Synthesis of Chiral Polycyclic Indoles via Pd(II)-Catalyzed Sequential Cyclization and Carbonylation

Asymmetric tandem Heck and carbonylation reactions provide an efficient route to synthesize biologically important chiral cyclic compounds with a carbonyl group and have attracted increasing research interests. However, this type of reaction relies on the initiation from the oxidative addition of aryl halides or pseudo halides, resulting in a low atomic economy of the reaction. In addition, this protocol has not adequately demonstrated the reactivity and generality of heteroarene halides. Meanwhile, the asymmetric Wacker-type cyclization and carbonylation reactions are plagued by narrow substrate scope and low enantioselectivity and remain underexplored. Herein, we describe a Pd(II)-catalyzed asymmetric sequential cyclization and carbonylation reaction of 1,6-enynes and analogues with carbon monoxide (CO). This catalytic system tolerates a broad scope of nucleophiles, including phenols, alcohols, and amines. This reaction sequence forms four chemical bonds, two rings, and up to three stereocenters in a single step. This strategy allows for the convenient access to a variety of polycyclic compounds in good yields with good enantio- and diastereoselectivities, including indoles, benzofurans, indole- or benzofuran-fused bicyclo[3.2.1]octanes, and indole-fused bicyclo[4.2.1]nonane.