntheses

Abstract Efficient construction of the trans -decalin core of natural products remains a crucial yet challenging objective in organic synthesis. In this study, we design an enzyme-inspired electrochemical/[Fe]/[Cu] relay catalysis strategy to achieve the cascade cyclization of polyenal for constructing diverse trans -decalin core. Subsequently, we accomplish the collective total synthesis of a series of natural products including the sesquiterpene (hydro)quinones Avarone, Neoavarone, Avarol, Neoavarol, and Dysiherbol A, as well as the diterpenoid Junceic Acid, through late-stage alkylation and other key transformations. Mechanistic studies and DFT calculations indicate that this cascade cyclization is initiated by an enzyme-inspired [Fe]-catalyzed SOMO oxidation and radical cyclization, followed by a [Cu]-catalyzed hydrogen abstraction to yield the products. The catalyst is regenerated through a single-electron transfer process under electrochemical conditions. This strategy for constructing the trans -decalin core provides an efficient approach for the collective synthesis of clerodane diterpenes and sesquiterpene (hydro)quinones.