A Palladium(II) Complex of a C₄ Chelating Bis(NHC) Diphosphonium Bis(ylide) Ligand

The preparation and the structure of a palladium­(II) complex bearing an extremely electron rich C₄ chelating bis­(NHC) diphosphonium bis­(ylide) ligand are described. This Pd complex is obtained as a single diastereoisomer via a four-step synthesis from the bis­(imidazol-1-yl)­methane in 43% overall yield. It results from two fully selective processes: the deprotonation of two imidazolium moieties in the presence of phosphonium centers and the coordination of two phosphonium ylides at the metal center. Steric and electrostatic constraints between the triphenylphosphonio substituents at the C-ylidic positions are proposed to explain the diastereoselectivity of the C₂ coordination in favor of the <i>dl</i> form (<i>RR</i>/<i>SS</i>)

Electrostatic Control of Pd²⁺ → Ag⁺ Transmetalation of a Bis-Imidazoliophosphine Ligand

Attempts to prepare a tetracationic Pd²⁺ complex of the dicationic bis-imidazoliophosphine ligand <b>1</b> by AgOTf-mediated chloride abstraction from the corresponding PdCl₂ complex led to the observation of a Pd²⁺ → Ag⁺ transmetalation giving a tricationic (<b>1</b>)­Ag⁺ complex. The driving force of the process is attributed to the relaxation of electrostatic repulsion between the formal positive charges. VTP ³¹P NMR experiments in CD₂Cl₂ afford evidence of a fast equilibrium between the mononuclear (<b>1</b>)­Ag⁺ complex and its dimer. The X-ray crystal structure of the latter reveals that bridging TfO^– anions allow maintenance of the overall cohesion of the structure through attractive electrostatic interactions

Electrostatic Control of Pd²⁺ → Ag⁺ Transmetalation of a Bis-Imidazoliophosphine Ligand

Attempts to prepare a tetracationic Pd²⁺ complex of the dicationic bis-imidazoliophosphine ligand <b>1</b> by AgOTf-mediated chloride abstraction from the corresponding PdCl₂ complex led to the observation of a Pd²⁺ → Ag⁺ transmetalation giving a tricationic (<b>1</b>)­Ag⁺ complex. The driving force of the process is attributed to the relaxation of electrostatic repulsion between the formal positive charges. VTP ³¹P NMR experiments in CD₂Cl₂ afford evidence of a fast equilibrium between the mononuclear (<b>1</b>)­Ag⁺ complex and its dimer. The X-ray crystal structure of the latter reveals that bridging TfO^– anions allow maintenance of the overall cohesion of the structure through attractive electrostatic interactions

Copper Coordination to Native N‑Terminally Modified versus Full-Length Amyloid-β: Second-Sphere Effects Determine the Species Present at Physiological pH

Alzheimer’s disease is characterized by senile plaques in which metallic ions (copper, zinc, and iron) are colocalized with amyloid-β peptides of different sequences in aggregated forms. In addition to the full-length peptides (Aβ1-40/42), N-terminally truncated Aβ3-40/42 forms and their pyroglutamate counterparts, Aβp3-40/42, have been proposed to play key features in the aggregation process, leading to the senile plaques. Furthermore, they have been shown to be more toxic than the full-length Aβ, which made them central targets for therapeutic approaches. In order to better disentangle the possible role of metallic ions in the aggregation process, copper­(II) coordination to the full-length amyloid peptides has been extensively studied in the last years. However, regarding the N-terminally modified forms at position 3, very little is known. Therefore, copper­(I) and copper­(II) coordination to those peptides have been investigated in the present report using a variety of complementary techniques and as a function of pH. Copper­(I) coordination is not affected by the N-terminal modifications. In contrast, copper­(II) coordination is different from that previously reported for the full-length peptide. In the case of the pyroglutamate form, this is due to preclusion of N-terminal amine binding. In the case of the N-terminally truncated form, alteration in copper­(II) coordination is caused by second-sphere effects that impact the first binding shell and the pH-dependent repartition of the various [Cu­(peptide)] complexes. Such second-sphere effects are anticipated to apply to a variety of metal ions and peptides, and their importance on changing the first binding shell has not been fully recognized yet

pH-Dependent Cu(II) Coordination to Amyloid-β Peptide: Impact of Sequence Alterations, Including the H6R and D7N Familial Mutations.

Copper ions have been proposed to intervene in deleterious processes linked to the development of Alzheimer’s disease (AD). As a direct consequence, delineating how Cu(II) can be bound to amyloid-β (Aβ) peptide, the amyloidogenic peptide encountered in AD, is of paramount importance. Two different forms of [Cu^II(Aβ)] complexes are present near physiological pH, usually noted components <b>I</b> and <b>II</b>, the nature of which is still widely debated in the literature, especially for <b>II</b>. In the present report, the phenomenological pH-dependent study of Cu(II) coordination to Aβ and to ten mutants by EPR, CD, and NMR techniques is described. Although only indirect insights can be obtained from the study of Cu(II) binding to mutated peptides, they reveal very useful for better defining Cu(II) coordination sites in the native Aβ peptide. Four components were identified between pH 6 and 12, namely, components <b>I</b>, <b>II</b>, <b>III</b> and <b>IV</b>, in which the predominant Cu(II) equatorial sites are {−NH₂, CO (Asp1–Ala2), N_im (His6), N_im (His13 or His14)}, {−NH₂, N^– (Asp1–Ala2), CO (Ala2–Glu3), N_im}, {−NH₂, N^– (Asp1–Ala2), N^– (Ala2–Glu3), N_im} and {−NH₂, N^– (Asp1–Ala2), N^– (Ala2–Glu3), N^– (Glu3–Phe4)}, respectively, in line with classical pH-induced deprotonation of the peptide backbone encountered in Cu(II) peptidic complexes formation. The structure proposed for component <b>II</b> is discussed with respect to another coordination model reported in the literature, that is, {CO (Ala2–Glu3), 3 N_im}. Cu(II) binding to the H6R-Aβ and D7N-Aβ peptides, where the familial H6R and D7N mutations have been linked to early onset of AD, has also been investigated. In case of the H6R mutation, some different structural features (compared to those encountered in the native [Cu^II(Aβ)] species) have been evidenced and are anticipated to be important for the aggregating properties of the H6R-Aβ peptide in presence of Cu(II)

Stabilization of Trans Disilyl Coordination at Square-Planar Platinum Complexes

By using two different multidentate phosphinosilyl ligands, we prepared the two platinum complexes [Pt­{PhP­((<i>o</i>-C₆H₄)­CH₂SiMe₂)₂}­PPh₃] (<b>3</b>) and [Pt­{P­((<i>o</i>-C₆H₄)­CH₂SiMe₂)₂(<i>o</i>-C₆H₄)­CHSiMe₂)}­PPh₃] (<b>4</b>) exhibiting a trans configuration of the silicon atoms in a typical square-planar geometry around a Pt­(II) center. Complex <b>4</b> results from intramolecular C–H activation of a methylene moiety by the third silicon atom of the original ligand and displays an anagostic C–H···Pt interaction, as supported by solution NMR data and solid-state X-ray diffraction analysis. The reactivity of <b>3</b> toward small molecules is also discussed. In the case of H₂ and CO, the corresponding dihydride [PtH₂{PhP­((<i>o</i>-C₆H₄)­CH₂SiMe₂)₂}­PPh₃] (<b>5</b>) and dicarbonyl [Pt­{PhP­((<i>o</i>-C₆H₄)­CH₂SiMe₂)₂}­(CO)₂] (<b>6</b>) complexes were characterized, whereas reduction to Pt(0) and release of PPh₃ and HSiMe₃ were observed upon thermolysis in the presence of HBpin

Probing Highly Selective H/D Exchange Processes with a Ruthenium Complex through Neutron Diffraction and Multinuclear NMR Studies.

Deuterium labeling is a powerful way to gain mechanistic information in biology and chemistry. However, selectivity is hard to control experimentally, and labeled sites can be difficult to assign both in solution and in the solid state. Here we show that very selective high-deuterium contents can be achieved for the polyhydride ruthenium phosphine complex [RuH₂(H₂)₂(PCyp₃)₂] (<b>1</b>) (PCyp₃ = P­(C₅H₉)₃). The selectivity of the H/D exchange process is demonstrated by multinuclear NMR and neutron diffraction analyses. It has also been investigated through density functional theory (DFT) calculations. The reactions are performed under mild conditions at room temperature, and the extent of deuterium incorporation, involving selective C–H bond activation within the cyclopentyl rings of the phosphine ligands, can easily be tuned (solvent effects, D₂ pressure). It is shown that D₂ gas can inhibit the C–H/C–D exchange process

Probing Highly Selective H/D Exchange Processes with a Ruthenium Complex through Neutron Diffraction and Multinuclear NMR Studies.

Deuterium labeling is a powerful way to gain mechanistic information in biology and chemistry. However, selectivity is hard to control experimentally, and labeled sites can be difficult to assign both in solution and in the solid state. Here we show that very selective high-deuterium contents can be achieved for the polyhydride ruthenium phosphine complex [RuH₂(H₂)₂(PCyp₃)₂] (<b>1</b>) (PCyp₃ = P­(C₅H₉)₃). The selectivity of the H/D exchange process is demonstrated by multinuclear NMR and neutron diffraction analyses. It has also been investigated through density functional theory (DFT) calculations. The reactions are performed under mild conditions at room temperature, and the extent of deuterium incorporation, involving selective C–H bond activation within the cyclopentyl rings of the phosphine ligands, can easily be tuned (solvent effects, D₂ pressure). It is shown that D₂ gas can inhibit the C–H/C–D exchange process

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions