Total Synthesis of (±)-Brussonol and (±)-Komaroviquinone via a Regioselective Cross-Electrophile Coupling of Aryl bromides and Epoxides

This paper details the total synthesis of two related natural diterpenes, (±)-Brussonol and (±)-Komaroviquinone. The authors utilize a metal-catalyzed cross-electrophile coupling strategy to join an aryl bromide with a functionalized epoxide, serving as the foundation for building the complex carbon skeletons of these molecules. By employing nickel-catalyzed conditions with zinc dust as a reductant, they achieve a regioselective coupling that facilitates access to the desired molecular architectures.

The synthetic route begins with the construction of a spiro-epoxide intermediate from a substituted cyclohexanone derivative. This epoxide is then coupled with an aryl bromide in the presence of a nickel catalyst and specialized ligand (4,4'-dimethoxy-2,2'-bipyridine). This key coupling effectively joins the aromatic portion of the natural product to the bicyclic core. The resulting intermediate is subsequently elaborated through a series of transformations—including acetal formation, cyclization, and oxidative treatments—to reach the final products. The methodology is showcased by the efficient delivery of both (±)-Brussonol and (±)-Komaroviquinone, with spectral data matching previously reported values for these compounds.

Total synthesis of natural products like Brussonol and Komaroviquinone is essential for confirming structural assignments and establishing scalable pathways to biologically active structures. The use of nickel-catalyzed cross-electrophile coupling, an increasingly powerful tool in synthetic organic chemistry, demonstrates a modern approach to assembling complex structures without the need for traditional pre-functionalized organometallic reagents. This route highlights the utility of coupling simple, readily available precursors to reach sophisticated scaffolds efficiently.