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Enzymes have evolved to catalyze a range of biochemical transformations with high efficiencies and unparalleled selectivities, including stereoselectivities, regioselectivities, chemoselectivities, and substrate selectivities, while typically operating under mild aqueous conditions. These properties have motivated extensive research to identify or create enzymes with reactivity that complements or even surpasses the reactivity of small-molecule catalysts for chemical reactions. One of the limitations preventing the wider use of enzymes in chemical synthesis, however, is the narrow range of bond constructions catalyzed by native enzymes. One strategy to overcome this limitation is to create artificial metalloenzymes (ArMs) that combine the molecular recognition of nature with the reactivity discovered by chemists. This Account describes a new approach for generating ArMs by the formal replacement of the natural iron found in the porphyrin IX (PIX) of hemoproteins with noble metals. Analytical techniques coupled with studies of chemical reactivity have demonstrated that expression of apomyoglobins and apocytochrome P450s (for which "apo-" denotes the cofactor-free protein) followed by reconstitution with metal-PIX cofactors in vitro creates proteins with little perturbation of the native structure, suggesting that the cofactors likely reside within the native active site. By means of this metal substitution strategy, a large number of ArMs have been constructed that contain varying metalloporphyrins and mutations of the protein. The studies discussed in this Account encompass the use of ArMs containing noble metals to catalyze a range of abiological transformations with high chemoselectivity, enantioselectivity, diastereoselectivity, and regioselectivity. These transformations include intramolecular and intermolecular insertion of carbenes into C-H, N-H, and S-H bonds, cyclopropanation of vinylarenes and of internal and nonconjugated alkenes, and intramolecular insertions of nitrenes into C-H bonds. The rates of intramolecular insertions into C-H bonds catalyzed by thermophilic P450 enzymes reconstituted with an Ir(Me)-PIX cofactor are now comparable to the rates of reactions catalyzed by native enzymes and, to date, 1000 times greater than those of any previously reported ArM. This reactivity also encompasses the selective intermolecular insertion of the carbene from ethyl diazoacetate into C-H bonds over dimerization of the carbene to form alkenes, a class of carbene insertion or selectivity not reported to occur with small-molecule catalysts. These combined results highlight the potential of well-designed ArMs to catalyze abiological transformations that have been challenging to achieve with any type of catalyst. The metal substitution strategy described herein should complement the reactivity of native enzymes and expand the scope of enzyme-catalyzed reactions.

Noble−Metal Substitution in Hemoproteins: An Emerging Strategy for Abiological Catalysis