Catalytic Stereoselective Inverse Electron Demand Formal Aza-Diels–Alder: Access to Highly Congested Molecular Bowl-Shaped 3D Tertiary Amines

Abstract Diastereoselective sp3-rich heteroatom-based bowl-shaped polycyclic molecules are a key structural scaffold in various bioactive molecules. Due to the inherent steric congestion of these structures, achieving precise stereochemical control remains a significant challenge in contemporary synthetic chemistry. We herein disclose a practical iron-catalyzed assembly of an indole-derived tertiary amine-based pentacyclic molecule through an intermolecular, iminium-triggered dearomative inverse electron-demand formal aza-Diels–Alder (IEDFADA) reaction. Detailed computational and deuterium labelling experiments strongly suggest that the diastereoselective formation of this complex core involves a stepwise in situ generation of a short-lived, highly reactive azadiene. Moreover, the negative slope (ρ = –0.29) from the Hammett plot indicates the formation of a partial positive charge and that the electron-donating groups enhance the reaction rate. Notably, the concise tagging of drug molecules and downstream synthetic transformations with good yields and diastereoselectivity should highlight the potential applications of this methodology in drug discovery settings in medicinal chemistry.