The crystal structures of 3-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-6-O-triphenylmethyl-α-d-glucofuranose and its azide displacement product

The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated.

The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated. dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the molecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring molecules are linked by C-HÁ Á ÁO hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C-HÁ Á Á interactions, forming layers parallel to the ab plane. In the crystal of 4, molecules are also linked by C-HÁ Á ÁO hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C-HÁ Á Á interactions, forming a supramolecular framework.
In our development of novel iminosugars Soengas et al., 2012;Reed et al., 2013), we viewed the installation of a C-5 disposed double bond (through elimination) and the ability to stereoselectively substitute at C-5 (through substitution) as critical to analogue development. To effect these transformations in an orthogonal manner (Fig. 1), we probed the nature of the C-5 leaving group through the introduction of a mesylate (2) and a triflate moiety (3), which could then be either displaced or eliminated. We had previously noted that C-6 OH silylation (TES, TBDMS, TIPS) afforded a high degree of protecting-group lability; as such, this moiety was trityl protected. With analogues 2 and 3 in hand, treatment with sodium azide under S N 2 conditions afforded substituted azido product 4 in 88% yield. To confirm the stereochemistry of the starting triflate/mesylate (2 and 3) and azide 4, these analogues were carefully crystallized. Mesylate 3 was crystallized by diffusion from CH 2 Cl 2 /hexane to give colourless, block-like crystals while azide 4 was readily crystallized from an ethanol/toluene mixture affording large, colourless crystals. Reaction conditions to afford the regioselective elimination product/s with a C-4/C-5 and/or a C-5/C-6 disposed double bond are currently under investigation.

Structural commentary
The molecular structures of compounds 3 and 4 are illustrated in Figs. 2 and 3, respectively. Notable, and anticipated, is the inversion of configuration for the azido group on C5 in compound 4.

Figure 2
A view of the molecular structure of compound 3, with atom labelling and displacement ellipsoids drawn at the 30% probability level. For clarity, H atoms have been omitted.

Figure 3
A view of the molecular structure of compound 4, with atom labelling and displacement ellipsoids drawn at the 30% probability level. For clarity, H atoms have been omitted. bulky trityl moiety, which projects equatorially from C4. The 2,2-dimethyl-1,3-dioxolane ring (O2/O3/C1/C2/C7) also has a twisted conformation, on the O3-C7 bond, and its mean plane is inclined to the mean plane of the THF ring by 65.6 (7) .
The X-ray structure analysis of 4 shows that the THF ring has an envelope conformation with atom C4 as the flap. The pendant bonds adopt a conformation highly similar to that observed for 3 (Fig. 3). As in 3, the 2,2-dimethyl-1,3-dioxolane ring has a twisted conformation on the O3-C7 bond, and its mean plane is inclined to the mean plane of the THF ring by 66.21 (9) . The benzyl group is involved in a C-HÁ Á Á interaction with a phenyl ring of the triphenylmethyl moiety, C12-H12Á Á ÁCg5 (see Table 2 for details). The middle nitrogen atom of the azide, which is cationic, appears to be involved in a weak ion-dipole intramolecular interaction with the endocyclic THF oxygen atom [N2Á Á ÁO1 = 2.900 (2) Å ].

Supramolecular features
In the crystal of 3, molecules are linked by C-HÁ Á ÁO hydrogen bonds, forming chains propagating along the b-axis direction ( Table 1). The chains are linked by C-HÁ Á Á interactions, so forming layers lying parallel to the ab plane (Table 1 and Fig. 4).
In the crystal of 4, molecules are also linked by C-HÁ Á ÁO hydrogen bonds, forming 2 1 helices propagating along the aaxis direction ( Table 2). The helices are linked by a number of C-HÁ Á Á interactions, so forming a supramolecular framework (Table 2 and Fig. 5). In the crystal, there are voids with a potential solvent-accessible volume of ca 161 Å 3 (5% of the unit-cell volume). However, on examination of the final difference-Fourier map no evidence could be found of electron density being present in the channels.

Figure 4
A view along the a axis of the crystal packing of compound 3. The C-HÁ Á ÁO and C-HÁ Á Á interactions (see Table 1) are shown as dashed lines. For clarity, only the H atoms involved in these interactions have been included.

Synthesis and crystallization
The reagents and conditions used for the syntheses of compounds 3 and 4 are outlined in Fig. 1. Reactions were performed under an atmosphere of nitrogen gas and maintained using an inflated balloon. Further general experimental details are included in the archived CIF. Synthesis of compound 3: 3-O-benzyl-1,2-O-isopropylidene-6-O-triphenylmethyl--d-glucofuranose 1 (520 mg, 0.943 mmol) was dissolved in CH 2 Cl 2 (12 ml) with pyridine (260 mL, 3.262 mmol) and 4-dimethylaminopyridine (40 mg, 0.327 mmol). Methanesulfonyl chloride (180 mL, 2.325 mmol) was added and the reaction mixture heated to reflux for 25 h. Thin layer chromatographic (TLC) analysis (1:4 ethyl acetate/ hexane) revealed complete consumption of the starting material (R f = 0.46) and formation of the desired product (R f = 0.52). The reaction mixture was pre-absorbed on silica gel and compond 3 was isolated by flash chromatography to give an off-white foam (449 mg, 76%) and recrystallized from CH 2 Cl 2 / hexanes yielding colourless block-shaped crystals [m.p. 397-403 K (433-434 K;Saeki et al., 1968 Synthesis of compound 4: (1.00 g, 1.81 mmol) was dissolved in CH 2 Cl 2 (20 ml) and cooled to 243 K. Pyridine (291 mL, 3.62 mmol) was added and stirred for 10 min. Trifluoromethanesulfonic anhydride (607 mL, 3.62 mmol) was added dropwise with continued stirring. TLC analysis (1:4 ethyl acetate/hexanes) after 45 min showed complete consumption of the starting material (R f = 0.42) and formation of a new product (R f = 0.67). The reaction mixture was acidified with glacial acetic acid (5 ml) and washed with brine (3 Â 20 ml). The organic layer was concentrated in vacuo and dissolved in N,N-dimethylformamide (25 ml    solution was cooled to 243 K and sodium azide (345 mg, 5.31 mmol) was added. The reaction mixture was left to warm up to room temperature while stirring for 12 h. Analysis by TLC (1:4 ethyl acetate/hexane) showed complete consumption of the triflate intermediate (R f = 0.67) and formation of product (R f = 0.38). Lithium chloride solution (30 ml, 5% w/v) was added followed by extraction with CH 2 Cl 2 (3 Â 30 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The product, compound 4, was recrystallized from chloroform and ethanol yielding colourless prismatic crystals (

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. For both compounds, the H atoms were included in calculated positions and treated as riding: C-H = 0.95-1.00 Å with U iso (H) = 1.5U eq (C-methyl) and 1.2U eq (C) for other H atoms. The methanesulfonyl group suffers from thermal disorder but attempts to split all S, O and C atoms did not significantly improve the refined structure.

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.