Construction of Fused–Bridged Tricycles by Molecular Reorganization Involving Prins Cyclization/Dicycloexpansion

Abstract The development of efficient methods for constructing structurally complex and diverse polycyclic carbon frameworks remains in high demand for the synthesis of pharmaceuticals and bioactive natural products. One such method lies in engineered one‐step molecular reorganization through the cascade cyclization/cycloexpansion of rationally designed precursors with interconnected small‐ring systems. Here, we have strategically designed and developed a synthetically valuable method to construct fused‐bridged tricyclic systems through cascade Prins cyclization/dicycloexpansion of substrates with a cycloalkylidene (CAD) tethered to a cycloketones. This methodology features high step economy, reaction efficiency, and selectivity, as well as a broad substrate tolerance. Diversification through variation of the size of the small ring, the linker length, and the linking site has enabled the efficient synthesis of six types of fused‐bridged tricyclic scaffolds, which are found frequently in bioactive natural products. Based on supporting experiments and DFT calculations, a plausible reaction mechanism is also proposed.