4-De­oxy-4-fluoro-β-D-gluco­pyranose

4-De­oxy-4-fluoro-β-D-glucopyran­ose, C₆H₁₁FO₅, (I), crystallizes from water at room temperature in a slightly distorted ⁴C₁ chair con­formation. The observed chair distortion differs from that observed in β-D-glucopyran­ose [Kouwijzer, van Eijck, Kooijman & Kroon (1995). Acta Cryst. B51, 209–220], (II), with the former skewed toward a B^C3,O5 (boat) conformer and the latter toward an ^O5TB_C2 (twist–boat) conformer, based on Cremer–Pople analysis. The exocyclic hy­droxy­methyl group conformations in (I) and (II) are similar; in both cases, the O—C—C—O torsion angle is ∼−60° (gg con­former). Inter­molecular hydrogen bonding in the crystal structures of (I) and (II) is conserved in that identical patterns of donors and acceptors are observed for the exocyclic substituents and the ring O atom of each monosaccharide. Inspection of the crystal packing structures of (I) and (II) reveals an essentially identical packing configuration.

S1. Comment

Fluorosugars find diverse applications in saccharide chemistry and biochemistry (Taylor, 1988), ranging from their use as activated donors in chemical glycosylations (e.g. glycosyl fluorides) (Yokoyama, 2000) to their use as molecular probes of enzyme reaction mechanisms (e.g. a covalent mechanism for lysozyme) (White et al., 1996). In this laboratory, specific fluorosugars have been prepared recently to investigate the mechanisms of protein-bound saccharide rearrangements that accompany non-enzyme-catalysed protein glycation. One of these fluorosugars, 4-deoxy-4-fluoro-β-D-ribo-hexopyranose (4-deoxy-4-fluoro-β-D-glucose), (I), crystallizes from water in the β-pyranose form (Fig. 1), which is the predominant tautomer of (I) observed in aqueous solution (~64%) based on NMR studies (Zhang & Serianni, unpublished results).

An inspection of the Cremer–Pople puckering parameters (Cremer & Pople, 1975) for (I) and for the related aldohexopyranose, β-D-glucopyranose, (II) (Kouwijzer et al., 1995) (Table 1), shows that both structures are slightly distorted ⁴C₁ chair forms (q₃ >> q₂). The degree of distortion varies slightly with structure, with θ_II > θ_I. The direction of distortion, embodied in the ϕ value, is different for (I) and (II), with a boat-like (B^C3,O5) distortion observed in (I) and a twist–boat (^O5TB_C2) distortion observed in (II) (Fig. 2), based on idealized ϕ values of 0° for (I) and 330° for (II). Comparison with the crystal structure of 3-deoxy-β-D-ribo-hexopyranose (3-deoxy-β-D-glucopyranose; θ = 4.9° and ϕ = 58.6°; Zhang et al., 2007) shows that C4 fluorination (θ = 7.3°) distorts the β-D-glucopyranose ring (θ = 7.9°) slightly less than does C3 deoxygenation.

The structural parameters for (I) and (II) are compared in Table 2. The endocyclic C—C bond lengths vary by ~0.01 Å between the two structures, with C1—C2, C2—C3 and C4—C5 elongated and C3—C4 shortened in the fluorosugar. The exocyclic C5—C6 bond is essentially unchanged in the two structures. The endocyclic C1—O5 bond is ~0.01 Å longer in (I), whereas the C5—O5 bond is ~0.01 Å shorter. It is noteworthy that the largest difference in exocyclic C—O bond lengths occurs for C1—O1, which is nearly 0.03 Å shorter in the fluorosugar, (I). This latter effect is notable, considering that the site of F substitution is maximally displaced from the C1—O1 bond in terms of numbers of intervening covalent bonds. As expected, the exocyclic C4—F bond in (I) is about 0.02 Å shorter than the corresponding C4—O4 bond in (II).

Of the three endocyclic C—C—C bond angles, the C3—C4—C5 bond angle shows the greatest change, increasing by 2.5° in the fluorosugar. In contrast, the exocyclic C4—C5—C6 bond angle is 1.9° smaller in the fluorosugar. The C4—C5—O5 and C5—O5—C1 bond angles are essentially the same in (I) and (II).

Endocyclic torsion angles (absolute values) range from 50 to 66° in both (I) and (II), indicative of non-ideal chair conformations. Exocyclic hydroxymethyl conformations in (I) and (II) are gg (H5 anti to O6), with virtually identical O5—C5—C6—O6 torsion angles (-59.5 and -60.4°).

All of the hydroxyl H atoms in (I) serve as intermolecular hydrogen-bond donors, and atoms O2, O3, O5 and O6 serve as mono-acceptors in intermolecular hydrogen bonds. Atoms O1 and F do not act as hydrogen-bond acceptors within the hydrogen-bonding scheme. In comparison, all of the hydroxyls in (II) serve as hydrogen-bond donors (the O4—H4···O2' distance and angle are 3.144 Å and 138.4°, respectively) and atoms O1 and O4 do not act as hydrogen-bond acceptors. Remarkably, the overall packing motifs of (I) and (II) are essentially identical (Fig. 3) and the primary differences are minor changes in the cell parameters, notably a slight contraction of the b axis [9.2055 (3) cf 9.014 (2) Å] and an expansion of the c axis [12.6007 (3) cf 12.720 (2) Å].

Hydroxyl atom O1 was found to be disordered over two sites. The component occupancies were refined and summed to unity, yielding an approximately 0.95:0.05 ratio [0.94 (1):0.06 (1) in CIF tables - please clarify]. The NMR spectra indicate that (I) is pure. However, saccharides are known to undergo spontaneous anomerization in aqueous solution and it is plausible that this occurred during crystallization, resulting in the minor component observed.

S2. Experimental

Synthesis details for the preparation of 4-deoxy-4-fluoro-D-[2-¹³C]glucopyranose are given in the Supplementary material. After isolation and purification, this ¹³C isotopomer of (I) was dissolved in a minimal volume of distilled water and the solution was left at room temperature. Crystals of the β-pyranose, (I), formed slowly and were harvested for structure determination.

S3. Refinement

The hydroxyl atom O1 was found to be partially disordered with a very minor α-anomer component. The model was refined with the site occupancies of O1 and O1A summed to unity, yielding a ratio of 0.94 (1):0.06 (1). Due to the weak electron density at the minor component site, the C—O bond distances were restrained to be the same within experimental error. The minor-component bond distances and angles are reported in the tables.

H atoms were positioned geometrically and treated as riding, with C—H = 0.99-1.00 Å and O—H = 0.84 Å, and with U_iso(H) = 1.2U_eq(C,O).

Computing details

Data collection: APEX2 (Bruker Nonius, 2008); cell refinement: SAINT (Bruker Nonius, 2008); data reduction: SAINT (Bruker Nonius, 2008); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP (Sheldrick, 2008), POV-RAY (Cason, 2003) and DIAMOND (Brandenburg, 2009); software used to prepare material for publication: XCIF (Sheldrick, 2008), enCIFer (Allen et al., 2004) and publCIF (Westrip, 2010).

Figures

	Fig. 1. The structure of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. The minor component of the disorder has been removed for clarity.
	Fig. 2. Ring distortions observed in compounds (I) and (II), based on Cremer–Pople parameters. B denotes the boat form and TB denotes the twist–boat form. The definition of ϕ is given in Cremer & Pople (1975).
	Fig. 3. Packing diagrams of (I) and (II), viewed along the a axis. Dashed lines indicate hydrogen bonds [Please check added text].

4-Deoxy-4-fluoro-β-D-ribo-hexopyranose

Crystal data

C6H11FO5	F(000) = 384
Mr = 182.15	Dx = 1.597 Mg m^−3
Orthorhombic, P212121	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2ab	Cell parameters from 4938 reflections
a = 6.5323 (2) Å	θ = 6.0–68.6°
b = 9.2055 (3) Å	µ = 1.35 mm^−1
c = 12.6007 (3) Å	T = 100 K
V = 757.72 (4) Å^3	Block, colourless
Z = 4	0.34 × 0.15 × 0.10 mm

Data collection

Bruker APEX diffractometer	1387 independent reflections
Radiation source: fine-focus sealed tube	1370 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.022
Detector resolution: 8.33 pixels mm^-1	θmax = 69.5°, θmin = 6.0°
ω and ϕ scans	h = −7→7
Absorption correction: numerical (SADABS; Sheldrick, 2008)	k = −11→11
Tmin = 0.725, Tmax = 0.928	l = −14→15
7231 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.025	H-atom parameters constrained
wR(F^2) = 0.067	w = 1/[σ^2(Fo^2) + (0.0378P)^2 + 0.227P] where P = (Fo^2 + 2Fc^2)/3
S = 1.08	(Δ/σ)max < 0.001
1387 reflections	Δρmax = 0.28 e Å^−3
114 parameters	Δρmin = −0.18 e Å^−3
1 restraint	Absolute structure: Flack (1983), with how many Friedel pairs?
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.10 (17)

Special details

Experimental. Methyl α-D-[2-¹³C]galactopyranoside (2.80 g, 14.36 mmol) was dissolved in dry pyridine (40 ml) and benzoyl chloride (5.33 ml, 45.88 mmol) was added dropwise with stirring at 273 K. The reaction mixture was stirred at room temperature for 2 d and then water (50 ml) was added to the reaction mixture. The aqueous mixture was extracted with ethyl acetate (50 ml × 2), and the ethyl acetate layer was washed with water and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the residue was purified by silica-gel column chromatography (hexane–ethyl acetate, 4:1 v/v) to afford methyl 2,3,6-tri-O-benzoyl-α-D-[2-¹³C]galactopyranoside (4.07 g, 56%) (Reist et al., 1965).

Methyl 2,3,6-tri-O-benzoyl-α-D-[2-¹³C]galactopyranoside (2.61 g, 5.15 mmol) and 4-(dimethylamino)pyridine (1.26 g, 10.30 mmol) were dissolved in anhydrous CH₂Cl₂ (40 ml), and DAST (diethylaminosulfur trifluoride) (1.36 ml, 10.30 mmol) was slowly added over a period of 10 min to the stirred reaction mixture cooled in dry-ice bath. The mixture was slowly warmed to room temperature and stirred for 24 h. Methanol (5 ml) was then added to the reaction mixture at 273 K to decompose excess reagents. After evaporation of the solvent in vacuo, the residue was purified by silica-gel column chromatography (hexane–ethyl acetate, 4:1 v/v) to afford methyl 2,3,6-tri-O-benzoyl-4-deoxy-4-fluoro-α-D-[2-¹³C]glucopyranoside (1.78 g, 68%) (Withers et al., 1986; Card, 1983).

Methyl 2,3,6-tri-O-benzoyl-4-deoxy-4-fluoro-α-D-[2-¹³C]glucopyranoside (1.50 g, 2.95 mmol) was dissolved in methanol (20 ml), and the solution was saturated with NH₃ and stirred overnight (Ning et al., 2003). The reaction mixture was then concentrated to dryness at 303 K in vacuo and the pure product was obtained by recrystallization from ethyl acetate–methanol (1:1, v/v). The mother liquor was concentrated in vacuo and applied to a silica-gel column (ethyl acetate–methanol, 10:1 v/v) to afford additional pure product. In total, a yield of 0.52 g of methyl 4-deoxy-4-fluoro-α-D-[2-¹³C]glucopyranoside was obtained (89%).

Methyl 4-deoxy-4-fluoro-α-D-[2-¹³C]glucopyranoside (0.40 g, 2.03 mmol) was dissolved in water (40 ml), Dowex 50 × 8 (200–400 mesh, H⁺) ion-exchange resin (2 g) was added and the suspension was refluxed with stirring for 3 d. After cooling, the resin was removed by filtration and the solution was concentrated at 303 K in vacuo. Crystallization from methanol gave pure 4-deoxy-4-fluoro-D-[2-¹³C]glucopyranose (0.33 g, 89%).

4-Deoxy-4-fluoro-D-[2-¹³C]glucopyranose was dissolved in a minimal volume of distilled water and the solution was left at room temperature. Crystals of the β-pyranose, (I), formed slowly and were harvested for structure determination.

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

The hydroxyl O1 was found to be partially disordered with a very minor α-anomer component. The model was refined with site occupancies of O1 and O1A summed to unity yielding an approximately 0.95:0.05 ratio. Due to the weak electron density at the minor component site, the C–O bond distances were restrained to be the same (SADI) within experimental error. The minor component bond distances and angles are reported in the tables.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
F1	0.56428 (14)	0.16570 (10)	0.48204 (6)	0.0236 (2)
O1	−0.08223 (17)	−0.07264 (11)	0.27767 (8)	0.0178 (3)	0.941 (4)
H1	−0.1731	−0.0200	0.2503	0.021*	0.941 (4)
C1	0.0426 (2)	0.01068 (15)	0.34008 (11)	0.0156 (3)	0.941 (4)
H1A	−0.0342	0.0955	0.3697	0.019*	0.941 (4)
O1A	−0.087 (3)	0.112 (2)	0.3624 (16)	0.031 (6)*	0.059 (4)
H1'	−0.1217	0.1549	0.3064	0.037*	0.059 (4)
C1A	0.0426 (2)	0.01068 (15)	0.34008 (11)	0.0156 (3)	0.059 (4)
H1''	−0.0349	−0.0585	0.2939	0.019*	0.059 (4)
O2	−0.03205 (15)	−0.12883 (11)	0.49724 (8)	0.0184 (2)
H2	−0.0732	−0.2113	0.4782	0.022*
O3	0.38767 (16)	−0.09828 (10)	0.56534 (7)	0.0177 (2)
H3	0.3526	−0.0798	0.6280	0.021*
O5	0.21163 (15)	0.05906 (11)	0.27557 (7)	0.0150 (2)
O6	0.61590 (16)	0.09796 (11)	0.20418 (8)	0.0199 (2)
H6	0.5935	0.0973	0.1385	0.024*
C2	0.1289 (2)	−0.08277 (15)	0.42899 (11)	0.0148 (3)
H2A	0.1955	−0.1704	0.3973	0.018*
C3	0.2874 (2)	−0.00016 (14)	0.49472 (11)	0.0144 (3)
H3A	0.2174	0.0775	0.5367	0.017*
C4	0.4459 (2)	0.06832 (15)	0.42247 (10)	0.0155 (3)
H4A	0.5362	−0.0092	0.3925	0.019*
C5	0.3468 (2)	0.15405 (15)	0.33150 (11)	0.0151 (3)
H5A	0.2664	0.2368	0.3616	0.018*
C6	0.5011 (3)	0.21230 (16)	0.25249 (13)	0.0181 (3)
H6A	0.4285	0.2679	0.1968	0.022*
H6B	0.5960	0.2794	0.2892	0.022*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.0285 (5)	0.0250 (4)	0.0172 (4)	−0.0121 (4)	−0.0055 (4)	−0.0007 (3)
O1	0.0161 (5)	0.0205 (6)	0.0169 (6)	−0.0015 (4)	−0.0044 (4)	0.0017 (4)
C1	0.0132 (7)	0.0175 (7)	0.0160 (7)	−0.0007 (6)	0.0017 (5)	0.0014 (6)
C1A	0.0132 (7)	0.0175 (7)	0.0160 (7)	−0.0007 (6)	0.0017 (5)	0.0014 (6)
O2	0.0218 (5)	0.0196 (5)	0.0139 (5)	−0.0052 (4)	0.0051 (4)	−0.0007 (4)
O3	0.0242 (5)	0.0206 (5)	0.0082 (4)	0.0046 (4)	−0.0004 (4)	0.0013 (4)
O5	0.0149 (5)	0.0194 (5)	0.0105 (5)	−0.0022 (4)	0.0000 (4)	0.0020 (4)
O6	0.0174 (5)	0.0296 (5)	0.0126 (5)	0.0033 (4)	0.0001 (4)	0.0035 (4)
C2	0.0165 (7)	0.0153 (6)	0.0125 (6)	0.0011 (6)	0.0033 (5)	0.0005 (5)
C3	0.0183 (7)	0.0139 (6)	0.0110 (6)	0.0027 (5)	−0.0003 (6)	0.0002 (5)
C4	0.0176 (7)	0.0169 (6)	0.0121 (6)	−0.0012 (6)	−0.0032 (5)	−0.0010 (5)
C5	0.0171 (7)	0.0146 (6)	0.0136 (6)	−0.0013 (6)	−0.0011 (5)	−0.0006 (6)
C6	0.0203 (7)	0.0184 (7)	0.0156 (6)	−0.0034 (6)	0.0002 (6)	0.0016 (5)

Geometric parameters (Å, º)

F1—C4	1.4019 (16)	O6—H6	0.8400
O1—C1	1.3682 (17)	C2—C3	1.5286 (19)
O1—H1	0.8400	C2—H2A	1.0000
C1—O5	1.4415 (16)	C3—C4	1.5158 (19)
C1—C2	1.5208 (18)	C3—H3A	1.0000
C1—H1A	1.0000	C4—C5	1.5348 (18)
O1A—H1'	0.8400	C4—H4A	1.0000
O2—C2	1.4228 (16)	C5—C6	1.515 (2)
O2—H2	0.8400	C5—H5A	1.0000
O3—C3	1.4272 (16)	C6—H6A	0.9900
O3—H3	0.8400	C6—H6B	0.9900
O5—C5	1.4285 (17)	C1A—O1A	1.291 (15)
O6—C6	1.4286 (19)
C1—O1—H1	109.5	C2—C3—H3A	109.4
O1—C1—O5	107.80 (11)	F1—C4—C3	108.74 (10)
O1—C1—C2	109.10 (11)	F1—C4—C5	107.68 (11)
O5—C1—C2	107.84 (11)	C3—C4—C5	111.98 (12)
O1—C1—H1A	110.7	F1—C4—H4A	109.5
O5—C1—H1A	110.7	C3—C4—H4A	109.5
C2—C1—H1A	110.7	C5—C4—H4A	109.5
C2—O2—H2	109.5	O5—C5—C6	107.68 (11)
C3—O3—H3	109.5	O5—C5—C4	108.32 (11)
C5—O5—C1	112.60 (10)	C6—C5—C4	113.09 (12)
C6—O6—H6	109.5	O5—C5—H5A	109.2
O2—C2—C1	109.88 (11)	C6—C5—H5A	109.2
O2—C2—C3	108.74 (11)	C4—C5—H5A	109.2
C1—C2—C3	111.63 (11)	O6—C6—C5	111.62 (12)
O2—C2—H2A	108.8	O6—C6—H6A	109.3
C1—C2—H2A	108.8	C5—C6—H6A	109.3
C3—C2—H2A	108.8	O6—C6—H6B	109.3
O3—C3—C4	108.92 (11)	C5—C6—H6B	109.3
O3—C3—C2	109.51 (11)	H6A—C6—H6B	108.0
C4—C3—C2	110.13 (11)	O5—C1A—O1A	113.6 (9)
O3—C3—H3A	109.4	C2—C1A—O1A	119.4 (9)
C4—C3—H3A	109.4
O1—C1—O5—C5	176.79 (11)	C2—C3—C4—F1	168.55 (11)
C2—C1—O5—C5	−65.54 (13)	O3—C3—C4—C5	169.78 (11)
O1—C1—C2—O2	−65.30 (13)	C2—C3—C4—C5	49.68 (14)
O5—C1—C2—O2	177.88 (10)	C1—O5—C5—C6	−172.90 (11)
O1—C1—C2—C3	173.97 (11)	C1—O5—C5—C4	64.47 (14)
O5—C1—C2—C3	57.15 (14)	F1—C4—C5—O5	−175.04 (10)
O2—C2—C3—O3	68.05 (14)	C3—C4—C5—O5	−55.55 (14)
C1—C2—C3—O3	−170.56 (10)	F1—C4—C5—C6	65.69 (15)
O2—C2—C3—C4	−172.20 (10)	C3—C4—C5—C6	−174.82 (12)
C1—C2—C3—C4	−50.81 (14)	O5—C5—C6—O6	−59.56 (15)
O3—C3—C4—F1	−71.34 (13)	C4—C5—C6—O6	60.08 (16)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O6^i	0.84	1.85	2.6855 (14)	174
O2—H2···O3^ii	0.84	1.85	2.6847 (14)	169
O3—H3···O5^iii	0.84	1.92	2.7511 (13)	173
O6—H6···O2^iv	0.84	1.85	2.6796 (14)	170

Symmetry codes: (i) x−1, y, z; (ii) x−1/2, −y−1/2, −z+1; (iii) −x+1/2, −y, z+1/2; (iv) −x+1/2, −y, z−1/2.