Shaping of a Reactive Manganese Catalyst Enables Access to Polyfunctionalized Cyclohexanes via Enantioselective C(sp3)−H Bond Oxidation of 1,3-meso Diethers

Abstract

Chiral polyoxygenated cyclohexanes are valuable constituents of biologically relevant products. Herein, we report a protocol for the direct access to these scaffolds via site- and enantioselective non-directed oxidation of cyclohexyl-3,5-meso-diethers using aqueous H2O2. Structural shaping of a highly reactive chiral Mn-oxo species, achieved through the combination of a sterically encumbered ligand and a bulky carboxylic acid, promotes a precise fit of the substrate within the catalyst pocket, which translate into exceptional enantioselectivity (up to >99% ee). Computational studies reveal that C–H oxidation proceeds via an initial hydrogen atom transfer, followed by electron transfer, leading to the formation of a chiral cationic intermediate. The resulting desymmetrized 3-methoxycyclohexanone products serve as valuable intermediates for the synthesis of bioactive cores, as they can undergo orthogonal chemical modifications to enable further structural diversification