Crystal structure of 6-azido-6-deoxy-1,2-O-isopropylidene-α-d-glucofuranose

Short syntheses to high Fsp 3 index natural-product analogues such as iminosugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. In this case only an isopropylidene group was employed towards the synthesis of seven-membered ring iminosugars.


Chemical context
The installation of various functionalities via N-and/or O-alkylation has been shown to impart improved biological profiles and potencies to iminosugars (Š está k et al., 2018;Prichard et al., 2018;Simone et al., 2012;Sayce et al., 2016, Woodhouse et al., 2008Johnson & Houston, 2002). Diminishing the number of synthetic steps to the iminosugar building blocks that are precursors to their alkylated congeners is advantageous. Many iminosugar syntheses start from monosaccharide starting materials (Wood et al., 2018;Lee et al., 2012;Rasmussen & Jensen, 2011). Reducing the number of protecting groups and removing the need for purification by chromatography are useful strategies to a more expedited synthesis of analogues (Katritzky et al., 1991;Liu et al., 2014).
In the present study, the only protecting group that was used to synthesize seven-membered ring iminosugars was an isopropylidene group (acetonide) to make intermediate 1 from d-glucose. Selective tosylation of the primary hydroxyl group, followed by nucleophilic displacement with sodium azide afforded the title compound 3, C 9 H 15 N 3 O 5 (Tsuchiya et al., 1981;Fleet et al., 1989), see Scheme 1.
Primary alcohols can be tosylated regioselectively over secondary alcohols (Johnson et al., 1963). There are examples of monotosylation of monosaccharides and analogues using di-n-butyltin oxide and dimethylaminopyridine as catalyst (Tsuda et al., 1991) and of cyclodextrins (Yamamura & Fujita, 1991;Ashton et al., 1991;Fujita et al., 1992). Any mechanistic ambiguities that may have arisen from the S N 2 reaction with azide ions was clarified by X-ray crystallographic analysis, which confirmed the structure of the title compound as described below.

Structural commentary
In compound 3 (Fig. 1), the tetrahydrofuran (THF) ring is best described as twisted with atoms C3 and C4 displaced by 0.169 (3) and À0.384 (2) Å , respectively, from the plane through C5/C6/O1. The fused dioxolane ring adopts an envelope conformation with O3 displaced by 0.402 (2) Å from the mean plane of the other ring atoms (C5/C6/O4/C7; r.m.s. deviation = 0.005 Å ). The dihedral angle between the fivemembered rings (all atoms) is 67.50 (13) . The hydroxyl group O2-H2A and the acetonide oxygen atom O3 project axially from the THF ring, lying respectively above and below in a trans arrangement from one another [O2-C4-C5-O3 = 164.46 (18) ]. The other two groups projecting from the THF ring are O4 of the acetonide and the side chain attached to C3, which sit equatorially. The absolute structure of 3 was not definitively established in the refinement but the configurations of the stereogenic atoms (C2 R, C3 R, C4 S, C5 R and C6 R) were set to match those of the starting material.

Figure 2
Partial packing diagram for 3 showing hydrogen bonds as dashed lines.

Figure 1
The molecular structure of 3 showing 50% displacement ellipsoids.
a copper-catalysed azide-alkyne cycloaddition of the tribenzyl ether analogue of 3 followed by deprotection with NH 3 /NaOH (Pradere et al., 2008). Conversion of the azide to a triazole removes the hydrogen-bonding capability of the proximal N atom and the packing in this structure is distinctly different with a hydrogen-bonded network being present. Other points of difference in structure 4 relative to 3 include the free hydroxyl group on the THF ring, which adopts an axial conformation, and the dioxolane ring methyl groups tilted closer to the THF ring.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All H atoms were positioned geometrically (O-H = 0.84, C-H = 0.98-1.00 Å ) and refined as riding with U iso (H) = 1.2U eq (O,C) or 1.5U eq (C-methyl).

Funding information
The B18