Electrophilic Ligands Research Articles

Aminomethyl Salicylaldehydes Lock onto a Surface Lysine by Forming an Extended Intramolecular Hydrogen Bond Network.

The development of electrophilic ligands that rapidly modify specific lysine residues remains a major challenge. Salicylaldehyde-based inhibitors have been reported to form stable imine adducts with the catalytic lysine of protein kinases. However, the targeted lysine in these examples is buried in a hydrophobic environment. A key unanswered question is whether this strategy can be applied to a lysine on the surface of a protein, where rapid hydrolysis of the resulting salicylaldimine is more likely. Here, we describe a series of aminomethyl-substituted salicylaldehydes that target a fully solvated lysine on the surface of the ATPase domain of Hsp90. By systematically varying the orientation of the salicylaldehyde, we discovered ligands with long residence times, the best of which engages Hsp90 in a quasi-irreversible manner. Crystallographic analysis revealed a daisy-chain network of intramolecular hydrogen bonds in which the salicylaldimine is locked into position by the adjacent piperidine linker. This study highlights the potential of aminomethyl salicylaldehydes to generate conformationally stabilized, hydrolysis-resistant imines, even when the targeted lysine is far from the ligand binding site and is exposed to bulk solvent.

H2 Pressure Dependence in the Homogeneously Catalyzed Guerbet Reaction of Ethanol to Butanol using Mn(I) and Ru(II)

AbstractThe homogeneously catalyzed Guerbet upgrading of ethanol to butanol can be modulated by the application of partial H2 pressure before the reaction. Ruthenium(II) PNP pincer complexes with methylene‐extended acridine‐based ligands and singly‐chelated ruthenium(II) complexes with PN ligands perform best at very low catalyst loadings and upon the application of catalyst‐specific pre‐reaction partial H2 pressure. The combination of ruthenium(II) PNP pincer complexes and manganese(I) pincer complexes with MACHO‐type PNP ligands allows for even lower ruthenium loadings while retaining low base load and consumption, thus enabling high space‐time yields, catalyst productivity and recyclability. Mechanistically, Mn is proposed to stabilize coordinatively unsaturated Ru species and allow coordination of ethoxide to Ru instead of attacking the electrophilic ligand backbone based on NMR spectroscopy and X‐ray crystallography.

Mutate and Conjugate: A Method to Enable Rapid In-Cell Target Validation.

Target validation remains a challenge in drug discovery, which leads to a high attrition rate in the drug discovery process, particularly in Phase II clinical trials. Consequently, new approaches to enhance target validation are valuable tools to improve the drug discovery process. Here, we report the combination of site-directed mutagenesis and electrophilic fragments to enable the rapid identification of small molecules that selectively inhibit the mutant protein. Using the bromodomain-containing protein BRD4 as an example, we employed a structure-based approach to identify the L94C mutation in the first bromodomain of BRD4 [BRD4(1)] as having a minimal effect on BRD4(1) function. We then screened a focused, KAc mimic-containing fragment set and a diverse fragment library against the mutant and wild-type proteins and identified a series of fragments that showed high selectivity for the mutant protein. These compounds were elaborated to include an alkyne click tag to enable the attachment of a fluorescent dye. These clickable compounds were then assessed in HEK293T cells, transiently expressing BRD4(1)WT or BRD4(1)L94C, to determine their selectivity for BRD4(1)L94C over other possible cellular targets. One compound was identified that shows very high selectivity for BRD4(1)L94C over all other proteins. This work provides a proof-of-concept that the combination of site-directed mutagenesis and electrophilic fragments, in a mutate and conjugate approach, can enable rapid identification of small molecule inhibitors for an appropriately mutated protein of interest. This technology can be used to assess the cellular phenotype of inhibiting the protein of interest, and the electrophilic ligand provides a starting point for noncovalent ligand development.

CovPDB: a high-resolution coverage of the covalent protein-ligand interactome.

In recent years, the drug discovery paradigm has shifted toward compounds that covalently modify disease-associated target proteins, because they tend to possess high potency, selectivity, and duration of action. The rational design of novel targeted covalent inhibitors (TCIs) typically starts from resolved macromolecular structures of target proteins in their apo or holo forms. However, the existing TCI databases contain only a paucity of covalent protein–ligand (cP–L) complexes. Herein, we report CovPDB, the first database solely dedicated to high-resolution cocrystal structures of biologically relevant cP–L complexes, curated from the Protein Data Bank. For these curated complexes, the chemical structures and warheads of pre-reactive electrophilic ligands as well as the covalent bonding mechanisms to their target proteins were expertly manually annotated. Totally, CovPDB contains 733 proteins and 1,501 ligands, relating to 2,294 cP–L complexes, 93 reactive warheads, 14 targetable residues, and 21 covalent mechanisms. Users are provided with an intuitive and interactive web interface that allows multiple search and browsing options to explore the covalent interactome at a molecular level in order to develop novel TCIs. CovPDB is freely accessible at http://www.pharmbioinf.uni-freiburg.de/covpdb/ and its contents are available for download as flat files of various formats.

ZIF‐Based Nanoparticles Combine X‐Ray‐Induced Nitrosative Stress with Autophagy Management for Hypoxic Prostate Cancer Therapy

AbstractAlthough reactive oxygen species (ROS)‐mediated tumor treatments are predominant in clinical applications, ROS‐induced protective autophagy promotes cell survival, especially in hypoxic tumors. Herein, X‐ray triggered nitrite (NO2−) is used for hypoxic prostate cancer therapy by inhibiting autophagy and inducing nitrosative stress based on an electrophilic zeolitic imidazole framework (ZIF‐82‐PVP). After internalization of pH‐responsive ZIF‐82‐PVP nanoparticles, electrophilic ligands and Zn2+ are delivered into cancer cells. Electrophilic ligands can not only consume GSH under hypoxia but also capture low‐energy electrons derived from X‐rays to generate NO2−, which inhibits autophagy and further elevates lethal nitrosative stress levels. In addition, dissociated Zn2+ specifically limits the migration and invasion of prostate cancer cells through ion interference. In vitro and in vivo results indicate that ZIF‐82‐PVP nanoparticles under X‐ray irradiation can effectively promote the apoptosis of hypoxic prostate cancer cells. Overall, this nitrosative stress‐mediated tumor therapy strategy provides a novel approach targeting hypoxic tumors.

ZIF-Based Nanoparticles Combine X-Ray-Induced Nitrosative Stress with Autophagy Management for Hypoxic Prostate Cancer Therapy.

Although reactive oxygen species (ROS)-mediated tumor treatments are predominant in clinical applications, ROS-induced protective autophagy promotes cell survival, especially in hypoxic tumors. Herein, X-ray triggered nitrite (NO2- ) is used for hypoxic prostate cancer therapy by inhibiting autophagy and inducing nitrosative stress based on an electrophilic zeolitic imidazole framework (ZIF-82-PVP). After internalization of pH-responsive ZIF-82-PVP nanoparticles, electrophilic ligands and Zn2+ are delivered into cancer cells. Electrophilic ligands can not only consume GSH under hypoxia but also capture low-energy electrons derived from X-rays to generate NO2- , which inhibits autophagy and further elevates lethal nitrosative stress levels. In addition, dissociated Zn2+ specifically limits the migration and invasion of prostate cancer cells through ion interference. In vitro and in vivo results indicate that ZIF-82-PVP nanoparticles under X-ray irradiation can effectively promote the apoptosis of hypoxic prostate cancer cells. Overall, this nitrosative stress-mediated tumor therapy strategy provides a novel approach targeting hypoxic tumors.

Redox Dyshomeostasis Strategy for Hypoxic Tumor Therapy Based on DNAzyme‐Loaded Electrophilic ZIFs

AbstractRedox homeostasis is one of the main reasons for reactive oxygen species (ROS) tolerance in hypoxic tumors, limiting ROS‐mediated tumor therapy. Proposed herein is a redox dyshomeostasis (RDH) strategy based on a nanoplatform, FeCysPW@ZIF‐82@CAT Dz, to disrupt redox homeostasis, and its application to improve ROS‐mediated hypoxic tumor therapy. Once endocytosed by tumor cells, the catalase DNAzyme (CAT Dz) loaded zeolitic imidazole framework‐82 (ZIF‐82@CAT Dz) shell can be degraded into Zn2+ as cofactors for CAT Dz mediated CAT silencing and electrophilic ligands for glutathione (GSH) depletion under hypoxia, both of which lead to intracellular RDH and H2O2 accumulation. These “disordered” cells show reduced resistance to ROS and are effectively killed by ferrous cysteine‐phosphotungstate (FeCysPW) induced chemodynamic therapy (CDT). In vitro and in vivo data demonstrate that the pH/hypoxia/H2O2 triple stimuli responsive nanocomposite can efficiently kill hypoxic tumors. Overall, the RDH strategy provides a new way of thinking about ROS‐mediated treatment of hypoxic tumors.

Redox Dyshomeostasis Strategy for Hypoxic Tumor Therapy Based on DNAzyme-Loaded Electrophilic ZIFs.

Redox homeostasis is one of the main reasons for reactive oxygen species (ROS) tolerance in hypoxic tumors, limiting ROS-mediated tumor therapy. Proposed herein is a redox dyshomeostasis (RDH) strategy based on a nanoplatform, FeCysPW@ZIF-82@CAT Dz, to disrupt redox homeostasis, and its application to improve ROS-mediated hypoxic tumor therapy. Once endocytosed by tumor cells, the catalase DNAzyme (CAT Dz) loaded zeolitic imidazole framework-82 (ZIF-82@CAT Dz) shell can be degraded into Zn2+ as cofactors for CAT Dz mediated CAT silencing and electrophilic ligands for glutathione (GSH) depletion under hypoxia, both of which lead to intracellular RDH and H2 O2 accumulation. These "disordered" cells show reduced resistance to ROS and are effectively killed by ferrous cysteine-phosphotungstate (FeCysPW) induced chemodynamic therapy (CDT). In vitro and in vivo data demonstrate that the pH/hypoxia/H2 O2 triple stimuli responsive nanocomposite can efficiently kill hypoxic tumors. Overall, the RDH strategy provides a new way of thinking about ROS-mediated treatment of hypoxic tumors.

Fragment Screening Hit Draws Attention to a Novel Transient Pocket Adjacent to the Recognition Site of the tRNA-Modifying Enzyme TGT.

Fragment-based lead discovery was applied to tRNA-guanine transglycosylase, an enzyme modifying post-transcriptionally tRNAs in Shigella, the causative agent of shigellosis. TGT inhibition prevents translation of Shigella's virulence factor VirF, hence reducing pathogenicity. One discovered fragment opens a transient subpocket in the preQ1-recognition site by pushing back an aspartate residue. This step is associated with reorganization of further amino acids structurally transforming a loop adjacent to the recognition site by duplicating the volume of the preQ1-recognition pocket. We synthesized 6-carboxamido-, 6-hydrazido-, and 4-guanidino-benzimidazoles to target the opened pocket, including a dihydro-imidazoquinazoline with a propyn-1-yl exit vector pointing into the transient pocket and displacing a conserved water network. MD simulations and hydration-site analysis suggest water displacement to contribute favorably to ligand binding. A cysteine residue, exclusively present in bacterial TGTs, serves as gatekeeper of the transient subpocket. It becomes accessible upon pocket opening for selective covalent attachment of electrophilic ligands in eubacterial TGTs.

Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands.

We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1-4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1-4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.

Structural insights into the molecular mechanism of mouse TRPA1 activation and inhibition.

Pain, though serving the beneficial function of provoking a response to dangerous situations, is an unpleasant sensory and emotional experience. Transient receptor potential ankyrin 1 (TRPA1) is a member of the transient receptor potential (TRP) cation channel family and is localized in "nociceptors," where it plays a key role in the transduction of chemical, inflammatory, and neuropathic pain. TRPA1 is a Ca2+-permeable, nonselective cation channel that is activated by a large variety of structurally unrelated electrophilic and nonelectrophilic chemical compounds. Electrophilic ligands are able to activate TRPA1 channels by interacting with critical cysteine residues on the N terminus of the channels via covalent modification and/or disulfide bonds. Activation by electrophilic compounds is dependent on their thiol-reactive moieties, accounting for the structural diversity of the group. On the other hand, nonelectrophilic ligands do not interact with critical cysteines on the channel, so the structural diversity of this group is unexplained. Although near-atomic-resolution structures of TRPA1 were resolved recently by cryo-electron microscopy, in the presence of both agonists and antagonists, detailed mechanisms of channel activation and inhibition by these modulators could not be determined. Here, we investigate the effect of both electrophilic and nonelectrophilic ligands on TRPA1 channel conformational rearrangements with limited proteolysis and mass spectrometry. Collectively, our results reveal that channel modulation results in conformational rearrangements in the N-terminal ankyrin repeats, the pre-S1 helix, the TRP-like domain, and the linker regions of the channel.

Regioselectivity in ligand substitution reactions on diiron complexes governed by nucleophilic and electrophilic ligand properties.

The discovery of a diiron organometallic site in nature within the diiron hydrogenase, [FeFe]-H2ase, active site has prompted revisits of the classic organometallic chemistry involving the Fe-Fe bond and bridging ligands, particularly of the (μ-SCH2XCH2S)[Fe(CO)3]2 and (μ-SCH2XCH2S)[Fe(CO)2L]2 (X = CH2, NH; L = PMe3, CN(-), and NHC's (NHC = N-heterocyclic carbene)), derived from CO/L exchange reactions. Through the synergy of synthetic chemistry and density functional theory computations, the regioselectivity of nucleophilic (PMe3 or CN(-)) and electrophilic (nitrosonium, NO(+)) ligand substitution on the diiron dithiolate framework of the (μ-pdt)[Fe(CO)2NHC][Fe(CO)3] complex (pdt = propanedithiolate) reveals the electron density shifts in the diiron core of such complexes that mimic the [FeFe]-H2ase active site. While CO substitution by PMe3, followed by reaction with NO(+), produces (μ-pdt)(μ-CO)[Fe(NHC)(NO)][Fe(CO)2PMe3](+), the alternate order of reagent addition produces the structural isomer (μ-pdt)[Fe(NHC)(NO)PMe3][Fe(CO)3](+), illustrating how the nucleophile and electrophile choose the electron-poor metal and the electron-rich metal, respectively. Theoretical explorations of simpler analogues, (μ-pdt)[Fe(CO)2CN][Fe(CO)3](-), (μ-pdt)[Fe(CO)3]2, and (μ-pdt)[Fe(CO)2NO][Fe(CO)3](+), provide an explanation for the role that the electron-rich iron moiety plays in inducing the rotation of the electron-poor iron moiety to produce a bridging CO ligand, a key factor in stabilizing the electron-rich iron moiety and for support of the rotated structure as found in the enzyme active site.

Identification of Significant Amino Acids in Multiple Transmembrane Domains of Human Transient Receptor Potential Ankyrin 1 (TRPA1) for Activation by Eudesmol, an Oxygenized Sesquiterpene in Hop Essential Oil

Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable non-selective cation channel that is activated by various noxious or irritant substances in nature, including spicy compounds. Many TRPA1 chemical activators have been reported; however, only limited information is available regarding the amino acid residues that contribute to the activation by non-electrophilic activators, whereas activation mechanisms by electrophilic ligands have been well characterized. We used intracellular Ca(2+) measurements and whole-cell patch clamp recordings to show that eudesmol, an oxygenated sesquiterpene present at high concentrations in the essential oil of hop cultivar Hallertau Hersbrucker, could activate human TRPA1. Gradual activation of inward currents with outward rectification by eudesmol was observed in human embryonic kidney-derived 293 cells expressing human TRPA1. This activation was completely blocked by a TRPA1-specific inhibitor, HC03-0031. We identified three critical amino acid residues in human TRPA1 in putative transmembrane domains 3, 4, and 5, namely threonine at 813, tyrosine at 840, and serine at 873, for activation by β-eudesmol in a systematic mutational study. Our results revealed a new TRPA1 activator in hop essential oil and provide a novel insight into mechanisms of human TRPA1 activation by non-electrophilic chemicals.

Isothiocyanates from Wasabia japonica Activate Transient Receptor Potential Ankyrin 1 Channel

6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) and 6-(methylthio)hexyl isothiocyanate (6-MTITC) have low pungency and are responsible for the fresh flavor of wasabi (Wasabia japonica [Miq] Matsumura). In this study, we found that these two isothiocyanates activate transient receptor potential ankyrin 1 (TRPA1), and 6-MSITC activates transient receptor potential vanilloid 1 (TRPV1), but not other transient receptor potential channels expressed in sensory neurons. Both 6-MSITC and 6-MTITCinduced intracellular Ca(2+) increases in human embryonic kidney-derived 293 cells expressing mouse TRPA1 (mTRPA1) as measured by Ca(2+) imaging. In whole-cell patch-clamp recordings, 6-MSITC and 6-MTITC dose-dependently activated both mTRPA1 (EC(50) = 147±26 µM for 6-MSITC and 30±3 µM for 6-MTITC) and human TRPA1 (hTRPA1; EC(50) = 39±4 µM for 6-MSITC and 34±3 µM for 6-MTITC). In addition, TRPA1 N-terminal cysteines, which are reported to be important for channel activation by electrophilic ligands, were involved in 6-MSITC- and 6-MTITC-evoked TRPA1 activation. These isothiocyanates also activated endogenous TRPA1 expressed in mouse dorsal root ganglion neurons and intraplantar injection of 10-30 mM 6-MSITC-evoked pain-related behaviors in mice. These results indicate the following: 1) 6-MSITC and 6-MTITC activate both mTRPA1 and hTRPA1; 2) 6-MSITC activates mTRPV1; and 3) the pharmacological functions of these isothiocyanates could be derived from TRPA1 activation.

Identification of in Vivo Disulfide Conformation of TRPA1 Ion Channel

TRPA1 (transient receptor potential ankyrin 1) is an ion channel expressed in the termini of sensory neurons and is activated in response to a broad array of noxious exogenous and endogenous thiol-reactive compounds, making it a crucial player in chemical nociception. A number of conserved cysteine residues on the N-terminal domain of the channel have been identified as critical for sensing these electrophilic pungent chemicals, and our recent EM structure with modeled domains predicts that these cysteines form a ligand-binding pocket, allowing for the possibility of disulfide bonding between the cysteine residues. Here, we present a comprehensive mass spectrometry investigation of the in vivo disulfide bonding conformation and in vitro reactivity of 30 of the 31 cysteine residues in the TRPA1 ion channel. Four disulfide bonds were detected in the in vivo TRPA1 structure: Cys-666-Cys-622, Cys-666-Cys-463, Cys-622-Cys-609, and Cys-666-Cys-193. All of the cysteines detected were reactive to N-methylmaleimide (NMM) in vitro, with varying degrees of labeling efficiency. Comparison of the ratio of the labeling efficiency at 300 μM versus 2 mM NMM identified a number of cysteine residues that were outliers from the mean labeling ratio, suggesting that protein conformation changes rendered these cysteines either more or less protected from labeling at the higher NMM concentrations. These results indicate that the activation mechanism of TRPA1 may involve N-terminal conformation changes and disulfide bonding between critical cysteine residues.

On the maximum bond multiplicity of carbon: unusual C≣U quadruple bonding in molecular CUO

Carbon is known to form single, double and triple bonds. An educated search led us to a novel view on the bonding of carbon in the triatomic uranium carbide oxide molecule CUO. When comparing various empirical properties and theoretical indices of a whole set of related species, some of those molecules are best described with carbon being quadruply bonded, with the ubiquitous one σ- and two π-bonds, plus a non-negligible, albeit weak, rearward σ-bond. Observable indicators of bond strength suggest a rather high C–U bond order, significantly above three for a series of CUE molecules with different electrophilic ligands E. Several orbital-based indices count only a little more than three C–U bonds, although with additional ionic bonding. The bonding in the CU unit of CUE differs from the recently claimed quadruple bonding in C2 owing to the rich U-pfds valence shell. CUE molecules are comparatively stable units with a high nucleophilicity at the carbon end, and they may become chemically interesting intermediates, for instance in water decomposition reactions.

Δ12-Prostaglandin J2 as a Product and Ligand of Human Serum Albumin: Formation of an Unusual Covalent Adduct at His146

Human serum albumin (HSA), the most abundant protein in plasma, has a very unique function, catalyzing the conversion of prostaglandin J(2) (PGJ(2)), a dehydration product of PGD(2), to yield Delta(12)-PGJ(2). These PGD(2) metabolites are actively transported into cells and accumulated in the nuclei, where they act as potent inducers of cell growth inhibition and cell differentiation, and exhibit their own unique spectrum of biological effects. The facts that (i) arachidonic acid metabolites bind to human serum albumin (HSA) and the metabolism of these molecules is altered as a result of binding, (ii) HSA catalyzes the transformation of PGJ(2) into Delta(12)-PGJ(2), and (iii) Delta(12)-PGJ(2) is stable in serum suggest that HSA may bind and stabilize Delta(12)-PGJ(2) in a specific manner. A molecular interaction analysis using surface plasmon resonance (Biacore) indeed suggested the presence of a specific Delta(12)-PGJ(2)-binding site in HSA. To investigate the molecular details of the binding of this PGD(2) metabolite to albumin, we analyzed the cocrystal structure of the HSA-Delta(12)-PGJ(2)-myristate complex by X-ray crystallography and found that two Delta(12)-PGJ(2) molecules bind to a primary site in subdomain IB of the protein. The electron density results suggested that one of the two Delta(12)-PGJ(2) molecules that specifically bind to the site covalently interacted with a histidine residue (His146). Using nano-LC-MS/MS analysis of the HSA-Delta(12)-PGJ(2) complex, the formation of an unusual Delta(12)-PGJ(2)-histidine adduct at His146 was confirmed. Thus, our crystallographic and mass spectrometric analyses of the HSA-Delta(12)-PGJ(2) complex provided intriguing new insights into the molecular details of how this electrophilic ligand interacts with its primary producer and transporter.

Cysteinylated Protein as Reactive Disulfide: An Alternative Route to Affinity Labeling

Engineering the permanent formation of a receptor-ligand complex has a number of promising applications in chemistry, biology, and medicine. Antibodies and other proteins can be excellent receptors for synthetic ligands such as probes or drugs. Because proteins possess an array of nucleophilic sites, the placement of an electrophile on the synthetic ligand to react with a nucleophile on the macromolecule is a standard practice. Previously, we have used the site-directed incorporation of cysteine nucleophiles at the periphery of an antibody's binding site, paired with the chemical design of weakly electrophilic ligands, to produce receptor-ligand pairs that conjugate specifically and permanently (Corneillie et al. (2004) Bioconjugate Chem. 15, 1392-1402 and references therein). After protein expression in Drosophila S2 cells, we found, as is frequently observed, that the engineered cysteine was reversibly blocked by disulfide linkage to a cysteine monomer (cysteinylated). Removal of the cysteine monomer requires some care because of the need to preserve other disulfide linkages in the protein. Here, we report that cysteinylation can be used to advantage by treating the cysteine monomer as a leaving group and the protein disulfide as an electrophile with special affinity for thiols. Two ligands bearing thiol side chains were synthesized and incubated with the cysteinylated antibody Fab fragment 2D12.5 G54C, with the finding that both ligands become covalently attached within a few minutes under physiological conditions. The attachment is robust even in the presence of excess thiol reagents. This rapid, specific conjugation is particularly interesting for biomedical applications.

Phospha‐ and Arsaalkenes RE=C(NMe2)2 (E = P, As) as Novel Phosphinidene‐ and Arsinidene‐Transfer Reagents (Eur. J. Inorg. Chem. 26/2007)

AbstractThe cover picture shows the reaction between the phosphavinylidene complexes [(η5‐C5H5)(CO)2M=P=C(SiMe3)2] and the inversely polarized phosphaalkene tBuP=C(NMe2)2, which affords η3‐1,2‐diphosphaallyl complexes by smooth transfer of the phosphinidene unit onto the electrophilic ligand of the precursors. The molecular structure underlines the unsymmetrical η3‐ligation of the heteroallyl ligand to the metal with the tert‐butyl substituent syn to the central phosphorus atom. Treatment of the phosphavinylidene complexes with P‐aroylphosphaalkenes leads to decomposition. In contrast, phosphavinylidene complexes and As‐aroylarsaalkenes yield complexes featuring cyclic phosphenium ligands with an As=C bond. It is believed that the first step of this process is a formal [2+1] cycloaddition between the P=C bond and the aroylarsinidine to give a three‐membered ring, which subsequently incorporates the CO unit to afford the final product. In all cases, tetrakis(dimethylamino)ethene is formed as a byproduct. Details are presented in the Microreview by L. Weber on p. 4095 ff.

PCP Pincer Palladium Complexes and Their Catalytic Properties: Synthesis via the Electrophilic Ligand Introduction Route

A variety of PCP pincer palladium complexes having phosphinito groups [2,6-(R2PO)2C6H3PdI (R = alkyl, aryl and Et2N)] were synthesized via the electrophilic ligand introduction route with high efficiency. Thus, trans-(2,6-dihydroxyphenyl)iodobis(triphenylphosphine)palladium was prepared by the reaction of 2-iodoresorcinol with tetrakis(triphenylphosphine)palladium, and the palladium complex was converted to the PCP pincer palladium complexes by treatment with chlorophosphines in the presence of triethylamine in 82−95% yield. X-ray molecular structure analyses of the pincer complexes revealed that the molecules adopted distorted square-planar geometries. The Suzuki coupling reaction of 4-bromoacetophenone with phenylboronic acid took place in the presence of 0.1−0.01 mol % of the pincer complexes to give 4-acetylbiphenyl with turnover numbers of 328−5790.