Dynamic Phenomena and Complexation Effects in the α-Lithiation and Asymmetric Functionalization of Azetidines.

In this work it is demonstrated that enantiomerically enriched N-alkyl 2-oxazolinylazetidines undergo exclusive α-lithiation, and that the resulting lithiated intermediate is chemically stable but configurationally labile under the given experimental conditions that afford enantioenriched N-alkyl-2,2-disubstituted azetidines. Although this study reveals the configurational instability of the diastereomeric lithiated azetidines, it points out an interesting stereoconvergence of such lithiated intermediates towards the thermodynamically stable species, making the overall process highly stereoselective (er > 95:5, dr > 85:15) after trapping with electrophiles. This peculiar behavior has been rationalized by considering the dynamics at the azetidine nitrogen atom, the inversion at the C-Li center supported by in situ FT-IR experiments, and DFT calculations that suggested the presence of η3-coordinated species for diastereomeric lithiated azetidines. The described situation contrasted with the demonstrated stability of the smaller lithiated aziridine analogue. The capability of oxazolinylazetidines to undergo different reaction patterns with organolithium bases supports the model termed "dynamic control of reactivity" of relevance in organolithium chemistry. It has been demonstrated that only 2,2-substituted oxazolinylazetidines with suitable stereochemical requirements could undergo C=N addition of organolithiums in non-coordinating solvents, leading to useful precursors of chiral (er > 95:5) ketoazetidines.

Metal-based Heterogeneous Catalysts for One-Pot Synthesis of Secondary Anilines from Nitroarenes and Aldehydes.

Recently, N-substituted anilines have been the object of increasing research interest in the field of organic chemistry due to their role as key intermediates for the synthesis of important compounds such as polymers, dyes, drugs, agrochemicals and pharmaceutical products. Among the various methods reported in literature for the formation of C-N bonds to access secondary anilines, the one-pot reductive amination of aldehydes with nitroarenes is the most interesting procedure, because it allows to obtain diverse N-substituted aryl amines by simple reduction of nitro compounds followed by condensation with aldehydes and subsequent reduction of the imine intermediates. These kinds of tandem reactions are generally catalyzed by transition metal-based catalysts, mainly potentially reusable metal nanoparticles. The rapid growth in the last years in the field of metal-based heterogeneous catalysts for the one-pot reductive amination of aldehydes with nitroarenes demands for a review on the state of the art with a special emphasis on the different kinds of metals used as catalysts and their recyclability features.

Synthesis of glycosyl sulfoximines by a highly chemo- and stereoselective NH- and O-transfer to thioglycosides.

A synthesis of unprecedented and stable glycosyl sulfoximines is reported. The developed strategies represent the first example of highly stereoselective sulfoximine formation directly from thioglycosides. This synthetic protocol has been tested on several ß-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucose, mannose and galactose as glycosyl units. The process has been extended to a lactose derived thioglycoside and to a glucose derived sulfenamide. The process was chemo- and stereoselective, and X-ray analysis confirmed the structure and provided stereochemical information on the configuration at the sulfur atom. A model for the stereochemical outcome is proposed based on the steric environment of the sulfide.

Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization.

The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH3 group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed.

Exploiting a "Beast" in Carbenoid Chemistry: Development of a Straightforward Direct Nucleophilic Fluoromethylation Strategy.

The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.

Regio- and Stereoselective Synthesis of Sulfur-Bearing Four-Membered Heterocycles: Direct Access to 2,4-Disubstituted Thietane 1-Oxides.

Starting from readily available C2-substituted thietane 1-oxides, a straightforward synthesis of new C2,C4-disubstituted thietane 1-oxides has been developed by using a lithiation/electrophilic trapping sequence. The chemical and configurational stability of lithiated C2-substituted thietane 1-oxides has been investigated as well as the stereochemical implications for this process. The results demonstrate that a stereoselective functionalization at the C2, C4 positions of a thietane is feasible, leaving intact the four-membered ring.

Hydrogen-bonded organic semiconductor micro- and nanocrystals: from colloidal syntheses to (opto-)electronic devices.

Organic pigments such as indigos, quinacridones, and phthalocyanines are widely produced industrially as colorants for everyday products as various as cosmetics and printing inks. Herein we introduce a general procedure to transform commercially available insoluble microcrystalline pigment powders into colloidal solutions of variously sized and shaped semiconductor micro- and nanocrystals. The synthesis is based on the transformation of the pigments into soluble dyes by introducing transient protecting groups on the secondary amine moieties, followed by controlled deprotection in solution. Three deprotection methods are demonstrated: thermal cleavage, acid-catalyzed deprotection, and amine-induced deprotection. During these processes, ligands are introduced to afford colloidal stability and to provide dedicated surface functionality and for size and shape control. The resulting micro- and nanocrystals exhibit a wide range of optical absorption and photoluminescence over spectral regions from the visible to the near-infrared. Due to excellent colloidal solubility offered by the ligands, the achieved organic nanocrystals are suitable for solution processing of (opto)electronic devices. As examples, phthalocyanine nanowire transistors as well as quinacridone nanocrystal photodetectors, with photoresponsivity values by far outperforming those of vacuum deposited reference samples, are demonstrated. The high responsivity is enabled by photoinduced charge transfer between the nanocrystals and the directly attached electron-accepting vitamin B2 ligands. The semiconducting nanocrystals described here offer a cheap, nontoxic, and environmentally friendly alternative to inorganic nanocrystals as well as a new paradigm for obtaining organic semiconductor materials from commercial colorants.

Harnessing the ortho-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes.

This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.

Straightforward access to 4-membered sulfurated heterocycles: introducing a strategy for the single and double functionalization of thietane 1-oxide.

A strategy for the stereoselective functionalization of thietane 1-oxide has been developed. Mono (C2 substituted) and doubly (C2, C4 disubstituted) functionalized thietanes have been obtained from the readily available thietane 1-oxide by using the corresponding organometallic intermediates that reacted with electrophiles leaving intact the 4-membered ring.

Synthesis of alcohols: streamlined C1 to Cn hydroxyalkylation through photoredox catalysis.

Naturally occurring and readily available α-hydroxy carboxylic acids (AHAs) are utilized as platforms for visible light-mediated oxidative CO2-extrusion furnishing α-hydroxy radicals proved to be versatile C1 to Cn hydroxyalkylating agents. The direct decarboxylative Giese reaction (DDGR) is operationally simple, not requiring activator or sacrificial oxidants, and enables the synthesis of a diverse range of hydroxylated products, introducing connectivity typically precluded from conventional polar domains. Notably, the methodology has been extended to widely used glycolic acid resulting in a highly efficient and unprecedented C1 hydroxyhomologation tactic. The use of flow technology further facilitates scalability and adds green credentials to this synthetic methodology.

Improved identification of pollution source attribution by using PAH ratios combined with multivariate statistics.

Polycyclic aromatic hydrocarbons (PAHs) are contaminants introduced by different pathways in the marine ecosystem, affecting both aquatic and sediment bodies. Identification of their sources is of vital importance for protecting the marine ecosystem. The attribution of the pollution sources is usually made by using diagnostic molecular ratios of PAHs isomers. The reliability of this approach diminishes when PAHs contents are measured far from their original source, for example in water bodies or in bottom sediments. Conventionally the source attribution is based on time consuming univariate methods. In the present work coupling of molecular ratios with advanced supervised statistical techniques was used to increase the accuracy of the PAH source attribution in bottom sediments. Data on PAHs distribution within 5 port areas, with known pattern port activity, were collected. Evaluation of multiple PAHs ratios at once by means of supervised OPLS-DA technique was performed. A robust descriptive and predictive model was set up and successfully validated. The proposed methodology helps identify PAH transport pathways, highlighting interactions between pollution patterns, port activities and coastal land-use supporting decision makers in defining monitoring and mitigation procedures.

A recyclable nanoparticle-supported rhodium catalyst for hydrogenation reactions.

Catalytic hydrogenation under mild conditions of olefins, unsaturated aldeydes and ketones, nitriles and nitroarenes was investigated, using a supported rhodium complex obtained by copolymerization of Rh(cod)(aaema) [cod: 1,5-cyclooctadiene, aaema-: deprotonated form of 2-(acetoacetoxy)ethyl methacrylate] with acrylamides. In particular, the hydrogenation reaction of halonitroarenes was carried out under 20 bar hydrogen pressure with ethanol as solvent at room temperature, in order to minimize hydro-dehalogenation. The yields in haloanilines ranged from 85% (bromoaniline) to 98% (chloroaniline).

Synthesis of Sulfinamidines and Sulfinimidate Esters by Transfer of Nitrogen to Sulfenamides.

In this work we report a new synthetic tactic for the straightforward preparation of hardly accessible sulfinamidines and sulfinamide esters, by using a simple metal-free protocol. The process is robust and uses readily available sulfenamides as the S-donor and sulfonyloxycarbamates as the N-source. The scope and mechanism have also been investigated.

Flow Microreactor Technology for Taming Highly Reactive Chloroiodomethyllithium Carbenoid: Direct and Chemoselective Synthesis of α-Chloroaldehydes.

A straightforward flow synthesis of α-chloro aldehydes has been developed. The strategy involves, for the first time, the thermal unstable chloroiodomethyllithium carbenoid and carbonyl compounds. A batch versus flow comparative study showcases the superb capability of flow technology in prolonging the lifetime of the lithiated carbenoid, even at -20 °C. Remarkably, the high chemoselectivity realized in flow allowed for preparing polyfunctionalized α-chloro aldehydes not easily accessible with traditional batch procedures.

Macrophage stimulating protein may promote tubular regeneration after acute injury.

Macrophage-stimulating protein (MSP) exerts proliferative and antiapoptotic effects, suggesting that it may play a role in tubular regeneration after acute kidney injury. In this study, elevated plasma levels of MSP were found both in critically ill patients with acute renal failure and in recipients of renal allografts during the first week after transplantation. In addition, MSP and its receptor, RON, were markedly upregulated in the regenerative phase after glycerol-induced tubular injury in mice. In vitro, MSP stimulated tubular epithelial cell proliferation and conferred resistance to cisplatin-induced apoptosis by inhibiting caspase activation and modulating Fas, mitochondrial proteins, Akt, and extracellular signal-regulated kinase. MSP also enhanced migration, scattering, branching morphogenesis, tubulogenesis, and mesenchymal de-differentiation of surviving tubular cells. In addition, MSP induced an embryonic phenotype characterized by Pax-2 expression. In conclusion, MSP is upregulated during the regeneration of injured tubular cells, and it exerts multiple biologic effects that may aid recovery from acute kidney injury.

Biomathematical model for simulating abnormal orifice patterns in colonic crypts.

Colonic polyps, which are abnormal growths in the colon, are a major concern in colon cancer diagnosis and prevention. Medical studies evidence that there is a correlation between histopathology and the shapes of the orifices in colonic crypts. We propose a biomathematical model for simulating the appearance of anomalous shapes for the orifices of colonic crypts, associated to an abnormal cell proliferation. It couples a mechanical model that is a mixed elastic/viscoelastic quasi-static model describing the deformation of the crypt orifice, with a convection-diffusion model that simulates the crypt cell dynamics in space and time. The coupling resides in the variation of pressure generated by abnormal proliferative cells that induce a mechanical force and originate the change in shape of the crypt orifice. Furthermore the model is formulated in a two-dimensional setting, for emulating the top view of the colonic mucosa, observed in vivo in colonoscopy images. The primary focus of this study is on the modeling of this complex biological phenomenon, by defining an appropriate reduced biomathematical model. Additionally, a numerical procedure to determine its solution is also addressed. The overall numerical simulations indicate that an excess of cell proliferation, in different crypt locations, creates some of the anomalous patterns of the colonic crypt orifices, observed in vivo in medical images.

Data on long-term monitoring programs to assess environmental pressures on coastal area.

The concentration of six metals/metalloids, five congeners of high molecular weight Polycyclic Aromatic Hydrocarbons (PAHs), and sum of five congeners of Polychlorinated Biphenyls (PCBs) determined within marine-coastal sediments of the Apulia Coast during a 5-year long-term monitoring program, are reported through tables and radial graphs. The data are referred to the pollutant concentration determined within 70 sites alongside two marine transects (500 m from coastline and 1750 m of coastline) representing different morphologic features of the coast and different pollution stressors loading [1]. Concentration variability during the five monitored years and data generated by the non-parametric correlation analyses among sediment physical-chemical main parameters and metal concentrations are also included.

A Study of Graphene-Based Copper Catalysts: Copper(I) Nanoplatelets for Batch and Continuous-Flow Applications.

The use of graphene derivatives as supports improves the properties of heterogeneous catalysts, with graphene oxide (GO) being the most frequently employed. To explore greener possibilities as well as to get some insights into the role of the different graphenic supports (GO, rGO, carbon black, and graphite nanoplatelets), we prepared, under the same standard conditions, a variety of heterogeneous Cu catalysts and systematically evaluated their composition and catalytic activity in azide-alkyne cycloadditions as a model reaction. The use of sustainable graphite nanoplatelets (GNPs) afforded a stable CuI catalyst with good recyclability properties, which are compatible with flow conditions, and able to catalyze other reactions such as the regio- and stereoselective sulfonylation of alkynes (addition reaction) and the Meerwein arylation (single electron transfer process).

Polymyxin-B hemoperfusion inactivates circulating proapoptotic factors.

OBJECTIVE: To test the hypothesis that extracorporeal therapy with polymyxin B (PMX-B) may prevent Gram-negative sepsis-induced acute renal failure (ARF) by reducing the activity of proapoptotic circulating factors. SETTING: Medical-Surgical Intensive Care Units. PATIENTS AND INTERVENTIONS: Sixteen patients with Gram-negative sepsis were randomized to receive standard care (Surviving Sepsis Campaign guidelines) or standard care plus extracorporeal therapy with PMX-B. MEASUREMENTS AND RESULTS: Cell viability, apoptosis, polarity, morphogenesis, and epithelial integrity were evaluated in cultured tubular cells and glomerular podocytes incubated with plasma from patients of both groups. Renal function was evaluated as SOFA and RIFLE scores, proteinuria, and tubular enzymes. A significant decrease of plasma-induced proapoptotic activity was observed after PMX-B treatment on cultured renal cells. SOFA and RIFLE scores, proteinuria, and urine tubular enzymes were all significantly reduced after PMX-B treatment. Loss of plasma-induced polarity and permeability of cell cultures was abrogated with the plasma of patients treated with PMX-B. These results were associated to a preserved expression of molecules crucial for tubular and glomerular functional integrity. CONCLUSIONS: Extracorporeal therapy with PMX-B reduces the proapoptotic activity of the plasma of septic patients on cultured renal cells. These data confirm the role of apoptosis in the development of sepsis-related ARF.

Circulating plasma factors induce tubular and glomerular alterations in septic burns patients.

BACKGROUND: Severe burn is a systemic illness often complicated by sepsis. Kidney is one of the organs invariably affected, and proteinuria is a constant clinical finding. We studied the relationships between proteinuria and patient outcome, severity of renal dysfunction and systemic inflammatory state in burns patients who developed sepsis-associated acute renal failure (ARF). We then tested the hypothesis that plasma in these patients induces apoptosis and functional alterations that could account for proteinuria and severity of renal dysfunction in tubular cells and podocytes. METHODS: We studied the correlation between proteinuria and indexes of systemic inflammation or renal function prospectively in 19 severe burns patients with septic shock and ARF, and we evaluated the effect of plasma on apoptosis, polarity and functional alterations in cultured human tubular cells and podocytes. As controls, we collected plasma from 10 burns patients with septic shock but without ARF, 10 burns patients with septic shock and ARF, 10 non-burns patients with septic shock without ARF, 10 chronic uremic patients and 10 healthy volunteers. RESULTS: Septic burns patients with ARF presented a severe proteinuria that correlated to outcome, glomerular (creatinine/urea clearance) and tubular (fractional excretion of sodium and potassium) functional impairment and systemic inflammation (white blood cell (WBC) and platelet counts). Plasma from these patients induced a pro-apoptotic effect in tubular cells and podocytes that correlated with the extent of proteinuria. Plasma-induced apoptosis was significantly higher in septic severe burns patients with ARF with respect to those without ARF or with septic shock without burns. Moreover, plasma from septic burns patients induced an alteration of polarity in tubular cells, as well as reduced expression of the tight junction protein ZO-1 and of the endocytic receptor megalin. In podocytes, plasma from septic burns patients increased permeability to albumin and decreased the expression of the slit diaphragm protein nephrin. CONCLUSION: Plasma from burns patients with sepsis-associated ARF contains factors that affect the function and survival of tubular cells and podocytes. These factors are likely to be involved in the pathogenesis of acute tubular injury and proteinuria, which is a negative prognostic factor and an index of renal involvement in the systemic inflammatory reaction.