A Chiron approach towards the stereoselective synthesis of polyfluorinated carbohydrates

The replacement of hydroxyl groups by fluorine atoms on hexopyranose scaffolds may allow access to the discovery of new chemical entities possessing unique physical, chemical and ultimately even biological properties. The prospect of significant effects generated by such multiple and controlled substitutions encouraged us to develop diverse synthetic routes towards the stereoselective synthesis of polyfluorinated hexopyranoses, six of which are unprecedented. Hence, we report the synthesis of heavily fluorinated galactose, glucose, mannose, talose, allose, fucose, and galacturonic acid methyl ester using a Chiron approach from inexpensive levoglucosan. Structural analysis of single-crystal X-ray diffractions and NMR studies confirm the conservation of favored 4C1 conformation for fluorinated carbohydrate analogs, while a slightly distorted conformation due to repulsive 1,3-diaxial F···F interaction is observed for the trifluorinated talose derivative. Finally, the relative stereochemistry of multi-vicinal fluorine atoms has a strong effect on the lipophilicities (logP).


General Methods
All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Methylene chloride (CH2Cl2) was distilled from CaH2 and tetrahydrofuran (THF) was distilled from Na/benzophenone immediately before use. Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous materials, unless otherwise stated.
Reagents were purchased at the highest commercial quality available and used without further purification, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and charring with a solution of 3 g of PhOH and 5 mL of H2SO4 in 100 mL of EtOH, followed by heating with a heatgun. SiliaFlash® P60 40-63 µm (230-400 mesh) was used for flash column chromatography. NMR spectra were recorded with an Agilent DD2 500 MHz spectrometer and calibrated using residual undeuterated solvent (CDCl3: 1 H δ = 7.26 ppm, 13 C δ = 77.16 ppm) as an internal reference. Calibration of 19 F NMR was performed using hexafluorobenzene, which have been measured at -162.29 ppm compared to the chemical shift of reference compound CFCl3. Coupling constants (J) are reported in Hertz (Hz), and the following abbreviations were used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet, br = broad. Assignments of NMR signals were made by homonuclear (COSY) and heteronuclear (HSQC, HMBC, HOESY, 19 F c2HSQC) two-dimensional correlation spectroscopy. Infrared spectra were recorded using a Thermo Scientific Nicolet 380 FT-IR spectrometer. The absorptions are given in wavenumbers (cm −1 ). High-resolution mass spectra (HRMS) were measured with an Agilent 6210 LC Time of Flight mass spectrometer in electrospray mode. Either 7 equiv.). The mixture was heated under reflux (~200 °C) for 2.5 h. After cooling to room temperature, the reaction was quenched with an aqueous 5% K2CO3 solution (200 mL) and stirred for 5 min. The mixture was then extracted with CHCl3 (5 × 300 mL), and the combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (silica gel, acetone/CHCl3, 1:19 → 1:9) to give 14 as a pale yellow amorphous solid (4.13 g, 16.24 mmol, 73% yield). Rf = 0.47 (silica, acetone/CHCl3, 1:19); The spectroscopic data derived from compound 15 match those reported in the literature.
The mixture was cooled down to room temperature and quenched with water (30 mL). The mixture was extracted with CH2Cl2 (3 × 20 mL) and the combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL). The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel, Et2O/CH2Cl2, 1:19) to give 15 as a pale yellow oil (1.51 g, 5.76 mmol, 87% yield). The spectroscopic data derived from compound 15 match those reported in the literature.
The mixture was extracted with EtOAc (3 × 20 mL), and the combined organic phases were successively washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (silica gel, EtOAc/ hexanes, 2:3) to give 16 as a white amorphous solid (658 mg, 3.96 mmol, 66% yield).
The mixture was stirred at 0 °C for 15 min and then quenched with water (5 mL). The mixture was extracted with CH2Cl2 (3 × 5 mL), and the combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (10 mL), aqueous 1M HCl solution (10 mL), and brine (10 mL). The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude triflate 23 was used for the next step without further purification and was dissolved in a dry 1M TBAF solution in THF (0.5 mL, 0.5 mmol, 18 equiv.). The mixture was stirred at room temperature for 1 h and then quenched with water (5 mL). The mixture was extracted with CH2Cl2 (3 × 5 mL), and the combined organic phases were successively washed with a saturated aqueous NaHCO3 solution (10 mL), and brine (10 mL). The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure.
The resulting crude was purified by flash column chromatography (silica gel, toluene/CH2Cl2
After cooling to room temperature, the reaction was quenched with water (60 mL) and brine (1 mL). The mixture was extracted with EtOAc (4 × 30 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated under a gentle stream of air (avoiding reduced pressure is important because of volatility issues). The resulting crude was purified through a short silica gel pad (Et2O/CH2Cl2, 9:1) to give 31 as a white amorphous solid (180 mg, 1.08 mmol, 95%). Rf = 0.31 (silica, EtOAc/hexanes, 2:3);
The mixture was irradiated in a microwave reactor at 100 °C for 1 h. After this time, the mixture was cooled to 0 °C and Ac2O (1.12 mL, 11.85 mmol, 30 equiv.) and H2SO4 (211 µL, 3.955 mmol, 10 equiv.) were added. The mixture was stirred at room temperature for 16 h. After cooling to 0 °C, NaOAc (649 mg, 7.91 mmol, 20 equiv.) was added and the mixture was stirred for an additional 20 min. Water (10 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were

Supplementary Discussion
Density functional theory (DFT) calculations were performed with the CAM-B3LYP functional using Grimme's D3 correction and the 6-31+G(d,p) basis set. Gaussian 09 rev E.01 was used was used for all calculations. To study possible solvent effects, we employed the polarizable continuum model (PCM) specifically for acetone. While all calculations in the main body employed PCM, those that do so in the supporting information will be clearly labelled.
A scan of the H5-C5-C6-F6 dihedral was performed for molecule 27. Three stable structures were found, the least stable of which is that observed in the crystal structure (GG conformer The implicit solvation model predicts that the GT conformer is the most stable, though the TG conformer is very close in terms of free energy. This difference is small enough that both conformers might be observed at room temperature. The dipole moments of the molecules in PCM are larger, though the trend does not change. To understand the arrangement in the solid state we studied monomers and small clusters of repeat units of the three staggered conformers (Supplementary Figure 1) and data are summarized in Supplementary Table 10. In the calculations that follow, the molecules are in the geometry of the crystal structure with the fluoromethyl group rotated to adopt the three conformers.
The TG conformer and small clusters of the TG conformer are the most stable, but the gap shrinks by more than a kcal/mol already in the structure with 3 repeated units. The GG conformer benefits most with repeating units. This becomes clearer if we look at a stabilization energy, which we define as the benefit of each structure from being in the cluster. Numerically, it is the difference between the energy of the cluster minus the energy of the isolated individual units. The stabilization energy of the Dimer of the GG conformer (entry 4) is substantially larger than that of the dimer of the GT conformer (entry 5) and the dimer of the GG conformer (6). Similarly, the stabilization energy of the trimer of the GG conformer (entry 7) is also much larger than the other 2 trimers (entry 8 and 9). Further, the stabilization of trimer of the GG conformer (entry 7) is more than twice that the dimer of the same conformer (entry 4), while the others are about twice.
The orientation of the fluorine atom at C6 has a large effect on the molecular dipole. We performed analysis of the three staggered conformers of molecule 27, along with small clusters of the GG conformer (Supplementary Table 11).
In the crystal structure, a number of hydrogen fluorine distances are potential hydrogen bonds. We