The role of geometric structure in avoidance of oxygen rebound to enable aliphatic halogenation and oxacyclization by non-heme Fe(IV)-oxo (ferryl) complexes

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Project Summary/Abstract Iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) oxygenases catalyze hydroxylation, halogenation, cyclization, dehydrogenation, and stereoinversion of aliphatic carbon centers, C–H-bond-activation reactions that collectively represent a holy grail of synthetic chemistry. Biosynthetic pathways to important natural- product drugs are replete with these enzymes, and the pharmaceutical industry is beginning to leverage evolved versions of Fe/2OG oxygenases as biocatalysts for "green" processes to their synthetic drugs. Recent studies of Fe/2OG hydroxylases, halogenases and cyclases by the Penn State group show that the disposition of the substrate relative to the common iron(IV)-oxo (ferryl) and iron(III)-hydroxo/substrate-radical intermediates may be crucial for control of reaction outcome. On the basis of data available so far, we hypothesize that the structural rearrangement of the metallocofactor rather than the substrate positioning is the primary factor directing regioselectivity. Therefore, in this work, we will perform spectroscopic characterization of faithful reactive-state analogs to gain first-hand insight as to how the individual enzymes adjust the structure of the active complex and to uncover common modes that direct reactivities in the superfamily of Fe/2OG oxygenases. In this project, we will innovate and deploy a suite of novel intermediate mimics and spectroscopic probes/methodologies to resolve the geometries of the key intermediate states in the pharmaceutically relevant subclasses of Fe/2OG enzymes. Our elucidation of how the cofactor structures and relative dispositions of the substrates dictate the divergent outcomes will inform efforts to discover novel members of this superfamily and assign their phenotypes. Ultimately, information obtained in this project will be instrumental in developing new biocatalysts for drug synthesis.