The synthesis of 2,3-dideoxy-2,3-difluoro-D-glucose and 2,3-dideoxy-3-fluoro-D-glucose is reported in respectively 5 and 6 steps from D-glucal, using a fluorination strategy.

There is an increasing interest in investigating how polyfluorination of carbohydrates modifies their physical and biological properties. An example that has caught much attention is 2,3,4-trideoxy-2,3,4-trifluoroglucose. Four syntheses of this compound have been reported, which are either low yielding or long (13 or more steps). We report a 6-step synthesis of 2,3,4-trideoxy-2,3,4-trifluoroglucose starting from levoglucosan. The solution-phase structure of an intermediate, 1,6-anhydro-2,4-dideoxy-2,4-difluoroallose, features a rare example of a bifurcated F···H­(O)···F hydrogen bond and is compared to its crystal structure.

Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH···O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine.

25Five 19 F-substituted glucose analogues were used to probe the activity and mechanism of the 26 enzyme mutarotase by using magnetisation-exchange NMR spectroscopy. The sugars fluoro-2-deoxy-D-glucose, FDG2; 3-fluoro-3-deoxy-D-glucose, FDG3; 4-fluoro-4-deoxy-D-28 glucose, FDG4; 2,3-difluoro-2,3-dideoxy-D-glucose, FDG23; and 2,2,3,3-tetrafluoro-2,3-29 dideoxy-D-glucose (2,3-dideoxy-2,2,3,3-tetrafluoro-D-erythro-hexopyranose), FDG2233] 30 showed separate 19 F NMR spectral resonances from their respective αand β-anomers, thus 31 allowing two-dimensional exchange spectroscopy measurements of the anomeric 32 interconversion at equilibrium, on the time scale of a few seconds. Mutarotase catalysed the 33 rapid exchange between the anomers of FDG4, but not the other four sugars. This finding, 34 combined with previous work identifying the mechanism of the anomerisation by mutarotase, 35 suggests that the rotation around the C1-C2 bond of the pyranose ring is the rate-limiting 36 reaction step. In addition to D-glucose itself, it was shown that all other fluorinated sugars 37 inhibited the FDG4 anomerisation, with the tetrafluorinated FDG2233 being the best inhibitor. 38 Inhibition of mutarotase by F-sugars paves the way for development of novel fluorinated 39 compounds that are able to affect the activity of this enzyme in vitro and in vivo.40 41Mutarotase (aldose 1-epimerase; EC. 5.1.3.3) is the enzyme that catalyses the interconversion 42 between two anomeric forms of several monosaccharides, reactions that usually occurs on a 43 time scale of several minutes/hours in the absence of the enzyme (see the previous paper in this 44 Special Edition). The human mutarotase was initially purified from erythrocytes (red blood 45 cells; RBCs) in the 1960s [1][2] where, paradoxically, its activity is relatively low. [3] In fact, the 46 highest activities of the enzyme in mammalian tissues have been reported in the kidney [4] and 47 the corresponding gene was identified and cloned in 2003. [5] 48 Mutarotase is known to play an important role in the Leloir pathway of catabolism of D-49 galactose, by enhancing the rate of interconversion between the two sugar anomers. This is 50 critical for some organisms because only α-D-galactose is processed by the next enzyme in the 51 pathway, galactokinase (EC 2.7.1.6). [6][7] Thus, despite spontaneous mutarotation, the enzyme 52 is required for efficient catabolism of lactose by E. coli; and strains with a 'restrictive' mutation 53 in their mutarotase gene grow more slowly in cultured minimal media. [8] Hence, it is of clinical 54 interest to develop novel inhibitors of mutarotase, as they might have use as antimicrobial 55 agents, and to probe various aspects of the "metabolic subculture" of sugars. (See the previous 56 paper in this Special Edition for a general discussion of this topic.) 57Kinetic assays 58 The classical way of conducting kinetic assays of mutarotase is to start the reaction with one 59 of the anomeric forms of a monosaccharide and monitor the reaction by ...

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.