Highly Enantioselective Oxidation of Nonactivated Aliphatic C–H Bonds with Hydrogen Peroxide Catalyzed by Manganese Complexes

Monosubstituted
cycloalkanes undergo regio- and enantioselective aliphatic C–H
oxidation with H2O2 catalyzed by biologically
inspired manganese catalysts. The reaction furnishes the corresponding
ketones resulting from oxidation at C3 and C4 methylenic sites (K3 and K4, respectively) leading to a chiral desymmetrization
that proceeds with remarkable enantioselectivity (64% ee) but modest
regioselectivity at C3 (K3/K4 ≈ 2) for tert-butylcyclohexane, and with up to 96% ee and exquisite
regioselectity toward C3 (up to K3/K4 > 99)
when N-cyclohexylalkanamides are employed as substrates.
Efficient H2O2 activation, high yield, and highly
enantioselective C–H oxidation rely on the synergistic cooperation
of a sterically bulky manganese catalyst and an oxidatively robust
alkanoic acid. This represents the first example of nonenzymatic highly
enantioselective oxidation of nonactivated methylenic sites. Furthermore,
the principles of catalyst design disclosed in this work constitute
a unique platform for further development of stereoselective C–H
oxidation reactions.