Fluorine | EPFL Graph Search

Fluorine is a chemical element with the symbol F and atomic number 9. It is the lightest halogen and exists at standard conditions as a highly toxic, pale yellow diatomic gas. As the most electronegative reactive element, it is extremely reactive, as it reacts with all other elements except for the light inert gases. Among the elements, fluorine ranks 24th in universal abundance and 13th in terrestrial abundance. Fluorite, the primary mineral source of fluorine which gave the element its name, was first described in 1529; as it was added to metal ores to lower their melting points for smelting, the Latin verb fluo meaning 'flow' gave the mineral its name. Proposed as an element in 1810, fluorine proved difficult and dangerous to separate from its compounds, and several early experimenters died or sustained injuries from their attempts. Only in 1886 did French chemist Henri Moissan isolate elemental fluorine using low-temperature electrolysis, a process still employed for modern produc

Synthesis of C-linked Disaccharides and Analogues as Biomimetics of the TF Epitope

Maria Kolympadi

Glycoproteins and glycolipids are major components of the outer surface of mammalian cells. Their carbohydrate moieties, which are directed into the outer environment, serve as ligands for receptor proteins, such as lectins, pathogen proteins and antibodies. Recognition processes between the receptor proteins and the carbohydrates have a significant impact on different aspects of cell biology as they turn structure into biological response in a selective way. Cellular carbohydrate structures are found to change dramatically during embryonic development or under pathological conditions including malignant transformation. One example is the Thomsen-Friedenreich (TF) epitope, a disaccharide consisting of galactose-β-(1→3)-N-acetyl-galactosamine α-linked to a serine or threonine of a carrier protein. The TF epitope is considered as a cancer-specific carbohydrate antigen that is found on various epithelial carcinomas of human adults and can be recognized by the anti-TF antibody. It has been demonstrated that synthetic glycoconjugates of the TF epitope can act as anti-cancer vaccines by stimulating the immune system against tumor growth and proliferation. Native carbohydrates are liable to chemical and enzymatic hydrolysis of their glycosidic bonds and therefore short-lived in the blood. Their stable C-analogues in which the glycosidic oxygens have been replaced by methylene or substituted methylene units are particularly interesting as therapeutic agents. We report herein our efforts to synthesize non-hydrolysable methylene and fluorinated methylene linked disaccharides analogues of the TF epitope. Our synthesis follows a methodology previously developed in our laboratory for the preparation of C(1→3)-disaccharides. The key step is an Oshima-Nozaki coupling between a β-C-galactosyl carbaldehyde and an enone, isolevoglucosenone. The hydroxyl methylene linker that is created by this coupling can be deoxygenated or can be substituted by one fluorine atom (or two fluorine atoms via the corresponding ketone). 1,4-Addition of an amine to the enone derived from the Oshima-Nozaki coupling, ketone reduction and some protecting group manipulations gave an hydroxyl methylene linked disaccharide that could smoothly undergo Barton-McCombie deoxygenation. On the contrary, the attempts of nucleophilic fluorination of this substrate failed to give the desired outcome probably due to an intramolecular rearrangement. With the deoxygenated product in hand and after some protecting group transformations, we attempted C-allylation of the anomeric centre and at the same time cleavage of the 1,6-anhydro bridge. Some preliminary results are presented. An allyl-C-disaccharide can lead to a C-glycosyl amino acid according to the literature and therefore it can be used for preparing a C,C-analogue of the TF epitope. In our search for biomimetics of the TF epitope with less synthetic requirements, we attempted to replace the second saccharidic unit by a phenyl ring. Simple phenyl CH2- and CF2-galactosides were prepared starting from α- and β-C-galactosyl carbaldehydes. NMR studies in combination with theoretical calculations revealed that the conformational behaviour of these galactosides in solution depends on the substitution at pseudoanomeric center. Similarities and differences to their O-analogues are discussed. Additionally, NMR spectroscopy was used to detect binding to a lectin protein. The β-galactosyl carbaldehyde –common starting material for the synthesis of C-linked disaccharides and phenyl C-galactosides mentioned above – was also used to prepare a small library of CH2-galactosyl aryl ethers bearing different aromatic amides. The affinities of these derivatives towards some galactoside-specific lectins, the galectins, were measured. None of the synthesized C-galactosyl analogues appeared to be high-affinity ligand of galectins. However, such studies are useful for the future design of sugar analogues with the minimum of functionalities that assure strong binding to carbohydrate recognition proteins.

EPFL2011

Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes

Mingming Wang

Nitrogen-containing compounds are an important class of molecules in medicinal chemistry, chemical biology, biochemistry, material sciences or environmental sciences. Organic nitrogen occurs in many forms, ranging from small building blocks such as urea, amino acids, nucleotides, to complex natural products, drug molecules, proteins, nucleic acids, among others. The transformation of easily-accessed nitrogen-containing building blocks into more complex nitrogen-containing structures is therefore important for the synthesis of bioactive compounds or functional materials. Interested in donor-acceptor aminocyclopropanes and aminocyclobutanes, we first developed a Lewis-acid catalyzed formal [4+1] cycloaddition of donor-acceptor aminocyclobutanes with isocyanides, which resulted in the formation of cyclopentene-1,2-diamines. We then attempted to develop a formal [3+2] cycloaddition of donor-acceptor aminocyclopropanes with electron-deficient alkenes, which was mechanistically inspired by the Morita-Baylis-Hillman reaction. Apart from the donor-acceptor system, we were also attracted by simple aminocyclopropanes without electron-withdrawing group at vicinal position. We anticipated that the incorporation of cyclopropylamine into carboxylic-containing compounds followed by ring opening functionalization reactions could be used for the synthesis of more complex products. Therefore, we first disclosed an oxidative ring-opening strategy to transform acyl, sulfonyl or carbamate protected aminocyclopropanes into 1,3-dielectrophilic carbon intermediates bearing a halide atom (Br, I) and a N,O-acetal. Replacing the alkoxy group of the N,O-acetal was achieved under acidic conditions via an elimination-addition pathway, while substitution of the halides by nucleophiles was done under basic conditions via a SN2 pathway, generating a wide range of 1,3-difunctionalized propylamines. Based on the transformation described above, we further discovered an efficient synthesis of 4-amino thiochromans starting from simple aminocyclopropanes and thiophenols through a formal [3+3] annulation reaction. Next, we developed an oxidative ring-opening strategy to transform cyclopropylamides and cyclobutylamides into fluorinated imines. The imines can be isolated in their more stable hemiaminal form, with the fluorine atom installed selectively at the terminal position. Both cheap benzophenone with UV A light or organic and inorganic dyes with blue light could be used as photoredox catalysts to promote this process. Various fluorinated amines were then obtained by nucleophilic attack on the hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry. Finally, we turned our attention to the synthesis of diamines, which are essential building blocks for the synthesis of agrochemicals, drugs and organic materials, yet their synthesis remains challenging, as both nitrogen moieties need to be differentiated and diverse substitution patterns (1,2-, 1,3 or 1,4) are required. We described a new strategy giving access to 1,2-, 1,3- and 1,4- amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes and cyclobutanes.Other unsuccessful efforts over the last four years have also been described, together with some preliminary results of ring-opening cyanation and arylation reactions.

EPFL2022

Phase-contrast and fluorescence X-ray imaging of soft and bio matter

Vincent Gajdosik

The high brightness and coherence of X-ray synchrotron sources and steady development in X-ray optics are critical ingredients in novel imaging techniques for a variety of domains. We employed several different approaches and a wide energy spectrum of radiation to demonstrate the applicability of synchrotron X-ray imaging in soft granular matter and life science. We applied refraction-enhanced contrast tomography to the Distinct Element Method (DEM) to predict instant granular jamming in an hourglass. The validation of numerical simulations as a DEM is mostly confined to global properties. We present a stringent microscopic test in the case of instant flow jamming in hourglasses: synchrotron X-ray microtomography coupled to advanced image analysis. The results show that DEM is amazingly successful in predicting the actual microscopic position of individual particles from given initial conditions through to the end of the instant jamming process. We further report refraction-enhanced radiology employed in the study of Drosophila Melanogaster wing development. The objective of the study was to reveal the morphological difference between two different phenotypes of fruit flies. Refraction-enhanced radiology is highly sensitive to morphological information, whereas fluorescent X-ray microanalysis techniques can reveal the distribution of heavy elements containing molecules. Here we report the design of a fast fluorescence detection system coupled to an existing radiology setup at the B01A beamline, NSRRC, Taiwan and the successful test on cartilage samples. Since its invention in 1930, Zernike phase contrast has been a pillar in visible microscopy – and more recently in X-ray microscopy – of low-absorption-contrast objects such as biological specimens. We experimentally demonstrated hard-X-ray Zernike microscopy with lateral resolution beyond 30 nm, opening up many new research opportunities in biomedicine and materials science. In the soft X-ray regime we show that synchrotron X-ray fluorescence microscopy can map molecules with fluorine-containing labels and quantitatively measure the fluorine concentration with micrometer spatial resolution. This is an important result for life science since fluorine is a very widely used molecule label for a variety of investigations such as metabolic processes or therapeutic agents. Our results specifically concern Fluorodeoxyglucose and are therefore directly relevant to the crucial neurobiology issue of glucose metabolism.

EPFL2009