Bioinspired Manganese and Iron Complexes for Enantioselective Oxidation Reactions: Ligand Design, Catalytic Activity, and Beyond

The development of efficient methods for the enantioselective oxidation of organic molecules continues to be an important goal in organic synthesis; in particular, the use of earth-abundant metal catalysts and environmentally friendly oxidants in catalytic asymmetric oxidation reactions has attracted significant interest over the last several decades. In nature, metalloenzymes catalyze a wide range of oxidation reactions by activating dioxygen under mild conditions. Inspired by selective and efficient oxidation reactions catalyzed by metalloenzymes, researchers have developed a number of synthetic model compounds that mimic the functionality of metalloenzymes. Among the reported biomimetic model compounds, tetradentate aminopyridine (N4) ligands have emerged as appealing frameworks because of their easy synthesis and facile diversification, and their complexes with metals such as Fe and Mn have proven to be versatile and powerful catalysts for a variety of (enantioselective) oxidation reactions. In this Account, we describe our efforts on the design of chiral N4 ligands and the use of their manganese and iron complexes in asymmetric oxidation reactions with H2O2 as the terminal oxidant, aiming to show general strategies for asymmetric oxidation reactions that can guide the rational design of ligands and relevant metal catalysts. In studies of manganese catalysts, the aryl-substituted (R,R)-mcp mcp = N,N'-dimethyl-N,N'-bis(pyridine-2-ylmethyl)cyclohexane-1,2-diamine manganese complexes exhibited high enantioselectivity in the asymmetric epoxidation (AE) of various olefins with H2O2 while requiring stoichiometric acetic acid as an additive for the activation of H2O2. To address this issue, we established bulkier N4 ligands for this catalytic system in which a catalytic amount of sulfuric acid enables the manganese-complex-catalyzed AE with improved stereocontrol and efficiency. In addition, this system was found to be active for the oxidative kinetic resolution of secondary alcohols. Further exploration of the structure-reactivity relationships has shown that aminobenzimidazole N4 ligands derived from l-proline, in which the conventional pyridine donors are replaced by benzimidazoles, act as promising ligands. These novel C1-symmetric manganese catalysts showed dramatically improved activities with unprecedented turnover numbers in the AE reactions. Notably, this class of manganese complexes can catalyze the oxidation of the C-H bonds of spirocyclic hydrocarbons and spiroazacyclic compounds in a highly enantioselective manner, providing ready access to chiral spirocyclic β,β'-diketones and spirocyclic alcohols. Remarkably, iron catalysts with these chiral N4 ligands are effective for AE of olefins, enabling rare examples of highly enantioselective syntheses of epoxides by the iron catalysts. Finally, mechanistic studies provide valuable insights into the roles of the carboxylic acid and sulfuric acid in the catalytic oxidation reactions. Thus, the results described in this Account have demonstrated the importance of tunability and compatibility of the ligands for the development of efficient oxidation catalysts with earth-abundant transition metals and environmentally benign oxidants, and we hope that our study will pave the way for the discovery of efficient oxidation catalysis.