Artificial Iron Proteins: Modeling the Active Sites in Non-Heme Dioxygenases.

An important class of non-heme dioxygenases contains a conserved Fe binding site that consists of a 2-His-1-carboxylate facial triad. Results from structural biology show that, in the resting state, these proteins are six-coordinate with aqua ligands occupying the remaining three coordination sites. We have utilized biotin-streptavidin (Sav) technology to design new artificial Fe proteins (ArMs) that have many of the same structural features found within active sites of these non-heme dioxygenases. An Sav variant was isolated that contains the S112E mutation, which installed a carboxylate side chain in the appropriate position to bind to a synthetic FeII complex confined within Sav. Structural studies using X-ray diffraction (XRD) methods revealed a facial triad binding site that is composed of two N donors from the biotinylated ligand and the monodentate coordination of the carboxylate from S112E. Two aqua ligands complete the primary coordination sphere of the FeII center with both involved in hydrogen bond networks within Sav. The corresponding FeIII protein was also prepared and structurally characterized to show a six-coordinate complex with two exogenous acetato ligands. The FeIII protein was further shown to bind an exogenous azido ligand through replacement of one acetato ligand. Spectroscopic studies of the ArMs in solution support the results found by XRD.

Inverting Steric Effects: Using "Attractive" Noncovalent Interactions To Direct Silver-Catalyzed Nitrene Transfer.

Nitrene transfer (NT) reactions represent powerful and direct methods to convert C-H bonds into amine groups that are prevalent in many commodity chemicals and pharmaceuticals. The importance of the C-N bond has stimulated the development of numerous transition-metal complexes to effect chemo-, regio-, and diastereoselective NT. An ongoing challenge is to understand how subtle interactions between catalyst and substrate influence the site-selectivity of the C-H amination event. In this work, we explore the underlying reasons why Ag(tpa)OTf (tpa = tris(pyridylmethyl)amine) prefers to activate α-conjugated C-H bonds over 3° alkyl C(sp3)-H bonds and apply these insights to reaction optimization and catalyst design. Experimental results suggest possible roles of noncovalent interactions (NCIs) in directing the NT; computational studies support the involvement of π···π and Ag···π interactions between catalyst and substrate, primarily by lowering the energy of the directed transition state and reaction conformers. A simple Hess's law relationship can be employed to predict selectivities for new substrates containing competing NCIs. The insights presented herein are poised to inspire the design of other catalyst-controlled C-H functionalization reactions.