Facile Access to Tricyclic Molecular Architectures through Photo-Reversible Dearomative 6π-Desymmetrizations: Scope, Applications, Bioactivity Study, and Mechanistic Nuances

The synthesis of complex natural products bearing fused polycyclic architectures presents formidable synthetic challenges, yet offers significant opportunities for drug discovery. Herein, we report a photoreversible dearomative desymmetrization strategy that enables efficient access to structurally diverse tricyclic frameworks. Employing alkenyl phenol precursors, UV (ultraviolet) light (λ = 310 nm) triggers a stereoselective 6π-desymmetrization, affording four types of skeletons─including scaffolds with vicinal quaternary stereocenters. Additionally, visible light (λ = 450 nm) reverses this process, selectively deconstructing the tricyclic systems back to alkenyl phenol precursors. This methodology's utility is demonstrated through the scalable synthesis of the norzoanthamine alkaloid core, enabling the first total syntheses of 15-hydroxynorzoanthamine, norzoanthamide B, and norzoanthaminone. Subsequent anti-inflammatory profiling of these compounds revealed key structure-activity relationships (SAR) for IL-6 inhibition. Further, 6π-product <b>2r</b> emerged as a potent TNF-α inhibitor in lipopolysaccharide (LPS)-stimulated THP-1 cells, and norzoanthamine derivative <b>9</b> exhibited an antipulmonary fibrosis effect. Mechanistic studies via density functional theory (DFT) calculations elucidated the wavelength-dependent reversibility, correlating excited-state pathways with experimental photochemical control.