Design principles for site-selective hydroxylation by a Rieske oxygenase

Rieske oxygenases exploit the reactivity of iron to perform chemically challenging C–H bond functionalization reactions. Thus far, only a handful of Rieske oxygenases have been structurally characterized and remarkably little information exists regarding how these enzymes use a common architecture and set of metallocenters to facilitate a diverse range of reactions. Herein, we detail how two Rieske oxygenases SxtT and GxtA use different protein regions to influence the site-selectivity of their catalyzed monohydroxylation reactions. We present high resolution crystal structures of SxtT and GxtA with the native β-saxitoxinol and saxitoxin substrates bound in addition to a Xenon-pressurized structure of GxtA that reveals the location of a substrate access tunnel to the active site. Ultimately, this structural information allowed for the identification of six residues distributed between three regions of SxtT that together control the selectivity of the C–H hydroxylation event. Substitution of these residues produces a SxtT variant that is fully adapted to exhibit the non-native site-selectivity and substrate scope of GxtA. Importantly, we also found that these selectivity regions are conserved in other structurally characterized Rieske oxygenases, providing a framework for predictively repurposing and manipulating Rieske oxygenases as biocatalysts.

Enzyme-Like Hydroxylation of Aliphatic C–H Bonds From an Isolable Co-Oxo Complex

Selective hydroxylation of aliphatic C–H bonds remains a challenging but broadly useful transformation. Nature has evolved systems that excel at this reaction, exemplified by cytochrome P450 enzymes which use an iron-oxo intermediate to activate aliphatic C–H bonds with k1 > 1400 s–1 at 4 °C. Many synthetic catalysts have been inspired by these enzymes and are similarly proposed to use transition metal-oxo intermediates. However, most examples of well-characterized transition metal-oxo species are not capable of reacting with strong, aliphatic C–H bonds, resulting in a lack of understanding of what factors facilitate this reactivity. Here, we report the isolation and characterization of a new terminal CoIII-oxo complex, PhB(AdIm)3CoIIIO. Upon oxidation a transient CoIV-oxo intermediate is generated that is capable of hydroxylating aliphatic C–H bonds with an extrapolated k1 for C–H activation >130 s–1 at 4 °C, comparable to values observed in cytochrome P450 enzymes. Experimental thermodynamic values and DFT analysis demonstrate that although the initial C–H activation step in this reaction is endergonic, the overall reaction is driven by an extremely exergonic radical rebound step, similar to what has been proposed in cytochrome P450 enzymes. The rapid C–H hydroxylation reactivity displayed in this well-defined system provides insight into how hydroxylation is accomplished by biological systems and similarly potent synthetic oxidants.

Para-selective Hydroxylation of Alkyl Aryl Ethers

Para-selective hydroxylation of alkyl aryl ethers is established, which processes with ruthenium(II) catalyst, hypervalent iodine(III) and trifluoroacetic anhydride via a radical mechanism. This protocol tolerates a wide scope of substrates...

Selective hydroxylation of aryl iodides to produce phenols under mild conditions using a supported copper catalyst

Atomically dispersed Cu catalyst was designed for highly efficient hydroxylation of aryl iodides under mild conditions.

On the Ability of Nickel Complexes Derived from Tripodal Aminopyridine Ligands to Catalyze Arene Hydroxylations

The development of catalysts for the selective hydroxylation of aromatic C–H bonds is an essential challenge in current chemical research. The accomplishment of this goal requires the discovery of powerful metal-based oxidizing species capable of hydroxylating inert aromatic bonds in a selective manner, avoiding the generation of non-selective oxygen-centered radicals. Herein we show an investigation on the ability of nickel(ii) complexes supported by tripodal tetradentate aminopyridine ligands to catalyze the direct hydroxylation of benzene to phenol with H2O2 as oxidant. We have found that modifications on the ligand structure of the nickel complex do not translate into different reactivity, which differs from previous findings for nickel-based arene hydroxylations. Besides, several nickel(ii) salts have been found to be effective in the oxidation of aromatic C–H bonds. The use of fluorinated alcohols as solvent has been found to result in an increase in phenol yield; however, showing no more than two turn-overs per nickel. These findings raise questions on the nature of the oxidizing species responsible for the arene hydroxylation reaction.

Catalyst- and oxidant-free electrochemical para-selective hydroxylation of N-arylamides in batch and continuous-flow

A catalyst-, oxidant-, acidic solvent- and quaternary ammonium salt-free electrochemical para-selective hydroxylation of N-arylamides at rt in batch and continuous-flow was developed.