A Catalytic Asymmetric Intramolecular [4 + 1]-Cycloaddition for the Total Synthesis of Terpene Alkaloid Natural Products.

Intramolecular Diels-Alder reactions are privileged strategic disconnections in the synthesis of polycyclic natural products containing six-membered rings. The analogous [4 + 1]-cycloaddition may possess comparable utility in addressing [.3.0]-bicyclic frameworks. However, no viable methods suitable for natural product synthesis have been developed. Here, we report a nickel-catalyzed asymmetric intramolecular [4 + 1]-cycloaddition of a vinylidene and a 1,3-diene to form a [4.3.0]-azabicyclic product. The key vinylidene intermediate is generated reductively from a 1,1-dichloroalkene precursor, and DFT models suggest that addition to the 1,3-diene occurs by a stepwise sequence of [2 + 2]-cycloaddition, 1,3-migration, and reductive elimination. The cycloadduct features sterically differentiated tri- and tetrasubstituted alkenes that can be selectively functionalized to achieve divergent syntheses of 7--incarvilline, hydroxyincarvilline, isoincarvilline, incarvilline, tecomanine, 5-hydroxyskytanthine, and tecostanine.