Catalytic Asymmetric Synthesis of 3-Hydroxyindolenines Using Achiral Oxaziridines

Enantioenriched 3-hydroxyindolenines are highly attractive scaffolds owing to their prevalence in a wide range of indole alkaloids and their utility as key intermediates for the construction of chiral 2-oxindoles. The direct C-3 selective hydroxylation of indoles represents the most straightforward approach to accessing these structures. However, catalytic asymmetric hydroxylation of indoles for the synthesis of 3-hydroxyindolenines remains underexplored, with only one successful nonenzymatic method reported to date. Herein, by developing a novel <i>in situ</i>-generated magnesium catalyst and introducing <i>o</i>-nitrobenzene as a coordinating group, we achieved the C-3 selective hydroxylation of 2,3-disubstituted indole using racemic oxaziridine as the oxidant, affording enantioenriched products that were further applied in the total synthesis of hinckdentine A. Meanwhile, the nitro group could be utilized as a handle site for further coupling transformations. Additionally, the system proved to be effective for the kinetic resolution (KR) of common oxaziridines. Control and comparative experiments were conducted to identify the key reaction intermediate. DFT calculations revealed that the Mg(II) catalyst and the indole substrate form an enzyme-like catalytic pocket, which directs the oxaziridine into a well-controlled coordination geometry. This arrangement ensures high enantioselectivity in the hydroxylation while simultaneously enabling the KR process. Furthermore, given the divergent reaction pathways between indoles and oxaziridines, DFT calculations also provide insight into how the indole substrate dictates the reaction pathways.