Expanding the Clip-and-Cleave Concept: Approaching Enantioselective C–H Hydroxylations by Copper Imine Complexes Using O₂ and H₂O₂ as Oxidants

Copper-mediated aromatic and aliphatic C-H hydroxylations using benign oxidants (O₂ and H₂O₂) have been studied intensively in recent years to meet the growing demand for efficient and green C-H functionalizations. Herein, we report an enantioselective variant of the so-called clip-and-cleave concept for intramolecular ligand hydroxylations by the application of chiral diamines as directing groups. We tested the hydroxylation of cyclohexanone and 1-acetyladamantane under different oxidative conditions (Cu^I/O₂; Cu^I/H₂O₂; Cu^II/H₂O₂) in various solvents. As an outstanding example, we obtained (<i>R</i>)-1-acetyl-2-adamantol with a yield of 37% and >99:1 enantiomeric excess from hydroxylation in acetone using Cu^I and O₂. Low-temperature stopped-flow UV-vis measurements in combination with density functional theory (DFT) computations revealed that the hydroxylation proceeds via a bis(μ-oxido) dicopper intermediate. The reaction product represents a rare example of an enantiopure 1,2-difunctionalized adamantane derivative, which paves the way for potential pharmacological studies. Furthermore, we found that 1-acetyladamantane can be hydroxylated in a one-pot reaction under air with isolated yields up to 36% and enantiomeric ratios of 96:4 using Cu^II/H₂O₂ in MeOH.