Research Projects

This proposal aims to expand the scope of enzymatic C(sp³)–H functionalization chemistry by introducing non-natural reactions through synthetic models. The strategy focuses on non-heme iron-catalyzed targeted radical transfer, providing a novel approach for enabling halogenation, nitration, and azidation reactions within an enzymatic framework. This concept is based on the α-ketoglutarate–dependent non-heme iron(II) halogenase SyrB2, which plays a role in the syringomycin biosynthetic pathway of Pseudomonas syringae B301D. SyrB2 illustrates the mechanistic basis for the selective coupling of a carbon-centered radical from the substrate with a cis-positioned halide ligand instead of a hydroxyl ligand. While synthetic non-heme iron enzymes can catalyze diverse C(sp³)–H functionalizations, forming bonds with heteroatoms such as O, Cl, Br, and S, the introduction of fluorine groups and nitrogenous functional groups is notably lacking. Currently, enzymatic methods for C–F bond formation have been limited to nucleophilic fluoride substitution. A variety of α-ketoglutarate-dependent non-heme iron enzymes can halogenate substrates by activating O₂ and generating carbon-centered radicals through hydrogen atom transfer (HAT), mediated by (X)Fe(IV)=O species (where X = F, Cl, Br). Despite extensive research, attempts to convert non-heme iron halogenases into catalysts for different heteroatom functionalization at inert aliphatic carbon centers (halogenation and C–N coupling) have proven unsuccessful, mainly due to competing hydroxide rebound. These modifications can enhance molecular diversity, solubility, and bioactivity by introducing hydrogen-bond donors or acceptors and tuning electronic properties. The natural scarcity of enzymatic aliphatic heteroatom functionalization starkly contrasts with the common occurrence of these functional groups in bioactive compounds, highlighting the significant challenge of developing effective functionalization. To address this challenge, this proposal will utilize a series of non-heme iron(II) complexes supported by various tri-dentate ligands and incorporating different coligands. These complexes will utilize nucleophilic anions (e.g., X-, N3⁻, and NO2⁻) to form heteroatom bonds. The co-ligand-ligated iron(II) complexes are expected to activate dioxygen, leading to the formation of high-valent (X)Fe(IV)=O species, which facilitate hydrogen atom abstraction to generate carbon radicals, ultimately allowing for diverse group transfer outcomes. The proposed plan offers a powerful strategy to reduce the likelihood of hydroxyl radical rebound to the substrate radical. The unique spatial arrangement of the cofactor, along with the open coordination site located cis to the oxo group, is designed to preferentially facilitate functional group transfer. By selecting the appropriate ligand backbone and co-ligands, we aim to expand the catalytic potential, enabling a broader range of chemical transformations.