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Iron complexes with chiral tetradentate ligands based on the pdp scaffold (pdp = N,N′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine) are efficient and versatile catalysts for the highly enantioselective epoxidation of a wide range of olefins. The nature of the species responsible for oxygen atom transfer to the olefin in these reactions is under debate. In order to investigate this question, the enantioselectivity of the epoxidation reaction has been used as a mechanistic probe. The enantioselectivities obtained under different reaction conditions for two iron catalysts (S,S)-[Fe(CF3SO3)2(Me2Npdp)] ((S,S)Me2N1Fe) and (S,S)-[Fe(CF3SO3)2(dMMpdp)] ((S,S)dMM1Fe) have been analyzed. Reactions were performed with a series of peracids, and enantioselectivities of these reactions were compared with those obtained by combining peroxides and carboxylic acids. This analysis provides conclusive experimental evidence that the same oxidant is responsible for the asymmetric epoxidation reaction in both scenarios. The study al...

The selective oxidation of hydrocarbons is a challenging reaction for synthetic chemists, but common in nature. Iron oxygenases activate the O–O bond of dioxygen to perform oxidation of alkane and alkenes moieties with outstanding levels of regio-, chemo- and stereoselectivity. Along a bioinspired approach, iron coordination complexes which mimic structural and reactivity aspects of the active sites of nonheme iron oxygenases have been explored as oxidation catalysts. This review describes the evolution of this research field, from the early attempts to reproduce the basic reactivity of nonheme iron oxygenases to the development of effective iron oxidation catalysts. The work covers exclusively nonheme iron complexes which rely on H2O2 or O2 as terminal oxidants. First, it delineates the key steps and the essential catalyst design principles required to activate the peroxide bond at nonheme iron centers without (or at least minimizing) the release of free-diffusing radicals. It follows with a critical description of the mechanistic pathways which govern the reaction between iron complexes and H2O2 to generate the oxidizing species. Eventually, the work presents a state-of-the-art report on the use of these catalysts in aliphatic C–H oxidation, olefin epoxidation and alkene syn-dihydroxylation, under substrate-limiting conditions. A special focus is given on the main strategies elaborated to tune catalyst activity and selectivity by modification of its structure. The work is concluded by a concise discussion on the essential progresses of these oxidation catalysts together with the challenges that remain still to be tackled.

In order to identify new compounds to treat Chagas disease during the acute phase with higher activity and lower toxicity than the reference drug benznidazole (Bz), a series of tetraamine-based compounds was prepared and their trypanocidal effects against Trypanosoma cruzi were evaluated by light microscopy through the determination of IC50 values. Cytotoxicity was determined by flow cytometry assays against Vero cells. In vivo assays were performed in BALB/c mice, in which the parasitemia levels were quantified by fresh blood examination; the assignment of a cure was determined by PCR and reactivation of blood parasitemia levels after immunosuppression. The mechanism of action was elucidated at metabolic and ultra-structural levels by (1)H NMR and TEM studies. Finally, as tetraamines are potentially capable of casuing oxidative damage in the parasites, the study was completed by assessing their activity as potential iron superoxide dismutase (Fe-SOD) and trypanothione reductase (TR) inhibitors. High-selectivity indexes observed in vitro were the basis of promoting three of the tested compounds to in vivo assays. The tests on the murine model for the acute phase of Chagas disease showed better parasitemia inhibition values than those found for Bz. Tetraamines 2 and 3 induced a remarkable decrease in the reactivation of parasitemia after immunosuppression and curative rates of 33 and 50%, respectively. Tetraamine 3 turned out to be a great inhibitor of Fe-SOD and TR. The high anti-parasitic activity and low toxicity render these tetraamines appropriate molecules for the development of an affordable anti-Chagas agent.

The chiral tetradentate N4-donor ligand, 1-methyl-2-({(S)-2-[(S)-1-(1-methylbenzimidazol-2-yl methyl)pyrrolidin-2-yl]pyrrolidin-1-yl}methyl) benzimidazole (S,S-PDBzL), based on a chiral dipyrrolidine backbone, has been synthesized and its corresponding Fe(II) complex has been prepared and characterized. The X-ray structure of the complex reveals that the Fe(II) ion is in a distorted octahedral coordination environment with two cis-oriented coordination sites occupied by (labile) triflate anions. The ability of the iron complex to catalyze asymmetric epoxidation reactions of olefins with H2O2 was investigated, using 2-cyclohexen-1-one, 2-cyclopenten-1-one, cis-β-methylstyrene, isophorone, chalcones and tetralones as substrates. Different carboxylic acids were used as additives to enhance yields and enantioselectivities, and 2-ethylhexanoic acid was found to give the best results. The catalysis results indicate that the Fe(II) complex is capable of effecting comparatively high enantioselectivities (>80%) in the epoxidation reactions The research has been carried out within the frameworks of the International Research Training Group Metal sites in biomolecules: structures, regulation and mechanisms (http://www.biometals.eu), the Marie Sklodowska-Curie Innovative Training Network MSCAITN-2015-ETN 675020 and COST Action CM1003. M. M. thanks the European Commission for an Erasmus Mundus fellowship

Aquest mateix article està publicat a l'edició alemanya de la revista 'Angewandte Chemie' (ISSN 0044-8249, EISSN 1521-3757), vol. 127, núm. 9, p. 2767-2771. DOI http://dx.doi.org/10.1002/ange.201410557 Highly enantioselective epoxidation of -substituted styrenes with aqueous H2O2 is described by using a chiral iron complex as the catalyst and N-protected amino acids (AAs) as coligands. The amino acids synergistically cooperate with the iron center in promoting an efficient activation of H2O2 to catalyze epoxidation of this challenging class of substrates with good yields and stereoselectivities (up to 97%ee) in short reaction times We acknowledge group LIPPSO from UdG for providing amino acid samples and A. Riera (IRB) for access to a polarimeter. We acknowledge financial support from the European Research Council (ERC-2009-StG-239910), MINECO of Spain (CTQ2012-37420-C02-01/BQU, CSD2010-00065), and Generalitat de Catalunya (2009SGR637). J.L.-F. thanks MICINN for a RyC contract. X.R. and M.C. thank ICREA-Academia awards

A dual role of hydrogen sulfide (H2S) in inflammation is well-reported and recent studies demonstrated adipogenic effects of H2S in 3T3-L1 cells. Here, we aimed to investigate the effects of H2S on adipocyte differentiation and inflammation. H2S concentration in 3T3-L1 culture media was increased during adipocyte differentiation in parallel to adipogenic and Cth gene expression, and its inhibition using DL-Propargyl Glycine (PPG) impaired 3T3-L1 differentiation. GYY4137 and Na2S administration only in the first or in the last stage of adipocyte differentiation resulted in a significant increased expression of adipogenic genes. However, when GYY4137 or Na2S were administrated during all process no significant effects on adipogenic gene expression were found, suggesting that excessive H2S administration might exert negative effects on adipogenesis. In fact, continuous addition of Na2S, which resulted in Na2S excess, inhibited adipogenesis, whereas time-expired Na2S had no effect. In inflammatory conditions, GYY4137, but not Na2S, administration attenuated the negative effects of inflammation on adipogenesis and insulin signaling-related gene expression during adipocyte differentiation. In inflamed adipocytes, Na2S administration enhanced the negative effects of inflammatory process. Altogether these data showed that slow-releasing H2S improved adipocyte differentiation in inflammatory conditions, and that H2S proadipogenic effects depend on dose, donor and exposure time.

A non-heme iron complex that catalyzes highly enantioselective epoxidation of olefins with H2O2 is described. Improvement of enantiomeric excesses is attained by the use of catalytic amounts of carboxylic acid additives. Electronic effects imposed by the ligand on the iron center are shown to synergistically cooperate with catalytic amounts of carboxylic acids in promoting efficient O-O cleavage and creating highly chemo-and enantioselective epoxidizing species which provide a broad range of epoxides in synthetically valuable yields and short reaction times We acknowledge financial support from European Research Council (ERC-2009-StG-239910), MINECO of Spain (CTQ2012-37420-C02-01/BQU, Consolider-Ingenio CSD2010-00065), and the Catalan DIUE of the Generalitat de Catalunya (2009SGR637). J.Ll.-F. thanks MICINN for a RyC contract. X.R. and M.C. acknowledge ICREA-Academia awards. X.R. is grateful for financial support from INNPLAN-TA Project No. IPN-2011-0059-PCT-42000-ACT1. I.G.-B. thanks the European Community for an IOF Marie Curie fellowship. We acknowledge STRs from UdG for technical support

Bulky iron complexes are described that catalyze the site-selective oxidation of alkyl C-H bonds with hydrogen peroxide under mild conditions. Steric bulk at the iron center is introduced by appending trialkylsilyl groups at the meta-position of the pyridines in tetradentate aminopyridine ligands, and this effect translates into high product yields, an enhanced preferential oxidation of secondary over tertiary C-H bonds, and the ability to perform site-selective oxidation of methylenic sites in terpenoid and steroidal substrates. Unprecedented site selective oxidation at C6 and C12 methylenic sites in steroidal substrates is shown to be governed by the chirality of the catalysts.

An iron complex with a C1-symmetric tetradentate N-based ligand catalyzes the asymmetric epoxidation of cyclic enones and cyclohexene ketones with aqueous hydrogen peroxide, providing the corresponding epoxides in good to excellent yields and enantioselectivities (up to 99% yield, and 95% ee), under mild conditions and in short reaction times. Evidence is provided that reactions involve an electrophilic oxidant, and this element is employed in performing site selective epoxidation of enones containing two alkene sites.

A series of tetraamine-based compounds was prepared, and their trypanocidal effects against Trypanosoma cruzi and cytotoxicity were determined through the determination of IC50 values. In vivo assays were performed in mice, where parasitaemia levels were quantified by fresh blood examination and the assignment of a cure was determined by polymerase chain reaction and reactivation of blood parasitaemia levels after immunosuppression. The mechanisms of action were elucidated at metabolic and ultra-structural levels, by 1H NMR, Fe-SOD inhibition and TEM studies. The high-selectivity indexes observed in vitro were the basis of promoting one of the tested compounds to in vivo assays. Compound 6 induced a remarkable decrease in the reactivation of parasitaemia after immunosuppression and curative rates of 33%. The experiments allowed us to select compound 6 as a promising candidate for treating Chagas disease, but a further high-level study should be considered to obtain an improved efficiency.

The development of catalysts for the selective oxidation of readily available hydrocarbons or organic precursors into oxygenated products is a long-standing goal in organic synthesis. In the last decade, some iron coordination complexes have shown the potential to fit this role. These catalysts can mimic the O−O activation mode of far more sophisticated iron oxygenase enzymes, generating powerful yet selective oxidants. In this review, we report state-of-the-art C−H and C=C oxidations catalyzed by non-heme iron complexes and H2O2 as the oxidant. Finally, we briefly describe some novel oxidative reactivity and the perspectives of this chemistry We acknowledge financial support from the Ministry of Economy and Competitiveness (MINECO) of Spain and Fondo Europeo de Desarrollo Regional (CTQ2015-70795-P/BQU), Consolider-Ingenio (CSD2010-00065), and the Catalan Department for Innovation, Universities and Enterprise (DIUE) of the Generalitat de Catalunya (2009SGR637)

Iron coordination complexes with nitrogen and oxygen donor ligands have long since been known to react with peroxides producing powerful oxidizing species. These compounds can be regarded as simple structural and functional models of the active sites of non-heme iron dependent oxygenases. Research efforts during the last decade have uncovered basic principles and structural coordination chemistry motifs that permit us to control the chemistry that evolves when these iron complexes react with peroxides, in order to provide powerful metal-based, but at the same time selective, oxidising agents. Oxidation methodologies with synthetic value are currently emerging from this approach. The current review focuses on asymmetric epoxidation, a reaction which has large value in synthesis, and where iron/H2O2 based methodologies may represent not only a sustainable choice, but may also expand the scope of state-of-the-art oxidation methods. Basic principles that underlay catalyst design as well as H2O2 activation are discussed, whilst limitations and future perspectives are also reviewed.

Herein we show that species generated upon reaction of α-[Fe(CF3SO3)2(BPMCN)] (BPMCN = N,N′-bis(2-pyridylmethyl)-trans-1,2-diaminocyclohexane) with H2O2 (putatively [FeV(O)(OH)(BPMCN)]) is able to efficiently oxidize H2 to H2O even in the presence of organic substrates, while species formed in the presence of acetic acid (putatively [FeV(O)(OAc)(BPMCN)]) prefer organic substrate oxidation over H2 activation. Mechanistic implications have been analysed with the aid of computational methods., This work was supported by Spanish Ministerio de Economia y Competitividad (CTQ2012-37420-C02-02 and 01) European Research Council (StG 239910), and Generalitat de Catalunya(2014 SGR 862 and ICREA Academia award to MC). J.Ll.-F. thanks the CELLEX foundation for the starting career program for financial support.

Aquest mateix article esta publicat a l'edicio alemanya de la revista 'Angewandte Chemie' (ISSN 0044-8249, EISSN 1521-3757), vol. 127, num. 9, p. 2767-2771. DOI http://dx.doi.org/10.1002/ange.201410557

Iron coordination complexes with nitrogen and oxygen donor ligands have long since been known to react with peroxides producing powerful oxidizing species. These compounds can be regarded as simple structural and functional models of the active sites of non-heme iron dependent oxygenases. Research efforts during the last decade have uncovered basic principles and structural coordination chemistry motifs that permit us to control the chemistry that evolves when these iron complexes react with peroxides, in order to provide powerful metal-based, but at the same time selective, oxidising agents. Oxidation methodologies with synthetic value are currently emerging from this approach. The current review focuses on asymmetric epoxidation, a reaction which has large value in synthesis, and where iron/H2O2 based methodologies may represent not only a sustainable choice, but may also expand the scope of state-of-the-art oxidation methods. Basic principles that underlay catalyst design as well as H2O2 activation are discussed, whilst limitations and future perspectives are also reviewed We acknowledge help from Dr Christopher Whiteoak in proofreading the manuscript and providing valuable suggestions. We acknowledge financial support from the European Research Council (ERC-2009-StG-239910), MINECO of Spain (CTQ2012-37420-C02-01/BQU, CSD2010-00065), and Generalitat de Catalunya (2014 SGR 862). X.R. and M.C. thank ICREA-Academia awards

Differential redox homeostasis in normal and malignant cells suggests that pro-oxidant-induced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a pro-oxidant deviation well-tolerated by nonmalignant cells might rapidly reach a cell-death threshold in malignant cells already at a high setpoint of constitutive oxidative stress. To test this hypothesis, we took advantage of a selected number of amine-pyridine-based Fe (II) complexes that operate as efficient and robust oxidation catalysts of organic substrates upon reaction with peroxides. Five of these Fe(II)-complexes and the corresponding aminopyridine ligands were selected to evaluate their anticancer properties. We found that the iron complexes failed to display any relevant activity, while the corresponding ligands exhibited significant antiproliferative activity. Among the ligands, none of which were hemolytic, compounds 1, 2 and 5 were cytotoxic in the low micromolar range against a panel of molecularly diverse human cancer cell lines. Importantly, the cytotoxic activity profile of some compounds remained unaltered in epithelial-to-mesenchymal (EMT)-induced stable populations of cancer stem-like cells, which acquired resistance to the well-known ROS inducer doxorubicin. Compounds 1, 2 and 5 inhibited the clonogenicity of cancer cells and induced apoptotic cell death accompanied by caspase 3/7 activation. Flow cytometry analyses indicated that ligands were strong inducers of oxidative stress, leading to a 7-fold increase in intracellular ROS levels. ROS induction was associated with their ability to bind intracellular iron and generate active coordination complexes inside of cells. In contrast, extracellular complexation of iron inhibited the activity of the ligands. Iron complexes showed a high proficiency to cleave DNA through oxidative-dependent mechanisms, suggesting a likely mechanism of cytotoxicity. In summary, we report that, upon chelation of intracellular iron, the pro-oxidant activity of amine-pyrimidine-based iron complexes efficiently kills cancer and cancer stem-like cells, thus providing functional evidence for an efficient family of redox-directed anti-cancer metallodrugs., This work was supported by grants from the Spanish Ministerio de Economia y Competitividad (MINECO), CONSOLIDER-INGENIO 2010 CSD2010-00065, and from the Ministerio de Ciencia e Innovacion (MICINN), SAF2012-38914, Plan Nacional de I+D+I.

Manganese catalysts of the type of MNN and MNO but with a different substitution pattern on the aromatic rings are synthesized and tested with respect to their catalytic activity in the epoxidation reaction of styrene derivatives and steroids.

Electronic effects in the iron catalyst are used to control the activation of hydrogen peroxide and oxygen transfer in a non-porphyrinic catalyst.

Fast, efficient, and highly stereoselective epoxidation with H2O2 is reached by manganese coordination complexes with e-rich aminopyridine tetradentate ligands. It is shown that the electronic properties of these catalysts vary systematically with the stereoselectivity of the O-atom transfer event and exert fine control over the activation of hydrogen peroxide, reducing the amount of carboxylic acid co-catalyst necessary for efficient operation.

A concise and efficient solid-phase synthesis of biaryl cyclic peptides containing a Phe-Tyr or a Tyr-Tyr linkage has been accomplished. The key steps include a Miyaura borylation of a resin-bound 3-iodotyrosine and a microwave-assisted Suzuki-Miyaura reaction for the formation of the macrocycle. First, the feasibility of the solid-phase Miyaura borylation of a 3-iodotyrosyltripeptide was established. Then, the Suzuki-Miyaura reaction was applied to the cross-coupling of linear 3-boronotyrosine-containing peptidyl resins with iodobenzene and with halogenated aromatic amino acids. Finally, this methodology was extended to the synthesis of biaryl cyclic peptides through the preparation of a linear peptidyl resin containing both the required boronate and halogenated derivatives, followed by a microwave-assisted Suzuki-Miyaura macrocyclization This work was supported by grant AGL2009-13255-C02-02/AGR from MICINN

Supramolecular systems resulting from the combination of peptides and a chiral iron coordination complex catalyze asymmetric epoxidation with aqueous hydrogen peroxide, providing good to excellent yields and high enantioselectivities in short reaction times. The peptide is shown to play a dual role; the terminal carboxylic acid assists the iron center in the efficient H 2 O 2 activation step, while its β-turn structure is crucial to induce high enantioselectivity in the oxygen delivering step. The high level of stereoselection (84-92% ee) obtained by these supramolecular catalysts in the epoxidation of 1,1′-alkyl ortho-substituted styrenes, a notoriously challenging class of substrates for asymmetric catalysis, is not attainable with any other epoxidation methodology described so far. The current work, combining an iron center ligated to N and O based ligands, and a peptide scaffold that shapes the second coordination sphere, may be seen as a bott om up approach towards the design of artificial oxygenases MC acknowledge nancial support from MINECO of Spain and Fondo Europeo de Desarrollo Regional (CTQ2015-70795-P/ BQU), and the Catalan Department for Innovation, Universities and Enterprise (DIUE) of the Generalitat de Catalunya (2009SGR637).