Iron-catalyzed synthesis of substituted 3-arylquinolin-2(1H)-ones via an intramolecular dehydrogenative coupling of amido-alcohols.

Here we report an iron-complex-catalyzed synthesis of various mono- and di-substituted quinolin-2(1H)-ones achieved via the intramolecular acceptorless dehydrogenative cyclization of amido-alcohols. This approach for the synthesis of N-heterocycles has provided access to underdescribed disubstituted quinolinones and represents an alternative to the well-known palladium-catalyzed coupling reactions.

Synthesis and antibacterial properties under blue LED light of conjugates between the siderophore desferrioxamine B (DFOB) and an Iridium(III) complex.

The decline of antibiotics efficacy worldwide has recently reached a critical point urging for the development of new strategies to regain upper hand on multidrug resistant bacterial strains. In this context, the raise of photodynamic therapy (PDT), initially based on organic photosensitizers (PS) and more recently on organometallic PS, offers promising perspectives. Many PS exert their biological effects through the generation of reactive oxygen species (ROS) able to freely diffuse into and to kill surrounding bacteria. Hijacking of the bacterial iron-uptake systems with siderophore-PS conjugates would specifically target pathogens. Here, we report the synthesis of unprecedented conjugates between the siderophore desferrioxamine B (DFOB) and an antibacterial iridium(III) PS. Redox properties of the new conjugates have been determined at excited states and compared to that of an antibacterial iridium PS previously reported by our groups. Tested on nosocomial pathogen Pseudomonas aeruginosa and other bacteria, these conjugates demonstrated significant inhibitory activity when activated with blue LED light. Ir(III) conjugate and iridium free DFOB-2,2'-dipyridylamine ligands were crystallized in complex with FoxA, the outer membrane transporter involved in DFOB uptake in P. aeruginosa and revealed details of the binding mode of these unprecedented conjugates.

Blue-Light Induced Iron-Catalyzed Synthesis of γ,δ-Unsaturated Ketones.

A visible-light-induced iron-catalyzed α-alkylation of ketones with allylic and propargylic alcohols as pro-electrophiles is reported. The diaminocyclopentadienone iron tricarbonyl complex plays a dual role by harvesting light and facilitating dehydrogenation and reduction steps without the help of any exogenous photosensitizer. γ,δ-Unsaturated ketones can now be accessed through this borrowing hydrogen methodology at room temperature. Mechanistic investigations revealed that the steric hindrance on the δ-position of either the dienone or ene-ynone intermediate is the key feature to prevent or decrease the competitive 1,6-reduction (and consequently the formation of the saturated ketone) and to favor the synthesis of a set of non-conjugated enones and ynones.

Blue-Light-Induced Iron-Catalyzed α-Alkylation of Ketones.

We report a visible-light-induced iron-catalyzed α-alkylation of ketones. The photocatalytic system is based on the single diaminocyclopentadienone iron tricarbonyl complex. Two catalytic intermediates of this complex are able to harvest light, allowing the synthesis of substituted aromatic and aliphatic ketones at room temperature using the borrowing hydrogen strategy in the presence of various substituted primary alcohols as alkylating reagents. Preliminary mechanistic studies unveil the role of light for both the dehydrogenation and reduction step.

A phosphine-free iron complex-catalyzed synthesis of cycloalkanes via the borrowing hydrogen strategy.

Herein we report a diaminocyclopentadienone iron tricarbonyl complex catalyzed synthesis of substituted cyclopentane, cyclohexane and cycloheptane compounds using the borrowing hydrogen strategy in the presence of various substituted primary and secondary 1,n diols as alkylating reagents. Deuterium labeling experiments confirm that the diols were the hydride source in this cascade process.

Solving the challenging synthesis of highly cytotoxic silver complexes bearing sterically hindered NHC ligands with mechanochemistry.

The use of ball-mills enabled the straightforward synthesis of a variety of silver(i) complexes featuring challenging NHC ligands. Sterically hindered including electron-poor or with very low solubility imidazolium salts were ground with silver(i) oxide to furnish heteroleptic or homoleptic complexes in high yields and short reaction times. The synthesis of heteroleptic bis-NHC silver(i) complexes was also performed for the first time in a ball mill. The efficiency and rapidity of the mechanochemical approach enabled the generation of a library of unprecedented NHC silver complexes, whose cytotoxicity on the HCT116 colorectal cancer cell line was evaluated providing a rare example of medicinal mechanochemistry. The cationic silver complexes were found to be more potent than the neutral analogues, with IC50 values down to 21 nM and 256 times more potent than cisplatin.

Aminomethylation of Oxabenzonorbornadienes via the Merger of Photoredox and Nickel Catalysis.

The first aminomethylation of oxabenzonorbornadienes using dual photoredox/nickel catalysis has been disclosed. This cascade reaction allowed the preparation of the cis-aminomethyl dihydronaphthalenols without any prefunctionalization or any use of nucleophilic organometallic species. The control of the regio- and stereoselectivity might be explained by a sequence involving insertion of nickel(0) into the C-O bond followed by the formation of a π-allyl intermediate.

Artificial iron hydrogenase made by covalent grafting of Knölker's complex into xylanase: Application in asymmetric hydrogenation of an aryl ketone in water.

We report a new artificial hydrogenase made by covalent anchoring of the iron Knölker's complex to a xylanase S212C variant. This artificial metalloenzyme was found to be able to catalyze efficiently the transfer hydrogenation of the benchmark substrate trifluoroacetophenone by sodium formate in water, yielding the corresponding secondary alcohol as a racemic. The reaction proceeded more than threefold faster with the XlnS212CK biohybrid than with the Knölker's complex alone. In addition, efficient conversion of trifluoroacetophenone to its corresponding alcohol was reached within 60 H with XlnS212CK, whereas a ≈2.5-fold lower conversion was observed with Knölker's complex alone as catalyst. Moreover, the data were rationalized with a computational strategy suggesting the key factors of the selectivity. These results suggested that the Knölker's complex was most likely flexible and could experience free rotational reorientation within the active-site pocket of Xln A, allowing it to access the subsite pocket populated by trifluoroacetophenone.

Iron-Catalyzed α-Alkylation of Ketones with Secondary Alcohols: Access to ß-Disubstituted Carbonyl Compounds.

An iron-catalyzed borrowing hydrogen strategy has been applied in the synthesis of ß-branched carbonyl compounds. Various secondary benzylic and aliphatic alcohols have been used as alkylating reagents under mild reaction conditions. The ketones have been isolated in good to excellent yield. Deuterium labeling experiments provide evidence that the alcohol is the hydride source in this reaction and that no reversible step or hydrogen/deuterium scrambling takes place during the process.

Cyclopentadienone Iron Tricarbonyl Complexes-Catalyzed Hydrogen Transfer in Water.

The development of efficient and low-cost catalytic systems is important for the replacement of robust noble metal complexes. The synthesis and application of a stable, phosphine-free, water-soluble cyclopentadienone iron tricarbonyl complex in the reduction of polarized double bonds in pure water is reported. In the presence of cationic bifunctional iron complexes, a variety of alcohols and amines were prepared in good yields under mild reaction conditions.

Iron-Catalyzed ß-Alkylation of Alcohols.

ß-Branched alkylated alcohols have been prepared in good yields using a double-hydrogen autotransfer strategy in the presence of our diaminocyclopentadienone iron tricarbonyl complex Fe1. The alkylation of some 2-arylethanol derivatives was successfully addressed with benzylic alcohols and methanol as alkylating reagents under mild conditions. Deuterium labeling experiments suggested that both alcohols (2-arylethanol and either methanol or benzyl alcohol) served as hydrogen donors in this cascade process.

Room-Temperature Chemoselective Reductive Alkylation of Amines Catalyzed by a Well-Defined Iron(II) Complex Using Hydrogen.

A transition-metal frustrated Lewis pair approach has been envisaged to enhance the catalytic activity of tricarbonyl phosphine-free iron complexes in reduction of amines. A new cyclopentadienyl iron(II) tricarbonyl complex has been isolated, fully characterized, and applied in hydrogenation. This phosphine-free iron complex is the first Earth-abundant metal complex that is able to catalyze chemoselective reductive alkylation of various functionalized amines with functionalized aldehydes. Such selectivity and functionality tolerance (alkenes, esters, ketones, acetals, unprotected hydroxyl groups, and phosphines) have been demonstrated also for the first time at room temperature with an Earth-abundant metal complex. This alkylation reaction was also performed without any preliminary condensation and generated only water as a byproduct. The resulting amines provided rapid access to potential building blocks, metal ligands, or drugs. Density functional theory calculations highlighted first that the formation of the 16 electron species, via the activation of the tricarbonyl complex Fe3, was facilitated and, second, that the hydrogen cleavage did not follow the same pathway as bond breaking, usually described with the known cyclopentadienone iron tricarbonyl complexes (Fe1 and Fe4). These calculations highlighted that the new complex Fe3 does not behave as a bifunctional catalyst, in contrast to its former congeners.

A MOF-assisted phosphine free bifunctional iron complex for the hydrogenation of carbon dioxide, sodium bicarbonate and carbonate to formate.

The hydrogenation of carbon dioxide into formic acid (FA) with Earth-abundant metals is a vibrant research area because FA is an attractive molecule for hydrogen storage. We report a cyclopentadienyl iron tricarbonyl complex that provides up to 3000 turnover number for carbon dioxide hydrogenation when combined with a catalytic amount of the chromium dicarboxylate MOF MIL-53(Cr). To date, this is the highest turnover number reported in the presence of a phosphine-free iron complex.

Iron-Catalyzed Tandem Three-Component Alkylation: Access to α-Methylated Substituted Ketones.

The borrowing hydrogen strategy has been applied in the synthesis of α-branched methylated ketones via a tandem three-component reaction catalyzed by a diaminocyclopentadienone iron tricarbonyl complex. Various alkyl and aromatic methyl ketones underwent dialkylation with various primary alcohols and methanol as alkylating agents in mild reaction conditions and good yields. Deuterium labeling experiments suggested that the benzylic alcohol was the hydrogen source in this tandem process.

Well-Defined Phosphine-Free Iron-Catalyzed N-Ethylation and N-Methylation of Amines with Ethanol and Methanol.

An iron(0) complex bearing a cyclopentadienone ligand catalyzed N-methylation and N-ethylation of aryl and aliphatic amines with methanol or ethanol in mild and basic conditions through a hydrogen autotransfer borrowing process is reported. A broad range of aromatic and aliphatic amines underwent mono- or dimethylation in high yields. DFT calculations suggest molecular hydrogen acts not only as a reducing agent but also as an additive to displace thermodynamic equilibria.

Iron-Catalyzed Chemoselective Reduction of α,ß-Unsaturated Ketones.

An iron-catalyzed chemo- and diastereoselective reduction of α,ß-unsaturated ketones into the corresponding saturated ketones in mild reaction conditions is reported herein. DFT calculations and experimental work underline that transfer hydride reduction is a more facile process than hydrogenation, unveiling the fundamental role of the base.

Highly active phosphine-free bifunctional iron complex for hydrogenation of bicarbonate and reductive amination.

Based on a "transition metal frustrated Lewis pair" approach, a cyclopentadienone iron tricarbonyl complex has been designed and applied in the reductive amination and hydrogenation of bicarbonate. This well-defined phosphine-free complex displays the best activities reported to date for an iron complex in the reduction of bicarbonate into formate and in reductive amination.

Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients.

BACKGROUND: Hyperphosphatemia necessitates the use of phosphate binders in most dialysis patients. Long-term efficacy and tolerability of the iron-based phosphate binder, sucroferric oxyhydroxide (previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study. METHODS: In the initial Phase III study, hemo- or peritoneal dialysis patients with hyperphosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0-3.0 g/day (2-6 tablets/day; n = 710) or sevelamer 2.4-14.4 g/day (3-18 tablets/day; n = 349) for 24 weeks. Eligible patients could enter the 28-week extension study, continuing the same treatment and dose they were receiving at the end of the initial study. RESULTS: Overall, 644 patients were available for efficacy analysis (n = 384 sucroferric oxyhydroxide; n = 260 sevelamer). Serum phosphorus concentrations were maintained during the extension study. Mean ± standard deviation (SD) change in serum phosphorus concentrations from extension study baseline to Week 52 end point was 0.02 ± 0.52 mmol/L with sucroferric oxyhydroxide and 0.09 ± 0.58 mmol/L with sevelamer. Mean serum phosphorus concentrations remained within Kidney Disease Outcomes Quality Initiative target range (1.13-1.78 mmol/L) for both treatment groups. Mean (SD) daily tablet number over the 28-week extension study was lower for sucroferric oxyhydroxide (4.0 ± 1.5) versus sevelamer (10.1 ± 6.6). Patient adherence was 86.2% with sucroferric oxyhydroxide versus 76.9% with sevelamer. Mean serum ferritin concentrations increased over the extension study in both treatment groups, but transferrin saturation (TSAT), iron and hemoglobin concentrations were generally stable. Gastrointestinal-related adverse events were similar and occurred early with both treatments, but decreased over time. CONCLUSIONS: The serum phosphorus-lowering effect of sucroferric oxyhydroxide was maintained over 1 year and associated with a lower pill burden, compared with sevelamer. Sucroferric oxyhydroxide was generally well tolerated long-term and there was no evidence of iron accumulation.

QTL analysis and candidate gene mapping for the polyphenol content in cider apple.

Polyphenols have favorable antioxidant potential on human health suggesting that their high content is responsible for the beneficial effects of apple consumption. They control the quality of ciders as they predominantly account for astringency, bitterness, color and aroma. In this study, we identified QTLs controlling phenolic compound concentrations and the average polymerization degree of flavanols in a cider apple progeny. Thirty-two compounds belonging to five groups of phenolic compounds were identified and quantified by reversed phase liquid chromatography on both fruit extract and juice, over three years. The average polymerization degree of flavanols was estimated in fruit by phloroglucinolysis coupled to HPLC. Parental maps were built using SSR and SNP markers and used for the QTL analysis. Sixty-nine and 72 QTLs were detected on 14 and 11 linkage groups of the female and male maps, respectively. A majority of the QTLs identified in this study are specific to this population, while others are consistent with previous studies. This study presents for the first time in apple, QTLs for the mean polymerization degree of procyanidins, for which the mechanisms involved remains unknown to this day. Identification of candidate genes underlying major QTLs was then performed in silico and permitted the identification of 18 enzymes of the polyphenol pathway and six transcription factors involved in the apple anthocyanin regulation. New markers were designed from sequences of the most interesting candidate genes in order to confirm their co-localization with underlying QTLs by genetic mapping. Finally, the potential use of these QTLs in breeding programs is discussed.