Copper‐Mediated Selective Hydroxylation of a Non‐activated C−H Bond in Steroids: A DFT Study of Schönecker's Reaction

Abstract

The regio- and stereoselective copper-mediated hydroxylation of a non-activated aliphatic C-H bond in steroids by dioxygen, initially reported by Schönecker et al. (Angew. Chem. Int. Ed. 2003, 42, 3240-3244), has recently evolved into a valuable synthetic tool. In the present work, a detailed mechanistic density functional theory (DFT) study addressing the origin of the remarkable selectivity of Schönecker's reaction is reported. The applied BLYP-D3/def2-TZVP(SDD) level of DFT is benchmarked against experimental and coupled-cluster reference data. The resulting mechanistic scenario involves formation of a bis-μ-oxo dicopper complex as key intermediate. In this complex three C-H bonds of the pendant steroid ligand are predisposed towards intramolecular activation by the bis-μ-oxo dicopper core. The lowest activation barrier (12.0 kcal mol^-1 ) is computed for β-hydroxylation at the C12 position, in agreement with the experimental observations. Natural bond orbital (NBO) analysis reveals stabilizing orbital interactions that favor the β-hydroxylation pathway over competing reaction channels.