Type I [4σ + 4π] vs [4σ + 4π ‐ 1] Cycloadditions Accessing Medium‐Sized Carbocycles and Discovery of a Liver X Receptor β‐Selective Ligand

The transition‐metal‐catalyzed [4 + 4] cycloaddition leading to cyclooctanoids has been centralizing on dimerization between 1,3‐diene type substrates. Here, we extend a [4σ + 4π ‐ 1] and [4σ + 4π] cycloaddition strategy to access the 7/8‐membered fused carbocycles through Rh‐catalyzed coupling between the 4σ‐donor (benzocyclobutenones) and pendant diene (4π) motifs. The two pathways can be controlled by adjusting the solvated CO concentration. A broad scope (>40 examples) of 5‐6‐7 and 5‐6‐8 polyfused carbocycles was obtained with good yields (up to 90%). The density functional theory (DFT) calculations, kinetic monitoring and 13C‐labeling experiments were carried out, suggesting a plausible mechanism. Notably, the 5‐6‐7 tricycle 2v was found to be a very rare, potent, and selective ligand for the liver X receptor β (KD=0.64 μM), which is a potential therapeutic target for cholesterol‐metabolism‐related fatal diseases.