Type I [4σ+4π] versus [4σ+4π-1] Cycloaddition To Access Medium-Sized Carbocycles and Discovery of a Liver X Receptor
Cheng Jiang1, Lingfei Hu2, Shuna Shen1
1Molecular Synthesis Center & Key Laboratory of Marine Drugs, Ministry of Education; School of Medicine and Pharmacy, Laboratory for Marine Drugs and Bioproducts of Marine Natural Products, Ocean University of China, 5 Yushan road, Qingdao, 266003, China.
Abstract:
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.
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