Regioselective copper-catalyzed domino synthesis of 7-iodobenzo[d]oxazoles as potential ERβ ligands.

Abstract

7-Halogenated benzoxazoles are a recurring motif in preclinical ligands for the estrogen receptor β (ERβ) and in other oxazole-based pharmacophores, yet selective and direct access to the 7-halo regiochemistry is not well served by classical condensation routes or by existing copper-catalyzed arylation methods. Here we report that 5-substituted 1,2,3-triiodobenzenes undergo a regioselective copper-catalyzed domino C-N/C-O arylation with primary amides to deliver 7-iodobenzoxazoles. Substrate-screening conditions implement the cascade as two in situ steps executed in a one-pot procedure. Across twenty substrate combinations explored under the two-stage protocol, yields reached up to 98% and the regiochemistry of the 7-iodo product was confirmed unambiguously by single-crystal X-ray diffraction of 7m. The reaction tolerates gram-scale execution (82% at 2.06 mmol). Using this methodology, human β-estrogen receptor 1 (7c) (AstraZeneca patent (WO2002051821)) is prepared in only one step with excellent regioselectivity and isolated yield. A subset of the 7-iodobenzoxazoles was evaluated in silico against the ERβ ligand-binding domain by convolutional-neural-network-guided and diffusion-based docking (GNINA and DiffDock), followed by 200 ns AMBER22 molecular dynamics and MM/GBSA free-energy calculations; 7g and 7e emerged as candidate scaffolds with MM/GBSA ΔGtotal values of -31.2 and -28.6 kcal mol-1, respectively, and reproducible binding poses centred on a conserved Met336 anchor.