Crystal structures of three bicyclic carbohydrate derivatives

The structures of three bicyclic carbohydrates derivatives containing cyclobutanone or cyclolactame beside the pyranose ring are reported and the conformation and configuration established.


Chemical context
Bicyclic carbohydrate derivatives have become attractive as inhibitors of glycoside hydrolases (Lahiri et al., 2013). In particular, the enzyme O-GlcNAcase (OGA) is a promising target for such small-molecule inhibitors, since the level of O-GlcNAc in our body influences diseases such as Alzheimer's (Yuzwa et al., 2012) or cancer (Ma & Vosseller, 2013). However, the synthesis of bicyclic carbohydrate derivatives is usually a multi-step procedure. During our studies on the syntheses of carbohydrate analogs (Yin & Linker, 2012), we developed an easy entry to such compounds by radical additions to commercially available glycals (Linker et al., 1997).
synthesis is S configured. The six-membered and the fivemembered rings are fused in the cis configuration. The C3a-C3 bond is axial and the C7a-N1 bond is bisectionally positioned with respect to the pyranose ring. The pyranose ring exhibits a strongly distorted chair conformation, with puckering parameters q = 0.555 (3) Å , = 20.4 (3) and ' = 267.9 (9) . The usual d-gluco configuration in the chair form 4 C 1 is found, in contrast to (I). The pyrrolidonyl ring is in an envelope conformation, closed puckering on C3a with a maximum deviation for that atom of 0.466 (5) Å from the plane formed by N1, C2, C3 and C7a. An intramolecular hydrogen bond is observed between C7 and O7 (Fig. 3, Table 3). In (I) and (II), the correct absolute configuration was assigned in agreement with the known chirality of the glycal precursors. Compound (III) was synthesized from (I) and thus its absolute configuration is known as well.

Supramolecular features
The crystal packing of (I) features weak non-classical C-HÁ Á ÁO hydrogen bonds, which are illustrated in Fig. 4 and listed in Table 1. The A molecules are hydrogen-bonded via C4A-H4AÁ Á ÁO3A i interactions screwing around the b-axis direction (Fig. 4). Between two infinite chains of A molecules (above and below in in Fig. 4) , the B molecules are located, again forming a screw via three hydrogen bonds (C2B-H21BÁ Á ÁO3B ii , C4B-H4BÁ Á ÁO3B ii and C12B-H125Á Á ÁO1B iii ). The A and B molecules are linked by two further hydrogen bonds (C10B-H104Á Á ÁO8A ii and C10B-H106Á Á ÁO7A ii ).
The crystal packing of (II) is similar to that of (I). Chains consisting only of A molecules are in an alternating arrangement with those consisting only of B molecules, both screwing along the b-axis direction (Fig. 5). In contrast to (I), more intermolecular hydrogen bonds can be observed. Strong hydrogen bonds occur between the OH groups and the oxygen atoms of the pyranose rings within each chain. Weak C-HÁ Á ÁO and C-HÁ Á ÁN hydrogen bonds act as linkers between the chains of molecules. The chains are further connected via a large number of hydrogen bonds. Hydrogen bond geometries are summarized in Table 2.

Figure 4
Part of the crystal of (I), with intermolecular hydrogen bonds shown as blue dashed lines. The view is along the a axis.

Figure 5
Part of the crystal of (II), with intermolecular hydrogen bonds shown as blue dashed lines. The minor disorder component has been omitted for clarity. The view is along the a axis.

Synthesis and crystallization
Cyclobutanone (I) was synthesized from tri-O-acetyl-d-glucal, commercially available or obtained by the procedure of Ferrier (1965). Trichloroacetyl chloride (2.18 g, 10 mmol) in diethyl ether (12 mL) was added to a mixture of zinc-copper couple (3.87 g, 30 mmol) and tri-O-acetyl-d-glucal (1.36 g, 5 mmol) in dry diethyl ether (30 mL) at room temperature over 30 min under an N 2 atmosphere. After completion of the reaction (TLC control), zinc dust (3.27 g, 50 mmol) was added at 273 K. Acetic acid (13 mL) was added within 10 min and the reaction mixture was stirred for 60 min. The reaction mixture was diluted with diethyl ether (60 mL) and the insoluble materials were filtered off through Celite, which was washed with diethyl ether (5 Â 50 mL) and methanol (50 mL). The filtrate was extracted with (3 Â 100 mL) water. The organic layer was dried over MgSO 4 and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane/ethyl acetate 5:1) to afford pure cyclobutanone (I) (1.41 g, 90%). Single crystals suitable for X-ray diffraction were prepared by slow evaporation of a solution of (I) in ethanol at room temperature. Oxime (II) was synthesized from di-O-acetyl-d-arabinal, obtained by the procedure of Ferrier (1965). Starting from di-O-acetyl-d-arabinal (1.0 g, 5.0 mmol) the corresponding cyclobutanone was synthesized as described above and isolated by column chromatography (hexane/ethyl acetate 5:1) in 83% yield. 242 mg (1.0 mmol) of this cyclobutanone was dissolved in ethanol (2 mL) and then added to a solution of sodium acetate (246 mg, 3.0 mmol) and hydroxylamine hydrochloride (208 mg, 3.0 mmol) in water (2 mL). The reaction mixture was stirred at 327 K for 2 h and then for 1 h at room temperature. The reaction mixture was washed with water (30 mL) and extracted with CH 2 Cl 2 (3 Â 50 mL). The organic layers were combined, dried over MgSO 4 , filtered and concentrated in vacuo. The oxime (II) was directly recrystallized from ethanol solution, whereupon single crystals suitable for X-ray diffraction were obtained.
Lactam (III) was synthesized from cyclobutanone (I) (314 mg, 1 mmol). This cyclobutanone was dissolved in ethanol (2 mL) and then added to a solution of sodium acetate (246 mg, 3.0 mmol) and hydroxylamine hydrochloride (208 mg, 3.0 mmol) in water (2 mL). The reaction mixture was stirred at 327 K for 2 h and then for 1 h at room temperature. The reaction mixture was washed with water (30 mL) and extracted with CH 2 Cl 2 (3 Â 50 mL). The organic layers were combined, dried over MgSO 4 , filtered and concentrated in vacuo. Thionyl chloride (217.5 mL, 3.0 mmol) was added to a solution of the crude oxime in 1,4-dioxane (4 mL), and stirred for 10 min at room temperature. The reaction was quenched with saturated aqueous NaHCO 3 (50 mL), and extracted with EtOAc (3 Â 100 mL). The organic extracts were washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate 1:4) to afford the lactam in analytically pure form (244 mg, 74%). Single crystals suitable for X-ray diffraction were prepared by slow evaporation of a solution of (III) in ethanol at room temperature.

Refinement
In compound (II), disorder was observed for molecule A, caused by flipping of the N-OH group. That disorder also causes disorder of the nearby ring atoms. Therefore the ring  Part of the crystal of (III), with intermolecular hydrogen bonds shown as blue dashed lines. The view is along the b axis.
atoms of both the five-and six-membered rings were included in the disorder (but the OAc groups were left out). The geometry of the minor component was restrained to be similar to that of the major one with SAME, SADI and SIMU 0.01 restraints. The refinement of the occupation factors revealed an occupation ratio of 0.802 (7)/0.198 (7) for the two disordered components (see Fig. 2). H atoms in the structures of (I), (III) and the ordered and major components of (II) were located from difference Fourier maps and refined as riding with U iso (H) = 1.2U eq (C) with the exception of methyl hydrogen atoms, which were placed in their expected positions with HFIX 137 and refined with U iso (H) = 1.5U eq (C). For the minor disordered component in compound (II), all H atoms were placed in their expected positions with C-H distances of 0.99 and 0.98 for CH and CH 2 groups (HFIX 13 and 23) and 0.83 Å for OH groups (HFIX 147), and with U iso (H) = 1.2U eq (C) and 1.5U eq (O). Crystal data, data collection and structure refinement details are summarized in Table 4   DIAMOND (Brandenburg, 2016); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015) and publCIF (Westrip, 2010).

Data collection
Stoe IPDS 2 diffractometer Radiation source: sealed X-ray tube Detector resolution: 6.67 pixels mm -1 rotation method scans Absorption correction: integration (X-RED; Stoe & Cie, 2011) T min = 0.800, T max = 0.890 10373 measured reflections 5034 independent reflections 4398 reflections with I > 2σ(I) Extinction correction: SHELXL2014 (Sheldrick, 2015), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0067 (15) Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 ) (14) 0.0311 (5) (18)   where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.28 e Å −3 Δρ min = −0.20 e Å −3 Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

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