Tuning P450 Enzymes as Oxidation Catalysts

The development of catalytic systems for the controlled oxidation of C−H bonds remains a highly sought-after goal in chemistry owing to the great utility of such transformation toward expediting the synthesis and functionalization of organic molecules. Cytochrome P450 monooxygenases are the catalysts of choice in the biological world for mediating the oxidation of sp and sp C−H bonds with a high degree of chemo-, regio-, and stereoselectivity and in a wide array of compounds of varying complexity. The efficiency of these enzymes, compared with chemical methods, to catalyze the insertion of oxygen into unactivated C−H bonds under mild reaction conditions has sparked interest among researchers toward investigating and exploiting P450s for a variety of synthetic applications. Realizing the synthetic potential of these enzymes, however, depends upon the availability of effective strategies to tune the reactivity of natural P450s to obtain viable oxidation catalysts for the desired transformation. This review describes recent efforts in this area involving the use of protein engineering, substrate engineering, guest/host activation, and functional screening strategies. The development of engineered P450s for drug metabolite production and emerging methodologies involving the integration of P450-catalyzed transformations in preparative-scale chemoenzymatic syntheses are also presented. Key challenges that need to be addressed to capitalize on P450 oxidation catalysis for chemical synthesis are discussed.