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

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• 作者：Dr. Puneet Gupta ; Dr. Martin Diefenbach ; Prof. Dr. Max C. Holthausen and Moritz Fö ; rster
• 刊名：Chemistry - A European Journal
• 出版年：2017
• 出版时间：January 26, 2017
• 年：2017
• 卷：23
• 期：6
• 页码：1427-1435
• 全文大小：3821K
• ISSN：1521-3765

文摘

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.