Fr Francium

This microreview focuses on the preparation of metal complexes with N-heterocyclic carbene ligands linked to cyclopentadienyl (and related indenyl and fluorenyl) rings. Since the description of the first Ti and V complexes in 2006, the field has grown to afford a large number of new complexes, in which the metals range from early to late transition metals. The ligands that are now available not only include a wide set of cyclopentadienyl-, indenyl- and fluorenyl-NHCs with a variety of tethers, but may even present chirality. Several catalytic applications of the new complexes are described, including borrowing hydrogen processes (transfer hydrogenation, β-alkylation of secondary alcohols, alkylation of amines with primary alcohols), hydrosilylation of aldehydes, epoxidation and hydroformylation of olefins, among others.

This microreview focuses on the preparation of new N-heterocyclic carbenes linked to cyclopentadienyl-, indenyl-, and fluorenyl rings and their coordination to early and late transition metals. Several catalytic applications of the new metal complexes are described.

The reaction between H₂O₂ and two water oxidation catalysts {[Cp*Ir(H₂O)₃](NO₃)₂ (1, Cp* = pentamethylcyclopentadienyl) and [Cp*Ir(bzpy)(NO₃)] (2, bzpy = 2-benzoylpyridine)} was studied by means of in situ 1D- and 2D-NMR experiments in order to elucidate if catalyst degradation proceeds through the initial functionalization of a quaternary carbon atom (C-attack) or by hydrogen abstraction (H-attack) of the Cp* –C–CH₃ moiety. It was shown that 1 underwent double functionalization of the –C–CH₃ moiety of Cp* leading to the formation of –C(OR)–CH₂OR (R = H or OH) in a strictly analogous manner to that previously observed for the reaction of 1 with Ce⁴⁺. On the contrary, two new intermediates associated with the oxidative degradation of 2, which are functionalized only at the quaternary carbon atom(s) of the –C–CH₃ moiety [–C(OR)–CH₃], were intercepted and characterized by NMR spectroscopy. This indicates that the oxidative degradation of water oxidation catalysts, featuring the –Cp* ancillary ligand, likely starts with preferential C-attack.

Degradation of water oxidation catalysts, featuring the IrCp* unit, proceeds through the initial functionalization of a quaternary carbon atom (C-attack) of the Cp* –C–CH₃ moiety, which is likely followed by substitution of a hydrogen atom by –OR (H-attack, R = H or OH).

Redox gold(I)/gold(III) catalytic cycles have been proposed as the productive mechanistic manifold in a number of gold mediated C–C and C–X bond forming reactions. These transformations rely on the use of stoichiometric oxidants such as iodonium salts and Selectfluor. We have studied the oxidation of electron deficient [Au(C₆F₅)(PPh₃)] (1) in the presence of such oxidizing agents. The reaction of 1 with PhI(OAc)₂ afforded cis-[Au(C₆F₅)₂Cl(PPh₃)] (3), which seemed to be produced by oxidation of the starting complex followed by a gold(I)/gold(III) transmetalation process or ligand exchange. The reaction of 1 with Selectfluor afforded an unprecedented gold(I)–gold(III) complex [Au(PPh₃)₂][Au(C₆F₅)₄] (7).

We have studied the oxidation of electron deficient [Au(C₆F₅)(PPh₃)] in the presence of PhI(Cl)₂, PhI(OAc)₂, and Selectfluor. cis-[Au(C₆F₅)₂Cl(PPh₃)] was obtained in the reaction with PhI(OAc)₂, which points towards the oxidation of the starting complex to gold(III) followed by gold(I)/gold(III) transmetalation or a ligand exchange pathway.

The inside cover picture shows the peculiar dual binding of the marine sponge metabolite Cladocoran A to the human secretory PLA2 enzyme, which is responsible for its relevant anti-inflammatory activity. For further details on the PLA2 inhibition mechanism at a molecular level, see the paper by A. Casapullo et al. on p. 2686 ff.

The cover picture shows the differential activation of macrophages by synthetic trehalose diesters of various chain lengths. Small-chain analogues (C₄–C₁₀) show no activity and medium-length analogues (C₁₈) show moderate activity; however, longer derivatives (C₂₀–C₂₆) lead to optimal activation of macrophages, as evidenced by NO production and the generation of cytokines such as IL-6 and IL-1β. For more details, see the paper by M. S. M. Timmer, B. L. Stocker et al. on p. 2572 ff.

We report the synthesis and properties of a photoactivatable caged RGD peptide and its application for phototriggering integrin- and cell-binding to surfaces. We analysed in detail 1) the differences in the integrin-binding affinity of the caged and uncaged forms by quartz crystal microbalance (QCM) studies, 2) the efficiency and yield of the photolytic uncaging reaction, 3) the biocompatibility of the photolysis by-products and irradiation conditions, 4) the possibility of site, temporal and density control of integrin-binding and therefore human cell attachment, and 5) the possibility of in situ generation of cell patterns and cell gradients by controlling the UV exposure. These studies provide a clear picture of the potential and limitations of caged RGD for integrin-mediated cell adhesion and demonstrate the application of this approach to the control and study of cell interactions and responses.

A photosensitive caged RGD peptide is used for efficient phototriggering of cell attachment. Spatiotemporal control over cell attachment and dose-dependent exposure allowed in situ generation of cell patterns and gradients onto well-defined RGD surface concentrations.

Protein tyrosine phosphatases (PTPs) are key regulators in living systems and thus are attractive drug targets. The development of potent, selective PTP inhibitors has been a difficult challenge mainly due to the high homology of the phosphotyrosine substrate pockets. Here, a strategy of dynamic substrate enhancement is described targeting the secondary binding sites of PTPs. By screening four different PTPs from bacterial (MptpA) and human origin (PTP1B, HePtp, Shp2) with this assay, specific fragments were identified. One highly specific fragment that binds to the secondary site of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) was characterized in order to validate the assay concept. Finally by covalently linking the secondary fragment to a phosphotyrosine mimetic, a moderately active but highly specific inhibitor of MptpA was obtained.

Looking into second site:p-Formyl-phenyl phosphate was identified as a generic substrate for protein tyrosine phosphatases (PTPs) and was used to scrutinize the proteins' secondary binding site for specifically binding fragments. Binding fragments were detected by an amplified turnover of the substrate in a dynamic ligation reaction and were developed to highly specific PTP inhibitors.