Frédéric Taran

Functionalized Chitosan as a Green, Recyclable, Biopolymer-Supported Catalyst for the 3+2 Huisgen Cycloaddition

Owing to increasing concern about environmental impact, tremendous effort has been made towards the development of new processes that minimize pollution in chemical synthesis. For this reason and others (catalyst removal, recovery, and recycling), heterogeneous catalysis is clearly on the rise, including in industry. Of the many systems that have been developed over the past decades, metallic species supported on inorganic materials (e.g. SiO2, Al2O3) or on charcoal are the most common. The immobilization of transition metals on polymer supports derived from petrochemicals (e.g. polystyrenes) has also been the focus of many efforts. Recent developments for cleaner, sustainable chemistry are being driven by a shift from petrochemical-based feedstocks to biological materials. There is considerable interest in exploiting natural polymer macrostructures, and in particular those of polysaccharides, to create high-performance and environmentally friendly catalysts. Indeed, polysaccharides present many advantages that may stimulate their use as polymeric supports for catalysis: 1) They are present in enormous quantity on earth, 2) they contain many functionalities that can be used readily for the anchoring of organometallic species, 3) they contain many stereogenic centers, and 4) they are chemically stable but biodegradable. Surprisingly, although there has been a worldwide realization that nature-derived polysaccharides can provide the raw materials needed for the production of numerous industrial consumer goods, their use as supports for catalysis is still in its infancy. Chitosan (Figure 1 A) is a particularly attractive polysaccharide for application in catalysis owing to the presence of readily functionalizable amino groups and its insolubility in organic solvents. A copolymer of b(1!4)-2-amino-2-deoxyd-glucopyranose and 2-acetamido-2-deoxy-d-glucopyranose, chitosan results from incomplete deacetylation of chitin. At least 10 gigatons of chitin are constantly present in the biosphere; thus, chitosan is a renewable green material. Of

Quantitative evaluation of multi-walled carbon nanotube uptake in wheat and rapeseed

Environmental contamination with carbon nanotubes would lead to plant exposure and particularly exposure of agricultural crops. The only quantitative exposure data available to date which can be used for risk assessment comes from computer modeling. The aim of this study was to provide quantitative data relative to multi-walled carbon nanotube (MWCNT) uptake and distribution in agricultural crops, and to correlate accumulation data with impact on plant development and physiology. Roots of wheat and rapeseed were exposed in hydroponics to uniformly (14)C-radiolabeled MWCNTs. Radioimaging, transmission electron microscopy and raman spectroscopy were used to identify CNT distribution. Radioactivity counting made it possible absolute quantification of CNT accumulation in plant leaves. Impact of CNTs on seed germination, root elongation, plant biomass, evapotranspiration, chlorophyll, thiobarbituric acid reactive species and H(2)O(2) contents was evaluated. We demonstrate that less than 0.005‰ of the applied MWCNT dose is taken up by plant roots and translocated to the leaves. This accumulation does not impact plant development and physiology. In addition, it does not induce any modifications in photosynthetic activity nor cause oxidative stress in plant leaves. Our results suggest that if environmental contamination occurs and MWCNTs are in the same physico-chemical state than the ones used in the present article, MWCNT transfer to the food chain via food crops would be very low.

Discovery of Chemoselective and Biocompatible Reactions Using a High‐Throughput Immunoassay Screening

The discovery of new chemical reactions is a long-standing goal of organic chemists. For decades, synthetic problems motivated the development of new methodologies to continuously expand the reaction toolkit in organic synthesis. As alternatives to purely rational approaches, strategies that offer more room for serendipity have recently emerged. In these approaches, the discovery is a result of the systematic exploration of a large number of chemical reactions through the use of robust high-throughput screening methods based either on mass spectrometry techniques or on DNA technologies. Although this strategy was already proven to be efficient with the discovery of several new interesting reactions, this does not guarantee the potential impact of the discovered reactions. A more powerful approach would be the increase of the level of selection in a manner that only powerful reliable reactions are discovered. Such a highly demanding selection should therefore be based not only on reaction efficiencies, but also on other parameters that would ensure the usefulness of the discovered reaction. In 2001, K. B. Sharpless introduced the concept of “click chemistry”, which has been widely and successfully applied since then, and listed a series of important criteria that may influence the extent and the impact of a chemical reaction. Among them, chemoselectivity, simplicity of reaction conditions, and high efficiency, even in complex media, are probably the most important ones. This can be highlighted by the startling number of applications in organic synthesis, materials science, and biotechnology of the copper-catalyzed alkyne–azide cycloaddition reaction (CuAAC), which is one of the most powerful click reactions described to date. Herein, we disclose an approach to accelerate the discovery of such important chemical reactions through the use of an immunoassay technique. As we previously described, sandwich immunoassays can be successfully applied to monitor cross-coupling reactions by connecting small-molecule tags to chemically reactive groups. Products of bondforming coupling reactions can then be specifically detected by two specific antitag monoclonal antibodies (mAbs) using standard ELISA techniques: one mAb captures the doubletagged coupling product on a solid phase and a second acts as a detector. We recently showed that the throughput of this adapted immunoassay (typically around 1000 analyses per day and person) allows the fast identification of new reactions among thousands of combinations of reactive functions and catalysts. One crucial advantage of this screening method relies on the high specificity of mAbs, permitting the precise and sensitive quantification of the double-tagged crosscoupling products in complex mixtures without work-up. Here, we decided to fully exploit this advantage by designing a series of successive screening in order to identify new, efficient, chemoselective, and biocompatible [3+2] cycloaddition reactions. Our approach (Figure 1) involves three main steps: 1) reactions of tagged dipoles, dipolarophiles, and transition metals, run in 96-well plates in a parallel manner, 2) immunoassays to identify active combinations, to optimize them, and to assess their kinetics, chemoselectivity, and biocompatibility, and 3) validation of hits by reproducing the reactions in flasks with nontagged functions. The core experiment was conducted with 11 tagged dipoles and 8 tagged dipolarophiles. All of these reactants were selected for their chemical stability and easy synthetic access, as simple reaction conditions that involve readily available reactants are a key requirement for powerful

Copper-chelating azides for efficient click conjugation reactions in complex media.

The concept of chelation-assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper-chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.

A Sensitive Zinc-Activated 129Xe MRI Probe†

The divalent zinc cation, Zn, is an indispensable and ubiquitous element of the body. As the second most abundant transition-metal ion in mammalian tissues, it is involved in many physiological and pathological processes. Zinc plays a vital role not only when bound to metalloproteins, but also in the form of mobile pools. A slight excess or lack of zinc ions can be connected to serious human afflictions, including heart disease, diabetes, cancer, and neurodegeneration such as Alzheimer s disease. Today, only two noninvasive techniques, optical imaging and magnetic resonance imaging (MRI), have the potential to offer real-time monitoring of the Zn distribution in different tissues of the body. However, optical methods suffer from limited penetration depth, which makes them unsuitable for global analysis of relatively large and opaque specimens, such as live animals. On the other hand, MRI is a particularly powerful modality used clinically for anatomic imaging and provides three-dimensional images with excellent resolution. However, conventional molecular MRI techniques that rely on the observation of water protons and require the introduction of contrast agents still suffer from reduced sensitivity and often lack selectivity. A few studies based on gadolinium complexes have been reported for Zn imaging. Nevertheless, to our knowledge, the detection threshold of free Zn ions is 30 mm, a value slightly above the total Zn concentration of 20 mm in blood. Therefore, the development of more sensitive methods is of crucial importance. Herein we propose the use of hyperpolarized Xe nuclear magnetic resonance (NMR) spectroscopy for the sensitive detection of Zn ions. To achieve this goal, the noble gas is encapsulated in dedicated host systems bearing a ligand that chelates the Zn ions. Cryptophanes, aromatic cage molecules made of cyclotriveratrylene groups, are perfectly suited to this purpose as 1) they can easily be rendered water-soluble, 2) the noble gas has a high affinity for their cavity, 3) when xenon is encapsulated, it takes a specific NMR frequency, and 4) xenon exchange in and out of the cavity insures a continuous refreshment of the Xe@cryptophane environment in hyperpolarization. Such a Xe biosensing approach has already been employed for detection of various biological systems, including enzymes and nucleic acids. Also, the first in-cell probing of biological events has been achieved: the endocytosis of transferrin could be detected by using Xe NMR spectroscopy. All these NMR spectroscopy studies based on the use of hyperpolarized xenon and molecular hosts are characterized by a high sensitivity. However, metal detection is a difficult challenge, which has never been achieved using such an approach. We aimed to design a responsive agent in which the chemical shift of encapsulated xenon would significantly vary when Zn ions are chelated to it. In this manner, a sensitive spectroscopic imaging based on this resonance-frequency variation can be envisioned. For this purpose, we designed sensor 1, which is made of three parts (Scheme 1): the cryptophane core hosting xenon, the spacer, and the chelating moiety. A short spacer was chosen to place the chelating moiety near the cryptophane cavity. As a zinc-chelating group we chose nitrilotriacetic acid (NTA), which is easily prepared from l-lysine. Sensor 1 was synthesized from cryptophane 2, which possesses six carboxylate groups ensuring solubility in water at physiological pH value. We were able to activate only one carboxylate group by esterification with N-hydroxysuccinimide. Then, the primary amino group of the enantiopure unit bearing the NTA moiety (l)-3 was directly coupled to this activated ester to form a chemically stable amide linkage. Thus, the use of host 2 in its racemic form (chirality is due to the helicity of the cryptophane) led to two diastereomers, which will be noted 1P and 1M (see the Supporting Information for the nomenclature). Compound 1 was obtained as a 50:50 diastereomeric mixture (1P + 1M), with a chemical purity higher than 95% after HPLC. For this sensor, the xenon binding constant is assumed to be in the same range as that of compound 2, that is, 6000m . As cryptophane 2 has already been shown to behave as a pH sensor, the present Xe NMR spectroscopy study was conducted in a phosphate buffer exempt of other ions, at pH 7.4. At this pH value, the affinity of the NTA group for Zn ions is well-documented (logK1> 10). [16] In the absence [*] N. Kotera, Dr. L. Delacour, Dr. T. Traor , D. A. Buisson, Dr. F. Taran, S. Coudert, Dr. B. Rousseau CEA Saclay, SCBM, iBiTec-S, Building 547, PC # 108 91191 Gif sur Yvette (France) E-mail: bernard.rousseau@cea.fr N. Tassali, E. L once, Dr. C. Boutin, Dr. P. Berthault CEA Saclay, IRAMIS, SIS2M, UMR CEA/CNRS 3299 Laboratoire Structure et Dynamique par R sonance Magn tique 91191 Gif sur Yvette (France) E-mail: patrick.berthault@cea.fr

Iridium-catalyzed cycloaddition of azides and 1-bromoalkynes at room temperature.

Iridium dimer complexes were found to catalyze the [3 + 2] cycloaddition reaction of azides with bromoalkynes, yielding 1,5-disubstituted 4-bromo-1,2,3-triazoles in reasonable to excellent yields under mild conditions. The reaction offers a direct route to new 1,4,5-trisubstituted triazoles.

Smart Detection of Toxic Metal Ions, Pb2+ and Cd2+, Using a 129Xe NMR-Based Sensor

An approach for sensitive magnetic resonance detection of metal cations is proposed. Combining the use of hyperpolarized (129)Xe NMR and of a cage-molecule functionalized by a ligand able to chelate different cations, we show that simultaneous detection of lead, zinc, and cadmium ions at nanomolar concentration is possible in short time, thanks to fast MRI sequences based on the HyperCEST scheme.

One-pot synthesis of 1,4-disubstituted pyrazoles from arylglycines via copper-catalyzed sydnone-alkyne cycloaddition reaction.

A robust method for constructing 1,4-pyrazoles from arylglycines was developed using the copper-catalyzed sydnone-alkyne cycloaddition reaction. The procedure offers a straightforward and general route to the pyrazole heterocycle through a three-step one-pot procedure.

Bisphosphonate sequestering agents. Synthesis and preliminary evaluation for in vitro and in vivo uranium(VI) chelation

A library of bisphosphonate-based ligands was prepared using solution-phase parallel synthesis and tested for its uranium-binding properties. With the help of a screening method, based on a chromophoric complex displacement procedure, 23 dipodal and tripodal chelates bearing bisphosphonate chelating functions were found to display very high affinity for the uranyl ion and were selected for evaluation of their in vivo uranyl-removal efficacy. Among them, 11 ligands induced a huge modification of the uranyl biodistribution by deviating the metal from kidney and bones to liver. Among the other ligands, the most potent was the dipodal bisphosphonate 3C which reduced the retention of uranyl and increased its excretion by around 10% of the injected metal.

A phosphine-mediated construction of 1,4-oxazepines and 1,3-oxazines.

A simple and efficient method for constructing 1,4-oxazepines and 1,3-oxazines was developed with use of a phosphine-mediated tandem reaction of ynones with 2-azido alcohols. The method offers a promising route to synthetically useful as well as biologically active heterocycles under mild conditions and may be exploited for the preparation of interesting chiral ligands.