CO-independent modification of K+ channels by tricarbonyldichlororuthenium(II) dimer (CORM-2)

Although toxic when inhaled in high concentrations, the gas carbon monoxide (CO) is endogenously produced in mammals, and various beneficial effects are reported. For potential medicinal applications and studying the molecular processes underlying the pharmacological action of CO, so-called CO-releasing molecules (CORMs), such as tricabonyldichlororuthenium(II) dimer (CORM-2), have been developed and widely used. Yet, it is not readily discriminated whether an observed effect of a CORM is caused by the released CO gas, the CORM itself, or any of its intermediate or final breakdown products. Focusing on Ca2+- and voltage-dependent K+ channels (KCa1.1) and voltage-gated K+ channels (Kv1.5, Kv11.1) relevant for cardiac safety pharmacology, we demonstrate that, in most cases, the functional impacts of CORM-2 on these channels are not mediated by CO. Instead, when dissolved in aqueous solutions, CORM-2 has the propensity of forming Ru(CO)2 adducts, preferentially to histidine residues, as demonstrated with synthetic peptides using mass-spectrometry analysis. For KCa1.1 channels we show that H365 and H394 in the cytosolic gating ring structure are affected by CORM-2. For Kv11.1 channels (hERG1) the extracellularly accessible histidines H578 and H587 are CORM-2 targets. The strong CO-independent action of CORM-2 on Kv11.1 and Kv1.5 channels can be completely abolished when CORM-2 is applied in the presence of an excess of free histidine or human serum albumin; cysteine and methionine are further potential targets. Off-site effects similar to those reported here for CORM-2 are found for CORM-3, another ruthenium-based CORM, but are diminished when using iron-based CORM-S1 and absent for manganese-based CORM-EDE1

Towards the preparation of stable cyclic amino(ylide)carbenes

Cyclic amino(ylide)carbenes (CAYCs) are the ylide-substituted analogues of $\it N$-heterocyclic Carbenes (NHCs). Due to the stronger $\pi$ donation of the ylide compared to an amino moiety they are stronger donors and thus are desirable ligands for catalysis. However, no stable CAYC has been reported until today. Here, we describe experimental and computational studies on the synthesis and stability of CAYCs based on pyrroles with trialkyl onium groups. Attempts to isolate two CAYCs with trialkyl phosphonium and sulfonium ylides resulted in the deprotonation of the alkyl groups instead of the formation of the desired CAYCs. In case of the $PCy_{3}$-substituted system, the corresponding ylide was isolated, while deprotonation of the $SMe_{2}$-functionalized compound led to the formation of ethene and the thioether. Detailed computational studies on various trialkyl onium groups showed that both the $\alpha$- and $\beta$-deprotonated compounds were energetically favored over the free carbene. The most stable candidates were revealed to be $\alpha$-hydrogen-free adamantyl-substituted onium groups, for which $\beta$-deprotonation is less favorable at the bridgehead position. Overall, the calculations showed that the isolation of CAYCs should be possible, but careful design is required to exclude decomposition pathways such as deprotonations at the onium group

Synthesis of low-valent dinuclear group 14 compounds with element–element bonds by transylidation

Dinuclear low-valent compounds of the heavy main group elements are rare species owing to their intrinsic reactivity. However, they represent desirable target molecules due to their unusual bonding situations as well as applications in bond activations and materials synthesis. The isolation of such compounds usually requires the use of substituents that provide sufficient stability and synthetic access. Herein, we report on the use of strongly donating ylide-substituents to access low-valent dinuclear group 14 compounds. The ylides not only impart steric and electronic stabilization, but also allow facile synthesis via transfer of an ylide from tetrylene precursors of type $^{R}Y_{2}E$ to ECl$_2$ (E=Ge, Sn; $^{R}$Y=TolSO$_2$(PR$_3$)C with R=Ph, Cy). This method allowed the isolation of dinuclear complexes amongst a germanium analogue of a vinyl cation, [($^{PH}$Y)$_2$GeGe($^{PH}$Y)]$^{+}$ with an electronic structure best described as a germylene-stabilized GeII cation and a ylide(chloro)digermene [$^{Cy}$Y(Cl)GeGe(Cl)$^{Cy}$Y] with an unusually unsymmetrical structure

Efficient Pd-catalyzed direct coupling of aryl chlorides with alkyllithium reagents

Organolithium compounds are amongst the most important organometallic reagents and frequently used in difficult metallation reactions. However, their direct use in the formation of C−C bonds is less established. Although remarkable advances in the coupling of aryllithium compounds have been achieved, Csp$^{2}$−Csp3 coupling reactions are very limited. Herein, we report the first general protocol for the coupling or aryl chlorides with alkyllithium reagents. Palladium catalysts based on ylide-substituted phosphines (YPhos) were found to be excellently suited for this transformation giving high selectivities at room temperature with a variety of aryl chlorides without the need for an additional transmetallation reagent. This is demonstrated in gram-scale synthesis including building blocks for materials chemistry and pharmaceutical industry. Furthermore, the direct coupling of aryllithiums as well as Grignard reagents with aryl chlorides was also easily accomplished at room temperature