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The acid-catalysed formation of glycosidic bonds is more difficult when glycosyl donors are fluorinated, especially at the 2-position. Here we report high-yielding glycosidation and glycosylation reactions of 2,3-difluorinated- and 2,3,4-trifluorinated gluco- and galactopyranoside donors with a variety of acceptors under conventional trichloroacetimidate/TMSOTf activation in moderate to high anomeric selectivities. This methodology allows access to highly fluorinated glycans, illustrated with the synthesis of a pentafluorinated disaccharide.

Fluorinated carbohydrates have found many applications in the glycosciences. Typically, these contain fluorination at a single position. There are not many applications involving polyfluorinated carbohydrates, here defined as monosaccharides in which more than one carbon has at least one fluorine substituent directly attached to it, with the notable exception of their use as mechanism-based inhibitors. The increasing attention to carbohydrate physical properties, especially around lipophilicity, has resulted in a surge of interest for this class of compounds. This review covers the considerable body of work towards the synthesis of polyfluorinated hexoses, pentoses, ketosugars, and aminosugars including sialic acids and nucleosides. An overview of the current state of the art of their glycosidation is also provided.

The highly strained cubane system is of great interest as a scaffold and rigid linker in both pharmaceutical and materials chemistry. A straightforward approach is reported for the scale–up of a [2+2] photocycloaddition step using convenient home–made flow photoreactors to access dimethyl 1,4–cubanedicarboxylate on decagram–scale in 33 – 40% over 8 steps. The process is demonstrated on 3.4 g.h-1 input with 30 minutes residence time, enabling to reduce the process time and to avoid the use of batch photoreactors. Completion of the characterisation of the photocycloadduct and its hydrates is reported.

This review provides an extensive summary of the effects of carbohydrate fluorination with regard to changes in physical, chemical and biological properties with respect to regular saccharides. The specific structural, conformational, stability, reactivity and interaction features of fluorinated sugars are described, as well as their applications as probes and in chemical biology.

The first synthesis of 3-deoxy-3-fluoro-l-fucose is presented, which employs a d- to l-sugar translation strategy, and involves an enzymatic oxidation of 3-deoxy-3-fluoro-l-fucitol. Enzymatic activation (FKP) and glycosylation using an -1,2 and an -1,3 fucosyltransferase to obtain two fluorinated trisaccharides demonstrates its potential as a novel versatile chemical probe in glycobiology.

This is the first paper in a sequential pair devoted to the enzyme mutarotase (aldose 1-epimerase; EC 5.1.3.3). Here, the broader context of the physiological role of mutarotase, among those enzymes considered to be part of 'metabolic structure', is reviewed. We also summarise the current knowledge about the molecular mechanism and substrate specificity of the enzyme, which is considered in the context of the binding of fluorinated glucose analogues to the enzyme's active site. This was done as a prelude to our experimental studies of the anomerisation of fluorinated sugars by mutarotase that are described in the following paper.

International audience; 20 iNKT cells recognize CD1d/-galactosylceramide (-GalCer) complexes via their invariant 21 TCR receptor and stimulate the immune response. Many -GalCer analogues have been 22 investigated to interrogate this interaction. Following our previous work related to the 23 modification of the hydrogen bond network between -GalCer and CD1d, we have now 24 focused our attention on the synthesis of 3-deoxy-3,3-difluoro-and 3,4-dideoxy-3,3,4,4-25 tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In 26 2 each case, deoxygenation at the indicated positions was accompanied by difluoro introduction 1 in order to evaluate the resulting electronic effect on the stability of the ternary 2 CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy-3 difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish 4 their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. 5 The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen 6 bond properties. 7 8

Carbohydrates typically have low affinities to protein binding sites, and the development of carbohydrate mimetics with improved binding is therefore of interest. Tetrafluorination of monosaccharides is one of the strategies currently under investigation for that purpose. The synthesis of the required tetrafluorinated monosaccharides is achieved by a fluorinated building block approach. The enantioselective synthesis of tetrafluorinated hexose derivatives is described here, both in the pyranose and furanose form. In particular, the optimization of the enantioselective synthesis of the previously reported 2,3-dideoxy-2,2,3,3-tetrafluoro-D-threo-hexopyranose 3, 2,3-dideoxy-2,2,3,3-tetrafluoro-D-threo-hexofuranose 4, and 2,3-dideoxy-2,2,3,3-tetrafluoro-D-erythro-hexopyranose 5 is described, as well as the synthesis of two novel sugar derivatives, 3,4-dideoxy-3,3,4,4-tetrafluoro-D-threo-hexopyranose 6 and 3,4-dideoxy-3,3,4,4-tetrafluoro-D-erythro-hexopyranose 7. The key step of all syntheses is a perfluoroalkyl lithium mediated C–C bond formation, either intramolecular or intermolecular, and proceeds in good to excellent yields. NMR and X-ray crystallographic analysis of the tetrafluorinated methyl pyranoside derivatives confirms their 4C1 conformation.

International audience; Carbohydrates typically have low affinities to protein binding sites, and the development of carbohydrate mimetics with improved binding is therefore of interest. Tetrafluorination of monosaccharides is one of the strategies currently under investigation for that purpose. The synthesis of the required tetrafluorinated monosaccharides is achieved by a fluorinated building block approach. The enantioselective synthesis of tetrafluorinated hexose derivatives is described here, in both pyranose and furanose forms. In particular, the optimization of the enantioselective synthesis of the previously reported 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexopyranose 3, 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexofuranose 4, and 2,3-dideoxy-2,2,3,3-tetrafluoro-d-erythro-hexopyranose 5 is described as is the synthesis of two novel sugar derivatives, 3,4-dideoxy-3,3,4,4-tetrafluoro-d-threo-hexopyranose 6 and 3,4-dideoxy-3,3,4,4-tetrafluoro-d-erythro-hexopyranose 7. The key step of all syntheses is a perfluoroalkyl lithium-mediated C–C bond formation, either intramolecular or intermolecular, which proceeds in good to excellent yields. NMR and X-ray crystallographic analyses of the tetrafluorinated methyl pyranoside derivatives confirm their 4C1 conformation.

International audience

International audience; Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH center dot center dot center dot F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time-and in contrast to earlier reports-the occurrence of OH center dot center dot center dot F IMHBs in acyclic saturated g-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding (h1)J(OH center dot center dot center dot F) values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9 Hz). The magnitude of OH center dot center dot center dot F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the ``rule of shielding'' applies to OH center dot center dot center dot F IMHB energies. Surprisingly, the predicted OH center dot center dot center dot F IMHB energies are only moderately weaker than these of the corresponding OH center dot center dot center dot OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.

A total synthesis of paroxetine is reported, with a diastereoselective and diastereoconvergent cobalt-catalysed sp3–sp2 coupling reaction involving a 3-substituted 4-bromo-N-Boc-piperidine (Boc = tert-butoxycarbonyl) substrate as a key step. A 9:1 diastereoselectivity was obtained, while a control experiment involving a conformationally locked 3-substituted 4-bromo-tert-butyl cyclohexane ring proceeded with essentially complete stereoselectivity

International audience

248th National Meeting of the American-Chemical-Society (ACS), San Francisco, CA, AUG 10-14, 2014; International audience

248th National Meeting of the American-Chemical-Society (ACS), San Francisco, CA, AUG 10-14, 2014; International audience

12 p.-7 fig.-1 chart.-1 graph. abst.-1 schem., The dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is an important receptor of the immune system. Besides its role as pathogen recognition receptor (PRR), it also interacts with endogenous glycoproteins through the specific recognition of self-glycan epitopes, like LeX. However, this lectin represents a paradigmatic case of glycan binding promiscuity, and it also has been shown to recognize antigens with α1−α2 linked fucose, such as the histo blood group antigens, with similar affinities to LeX. Herein, we have studied the interaction in solution between DC-SIGN and the blood group A and B antigens, to get insights into the atomic details of such interaction. With a combination of different NMR experiments, we demonstrate that the Fuc coordinates the primary Ca2+ ion with a single binding mode through 3-OH and 4-OH. The terminal αGal/αGalNAc affords marginal direct polar contacts with the protein, but provides a hydrophobic hook in which V351 of the lectin perfectly fits. Moreover, we have found that αGal, but not αGalNAc, is a weak binder itself for DC-SIGN, which could endow an additional binding mode for the blood group B antigen, but not for blood group A., We thank Agencia Estatal de Investigacion of Spain and the European Research Council for financial support. B.L., J.-B.V., and J.M. thank the Industrial Biotechnology Catalyst (Innovate UK, BBSRC, EPSRC, BB/M028941/1) and the EPSRC (core capability EP/K039466/1) for funding.