Cyclometalated and NNN Terpyridine Ruthenium Photocatalysts and Their Cytotoxic Activity.

The cyclometalated terpyridine complexes [Ru(η2-OAc)(NC-tpy)(PP)] (PP = dppb 1, (R,R)-Skewphos 4, (S,S)-Skewphos 5) are easily obtained from the acetate derivatives [Ru(η2-OAc)2(PP)] (PP = dppb, (R,R)-Skewphos 2, (S,S)-Skewphos 3) and tpy in methanol by elimination of AcOH. The precursors 2, 3 are prepared from [Ru(η2-OAc)2(PPh3)2] and Skewphos in cyclohexane. Conversely, the NNN complexes [Ru(η1-OAc)(NNN-tpy)(PP)]OAc (PP = (R,R)-Skewphos 6, (S,S)-Skewphos 7) are synthesized in a one pot reaction from [Ru(η2-OAc)2(PPh3)2], PP and tpy in methanol. The neutral NC-tpy 1, 4, 5 and cationic NNN-tpy 6, 7 complexes catalyze the transfer hydrogenation of acetophenone (S/C = 1000) in 2-propanol with NaOiPr under light irradiation at 30 °C. Formation of (S)-1-phenylethanol has been observed with 4, 6 in a MeOH/iPrOH mixture, whereas the R-enantiomer is obtained with 5, 7 (50-52% ee). The tpy complexes show cytotoxic activity against the anaplastic thyroid cancer 8505C and SW1736 cell lines (ED50 = 0.31-8.53 µM), with the cationic 7 displaying an ED50 of 0.31 µM, four times lower compared to the enantiomer 6.

Terpyridine Diphosphine Ruthenium Complexes as Efficient Photocatalysts for the Transfer Hydrogenation of Carbonyl Compounds.

The cationic achiral and chiral terpyridine diphosphine ruthenium complexes [RuCl(PP)(tpy)]Cl (PP=dppp (1), (R,R)-Skewphos (2) and (S,S)-Skewphos (3)) are easily obtained in 85-88 % yield through a one-pot synthesis from [RuCl2 (PPh3 )3 ], the diphosphine and 2,2':6',2''-terpyridine (tpy) in 1-butanol. Treatment of 1-3 with NaPF6 in methanol at RT affords quantitatively the corresponding derivatives [RuCl(PP)(tpy)]PF6 (PP=dppp (1 a), (R,R)-Skewphos (2 a) and (S,S)-Skewphos (3 a)). Reaction of [RuCl2 (PPh3 )3 ] with (S,R)-Josiphos or (R)-BINAP in toluene, followed by treatment with tpy in 1-butanol and finally with NaPF6 in MeOH gives [RuCl(PP)(tpy)]PF6 (PP=(S,R)-Josiphos (4 a), (R)-BINAP (5 a)) isolated in 78 % and 86 % yield, respectively. The chiral derivatives have been isolated as single stereoisomers and 3 a, 4 a have been characterized by single crystal X-ray diffraction studies. The tpy complexes with NaOiPr display high photocatalytic activity in the transfer hydrogenation (TH) of carbonyl compounds using 2-propanol as the only hydrogen donor and visible light at 30 °C, at remarkably high S/C (up to 5000) and TOF values up to 264 h-1 . The chiral enantiomers 2, 2 a and 3, 3 a induce the asymmetric photocatalytic TH of acetophenone, affording (S)- and (R)-1-phenylethanol with 51 and 52 % ee, respectively, in a MeOH/2-propanol mixture.

Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells.

The chiral cationic complex [Ru(η1 -OAc)(CO)((R,R)-Skewphos)(phen)]OAc (2R ), isolated from reaction of [Ru(η1 -OAc)(η2 -OAc)(R,R)-Skewphos)(CO)] (1R ) with phen, reacts with NaOPiv and KSAc affording [RuX(CO)((R,R)-Skewphos)(phen)]Y (X=Y=OPiv 3R ; X=SAc, Y=OAc 4R ). The corresponding enantiomers 2S -4S have been obtained from 1S containing (S,S)-Skewphos. Reaction of 2R and 2S with (S)-cysteine and NaPF6 at pH=9 gives the diastereoisomers [Ru((S)-Cys)(CO)(PP)(phen)]PF6 (PP=(R,R)-Skewphos 2R -Cys; (S,S)-Skewphos 2S -Cys). The DFT energetic profile for 2R with (S)-cysteine in H2 O indicates that aquo and hydroxo species are involved in formation of 2R -Cys. The stability of the ruthenium complexes in 0.9 % w/v NaCl solution, PBS and complete DMEM medium, as well as their n-octanol/water partition coefficient (logP), have been evaluated. The chiral complexes show high cytotoxic activity against SW1736, 8505 C, HCT-116 and A549 cell lines with EC50 values of 2.8-0.04 µM. The (R,R)-Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4R (EC50 =0.04 µM) being 14 times more cytotoxic than 4S against the anaplastic thyroid cancer 8505 C cell line.

Preparation of Neutral trans - cis [Ru(O2CR)2P2(NN)], Cationic [Ru(O2CR)P2(NN)](O2CR) and Pincer [Ru(O2CR)(CNN)P2] (P = PPh3, P2 = diphosphine) Carboxylate Complexes and their Application in the Catalytic Carbonyl Compounds Reduction.

The diacetate complexes trans-[Ru(κ1-OAc)2(PPh3)2(NN)] (NN = ethylenediamine (en) (1), 2-(aminomethyl)pyridine (ampy) (2), 2-(aminomethyl)pyrimidine (ampyrim) (3)) have been isolated in 76-88% yield by reaction of [Ru(κ2-OAc)2(PPh3)2] with the corresponding nitrogen ligands. The ampy-type derivatives 2 and 3 undergo isomerization to the thermodynamically most stable cationic complexes [Ru(κ1-OAc)(PPh3)2(NN)]OAc (2a and 3a) and cis-[Ru(κ1-OAc)2(PPh3)2(NN)] (2b and 3b) in methanol at RT. The trans-[Ru(κ1-OAc)2(P2)2] (P2 = dppm (4), dppe (5)) compounds have been synthesized from [Ru(κ2-OAc)2(PPh3)2] by reaction with the suitable diphosphine in toluene at 95 °C. The complex cis-[Ru(κ1-OAc)2(dppm)(ampy)](6) has been obtained from [Ru(κ2-OAc)2(PPh3)2] and dppm in toluene at reflux and reaction with ampy. The derivatives trans-[Ru(κ1-OAc)2P2(NN)] (7-16; NN = en, ampy, ampyrim, 8-aminoquinoline; P2 = dppp, dppb, dppf, (R)-BINAP) can be easily synthesized from [Ru(κ2-OAc)2(PPh3)2] with a diphosphine and treatment with the NN ligands at RT. Alternatively these compounds have been prepared from trans-[Ru(OAc)2(PPh3)2(NN)] by reaction with the diphosphine in MEK at 50 °C. The use of (R)-BINAP affords trans-[Ru(κ1-OAc)2((R)-BINAP)(NN)] (NN = ampy (11), ampyrim (15)) isolated as single stereoisomers. Treatment of the ampy-type complexes 8-15 with methanol at RT leads to isomerization to the cationic derivatives [Ru(κ2-OAc)P2(NN)]OAc (8a-15a; NN = ampy, ampyrim; P2 = dppp, dppb, dppf, (R)-BINAP). Similarly to 2, the dipivalate trans-[Ru(κ1-OPiv)2(PPh3)2(ampy)] (18) is prepared from [Ru(κ2-OPiv)2(PPh3)2] (17) and ampy in CHCl3. The pincer acetate [Ru(κ1-OAc)(CNNOMe)(PPh3)2] (19) has been synthesized from [Ru(κ2-OAc)2(PPh3)2] and HCNNOMe ligand in 2-propanol with NEt3 at reflux. In addition, the dppb pincer complexes [Ru(κ1-OAc)(CNN)(dppb)] (CNN = AMTP (20), AMBQPh (21)) have been obtained from [Ru(κ2-OAc)2(PPh3)2], dppb, and HAMTP or HAMBQPh with NEt3, respectively. The acetate NN and pincer complexes are active in transfer hydrogenation with 2-propanol and hydrogenation with H2 of carbonyl compounds at S/C values of up to 10000 and with TOF values of up to 160000 h-1.

Cationic carboxylate and thioacetate ruthenium(ii) complexes: synthesis and cytotoxic activity against anaplastic thyroid cancer cells.

The cationic acetate ruthenium complex [Ru(η1-OAc)(CO)(dppb)(phen)]OAc (1) is easily prepared in 83% yield from [Ru(η1-OAc)(η2-OAc)(CO)(dppb)] (dppb = 1,4-bis(diphenylphosphino)butane) and 1,10-phenanthroline (phen) in MeOH. The derivative 1 undergoes easy substitution of the coordinated acetate by reaction with NaOPiv, KSAc, and KSCN in MeOH, affording the corresponding complexes [RuX(CO)(dppb)(phen)]X (X = OPiv, 2; SAc, 3; and NCS, 4), whereas its reaction with NaCl and NH4PF6 affords [RuCl(CO)(dppb)(phen)]PF6 (5). Carboxylate complexes 1 and 2 show high solubility in water, enabling easy exchange of the coordinated carboxylate by water and other ligands (CH3CN, glutathione). Cationic complexes 1-5, compared to Cisplatin, display a strong cell viability decrease in two human anaplastic thyroid cancer cell lines (SW1736 and 8505C), ranging from 3.10 µM to 0.09 µM EC50 values. The most active compounds 1-3 show a marked increment of apoptosis and decrease of cancer cell aggressiveness, making them promising candidates for further evaluation studies.

CNN pincer ruthenium complexes for efficient transfer hydrogenation of biomass-derived carbonyl compounds.

The ligand HCNNOMe (6-(4-methoxyphenyl)-2-aminomethylpyridine) is easily prepared from the commercially available 6-(4-methoxyphenyl)pyridine-2-carbaldehyde by the reaction of hydroxylamine and hydrogenation (H2, 1 atm) with Pd/C. The pincer complexes cis-[RuCl(CNNOMe)(PPh3)2] (1) and [RuCl(CNNOMe)(PP)] (PP = dppb, 2; and dppf, 3) are synthesized from [RuCl2(PPh3)3], HCNNOMe and PP (for 2 and 3) in 2-propanol with NEt3 at reflux and are isolated in 85-93% yield. Carbonylation of 1 (CO, 1 atm) gives [RuCl(CNNOMe)(CO)(PPh3)] (4) (79% yield) which cleanly reacts with Na[BArf4] and PCy3, affording the cationic trans-[Ru(CNNOMe)(CO)(PCy3)(PPh3)][BArf4] (5) (92% yield). These robust pincer complexes display remarkably high catalytic activity in the transfer hydrogenation (TH) of lignocellulosic biomass carbonyl compounds, using 2-propanol at reflux in a basic medium (NaOiPr or K2CO3). Thus, furfural, 5-(hydroxymethyl)furfural and Cyrene are reduced to the corresponding alcohols with 2 and 3, at S/C in the range of 10 000-100 000, within minutes or hours (TOF up to 1 500 000 h-1). The monocarbonyl complex 5 was found to be extremely active in the TH of cinnamaldehyde, vanillin derivatives and ethyl levulinate at S/C in the range of 10 000-50 000. Vanillyl alcohol is also obtained by the TH of vanillin with 5 (S/C = 500) in 2-propanol in the presence of K2CO3.

Preparation of monocarbonyl ruthenium complexes bearing bidentate nitrogen and phosphine ligands and their catalytic activity in carbonyl compound reduction.

Monocarbonyl complexes [RuCl2(CO)(PR3)(NN)] (R = Cy, NN = en 1, ampy 2; R = iPr; NN = en 3) have been prepared in a one pot reaction from [RuCl2(CO)(dmf)(PPh3)2], PR3 and the NN ligand in CH2Cl2. Treatment of [Ru(OAc)2(CO)(PPh3)2] with NN ligands in methanol gives the cationic derivatives [Ru(OAc)(CO)(PPh3)(NN)]OAc (NN = en 4, ampy 5) in which one acetate acts as a bidentate ligand, whereas the other is not coordinated. Diphosphine complexes [RuCl2(CO)(PP)(PPh3)] (PP = dppb 6, dppf 7, (R)-BINAP 8, (R,Sp)-Josiphos 9 and (R,R)-Skewphos 10) have been obtained starting from [RuCl2(CO)(dmf)(PPh3)2] and the PP ligand in CHCl3 or toluene at reflux. The reaction of [Ru(OAc)2(CO)(PPh3)2] with PP in CH2Cl2 or toluene affords the fluxional acetate derivatives [Ru(OAc)2(CO)(PP)] (PP = dppb 11, dppf 12, (R)-BINAP 13, and (R,R)-Skewphos 14). The cationic diphosphine complexes [RuCl(CO)(PP)(en)]Cl (PP = dppb 15, dppf 16) are prepared from [RuCl2(CO)(dmf)(PPh3)2], PP and en in CH2Cl2 or, alternatively, from [RuCl2(CO)2]n or the 6, 7 derivatives. Similarly, [Ru(OAc)(CO)(PP)(NN)]OAc (PP = dppb, NN = en 17, ampy 18; PP = dppf, NN = en 19, ampy 20) are isolated starting from [Ru(OAc)2(CO)(PPh3)2], PP and NN ligands or from 11, 12. The derivatives [Ru(OAc)2(CO)(PP)] show a fluxional behavior in solution as the result of the flexible coordination of acetate ligands. These complexes are found to be active in the transfer hydrogenation and hydrogenation of ketones and aldehydes, including furfural derivatives, at an S/C up to 10 000 and a TOF up to 18 000 h-1.

A specific nanobody prevents amyloidogenesis of D76N ß2-microglobulin in vitro and modifies its tissue distribution in vivo.

Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of ß2-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type ß2-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The ß2-microglobulin -binding nanobody, Nb24, more potently inhibits D76N ß2-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In ß2-microglobulin knock out mice, the D76N ß2-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type ß2-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis.

Citrate-stabilized gold nanoparticles hinder fibrillogenesis of a pathological variant of ß2-microglobulin.

Nanoparticles have repeatedly been shown to enhance fibril formation when assayed with amyloidogenic proteins. Recently, however, evidence casting some doubt about the generality of this conclusion started to emerge. Therefore, to investigate further the influence of nanoparticles on the fibrillation process, we used a naturally occurring variant of the paradigmatic amyloidogenic protein ß2-microglobulin (ß2m), namely D76N ß2m where asparagine replaces aspartate at position 76. This variant is responsible for aggressive systemic amyloidosis. After characterizing the interaction of the variant with citrate-stabilized gold nanoparticles (Cit-AuNPs) by NMR and modeling, we analyzed the fibril formation by three different methods: thioflavin T fluorescence, native agarose gel electrophoresis and transmission electron microscopy. The NMR evidence indicated a fast-exchange interaction involving preferentially specific regions of the protein that proved, by subsequent modeling, to be consistent with a dimeric adduct interacting with Cit-AuNPs. The fibril detection assays showed that AuNPs are able to hamper D76N ß2m fibrillogenesis through an effective interaction that competes with protofibril formation or recruitment. These findings open promising perspectives for the optimization of the nanoparticle surface to design tunable interactions with proteins.

Functional expression of aryl hydrocarbon receptor on mast cells populating human endometriotic tissues.

Endometriosis is an inflammatory disease characterized by the presence of ectopic endometrial tissue outside the uterus. A diffuse infiltration of mast cells (MCs) is observed throughout endometriotic lesions, but little is known about how these cells contribute to the network of molecules that modulate the growth of ectopic endometrial implants and promote endometriosis-associated inflammation. The aryl hydrocarbon receptor (AhR), a transcription factor known to respond to environmental toxins and endogenous compounds, is present in MCs. In response to AhR activation, MCs produce IL-17 and reactive oxygen species, highlighting the potential impact of AhR ligands on inflammation via MCs. Here, we investigated the possibility that endometrial MCs promote an inflammatory microenvironment by sensing AhR ligands, thus sustaining endometriosis development. Using human endometriotic tissue (ET) samples, we performed the following experiments: (i) examined the cytokine expression profile; (ii) counted AhR-expressing MCs; (iii) verified the phenotype of AhR-expressing MCs to establish whether MCs have a tolerogenic (IL-10-positive) or inflammatory (IL-17-positive) phenotype; (iv) measured the presence of AhR ligands (tryptophan-derived kynurenine) and tryptophan-metabolizing enzymes (indoleamine 2,3-dioxygenase 1 (IDO1)); (v) treated ET organ cultures with an AhR antagonist in vitro to measure changes in the cytokine milieu; and (vi) measured the growth of endometrial stromal cells cultured with AhR-activated MC-conditioned medium. We found that ET tissue was conducive to cytokine production, orchestrating chronic inflammation and a population of AhR-expressing MCs that are both IL-17 and IL-10-positive. ET was rich in IDO1 and the AhR-ligand kynurenine compared with control tissue, possibly promoting MC activation through AhR. ET was susceptible to treatment with an AhR antagonist, and endometrial stromal cell growth was improved in the presence of soluble factors released by MCs on AhR activation. These results suggest a new mechanistic role of MCs in the pathogenesis of endometriosis.

Congenital pulmonary malformations: metabolomic profile of lung phenotype in infants.

BACKGROUND: The main hydrosoluble metabolites in three different human congenital pulmonary malformations are described by nuclear magnetic resonance (NMR) spectroscopy. METHODS: Bronchogenic cyst (BC), congenital lobar emphysema (CLE) and intrapulmonary sequestration (IPS), were analyzed with respect to a control sample. The extracted metabolites were submitted to high-resolution (1)H NMR-spectroscopy. RESULTS: Congenital lung malformations showed free choline, phosphocoline and myoinositol high levels. IPS and CLE were found increased in lactic acid/glucose ratio. Lactic acid and glucose values resulted to be more elevated in control sample. CONCLUSIONS: Congenital lung lesions showed different metabolomic profiles useful for early diagnosis.

Phospholipid profile of amniotic fluid in ovine model of congenital diaphragmatic hernia (CDH): the effect of fetal tracheal occlusion.

Fetal endoscopic tracheal occlusion has been proposed as a prenatal intervention to ameliorate congenital diaphragmatic hernia (CDH) prognosis. Tracheal occlusion (TO) prevents pulmonary fluid egress, leading to tissue expansion, reversal of lung hypoplasia, and potential maturation. Fetal lung maturity strongly correlates with amniotic fluid (AF) phospholipidic composition. In this preliminary study, we characterized the AF phospholipidic profile in CDH-induced, TO-treated, and healthy fetal lambs to define the prenatal treatment benefits of TO on lung maturity. CDH induction was performed at 70 days of gestation, TO was carried out at 102 days of gestation, and caesarean section was carried out at 136 days of gestation. AF samples, taken at 102-136 days of gestation, were evaluated using mass spectrometry. The analysis focused on phosphatidylcholines (PCs) and sphingomyelins (SMs). The most abundant phosphatidylcholine species retrieved in healthy AF was POPC [PC(18:1/16:0)], while the level of DPPC [PC(16:0/16:0)] was extremely low at both gestational ages. CDH induction caused a decrease in POPC and many other PCs. A substantial return of some PCs, in particular POPC, PC(34:2) and PC(18:0/16:0), to a more physiological level was prompted by TO. SMs were unaltered. The AF phospholipidic profile could provide prenatal prognostic markers of CDH and possible indices of lung maturation after fetal treatment.

Metabolomic profile of amniotic fluid to evaluate lung maturity: the diaphragmatic hernia lamb model.

BACKGROUND: Tracheal occlusion (TO) stimulates lung growth in fetuses affected with congenital diaphragmatic hernia (CDH) although the processes involved in lung maturation still remain unknown. The objective of this study was to evaluate the metabolomic profile of amniotic fluid (AF) following TO in fetal lamb model in order to obtain an indirect view of mechanisms involved in pulmonary reversal hypoplasia and biochemical maturity in response to fetal TO. METHODS: Liquid Chromatography Mass Spectrometry was performed on lamb AF samples at: age I (70 days' gestation); age II (102 days' gestation); age III (136 days' gestation). CDH was induced at age I and TO at age II. RESULTS: Betaine, choline, creatinine were found significantly increased during gestation in the control group. The CDH group showed choline (p =0.007) and creatinine (p =0.004) decreases during pregnancy. In the TO group choline and creatinine profiles were restored. CONCLUSIONS: Alveolar tissue and fetal global growth ameliorated after TO. Metabolomics provided useful information on biochemical details during lung maturation. Metabolomic profiling would help to identify the best time to perform TO, in order to increase survival of CDH affected patients.

BMP tests of source selected OFMSW to evaluate anaerobic codigestion with sewage sludge.

The aim of this study is to characterize different types of source selected organic fraction of municipal solid waste (SS-OFMSW) in order to optimize the upgrade of a sewage sludge anaerobic digestion unit by codigestion. Various SS-OFMSW samples were collected from canteens, supermarkets, restaurants, households, fruit-vegetable markets and bakery shops. The substrates characterization was carried out getting traditional chemical-physical parameters, performing elemental analysis and measuring fundamental anaerobic digestion macromolecular compounds such as carbohydrates, proteins, lipids and volatile fatty acids. Biochemical methane potential (BMP) tests were conducted at mesophilic temperature both on single substrates and in codigestion regime with different substrates mixing ratios. The maximum methane yield was observed for restaurant (675 NmlCH4/gVS) and canteens organic wastes (571 and 645 NmlCH4/gVS). The best codigestion BMP test has highlighted an increase of 47% in methane production respect sewage sludge digestion.

Metallation of pentaphyrin with Lu(III) dramatically increases reactive-oxygen species production and cell phototoxicity.

Photodynamic therapy (PDT) is an emerging cancer treatment modality based on the excitation of a nontoxic photosensitizer with harmless visible light to produce reactive-oxygen species (ROS) that induce apoptosis and/or necrosis in cancer cells. As the efficacy of this therapy strongly depends of the nature of the photosensitizer, there is a great interest to develop new photoactive molecules. Here we report for the first time the synthesis, characterization and bioactivity of metal complexes between the non-aromatic expanded porphyrin, namely 20-[[4'-(Trimethylsilyl)ethoxycarbonyl]phenyl-2,13-dimethyl-3,12-diethyl-[24] iso-pentaphyrin (PCRed) and Zn(II) [Zn(II)-PCRed] or Lu(III) [Lu(III)-PCRed]. The complexation of these two diamagnetic heavy metal ions to PCRed improved the properties of the free photosensitizer as a PDT drug. We discovered that the 1:1 complex between PCRed and Lu(III) significantly increases the cellular uptake, ROS production and antiproliferative capacity in four cancer cell lines. Our study shows that metal complexation is a useful strategy to potentiate iso-pentaphyrin as a PDT drug.

New benzo[h]quinoline-based ligands and their pincer Ru and Os complexes for efficient catalytic transfer hydrogenation of carbonyl compounds.

New benzo[h]quinoline ligands (HCN'N) containing a CHRNH2 (R=H (a), Me (b), tBu (c)) function in the 2-position were prepared starting from benzo[h]quinoline N-oxide (in the case of ligand a) and 2-chlorobenzo[h]quinoline (for ligands b and c). These compounds were used to prepare ruthenium and osmium complexes, which are excellent catalysts for the transfer hydrogenation (TH) of ketones. The reaction of a with [RuCl2(PPh3)3] in 2-propanol at reflux afforded the terdentate CN'N complex [RuCl(CN'N)(PPh3)2] (1), whereas the complexes [RuCl(CN'N)(dppb)] (2-4; dppb=Ph2P(CH2)4PPh2) were obtained from [RuCl2(PPh3)(dppb)] with a-c, respectively. Employment of (R,S)-Josiphos, (S,R)-Josiphos*, (S,S)-Skewphos, and (S)-MeO-Biphep in combination with [RuCl2(PPh3)3] and ligand a gave the chiral derivatives [RuCl(CN'N)(PP)] (5-8). The osmium complex [OsCl(CN'N)(dppb)] (12) was prepared by treatment of [OsCl2(PPh3)3] with dppb and ligand a. Reaction of the chloride 2 and 12 with NaOiPr in 2-propanol/toluene afforded the hydride complexes [MH(CN'N)(dppb)] (M=Ru 10, Os 14), through elimination of acetone from [M(OiPr)(CN'N)(dppb)] (M=Ru 9, Os 13). The species 9 and 13 easily reacted with 4,4'-difluorobenzophenone, via 10 and 14, respectively, affording the corresponding isolable alkoxides [M(OR)(CN'N)(dppb)] (M=Ru 11, Os 15). The complexes [MX(CN'N)(P2)] (1-15) (M=Ru, Os; X=Cl, H, OR; P=PPh3 and P2=diphosphane) are efficient catalysts for the TH of carbonyl compounds with 2-propanol in the presence of NaOiPr (2 mol %). Turnover frequency (TOF) values up to 1.8x10(6) h(-1) have been achieved using 0.02-0.001 mol % of catalyst. Much the same activity has been observed for the Ru--Cl, --H, --OR, and the Os--Cl derivatives, whereas the Os--H and Os--OR derivatives display significantly lower activity on account of their high oxygen sensitivity. The chiral Ru complexes 5-8 catalyze the asymmetric TH of methyl-aryl ketones with TOF approximately 10(5) h(-1) at 60 degrees C, up to 97 % enatiomeric excess (ee) and remarkably high productivity (0.005 mol % catalyst loading). High catalytic activity (TOF up to 2.2x10(5) h(-1)) and enantioselectivity (up to 98 % ee) have also been achieved with the in-situ-generated catalysts prepared from [MCl2(PPh3)3], (S,R)-Josiphos or (S,R)-Josiphos*, and the benzo[h]quinoline ligands a-c.

Role of the NH2 functionality and solvent in terdentate CNN alkoxide ruthenium complexes for the fast transfer hydrogenation of ketones in 2-propanol.

The reaction of [RuCl(CNN)(dppb)] (1; HCNN=6-(4-methylphenyl)-2-pyridylmethylamine) with NaOiPr in 2-propanol/C6D6 affords the alcohol adduct alkoxide [Ru(OiPr)(CNN)(dppb)].n iPrOH (5), containing the Ru-NH2 linkage. The alkoxide [Ru(OiPr)(CNN)(dppb)] (4) is formed by treatment of the hydride [Ru(H)(CNN)(dppb)] (2) with acetone in C6D6. Complex 5 in 2-propanol/C6D6 equilibrates quickly with hydride 2 and acetone with an exchange rate of (5.4+/-0.2) s(-1) at 25 degrees C, higher than that found between 4 and 2 ((2.9+/-0.4) s(-1)). This fast process, involving a beta-hydrogen elimination versus ketone insertion into the Ru-H bond, occurs within a hydrogen-bonding network favored by the Ru-NH2 motif. The cationic alcohol complex [Ru(CNN)(dppb)(iPrOH)](BAr(f)4) (6; Ar(f)=3,5-C6H3(CF3)2), obtained from 1, Na[BAr(f)4], and 2-propanol, reacts with NaOiPr to afford 5. Complex 5 reacts with either 4,4'-difluorobenzophenone through hydride 2 or with 4,4'-difluorobenzhydrol through protonation, affording the alkoxide [Ru(OCH(4-C6H4F)2)(CNN)(dppb)] (7) in 90 and 85 % yield of the isolated product. The chiral CNN-ruthenium compound [RuCl(CNN)((S,S)-Skewphos)] (8), obtained by the reaction of [RuCl2(PPh3)3] with (S,S)-Skewphos and orthometalation of HCNN in the presence of NEt3, is a highly active catalyst for the enantioselective transfer hydrogenation of methylaryl ketones (turnover frequencies (TOFs) of up to 1.4 x 10(6) h(-1) at reflux were obtained) with up to 89% ee. Also the ketone CF3CO(4-C6H4F), containing the strong electron-withdrawing CF3 group, is reduced to the R alcohol with 64% ee and a TOF of 1.5 x 10(4) h(-1). The chiral alkoxide [Ru(OiPr)(CNN)((S,S)-Skewphos)]n iPrOH (9), obtained from 8 and NaOiPr in the presence of 2-propanol, reacts with CF3CO(4-C6H4F) to afford a mixture of the diastereomer alkoxides [Ru(OCH(CF3)(4-C6H4F))(CNN)((S,S)-Skewphos)] (10/11; 74% yield) with 67% de. This value is very close to the enantiomeric excess of the alcohol (R)-CF3CH(OH)(4-C6H4F) formed in catalysis, thus suggesting that diastereoisomeric alkoxides with the Ru-NH2 linkage are key species in the catalytic asymmetric transfer hydrogenation reaction.

Osmium pyme complexes for fast hydrogenation and asymmetric transfer hydrogenation of ketones.

The osmium compound trans,cis-[OsCl2(PPh3)2(Pyme)] (1) (Pyme=1-(pyridin-2-yl)methanamine), obtained from [OsCl2(PPh3)3] and Pyme, thermally isomerizes to cis,cis-[OsCl2(PPh3)(2)(Pyme)] (2) in mesitylene at 150 degrees C. Reaction of [OsCl2(PPh3)3] with Ph2P(CH2)(4)PPh2 (dppb) and Pyme in mesitylene (150 degrees C, 4 h) leads to a mixture of trans-[OsCl2(dppb)(Pyme)] (3) and cis-[OsCl2(dppb)(Pyme)] (4) in about an 1:3 molar ratio. The complex trans-[OsCl2(dppb)(Pyet)] (5) (Pyet=2-(pyridin-2-yl)ethanamine) is formed by reaction of [OsCl2(PPh3)3] with dppb and Pyet in toluene at reflux. Compounds 1, 2, 5 and the mixture of isomers 3/4 efficiently catalyze the transfer hydrogenation (TH) of different ketones in refluxing 2-propanol and in the presence of NaOiPr (2.0 mol %). Interestingly, 3/4 has been proven to reduce different ketones (even bulky) by means of TH with a remarkably high turnover frequency (TOF up to 5.7 x 10(5) h(-1)) and at very low loading (0.05-0.001 mol %). The system 3/4 also efficiently catalyzes the hydrogenation of many ketones (H2, 5.0 atm) in ethanol with KOtBu (2.0 mol %) at 70 degrees C (TOF up to 1.5 x 10(4) h(-1)). The in-situ-generated catalysts prepared by the reaction of [OsCl2(PPh3)3] with Josiphos diphosphanes and (+/-)-1-alkyl-substituted Pyme ligands, promote the enantioselective TH of different ketones with 91-96 % ee (ee=enantiomeric excess) and with a TOF of up to 1.9 x 10(4) h(-1) at 60 degrees C.

PNA conjugated to high-molecular weight poly(ethylene glycol): synthesis and properties.

The conjugation of a bioactive, fluorescent PNA sequence to high-molecular weight poly(ethylene glycol) (PEG) is described and the properties of the PEG-PNA conjugate are evaluated.