Relationship of Thermostability and Binding Affinity in Metal-binding WW-Domain Minireceptors.

The design of metallo-miniproteins advances our understanding of the structural and functional roles of metals in proteins. We recently designed a metal-binding WW domain, WW-CA-Nle, which displays three histidine residues on its surface for coordination of divalent metals Ni(II), Zn(II) and Cu(II). However, WW-CA-Nle is a molten globule in the apo state and thus showed only moderate binding affinities with Kd values in the µM regime. In this report, we hypothesize that improved thermal stability of the apo state of the metal binding WW-domain scaffold should lead to improved preorganization of the metal-binding site and consequently to higher metal-binding affinities. By redesigning WW-CA-Nle, we obtained WW-CA variants, WW-CA-min and WW-CA-ANG, which were fully folded in the apo states and displayed moderate to excellent thermostabilities in the apo and holo states. We were able to show that the improved thermal stabilities led to improved metal binding, which was reflected in Kd values that were at least one order of magnitude lower compared to WW-CA-Nle. EPR spectroscopy and ITC measurements revealed a better defined and predisposed metal binding site in WW-CA-ANG.

Rebound or Cage Escape? The Role of the Rebound Barrier for the Reactivity of Non-Heme High-Valent FeIV =O Species.

Owing to their high reactivity and selectivity, variations in the spin ground state and a range of possible pathways, high-valent FeIV =O species are popular models with potential bioinspired applications. An interesting example of a structure-reactivity pattern is the detailed study with five nonheme amine-pyridine pentadentate ligand FeIV =O species, including N4py: [(L1 )FeIV =O]2+ (1), bntpen: [(L2 )FeIV =O]2+ (2), py2 tacn: [(L3 )FeIV =O]2+ (3), and two isomeric bispidine derivatives: [(L4 )FeIV =O]2+ (4) and [(L5 )FeIV =O]2+ (5). In this set, the order of increasing reactivity in the hydroxylation of cyclohexane differs from that with cyclohexadiene as substrate. A comprehensive DFT, ab initio CASSCF/NEVPT2 and DLPNO-CCSD(T) study is presented to untangle the observed patterns. These are well reproduced when both activation barriers for the C-H abstraction and the OH rebound are taken into account. An MO, NBO and deformation energy analysis reveals the importance of π(pyr) → π*xz (FeIII -OH) electron donation for weakening the FeIII -OH bond and thus reducing the rebound barrier. This requires that pyridine rings are oriented perpendicularly to the FeIII -OH bond and this is a subtle but crucial point in ligand design for non-heme iron alkane hydroxylation.

Mechanistic Insights into Amphoteric Reactivity of an Iron-Bispidine Complex.

The reactivity of FeIII -alkylperoxido complexes has remained a riddle to inorganic chemists owing to their thermal instability and impotency towards organic substrates. These iron-oxygen adducts have been known as sluggish oxidants towards oxidative electrophilic and nucleophilic reactions. Herein, we report the synthesis and spectroscopic characterization of a relatively stable mononuclear high-spin FeIII -alkylperoxido complex supported by an engineered bispidine framework. Against the notion, this FeIII -alkylperoxido complex serves as a rare example of versatile reactivity in both electrophilic and nucleophilic reactions. Detailed mechanistic studies and computational calculations reveal a novel reaction mechanism, where a putative superoxido intermediate orchestrates the amphoteric property of the oxidant. The design of the backbone is pivotal to convey stability and reactivity to alkylperoxido and superoxido intermediates. Contrary to the well-known O-O bond cleavage that generates an FeIV -oxido species, the FeIII -alkylperoxido complex reported here undergoes O-C bond scission to generate a superoxido moiety that is responsible for the amphiphilic reactivity.

64Cu tumor labeling with hexadentate picolinic acid-based bispidine immunoconjugates.

Discussed are two picolinate appended bispidine ligands (3,7-diazabicyclo[3.3.1]nonane derivatives) in comparison with an earlier described bis-pyridine derivative, which are all known to strongly bind CuII. The radiopharmacological characterization of the two isomeric bispidine complexes includes quantitative labeling with 64CuII at ambient conditions with high radiochemical purities and yields (molar activities >200 MBq/nmol). Challenge experiments in presence of EDTA, cyclam, human serum and SOD demonstrate high stability and inertness of the 64Cu-bispidine complexes. Biodistribution studies performed in Wistar rats indicate a rapid renal elimination for both 64Cu-labeled chelates. The bispidine ligand with the picolinate group in N7 position was selected for further biological experiments, and its backbone was therefore substituted with a benzyl-NCS group at C9. Two tumor target modules (TMs), targeting prostate stem cell antigen (PSCA), overexpressed in prostate cancer, and the fibroblast activation protein (FAP) in fibrosarcoma, were selected for thiourea coupling with the NCS-functionalized ligand and lysine residues of TMs. Small animal PET experiments on tumor-bearing mice showed specific accumulation of the 64Cu-labeled TMs in PSCA- and FAP-overexpressing tumors (standardized uptake value (SUV) for PC3: 2.7±0.6 and HT1080: 7.2±1.25) with almost no uptake in wild type tumors.

Synthesis, Characterization, and Reactivity of Bispidine-Iron(IV)-Tosylimido Species.

Reported are the synthesis and detailed studies of the iron(IV)-tosylimido complexes of two isomeric pentadentate bispidine ligands (bispidines are 3,7-diazabicyclo[3.3.1]nonane derivatives). This completes a series of five tosylimido complexes with comparable pentadentate amine/pyridine ligands, where the corresponding [(L)FeIV═O]2+ oxidants have been studied in detail. The characterization of the two new complexes in solution (UV-vis-NIR, Mössbauer, HR-ESI-MS) shows that these oxidants have an intermediate spin (S = 1) electronic ground state. The reactivities have been studied as oxidants in C-H activation at 1,3-cyclohexadiene and nitrogen atom transfer to thioanisole. For the latter substrate, the entire set of data for the five ligands and for both nitrogen and oxygen atom transfer is now available and the interesting observation is that oxygen atom transfer is, as expected, generally faster than nitrogen atom transfer, with the exception of the two ligands that have four and three pyridine groups oriented parallel to the Fe-O and Fe-N axes. A thorough DFT analysis indicates that this is due to steric effects in the case of the [(L)FeIV═O]2+ species, which are less important in the [(L)FeIV═NTs]2+ compounds due to partial electron transfer from the thioanisole substrate to the iron(IV)-tosylimido oxidant.

A Dicopper(II)-Based Carbonic Anhydrase Model-Quantum-Chemical Evaluation of the Mechanistic Pathway.

The cyanobacterium Prochloron didemni, an obligate symbiont of different species of colonial ascidians, occurring in the Pacific and Indian Oceans, produces a variety of cyclic peptides. These patellamide-type macrocycles lead to relatively stable dicopper(II) complexes that are extremely efficient carbonic anhydrase mimics, the most active model systems known so far. Importantly, it recently was shown that copper(II) is coordinated to patellamide derivatives in Prochloron cells. An interesting question therefore is, whether the biological function of patellamide-type macrocycles is related to the catalytic activity in CO2 hydration or its reverse. Here, we present a computational study to evaluate the energetics of the catalytic cycle in search of a possible answer to these questions and compare the computed energy barriers with the experimental kinetic data. It emerges that release of the bridging carbonate is a critical step and that the catalysis product inhibits catalysis at pH values above approx. 7. Therefore, carbonate transport rather than CO2 hydrolysis is proposed as the biological function of copper(II)-patellamide complexes in the Prochloron-Ascidian symbiosis.

Natural Abiotic Iron-Oxido-Mediated Formation of C1 and C2 Compounds from Environmentally Important Methyl-Substituted Substrates.

Organic and inorganic volatile compounds containing one carbon atom (C1), such as carbon dioxide, methane, methanol, formaldehyde, carbon monoxide, and chloromethane, are ubiquitous in the environment, are key components in global carbon cycling, play an important role in atmospheric physics and chemistry, e.g., as greenhouse gases, destroy stratospheric and tropospheric ozone, and control the atmospheric oxidation capacity. Up to now, most C1 compounds in the environment were associated with complex metabolic and enzymatic pathways in organisms or to combustion processes of organic matter. We now present compelling evidence that many C1 and C2 compounds have a common origin in methyl groups of methyl-substituted substrates that are cleaved by the iron oxide-mediated formation of methyl radicals. This scenario is derived from experiments with a mechanistically well-studied bispidine-iron-oxido complex as oxidant and dimethyl sulfoxide as the environmentally relevant model substrate and is supported by computational modeling based on density functional theory and ab initio quantum-chemical studies. The exhaustive experimental model studies, also involving extensive isotope labeling, are complemented with the substitution of the bispidine model system by environmentally relevant iron oxides and, finally, a collection of soils with varying iron and organic matter contents. The combination of all data suggests that the iron oxide-mediated formation of methyl radicals from methyl-substituted substrates is a common abiotic source for widespread C1 and C2 compounds in the environment.

An Engineered ß-Hairpin Peptide Forming Thermostable Complexes with ZnII , NiII , and CuII through a His3 Site.

The three-dimensional structure of a peptide, which determines its function, can denature at elevated temperatures, in the presence of chaotropic reagents, or in organic solvents. These factors limit the applicability of peptides. Herein, we present an engineered ß-hairpin peptide containing a His3 site that forms complexes with ZnII , NiII , and CuII . Circular dichroism spectroscopy shows that the peptide-metal complexes exhibit melting temperatures up to 80 °C and remain folded in 6 M guanidine hydrochloride as well as in organic solvents. Intrinsic fluorescence titration experiments were used to determine the dissociation constants of metal binding in the nano- to sub-nanomolar range. The coordination geometry of the peptide-CuII complex was studied by EPR spectroscopy, and a distorted square planar coordination geometry with weak interactions to axial ligands was revealed. Due to their impressive stability, the presented peptide-metal complexes open up interesting fields of application, such as the development of a new class of peptide-metal catalysts for stereoselective organic synthesis or the directed design of extremophilic ß-sheet peptides.

Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions.

Octadentate and specifically nonadentate ligands with a bispidine scaffold (3,7-diazabicyclo[3.3.1]nonane) are known to be efficiently coordinated to a range of metal ions of interest in radiopharmaceutical chemistry and lead to exceedingly stable and inert complexes. Nonadentate bispidine L2 (with a tridentate bipyridine acetate appended to N3 and a picolinate at N7) has been shown before to be an ideal chelator for 111In3+, 177Lu3+, and 225Ac3+, nuclides of interest for diagnosis and therapy, and a proof-of-principle study with an SSTR2-specific octreotate has shown potential for theranostic applications. We now have extended these studies in two directions. First, we present ligand derivative L3, in which the bipyridine acetate is substituted with terpyridine, a softer donor for metal ions with a preference for more covalency. L3 did not fulfill the hopes because complexation is much less efficient. While for Bi3+ and Pb2+ the ligand is an excellent chelator with properties similar to those of L2, Lu3+ and La3+ show very slow and inefficient complexation with L3 in contrast to L2, and 225Ac3+ is not fully coordinated, even at an increased temperature (92% radiochemical yield at 80 °C, 60 min, [L3] = 10-4 M). These observations have led to a hypothesis for the complexation pathway that is in line with all of the experimental data and supported by a preliminary density functional theory analysis, which is important for the design of further optimized bispidine chelators. Second, the coordination chemistry of L2 has been extended to Bi3+, La3+, and Pb2+, including solid state and solution structural work, complex stabilities, radiolabeling, and radiostability studies. All complexes of this ligand (La3+, Ac3+, Lu3+, Bi3+, In3+, and Pb2+), including nuclides for targeted α therapy (TAT), single-photon emission computed tomography, and positron emission tomography, are formed efficiently under physiological conditions, i.e., suitable for the labeling of delicate biological vectors such as antibodies, and the complexes are very stable and inert. Importantly, for TAT with 225Ac, the daughter nuclides 213Bi and 209Pb also form stable complexes, and this is important for reducing damage to healthy tissue.

Mn2+ Bispidine Complex Combining Exceptional Stability, Inertness, and MRI Efficiency.

As an essential metal ion and an efficient relaxation agent, Mn2+ holds a great promise to replace Gd3+ in magnetic resonance imaging (MRI) contrast agent applications, if its stable and inert complexation can be achieved. Toward this goal, four pyridine and one carboxylate pendants have been introduced in coordinating positions on the bispidine platform to yield ligand L3. Thanks to its rigid and preorganized structure and perfect size match for Mn2+, L3 provides remarkably high thermodynamic stability (log KMnL = 19.47), selectivity over the major biological competitor Zn2+ (log(KMnL/KZnL) = 4.4), and kinetic inertness. Solid-state X-ray data show that [MnL3(MeOH)](OTf)2 has an unusual eight-coordinate structure with a coordinated solvent molecule, in contrast to the six-coordinate structure of [ZnL3](OTf), underlining that the coordination cavity is perfectly adapted for Mn2+, while it is too large for Zn2+. In aqueous solution, 17O NMR data evidence one inner sphere water and dissociatively activated water exchange (kex298 = 13.5 × 107 s-1) for MnL3. Its water proton relaxivity (r1 = 4.44 mM-1 s-1 at 25 °C, 20 MHz) is about 30% higher than values for typical monohydrated Mn2+ complexes, which is related to its larger molecular size; its relaxation efficiency is similar to that of clinically used Gd3+-based agents. In vivo MRI experiments realized in control mice at 0.02 mmol/kg injected dose indicate good signal enhancement in the kidneys and fast renal clearance. Taken together, MnL3 is the first chelate that combines such excellent stability, selectivity, inertness and relaxation properties, all of primary importance for MRI use.

Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225.

We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177, and actinium-225 under mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of the bioconjugate; that is, it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability (inertness), it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di- and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40 °C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu- and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2-positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.

Efficient Synthesis for a Wide Variety of Patellamide Derivatives and Phosphatase Activity of Copper-Patellamide Complexes.

Copper complexes of patellamides have shown catalytic activity in a variety of reactions but their biological function remains unknown. There are significant differences between the natural macrocycles and synthetic analogues in the various catalytic activities. It therefore is essential to be able to perform in vivo and ex vivo reference measurements with the natural patellamide macrocycles, very similar derivatives and a large range of synthetic analogues. The preparative method described allows for a highly adaptable synthetic process producing building blocks for a large range of patellamide derivatives: apart from natural compounds, a new synthetic patellamide was prepared that does not have any substituents at any of the four heterocycles. Together with the variation of substituents at the aliphatic backbone, this allowed to elucidate the catalytic activity for phosphoester hydrolysis as a function of the structure and dynamics of the dicopper(II)-patellamide complexes, both by experiment and DFT-based mechanistic studies.

Non-Heme-Iron-Mediated Selective Halogenation of Unactivated Carbon-Hydrogen Bonds.

Oxidation of the iron(II) precursor [(L1 )FeII Cl2 ], where L1 is a tetradentate bispidine, with soluble iodosylbenzene (s PhIO) leads to the extremely reactive ferryl oxidant [(L1 )(Cl)FeIV =O]+ with a cis disposition of the chlorido and oxido coligands, as observed in non-heme halogenase enzymes. Experimental data indicate that, with cyclohexane as substrate, there is selective formation of chlorocyclohexane, the halogenation being initiated by C-H abstraction and the result of a rebound of the ensuing radical to an iron-bound Cl- . The time-resolved formation of the halogenation product indicates that this primarily results from s PhIO oxidation of an initially formed oxido-bridged diiron(III) resting state. The high yield of up to >70 % (stoichiometric reaction) as well as the differing reactivities of free Fe2+ and Fe3+ in comparison with [(L1 )FeII Cl2 ] indicate a high complex stability of the bispidine-iron complexes. DFT analysis shows that, due to a large driving force and small triplet-quintet gap, [(L1 )(Cl)FeIV =O]+ is the most reactive small-molecule halogenase model, that the FeIII /radical rebound intermediate has a relatively long lifetime (as supported by experimentally observed cage escape), and that this intermediate has, as observed experimentally, a lower energy barrier to the halogenation than the hydroxylation product; this is shown to primarily be due to steric effects.

Intermediate-spin iron(IV)-oxido species with record reactivity.

The nonheme iron(IV)-oxido complex trans-N3-[(L1)FeIVO(Cl)]+, where L1 is a derivative of the tetradentate bispidine 2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1]nonane-1-one, has an S = 1 electronic ground state and is the most reactive nonheme iron model system known so far, of a similar order of reactivity as nonheme iron enzymes (C-H abstraction of cyclohexane, -90 °C (propionitrile), t1/2 = 3.5 s). The reaction with cyclohexane selectively leads to chlorocyclohexane, but "cage escape" at the [(L1)FeIII(OH)(Cl)]+/cyclohexyl radical intermediate lowers the productivity. Ligand field theory is used herein to analyze the d-d transitions of [(L1)FeIVO(X)]n+ (X = Cl-, Br-, MeCN) in comparison with the thoroughly characterized ferryl complex of tetramethylcyclam (TMC = L2; [(L2)FeIVO(MeCN)]2+). The ligand field parameters and d-d transition energies are shown to provide important information on the triplet-quintet gap and its correlation with oxidation reactivity.

Possible Functional Roles of Patellamides in the Ascidian-Prochloron Symbiosis.

Patellamides are highly bioactive compounds found along with other cyanobactins in the symbiosis between didemnid ascidians and the enigmatic cyanobacterium Prochloron. The biosynthetic pathway of patellamide synthesis is well understood, the relevant operons have been identified in the Prochloron genome and genes involved in patellamide synthesis are among the most highly transcribed cyanobacterial genes in hospite. However, a more detailed study of the in vivo dynamics of patellamides and their function in the ascidian-Prochloron symbiosis is complicated by the fact that Prochloron remains uncultivated despite numerous attempts since its discovery in 1975. A major challenge is to account for the highly dynamic microenvironmental conditions experienced by Prochloron in hospite, where light-dark cycles drive rapid shifts between hyperoxia and anoxia as well as pH variations from pH ~6 to ~10. Recently, work on patellamide analogues has pointed out a range of different catalytic functions of patellamide that could prove essential for the ascidian-Prochloron symbiosis and could be modulated by the strong microenvironmental dynamics. Here, we review fundamental properties of patellamides and their occurrence and dynamics in vitro and in vivo. We discuss possible functions of patellamides in the ascidian-Prochloron symbiosis and identify important knowledge gaps and needs for further experimental studies.

Exceptional Manganese(II) Stability and Manganese(II)/Zinc(II) Selectivity with Rigid Polydentate Ligands.

While MnII complexes meet increasing interest in biomedical applications, ligands are lacking that enable high MnII complex stability and selectivity vs. ZnII , the most relevant biological competitor. We report here two new bispidine derivatives, which provide rigid and large coordination cavities that perfectly match the size of MnII , yielding eight-coordinate MnII complexes with record stabilities. In contrast, the smaller ZnII ion cannot accommodate all ligand donors, resulting in highly strained and less stable six-coordinate complexes. Combined theoretical and experimental data (X-ray crystallography, potentiometry, relaxometry and 1 H NMR spectroscopy) demonstrate unprecedented selectivity for MnII vs. ZnII (KMnL /KZnL of 108 -1010 ), in sharp contrast to the usual Irving-Williams behavior, and record MnII complex stabilities and inertness with logKMnL close to 25.

Pathways of the Extremely Reactive Iron(IV)-oxido complexes with Tetradentate Bispidine Ligands.

The nonheme iron(IV)-oxido complex trans-N3-[(L1 )FeIV =O(Cl)]+ , where L1 is a derivative of the tetradentate bispidine 2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1]nonane-1-one, is known to have an S=1 electronic ground state and to be an extremely reactive oxidant for oxygen atom transfer (OAT) and hydrogen atom abstraction (HAA) processes. Here we show that, in spite of this ferryl oxidant having the "wrong" spin ground state, it is the most reactive nonheme iron model system known so far and of a similar order of reactivity as nonheme iron enzymes (C-H abstraction of cyclohexane, -90 °C (propionitrile), t1/2 =3.5 sec). Discussed are spectroscopic and kinetic data, supported by a DFT-based theoretical analysis, which indicate that substrate oxidation is significantly faster than self-decay processes due to an intramolecular demethylation pathway and formation of an oxido-bridged diiron(III) intermediate. It is also shown that the iron(III)-chlorido-hydroxido/cyclohexyl radical intermediate, resulting from C-H abstraction, selectively produces chlorocyclohexane in a rebound process. However, the life-time of the intermediate is so long that other reaction channels (known as cage escape) become important, and much of the C-H abstraction therefore is unproductive. In bulk reactions at ambient temperature and at longer time scales, there is formation of significant amounts of oxidation product - selectively of chlorocyclohexane - and it is shown that this originates from oxidation of the oxido-bridged diiron(III) resting state.

Validation of Ab-Initio-Predicted Magnetic Anisotropies and Magneto-structural Correlations in Linear Hetero-trinuclear DyIII -NiII 2 Compounds.

Reported are single crystal SQUID and single crystal high-frequency/high-field EPR data of a trinuclear complex with a rare six-coordinate coordination sphere of a DyIII center coupled to two terminal six-coordinate NiII ions. The analysis of the single crystal spectroscopic parameters allows for an accurate description of the ground state wavefunction. The experimental analysis is supplemented by the analysis of the paramagnetic NMR spectra, allowing for a thorough description of the DyIII center. The experimental data are interpreted on the basis of an ab initio ligand field analysis, and the computed parameters are in good agreement with the experimental observations. This supports the quality of the theoretical approach based on a pseudo-spin Hamiltonian for the electronic ground state. Further support emerges from the ab initio ligand field theory based analysis of a structurally very similar system that, in contrast to the complex reported here, shows single molecule magnetic properties, and this is in agreement with the quantum-chemical prediction and analysis.

Excited State Properties of Lanthanide(III) Complexes with a Nonadentate Bispidine Ligand.

EuIII , TbIII , GdIII and YbIII complexes of the nonadentate bispidine derivative L2 (bispidine=3,7-diazabicyclo[3.3.1]nonane) were successfully synthesized and their emission properties studied. The X-ray crystallography reveals full encapsulation by the nonadentate ligand L2 that enforces to all LnIII cations a common highly symmetrical capped square antiprismatic (CSAPR) coordination geometry (pseudo C4v symmetry). The well-resolved identical emission spectra in solid state and in solution confirm equal structures in both media. As therefore expected, this results in long-lived excited states and high emission quantum yields ([EuIII L2 ]+ , H2 O, 298 K, τ=1.51 ms, ϕ=0.35; [TbIII L2 ]+ , H2 O, 298 K, τ=1.95 ms, ϕ=0.68). Together with the very high kinetic and thermodynamic stabilities, these complexes are a possible basis for interesting biological probes.

Phosphine-Catalyzed Vinylation at Low Acetylene Pressure.

The vinylation of various nucleophiles with acetylene at a maximum pressure of 1.5 bar is achieved by organocatalysis with easily accessible phosphines like tri-n-butylphosphine. A detailed mechanistic investigation by quantum-chemical and experimental methods supports a nucleophilic activation of acetylene by the phosphine catalyst. At 140 °C and typically 5 mol % catalyst loading, cyclic amides, oxazolidinones, ureas, unsaturated cyclic amines, and alcohols were successfully vinylated. Furthermore, the in situ generation of a vinyl phosphonium species can also be utilized in Wittig-type functionalization of aldehydes.