Diastereoselective Synthesis of Sulfoxide-Functionalised N-Heterocyclic Carbene Ruthenium Complexes, Experimental and Computational Study.

The synthesis of sulfoxide-functionalized NHC ligand precursors were carried out by direct and mild oxidation from corresponding thioether precursors with high selectivity. A series of cationic [Ru(II)(η6-p-cymene)(NHC-SO)Cl]+ complexes were obtained in excellent yields by the classical Ag2O transmetallation route. NMR analyses suggested a chelate structure for the metal complexes, and X-ray diffractometry studies of 4 complexes unambiguously confirmed the preference for the bidentate (κ2-C,S) coordination mode of the NHC-SO ligands. Interestingly, only one diastereomer, in the form of an enantiomeric pair, was observed both in 1H NMR and in the solid state for the complexes. DFT calculations showed a possible intrinsic energy difference between the two pairs of diastereomers. The calculated energy barriers suggested that inversion of the sulfoxide is only plausible from the higher energy diastereomer together with bulky substituents. Inverting the configuration at the Ru center instead shows a lower and accessible activation barrier to provide the most stable diastereomer through thermodynamic control, consistent with the observation of a single species by 1H NMR as a pair of enantiomers. All these complexes catalyse the ß-alkylation of secondary alcohols.

Triphenylphosphonium-functionalized N-heterocyclic carbene platinum complexes [(NHC-TPP+)Pt] induce cell death of human glioblastoma cancer stem cells.

A growing body of experimental and clinical evidence suggests that rare cell populations, known as cancer stem cells (CSCs), play an important role in the development and therapeutic resistance of several cancers, including glioblastoma. Elimination of these cells is therefore of paramount importance. Interestingly, recent results have shown that the use of drugs that specifically disrupt mitochondria or induce mitochondria-dependent apoptosis can efficiently kill cancer stem cells. In this context, a novel series of platinum(II) complexes bearing N-heterocyclic carbene (NHC) of the type [(NHC)PtI2(L)] modified with the mitochondria targeting group triphenylphosphonium were synthesized. After a complete characterization of the platinum complexes, the cytotoxicity against two different cancer cell lines, including a cancer stem cell line, was investigated. The best compound reduced the cell viability of both cell lines by 50% in the low µM range, with an approximately 300-fold higher anticancer activity on the CSC line compared to oxaliplatin. Finally, mechanistic studies showed that the triphenylphosphonium functionalized platinum complexes significantly altered mitochondrial function and also induced atypical cell death.

Rh(I) Complexes with Hemilabile Thioether-Functionalized NHC Ligands as Catalysts for [2 + 2 + 2] Cycloaddition of 1,5-Bisallenes and Alkynes.

The [2 + 2 + 2] cycloaddition of 1,5-bisallenes and alkynes under the catalysis of Rh(I) with hemilabile thioether-functionalized N-heterocyclic carbene ligands is described. This protocol effectively provides an entry to different trans-5,6-fused bicyclic systems with two exocyclic double bonds in the cyclohexene ring. The process is totally chemoselective with the two internal double bonds of the 1,5-bisallenes being involved in the cycloaddition. The complete mechanism of this transformation as well as the preference for the trans-fusion over the cis-fusion has been rationalized by density functional theory calculations. The reaction follows a typical [2 + 2 + 2] cycloaddition mechanism. The oxidative addition takes place between the alkyne and one of the allenes and it is when the second allene is inserted into the rhodacyclopentene that the trans-fusion is generated. Remarkably, the hemilabile character of the sulfur atom in the N-heterocyclic carbene ligand modulates the electron density in key intermediates, facilitating the overall transformation.

Polymerization/depolymerization of chiral metallo-supramolecular assembly induced by redox change.

We report on the polymerization/depolymerization of chiral metallo-supramolecular assembly by CuI /CuII redox change. By combining a monotopic enantiopure ligand with a ditopic ligand of opposite configuration, ML2 -type complexes are generated with chiral self-recognition or self-discrimination depending on the oxidation state of copper. In presence of CuI , the formation of heterochiral complexes is favored, thus generating dinuclear species whereas CuII advocates for the formation of homochiral species, namely, a mixture of mononuclear species and metallo-supramolecular polymeric species. Thus, cyclic voltammetry was used to study such a chirality-induced stimulus sensitive polymerization/depolymerization process.

Observation of hyperpositive non-linear effect in catalytic asymmetric organozinc additions to aldehydes.

Asymmetric amplification is a phenomenon that is believed to play a key role in the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been investigated to provide an understanding of how chiral amplification is possible, in particular based on non-linear effects. Interestingly, it has been proposed a quarter century ago that chiral catalysts, when not enantiopure might even be more enantioselective than their enantiopure counterparts. We show here that such hyperpositive non-linear effect in asymmetric catalysis is indeed possible. An in-depth study into the underlying mechanism was carried out, and the scheme we derive differs from the previous proposed models.

N-Heterocyclic Carbene Platinum(IV) as Metallodrug Candidates: Synthesis and 195Pt NMR Chemical Shift Trend.

A series of octahedral platinum(IV) complexes functionalized with both N-heterocyclic carbene (NHC) ligands were synthesized according to a straightforward procedure and characterized. The coordination sphere around the metal was varied, investigating the influence of the substituted NHC and the amine ligand in trans position to the NHC. The influence of those structural variations on the chemical shift of the platinum center were evaluated by 195Pt NMR. This spectroscopy provided more insights on the impact of the structural changes on the electronic density at the platinum center. Investigation of the in vitro cytotoxicities of representative complexes were carried on three cancer cell lines and showed IC50 values down to the low micromolar range that compare favorably with the benchmark cisplatin or their platinum(II) counterparts bearing NHC ligands.

Chiral stimuli-responsive metallo-supramolecular assembly induced by CuII/CuI redox change.

We investigated the selective formation of homoleptic and heteroleptic metal complexes controlled by means of the chiral molecular instruction of the ligand and the coordination geometry of the metal. Our results showed that chiral self-recognition or self-discrimination may be induced by the CuI/CuII redox transition using cyclic voltammetry. The further use of chiral ditopic ligands led to metallo-supramolecular copolymers with stimuli-responsive controlled arrangement.

Synthesis, characterization, catalytic and biological application of half-sandwich ruthenium complexes bearing hemilabile (κ2-C,S)-thioether-functionalised NHC ligands.

A series of cationic Ru(ii)(η6-p-cymene) complexes with thioether-functionalised N-heterocyclic carbene ligands have been prepared and fully characterized. Steric and electronic influence of the R thioether substituent on the coordination of the sulfur atom was investigated. The molecular structure of three of them has been determined by means of X-ray diffractrometry and confirmed the bidentate (κ2-C,S) coordination mode of the ligand. Interestingly, only a single diastereomer, as an enantiomeric couple, was observed in the solid state for complexes 1c, 1i and 1j. DFT calculations established a low energy inversion barrier between the two diastereomers through a sulfur pyramidal inversion pathway with R donating group while a dissociative/associative mechanism is more likely with R substituents that contain electron withdrawing group, thus suggesting that the only species observed by the 1H-NMR correspond to an average resonance position of a fluxional mixtures of isomers. All these complexes were found to catalyse the oxydant-free double dehydrogenation of primary amine into nitrile. Ru complex bearing NHC-functionalised S-tBu group was further investigated in a wide range of amines and was found more selective for alkyl amine substrates than for benzylamine derivatives. Finally, preliminary results of the biological effects on various human cancer cells of four selected Ru complexes are reported.

Hyperpositive non-linear effects: enantiodivergence and modelling.

The chiral ligand N-methylephedrine (NME) was found to catalyse the addition of dimethylzinc to benzaldehyde in an enantiodivergent way, with a monomeric and a homochiral dimeric complex both catalysing the reaction at a steady state and giving opposite product enantiomers. A change in the sign of the enantiomeric product was thus possible by simply varying the catalyst loading or the ligand ee, giving rise to an enantiodivergent non-linear effect. Simulations using a mathematical model confirmed the possibility of such behaviour and showed that this can lead to situations where a reaction gives racemic products, although the system is composed only of highly enantioselective individual catalysts. Furthermore, depending on the dimer's degree of participation in the catalytic conversion, enantiodivergence may or may not be observed experimentally, which raises questions about the possibility of enantiodivergence in other monomer/dimer-catalysed systems. Simulations of the reaction kinetics showed that the observed kinetic constant k obs is highly dependent on user-controlled parameters, such as the catalyst concentration and the ligand ee, and may thus vary in a distinct way from one experimental setup to another. This unusual dependency of k obs allowed us to confirm that a previously observed U-shaped catalyst order vs. catalyst loading-plot is linked to the simultaneous catalytic activity of both monomeric and dimeric complexes.

Chiral Self-Sorting Process with Ditopic Ligands: Alternate or Block Metallopolymer Assembly as a Function of the Metal Ion.

We report an extensive study on the coordination behavior of chiral ditopic bridging ligands, which lead to metallosupramolecular polymers in the presence of Zn(II) and Cu(II) in solution. With the help of UV-vis and circular dichroism spectroscopies, we show that the metallopolymer sequence can be controlled by chirality and by the choice of the metal ion. Although the formation of a block metallopolymer proceeds through the assembly of homoleptic complexes, an alternate metallopolymer may be obtained only when heteroleptic complexes are formed. This demonstrates how the prevalent coordination geometries at metal centers may be used to control the sequences of the metallopolymers.

Easy Ruthenium-Catalysed Oxidation of Primary Amines to Nitriles under Oxidant-Free Conditions.

A dehydrogenation of primary amine to give the corresponding nitrile under oxidant- and base-free conditions catalysed by simple [Ru(p-cym)Cl2 ]2 with no extra ligand is reported. The system is highly selective for alkyl amines, whereas benzylamine derivatives gave the nitrile product together with the imine in a ratio ranging from 14:1 to 4:1 depending on the substrate. Preliminary mechanistic investigations have been performed to identify the key factors that govern the selectivity.

Catalyst-free hydrophosphination of alkenes in presence of 2-methyltetrahydrofuran: a green and easy access to a wide range of tertiary phosphines.

A hydrophosphination reaction that is free of base, acid and catalyst, using only 2-methyltetrahydrofuran as additive has been performed. A new family of mono-, di-, tri- and tetra-phosphines compounds are obtained in good to excellent yields by adding diphenylphosphine to alkenes, mono- and polyfunctional acrylics (based on acrylate and methacrylate motifs) and acrylamide substrates. Addition of four equivalent of bio-mass derived 2-MeTHF into the reaction media improves both conversion and time of the reaction and reduces the sensitivity of the reactants over oxidation. This simple, straightforward and atom-economic method respects the principles of Green Chemistry. Furthermore, in each case this transformation shows an exclusive regioselectivity towards the anti-Markovnikov products.

Synthesis, characterization, and catalytic application in aldehyde hydrosilylation of half-sandwich nickel complexes bearing (κ1-C)- and hemilabile (κ2-C,S)-thioether-functionalised NHC ligands.

Neutral nickel-N-heterocyclic carbene complexes, (κ1-C)-[NiCpBr{R-NHC-(CH2)2SR'}] [Cp = η5-C5H5; R-NHC-(CH2)2SR' = 1-mesityl-3-[2-(tert-butylthio)ethyl]- (1a), 1-mesityl-3-[2-(phenylthio)ethyl]- (1b), 1-benzyl-3-[2-(tert-butylthio)ethyl]- (1c), 1-benzyl-3-[2-(phenylthio)ethyl]-imidazol-2-ylidene (1d)], which bear a N-bound thioether side arm, were prepared by the reaction of nickelocene with the corresponding imidazolium bromides [R-NHC-(CH2)2SR'·HBr] (a-d), via conventional or microwave heating. The 1H NMR spectra of the benzyl-substituted species 1c and 1d showed signals for diastereotopic NCH2CH2S protons at room temperature. However, structural studies established the absence of coordination of the sulphur atom in the solid state, and solvent DFT calculations showed that bromide displacement by sulphur is an unfavourable process (ΔG = +13.5 kcal mol-1 for 1d), thereby suggesting that the observed disatereotopicity is more likely due to significant steric congestion rather than to a possible C,S-chelation in solution. Treatment of these complexes with KPF6 in tetrahydrofuran (THF) led to bromide abstraction to afford the cationic complexes [NiCp{R-NHC-(CH2)2SR'}](PF6) (2a-c). Alternatively, 2a-c could also be prepared by the direct reaction of nickelocene with the corresponding imidazolium hexafluorophosphate salts [R-NHC-(CH2)2SR'·HPF6]. Inversely to the neutral species, whereas X-ray crystallography established C,S-chelation in the solid state, the 1H NMR spectra (CDCl3, CD2Cl2, or thf-d8) at room temperature showed no diastereotopic NCH2CH2S protons, thus suggesting the possible displacement of the sulphur atom by the respective solvents and/or very fast sulphur inversion. DFT calculations established a low energy inversion process in all cases (+9 ≤ΔG‡≤ +13 kcal mol-1) as well as a favourable solvent coordination process (ΔG‡≈ +11 kcal mol-1; ΔG≈-7 kcal mol-1) with a solvent such as THF, thus suggesting that sulphur inversion and/or solvent coordination can both account for the absence of diastereotopy at room temperature, depending on the solvent. While all complexes catalysed the hydrosilylation of benzaldehyde in the absence of any additive, the cationic C,S-chelated complexes 2 proved more active than the sterically constrained neutral species 1. In particular, 2c proved to be the most active pre-catalyst and its catalytic charge could be lowered down to 2 mol% with PhSiH3 as the hydrogen source.

Exploring diversity in platinum(iv) N-heterocyclic carbene complexes: synthesis, characterization, reactivity and biological evaluation.

Platinum(iv) complexes stabilized by N-heterocyclic carbene ligands of the type [(NHC)PtX4L], where L is a neutral nitrogen-based ligand and X is a halide anion (Br, Cl), were prepared by using straightforward and high-yielding synthetic routes and the scope was extended to amphiphilic derivatives. The complexes were fully characterized and the molecular structure of the three derivatives was determined by single-crystal X-ray analyses. The complexes demonstrated in vitro antiproliferative activities against several cancer cell lines. In particular, a representative Pt(iv) complex, namely, [(NHC)PtCl4(pyridine)], displayed efficient antiproliferative activity against cisplatin-resistant cancer cells. These results were correlated with their physicochemical properties, namely, solubility, stability and redox behavior by means of UV-vis spectroscopy, NMR or cyclic voltammetry, whereas in DMSO/water, these Pt(iv) complexes transform into biologically less active cis[(NHC)PtX2(DMSO)] species, in the presence of a bioreductant such as glutathione which quickly leads to the formation of a biologically active trans[(NHC)PtX2L] complex. Overall, these data show that NHC-Pt(iv) compounds are good candidates as anti-cancer prodrugs.

Advances in Homogeneous Catalysis Using Secondary Phosphine Oxides (SPOs): Pre-ligands for Metal Complexes.

The secondary phosphine oxides are known to exist in equilibrium between the pentavalent phosphine oxides (SPO) and the trivalent phosphinous acids (PA). This equilibrium can be displaced in favour of the trivalent tautomeric form upon coordination to late transition metals. This tutorial review provides the state of the art of the use of secondary phosphine oxides as pre-ligands in transition metal-catalysed reactions. Using a combination of SPOs and several metals such as Pd, Pt, Ru, Rh and Au, a series of effective and original transformations have been obtained and will be discussed here.

Synthesis of Spiro Ketals, Orthoesters, and Orthocarbonates by CpRu-Catalyzed Decomposition of α-Diazo-ß-ketoesters.

Reactions of α-diazo-ß-ketoesters with cyclic ketones, lactones, and carbonates are reported. Thanks to the combined use of salt [CpRu(CH3CN)3][BArF] and 1,10-phenanthroline as catalyst for the diazo decomposition, effective and practical syntheses of spiro bicyclic ketals, orthoesters, and orthocarbonates are afforded.

Original reactivity of α-diazo-ß- ketoesters catalyzed by CpRu complexes.

Using α-diazo-ß-ketoesters as reagents and combinations of CpRu fragments and diimine ligands as catalysts, a series of original transformations have been obtained that can be rationalized by the formation of metal carbenes and metal-bound ylide intermediates. Interesting 1,3-dioxole, enol-acetal and 1,4-dioxene motifs are obtained directly when the reactive mixture is reacted in presence of aldehydes or ketones, THF and epoxides.

[CpRu]-catalyzed carbene insertions into epoxides: 1,4-dioxene synthesis through S(N)1-like chemistry with retention of configuration.

Rather than lead to the usual deoxygenation pathway, metal carbenes derived from α-diazo-ß-ketoesters undergo three-atom insertions into epoxides using a combination of 1,10-phenanthroline and [CpRu(CH3CN)3][BAr(F)] as the catalyst. Original 1,4-dioxene motifs are obtained as single regio- and stereoisomers. A perfect syn stereochemistry (retention, e.r. up to 97:3) is observed for the ring opening, which behaves as an S(N)1-like transformation.

Assessment of the electronic properties of P ligands stemming from secondary phosphine oxides.

We report the study of the net donating ability of monodentate and bidentate P ligands stemming from secondary phosphine oxides (SPOs). We experimentally measured and/or calculated the frequencies of CO stretching modes of various metal carbonyl complexes. The inferred electronic properties of the ligands span an unprecedented range, going from π-accepting phosphite-like compounds, to extremely electron-donating ligands outclassing N-heterocyclic carbenes.