Cyclopalladated Compounds with Polyhalogenated Benzylphosphanes for the Mizoroki-Heck Reaction

Nine partially halogenated benzylphosphanes ArXCH2PR2 (ArX = 3,6-dichlorophenyl, 3,6- difluorophenyl and 3,4,5-trifluorophenyl; R = Ph, Cy, iPr) have been prepared and reacted with palladium acetate to obtain the cyclometallated dimers [Pd(μ-OAc)(κ2-C,P-ArXCH2PR2)]2. The acetate bridge has been exchanged by bromide using lithium bromide and the obtained dimers have been thoroughly characterised. The dimers with the non-halogenated phosphanes PhCH2PR2 (R = Ph, iPr) have also been prepared. Treatment with norbornadiene in the presence of silver tetrafluoroborate has furnished the cationic mononuclear complexes [Pd(κ2-C,P-ArXCH2PR2)(nbd)]BF4 as stable solids. These complexes and some of the bromide dimers have been used as catalytic precursors in the Mizoroki- Heck reaction between bromobenzene and butyl acrylate. The complexes efficiently catalyse this transformation and important differences of activity are found depending on the ligand. In general, fluorinated phosphanes give more active systems than chlorinated analogues

Ruthenium complexes of P-stereogenic phosphines with a heterocyclic substituent

The synthesis via phosphine-boranes of 13 new optically pure P-stereogenic diarylphosphines P(Het)PhR (Het = 4-dibenzofuranyl (DBF), 4-dibenzothiophenyl (DBT), 4-dibenzothiophenyl-S,S-dioxide (DBTO2) and 1-thianthrenyl (TA); R = OMe, Me, i-Pr, Fc (ferrocenyl)) following the Jugé-Stephan method is described. The ligands were designed with the aim of having a heteroatom in a position capable of interacting with a metal upon coordination. The ligands and their precursors have been fully characterised, including the determination of two crystal structures of phosphine-boranes. Ru neutral complexes of the type [RuCl2(η6-arene)(κP-P)] (arene = p-cymene and methyl benzoate) have been prepared and characterised, including three crystal structure determinations. Treatment of solutions of the complexes with TlPF6 allowed the preparation of well-defined cationic complexes [RuCl(η6-arene)(κ2P,S-P)]PF6 for DBT- and TA-based phosphines. The complexes possess a stereogenic Ru atom and in most of the cases they are present as a single isomer in solution. All the Ru complexes have been used in the asymmetric transfer hydrogenation of acetophenone in refluxing 2-propanol, with good activities and up to 70% ee

Diphosphorus Ligands Containing a P-Stereogenic Phosphane and a Chiral Phosphite or Phosphorodiamidite - Evaluation in Pd-Catalysed Asymmetric Allylic Substitution Reactions

The synthesis of 14 new optically pure C 1‐symmetric phosphane-phosphinite (1 -4 ), phosphane-phosphite (5 -9 ) and phosphane-phosphorodiamidite (10 -14 ) ligands is reported. The ligands were prepared through the condensation of (2‐hydroxyphenyl)phenylphosphanes PPh(2‐PhOH)R (R = Me, t Bu and Ph) with chlorodiisopropylphosphane (1 and 2 ), chlorodiphenylphosphane (3 and 4 ), the chlorodioxaphosphepine derived from both enantiomers of 1,1′‐bi‐2‐naphthol (5 -9 ) and the chlorodiazaphosphepine derived from both enantiomers of N ,N′ ‐dimethyl‐1,1′‐binaphthyl‐2,2′‐diamine (10 -14 ) in the presence of a base. With these ligands, cationic Pd complexes of the type [Pd(η3‐C4H7)(PP′)]PF6 (Pd1 -Pd14 ) were obtained and characterised; the crystal structures of Pd1 , Pd2 and Pd13 were obtained. In solution, the complexes are present as mixtures of two diastereomers because of the lack of symmetry of the ligand and the presence of the methallyl group. The Pd complexes catalyse the allylic alkylation with dimethyl malonate and the amination with benzylamine of the model substrate rac ‐3‐acetoxy‐1,3‐diphenyl‐1‐propene (I ). For the alkylation, full conversions and good enantioselectivities (up to 96 % ee with Pd14 ) were observed

Neutral and Cationic Palladium Complexes of P-Stereogenic Phosphanes Bearing a Heterocyclic Substituent

The coordination chemistry of 13 optically pure P ‐stereogenic diarylmonophosphanes P(Het)PhR [Het = 4‐dibenzofuranyl (DBF), 4‐dibenzothiophenyl (DBT), 4‐dibenzothiophenyl S ,S ‐dioxide (DBTO2) and 1‐thianthrenyl (TA); R = OMe, Me, i Pr, Fc (ferrocenyl)] to Pd‐allyl moieties is described. Both neutral [PdCl(η3‐(2‐methylallyl)(κP ‐P )] and cationic [Pd{η3‐(2‐methylallyl)(κP ‐P )2}]PF6 complexes have been prepared. Coordination of the heteroatom of the heterocycle was only possible in the case of TA‐based phosphanes; these furnished complexes of the type [Pd{η3‐(2‐methylallyl)(κ2P,S ‐P )}]PF6 after chloride abstraction with TlPF6. The crystal structure of the complex [Pd(η3‐2‐methylallyl)(κ2P,S ‐PPh(OMe)(1‐TA)]PF6 is reported. The neutral Pd complexes were found to be highly active in the hydrovinylation of styrene after activation with AgBF4, except for the TA‐based phosphanes. The cationic Pd complexes were evaluated in allylic alkylation and amination with the model substrate rac ‐trans ‐1,3‐diphenylprop‐2‐enyl acetate (rac ‐I ), achieving total conversions and up to 70 % ee

Palladium Allylic Complexes with enantiopure bis(diamidophosphite) ligands bearing a cyclohexane-1,2-diamine skeleton as catalysts in the allylic substitution reaction

A series of cationic allyl palladium complexes [Pd(η3-CH3-C3H5)(P-P)]X (X = PF6, 2a-c, 2e; and X = BPh4, 3a, 3b, 3d, 3e) and [Pd(η3-1,3-Ph2-C3H3)(P-P)]X (X = PF6, 6b; and X = BPh4, 7a) have been prepared. The bis(diamidophosphite) ligands (P-P) contain a diazaphospholidine terminal fragment derived from (R,R)- and (S,S)-N,N'-dibenzyl- and (R,R)-N,N'-dimethyl-cyclohexane-1,2-diamines and dialcoxy bridging fragment derived from (R,R)- and (S,S)-butanediol, (R,R)-cyclohexanediol, (4R,5R)- and (4S,5S)-4,5-di(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane and (R)- and (S)-binaphthol. Complexes [Pd(η3-CH3-C3H5l)P2]X (X = PF6, 4f, 4g; and X = BPh4, 5f), where P are monodentate diamidophosphite ligands with diazaphospholidine heterocyclic backbone obtained from (R,R)- and (S,S)-N,N'-dibenzylcyclohexane-1,2-diamine and alcoxy groups coming from (R)-phenyl-ethanol and (S)-borneol have been also prepared. Neutral palladium complexes [PdCl2(P-P)] (1a, 1c) were synthesized to prove the C2 symmetry of the P-P ligand. The new compounds were fully characterized in solution by NMR spectroscopy. The X-ray crystal structure determination for 2e-(R,R,Ral,Ral;R,R) and 1a-(S,S;Sal,Sal;S,S) has been achieved. The new allyl-palladium complexes were applied in the asymmetric allylic substitution reaction of the benchmark substrate rac-3-acetoxy-1,3-diphenyl-1-propene with dimethyl malonate and benzylamine as nucleophiles in order to test their catalytic potential. The best results were obtained with the 3a-(R,R;Ral,Ral;R,R) precursor (up to 84% ee) while complexes with the e ligand derived from the (R,R)-N,N'-dimethylcyclohexane-1,2-diamine terminal fragment resulted inactive in the process. The influence of the nature and the absolute configuration of both the bridging and the terminal fragments of the bis(diamidophosphite) ligand on the asymmetric induction is discussed. A preliminary study of the anion effect (PF6− vs. BPh4-) on the activity and the enantioselectivity of the Pd-catalysed allylic substitution has also been performed

Lipid profile with eslicarbazepine acetate and carbamazepine monotherapy in adult patients with newly diagnosed focal seizures: post hoc analysis of a phase III trial and open-label extension study

BACKGROUND: Antiseizure medications can have negative effects on plasma lipid levels. OBJECTIVES: To evaluate plasma lipid changes in patients with newly diagnosed focal epilepsy treated with eslicarbazepine acetate (ESL) or controlled-release carbamazepine (CBZ-CR) monotherapy during a phase III, randomized, double-blind (DB) trial and 2 years of ESL treatment in an open-label extension (OLE). DESIGN: Post hoc analysis of a phase III trial and OLE study. METHODS": Proportions of patients with elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol were assessed at DB baseline, OLE baseline (last visit of DB trial), and end of OLE. RESULTS: A total of 184 patients received ESL monotherapy during the OLE: 96 received ESL monotherapy in the DB trial and 88 patients received CBZ-CR monotherapy. The proportions of patients with elevated total cholesterol and LDL cholesterol increased significantly during the DB trial in those treated with CBZ-CR monotherapy [total cholesterol, +14.9% (p < 0.001); LDL cholesterol, +11.5% (p = 0.012)] but decreased significantly after switching to ESL monotherapy in the OLE [total cholesterol, −15.3% (p = 0.008); LDL cholesterol, −11.1% (p = 0.021)]. No significant changes were observed in those treated with ESL monotherapy during the DB trial and OLE. At the end of the DB trial, between-group differences (ESL–CBZ-CR) in the proportions of patients with elevated total and LDL cholesterol were −13.6% (p = 0.037) and −12.3% (p = 0.061), respectively; at the end of the OLE, these between-group differences were −6.0% (p = 0.360) and −0.6% (p = 1.000), respectively. CONCLUSION:A lower proportion of patients with newly diagnosed focal epilepsy had increased levels of total and LDL cholesterol, compared to baseline, following monotherapy with ESL versus CBZ-CR; after switching from CBZ-CR to ESL, the proportions of patients with increased levels decreased significantly. REGISTRATION: ClinicalTrials.gov NCT01162460/NCT02484001; EudraCT 2009-011135-13/2015-001243-36

Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer.

ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored