Decoding skeletal diversity and complexity: A biomimetic and photochemical remodeling strategy

Constructing three-dimensional polycyclic scaffolds from a single precursor is a long-standing challenge in organic synthesis. Inspired by our proposed biosynthetic pathway of marine natural product ocellatusone C ( 1 ), we achieved its concise biomimetic synthesis from tridachiahydropyrone ( 2 ) through an acid-triggered cascade featuring a Dieckmann-type cyclization. This transformation further established a platform for skeletal diversification, yielding a series of [3.3.1] bicyclic analogs with broad functional tolerance. Guided by density functional theory (DFT) calculations, we uncovered a light-induced skeletal reorganization that efficiently generates elusive polycyclic architectures. Mechanistic investigations integrating DFT calculations and quasi-classical dynamics simulations revealed that selectivity in a critical vinylcyclopropane-cyclopentene rearrangement arises from post-spin crossing dynamic effects. Cross-coupling further expanded these scaffolds into a focused library of complex molecules. The bioassays indicated that these architecturally diverse systems have substantial antimalarial bioactivity, highlighting their potential as drug leads.