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.
Keywords: Agonist; Benzocyclobutenone; C-C activation; LXRs; Type I and II cycloaddition.
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