We describe the discovery and characterization of the supersoft topical JAK inhibitor 3(R), which is potent in biochemical and cellular assays as well as in human skin models. In blood, the neutral ester 3(R) is rapidly hydrolyzed (t1/2 ∼ 6 min) to the corresponding charged carboxylic acid 4 exhibiting >30-fold reduced permeability. Consequently, acid 4 does not reach the intracellular JAK kinases and is inactive in cellular assays and in blood. Thus, hydrolysis by blood esterases leads to the rapid deactivation of topically active ester 3(R) at a rate beyond the maximal hepatic clearance.

FeIIIOOH and FeIVO intermediates have now been documented in a number of nonheme iron active sites. In this Current Opinion we use spectroscopy combined with electronic structure calculations to define the frontier molecular orbitals (FMOs) of these species and their contributions to reactivity. For the low-spin FeIIIOOH species in activated bleomycin we show that the reactivity of this nonheme iron intermediate is very different from that of the analogous Compound 0 of cytochrome P450. For FeIVO S = 1 model species we experimentally define the electronic structure and its contribution to reactivity, and computationally evaluate how this would change for the FeIVO S = 2 intermediates found in nonheme iron enzymes.

High-valent Fe-IV=O species are key intermediates in the catalytic cycles of many mononuclear non-heme iron enzymes and have been structurally defined in model systems. Variable-temperature magnetic circular dichroism (VT-MCD) spectroscopy has been used to evaluate the electronic structures and in particular the Fe-O bonds of three Fe-IV=O (S = 1) model complexes, [Fe-IV(O)(TMC)(NCMe)](2+), [Fe-IV(O)(TMC)(OC(O)CF3)](+), and [Fe-IV(O)(N4py)](2+). These complexes are characterized by their strong and covalent Fe-O pi-bonds. The MCD spectra show a vibronic progression in the nonbonding -> pi(*) excited state, providing the Fe-O stretching frequency and the Fe-O bond length in this excited state and quantifying the pi-contribution to the total Fe-O bond. Correlation of these experimental data to reactivity shows that the [Fe-IV(O)(N4py)](2+) complex, with the highest reactivity toward hydrogen-atom abstraction among the three, has the strongest Fe-O pi-bond. Density functional calculations were correlated to the data and support the experimental analysis. The strength and covalency of the Fe-O pi-bond result in high oxygen character in the important frontier molecular orbitals (FMOs) for this reaction, the unoccupied beta-spin d(xz/yz) orbitals, that activates these for electrophilic attack. An extension to biologically relevant Fe-IV=O (S = 2) enzyme intermediates shows that these can perform electrophilic attack reactions along the same mechanistic pathway (pi-FMO pathway) with similar reactivity but also have an additional reaction channel involving the unoccupied alpha-spin d(z(2)) orbital (sigma-FMO pathway). These studies experimentally probe the FMOs involved in the reactivity of Fe-IV=O (S = 1) model complexes resulting in a detailed understanding of the Fe-O bond and its contributions to reactivity.

(4-Hydroxy)mandelate synthase (HmaS) and (4-hydroxyphenyl)pyruvate dioxygenase (HPPD) are two α-keto acid dependent mononuclear non-heme iron enzymes that use the same substrate, (4-hydroxyphenyl)pyruvate, but exhibit two different general reactivities. HmaS performs hydrogen-atom abstraction to yield benzylic hydroxylated product ( S )-(4-hydroxy)mandelate, whereas HPPD utilizes an electrophilic attack mechanism that results in aromatic hydroxylated product homogentisate. These enzymes provide a unique opportunity to directly evaluate the similarities and differences in the reaction pathways used for these two reactivities. An Fe II methodology using CD, magnetic CD, and variable-temperature, variable-field magnetic CD spectroscopies was applied to HmaS and compared with that for HPPD to evaluate the factors that affect substrate interactions at the active site and to correlate these to the different reactivities exhibited by HmaS and HPPD to the same substrate. Combined with density functional theory calculations, we found that HmaS and HPPD have similar substrate-bound complexes and that the role of the protein pocket in determining the different reactivities exhibited by these enzymes (hydrogen-atom abstraction vs. aromatic electrophilic attack) is to properly orient the substrate, allowing for ligand field geometric changes along the reaction coordinate. Elongation of the Fe IV O bond in the transition state leads to dominant Fe III O •− character, which significantly contributes to the reactivity with either the aromatic π-system or the C H σ-bond.

High-valent iron-oxo intermediates are known or believed to be key oxidizing species in the catalytic mechanisms of many mononuclear and binuclear non-heme iron enzymes. So far only limited experimental data on their electronic structures are available. In this study we extend knowledge from the experimentally well characterized mononuclear Fe(IV)=O (S=1) biomimetic model system to computational insight into the spectroscopy and electronic structures of mono-and binuclear high-valent iron-oxo enzyme intermediates. In the mononuclear Fe(IV)=O complexes, we predict the spectroscopy and energies of the electronic transitions to be very different for the S=1 and S=2 spin states, but the iron-oxo bonding for both spin states to be very similar. A comparison of the S=2 mono- and binuclear high-valent iron-sites predicts similar electronic transitions. However, the bent iron-oxo bridge and interactions with the second iron-center in the dimer shift the transitions to higher energies and splits the d(xz/yz) orbital set. These electronic structure and TD-DFT results provide a basis for understanding the spectroscopy and electronic structures of high-valent intermediates in mono- and binuclear non-heme iron enzymes.

Mononuclear non-heme iron enzymes catalyze a variety of biological reactions requiring the binding and activation of dioxygen. Using spectroscopic methods and density functional calculations, the geometric and electronic structures of the oxygen intermediates and their reactivities are being defined to understand the catalytic mechanisms on a molecular level. A key intermediate is the Fe(IV)=O species. We present a detailed description of the electronic structure and Fe-O bonding of a non-heme Fe(IV)=O S=1 model complex and correlate these results to S=2 species, the ground state of non-heme enzyme intermediates [1]. In addition, the electronic structures of Fe(IV)=O S=1 heme and non-heme species are compared, with focus on the effects of the porphyrin π-system on the Fe-O bond, and their relative reactivities toward H-atom abstraction reactions are evaluated [2]. Copper enzymes also play important roles in oxygen binding and activation, i.e. noncoupled binuclear Cu proteins can perform H-atom abstraction reactions. We contrast the electronic structures of the key oxygen intermediates in iron and copper enzymes, and assess how these differences can relate to different reactivities and preferred reaction mechanisms [3].

Non-heme iron enzymes catalyze a wide range of O(2) reactions, paralleling those of heme systems. Non-heme iron active sites are, however, much more difficult to study because they do not exhibit the intense spectral features characteristic of the porphyrin ligand. A spectroscopic methodology was developed that provides significant mechanistic insight into the reactivity of non-heme ferrous active sites. These studies reveal a general mechanistic strategy used by these enzymes and differences in substrate and cofactor interactions dependent on their requirement for activation by iron. Contributions to O(2) activation have been elucidated for non-heme relative to heme ligand sets, and major differences in reactivity are defined with respect to the heterolytic and homolytic cleavage of O-O bonds.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Reactions of dry THF/MeCN solutions of Ca[(Re6S6Cl2i)-Cl-i(Cl-a)(6)] with silylated derivatives E(SiMe3)(2) (E = PhAs, PSiMe3, HN, O, S) and addition of trialkylphosphine PPr3 afford in high yields and at room temperature either the neutral clusters [(Re6S6X2i)-X-i(PPr3)(6)(a)] (1: X = As, 2: X = P) or the ionic compounds [(Re6S6X2i)-X-i(PPr3)(6)(a)](2+).[Re6S6Cl8](2-) (3: X = NH, 4: X = 0, 5: X = S). The compounds 1-5 were characterised by X-ray crystal structure analysis. A di-substitution reaction occurs on the ((Re6S6Cl2i)-Cl-i)(4+) cluster core, where the two inner mu(3)-chloro ligands Cl-i are substituted by X (X = As, P, NH, O, S) and all six terminal chloro ligands Cl-a are exchanged by terminal PPr3-ligands.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Ausgehend von Eisen(III)-chlorid oder Eisen(II)-chlorid sind durch Reaktionen mit Lithiumamiden Eisen–Stickstoffcluster mit Heterocubanstruktur zugänglich. Beispielsweise führt die Reaktion von FeCl3 mit Li2NPh zu dem ionischen Komplex [Li(THF)4][Li(THF)3][Fe4(μ3-NPh)4Cl4] (1). Bei Verwendung von LiNHtBu lassen sich die Verbindungen [Li(DME)3][Fe4(μ3-NtBu)4Cl4] (2) und [Fe4(μ3-NtBu)4Cl4] · Et3PNtBu (3) kristallisieren. FeCl2 reagiert mit LiNHtBu bei Anwesenheit von NaCp zu [Li(THF)4][Fe4(NHtBu)4(μ3-NtBu)4] (4). Dagegen bilden sich bei Umsetzungen von FeCl3 mit LiNHMes oder Li2NPh in Gegenwart von [NnBu4][PF6] die Komplexe {[Li(THF)2]2[Fe2(μ-NMes)2Cl4]} (5) und [NnBu4]2[Fe2(μ-NPh)2Cl4] (6). Die Strukturen von 1–6 konnten durch Einkristall-Röntgenstrukturanalysen aufgeklärt werden. Imidobridged Iron Clusters with Heterocubane-Type Structure. The Crystal Structures of [Li(THF)4][Li(THF)3][Fe4(μ3-NPh)4Cl4], [Li(DME)3][Fe4(μ3-NtBu)4Cl4], [Fe4(μ3-NtBu)4Cl4] · Et3PNtBu, [Li(THF)4][Fe4(NHtBu)4(μ3-NtBu)4], {[Li(THF)2]2[Fe2(μ-NMes)2Cl4]}, and [NnBu4]2[Fe2(μ-NPh)2Cl4] Starting with iron(III)chloride or iron(II)chloride iron–nitrogenclusters with heterocubane-type structure are available from reactions with lithiumamides. The reaction of FeCl3 with Li2NPh e. g. leads to the ionic complex [Li(THF)4][Li(THF)3][Fe4(μ3-NPh)4Cl4] (1). Using LiNHtBu, the compounds [Li(DME)3][Fe4(μ3-NtBu)4Cl4] (2) and [Fe4(μ3-NtBu)4Cl4] · Et3PNtBu (3) can be crystallized. [Li(THF)4][Fe4(NHtBu)4(μ3-NtBu)4] (4) can be obtained by the reaction of FeCl2 with LiNHtBu in presence of NaCp. Reactions of FeCl3 with LiNHMes or Li2NPh together with [NnBu4][PF6] lead to the complexes {[Li(THF)2]2[Fe2(μ-NMes)2Cl4]} (5) and [NnBu4]2[Fe2(μ-NPh)2Cl4] (6). The structures of 1–6 were characterized by single crystal X-ray structure analysis.

Halogenometallkomplexe und funktionalisierte Amine braucht man für die Synthese imidoverbrückter Übergangsmetallcluster. Auf diesem Weg gelingen auch Synthesen von Imidoclustern elektronenreicher Übergangsmetalle wie [Cu24(μ3‐NPh)8‐(μ4‐NPh)6]4− (die Struktur ist im Bild rechts gezeigt).magnified image

Metal halide complexes and functionalized amines react to form imidobridged transition metal clusters. This method can be used to synthesize imido clusters of electron-rich transition metals such as [Li(thf)4]4-“Cu24(μ3-NPh)8 μ4-NPh)6” 1 (the structure of the anion of 1 is depicted on the right).