Remote Stereocontrol in the C6-Functionalization of Indoles via Synergistic Ion-Pair Catalysis

Remote stereocontrol is a long-standing challenge in synthetic chemistry due to the diminishing influence of a catalyst’s chiral environment over extended distances. This limitation is particularly pronounced in the enantioselective C6-functionalization of indoles, a transformation of significant interest in pharmaceutical research and natural product synthesis. We herein present a visible-light-induced direct asymmetric C6-functionalization of indoles achieved through synergistic dual catalysis employing a chiral phosphoric acid and magnesium sulfate, which achieves precise remote stereocontrol. The reaction proceeds via an alkyne-carbonyl metathesis/1,6-addition cascade involving arylalkynes, benzoquinones, and indoles. This strategy facilitates the de novo synthesis of diverse enantioenriched indoles with acyclic all-carbon quaternary chiral centers at the C6 position, delivering high yields and enantioselectivities from simple and readily available starting materials. Moreover, the resulting products can be easily transformed into a range of structurally diverse molecules with all-carbon quaternary chiral centers, which are otherwise difficult to synthesize with a high enantiomeric purity. Several products also exhibit promising anticancer activities, highlighting their potential pharmaceutical relevance. Computational and experimental investigations reveal that magnesium sulfate significantly promotes the formation of the reaction precursor (binding free energy: −68.5 kcal/mol), demonstrating its strong capacity to bind reactant components even at low concentrations, which would markedly enhance the reaction productivity, as long as the reaction barrier is feasible. Moreover, magnesium sulfate promotes parallel π–π stacking interactions between the aromatic ring of the para-quinone methide intermediate and the indole ring, thereby enhancing both reactivity and enantioselectivity.