%0 Journal Article
%T Type I [4σ+4π] versus [4σ+4π-1] Cycloaddition To Access Medium-Sized Carbocycles and Discovery of a Liver X Receptor β-Selective Ligand.
%A Jiang C
%A Hu L
%A Shen S
%A Zhang J
%A Wang X
%A Ma D
%A Lu G
%A Xu T
%J Angew Chem Int Ed Engl
%V 63
%N 28
%D 2024 Jul 8
%M 38647574
%F 16.823
%R 10.1002/anie.202405838
%X 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.