Programmable Divergence in Conia-ene and Hydroarylation Pathways for Collective Synthesis of Skeletally Diverse Alkaloid-like Scaffolds

The divergent synthesis of nitrogen-containing multicyclic scaffolds with quaternary carbon centers at ring junctions remains a major challenge. This study has developed a versatile and programmable platform for the collective synthesis of four distinct tetracyclic alkaloid-like scaffolds 2–5 via regio-controlled intramolecular cyclizations of alkynyl-substituted azepinoindole precursors 1, a privileged scaffold relevant to biologically intriguing indole alkaloids with anticancer and antiaddictive properties. By integrating Zn(OTf)2-mediated and Au(I)-catalyzed strategies, we achieved precise control over divergent cyclization pathways. Zn(OTf)2-mediated Conia-ene-type reaction for monocarbonyl substrate 1 proceeded under neutral conditions in t-BuOH, affording the 5-exo product 2 (up to 76%) while effectively suppressing β-elimination. In contrast, Au(I)-catalyzed hydroarylation selectively afforded 6-exo spirocycle 3 (up to 90%). A phenyl-substituted alkyne enabled regio-controlled hydroarylation, furnishing the 7-endo spirocycle 5 (up to 78%) by stabilizing the transition state via resonance effects. Furthermore, the strategic use of methanesulfonic acid and protic solvents (hexafluoroisopropanol or t-BuOH) facilitated C5 enol formation, promoting Au(I)-catalyzed Conia-ene-type 6-endo pathways to afford 4 (up to 82%). This study establishes a systematic and rational approach for the programmable synthesis of skeletally diverse tetracyclic alkaloid-like scaffolds, demonstrating a versatile strategy for constricting quaternary carbon centers and intricate natural product-like architectures.