Metalloenzyme-Catalyzed Radical Reactions Unknown or Uncommon in Native Enzymology

The past decade has witnessed groundbreaking developments in metalloenzyme-catalyzed free radical transformations, which were previously unknown or uncommon in native metalloenzymology. Guided by mechanistic understandings from organic, organometallic, and biochemistry, an array of radical reactions has been developed using various metalloprotein catalysts based on first-row transition metal cofactors including Fe, Co, and Cu. The structural and functional diversity and the readily tunable active-site environment of metalloproteins offer an excellent opportunity to solve the challenging chemo-, regio-, and stereoselectivity problems in radical-mediated transformations facing synthetic chemists. In this Review, we summarize metalloprotein-catalyzed radical reactions based on the reactive intermediates involved, including carbon-centered radicals, nitrogen-centered radicals, oxygen-centered radicals, and metal carbenoids and nitrenoids with radical character. We further survey the reaction mechanism, enzyme engineering strategies, and substrate scope of these metalloprotein-catalyzed radical transformations, providing an overview of the current status of metalloenzymology that is unknown or uncommon in native biochemistry.