Type I [4σ+4π] versus [4σ+4π−1] Cycloaddition To Access Medium‐Sized Carbocycles and Discovery of a Liver X Receptor β‐Selective Ligand

Transition‐metal‐catalyzed [4+4] cycloaddition leading to cyclooctanoids has centered on dimerization between 1,3‐diene‐type substrates. Herein, we describe a [4σ+4π−1] and [4σ+4π] cycloaddition strategy to access 7/8‐membered fused carbocycles through rhodium‐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 range (>40 examples) of 5–6–7 and 5–6–8 polyfused carbocycles was obtained in good yields (up to 90 %). DFT calculations, kinetic monitoring and 13C‐labeling experiments were carried out, suggesting a plausible mechanism. Notably, one 5–6–7 tricycle 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. Type I [4σ+4π] and [4σ+4π−1] cycloadditions were developed to access synthetically challenging seven/eight‐membered fused carbocycles through rhodium‐catalyzed coupling between 4σ‐donor (benzocyclobutenones) and pendant diene (4π) motifs in good yields (up to 90 %). A mechanism was proposed based on kinetic and 13C‐labeling experiments. Notably, one product was found to be a potent and selective liver X receptor β binding ligand (KD=0.64 μM).