Rational Design of Bioinspired Catalysts for Selective Oxidations

Recognizing Nature’s unique ability to perform challenging oxygenation reactions with exquisite selectivity parameters at iron-dependent oxygenases, chemists have long sought to understand and mimic these enzymatic processes with artificial systems. In the last two decades, replication of the reactivity of non-heme iron oxygenases has become feasible even with simple coordination complexes of iron and manganese. A bona fide minimalistic functional model was the tetradentate-N4 ligand based iron complex [Fe­(tpa)­(CH3CN)2]2+(Fe­(tpa), tpa = tris­(2-methylpyridyl)­amine), which activates H2O2 via a mechanism that mirrors key steps of enzymatic O2 activation processes at mononuclear iron centers: controlled O–O bond cleavage, generation of a high-valent FeO oxidant, and promotion of almost the full spectrum of its oxidative reactivity (C–H hydroxylation, olefin epoxidation, syn-dihydroxylation, and desaturation). These landmark discoveries set the mechanistic framework to use iron coordination complexes with nitrogen-rich ligands as catalysts for oxidizing organic substrates under synthetically relevant conditions. Due to proof-of-concept demonstrations of the potential of these catalysts in organic synthesis, this chemistry has flourished over the past decade. In parallel to the realization of the potential of this class of catalysts in diverse organic transformations, effort has been spent to manipulate the catalyst structure with the aim of tuning both the reactivity and selectivity of the oxidation reactions. This perspective provides an overview of the progress of this research. Some key features of the archetypical Fe­(tpa) catalyst have stayed surprisingly true throughout this evolution, but a series of alterations that modulate its electronic, steric, or binding properties allowed a rational elicitation of a specific reactivity or selectivity. In some cases, the replacement of iron by manganese has also proven beneficial. Overall, the rational optimization of the catalyst structure has enabled the development of highly asymmetric olefin epoxidation, syn-dihydroxylation, and site-selective and even enantioselective C–H oxidation reactions.