Crystal packing in three related disaccharides: precursors to heparan sulfate oligosaccharides

The structures of three disaccharide molecules, precursors to novel therapeutics, as determined from weakly diffracting crystals are presented. The crystal packing depends mainly on weak C—H⋯O hydrogen-bond interactions, augmented by C—H⋯π contacts in the best-defined structure.

The three title compounds form part of a set of important precursor dissacharides which lead to novel therapeutics, in particular for Alzheimer's disease. All three crystallize as poorly diffracting crystals with one independent molecule in the asymmetric unit. Two of them are isostructural:

Chemical context
Heparan sulfate (HS) is a linear polysaccharide with a disaccharide repeating unit of d-glucosamine and l-iduronic or d-glucuronic acid, which can be O-or N-sulfated or N-acetylated. HS is involved in the regulation of many important biological processes (Bishop et al., 2007;Turnbull et al., 2001). Synthetic HS-oligosaccharides with high potency as -secretase (BACE1) inhibitors might have an application as novel therapeutics for Alzheimer's disease Scholefield et al., 2003).
In our recent paper (Schwö rer et al., 2013), we described the synthesis and inhibition data of a library of such oligosaccharides. At the centre of the synthetic methodology are highly orthogonally protected disaccharide building blocks, three of them being the subjects of this paper. The disaccharides can be converted into glycosyl donors by hydrolysis of the methoxyphenyl glycoside and formation of the corresponding trichloroacemidate; while the azide and the orthogonal ester protecting groups provide selective access to further functionalization later in the synthesis.

Database survey
There are only a few reported 2-azido pyranose-based disaccharide structures in the Cambridge Structural Database (Version 5.36, with February 2015 update;Groom & Allen, 2014): our published glucopyranoside (Gainsford et al., 2013;BILJAJ), a mannopyranoside (Luger & Paulsen, 1981; BABHUH) and one idopyranose (Lee et al., 2004;AQOGIW). We note another disaccharide glucopyranose (Abboud et al., 1997;RAVNAD) for comparison. The conformational data given in Tables 1 and 2 show the pyranose essential chair conformations have not been disturbed significantly, although the ring with the bound azide seems to be closer to a 'pure' chair conformation by the criteria (Cremer & Pople, 1975).

Synthesis and crystallization
The title compounds were prepared as described in Schwö rer et al. (2013). Crystals were obtained by vapour diffusion of petroleum ether into a solution of the title compounds in ethyl acetate (I) or toluene (II) and (III).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 6. Subject to variations noted below, the methyl H atoms were constrained to an ideal geometry (C-H = 0.98 Å ) with U iso (H) = 1.5U eq (C), but were allowed to rotate freely about the adjacent C-C bonds. All other H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with C-H distances of 0.95 (aromatic), 0.99 (methylene) or 1.00 (tertiary) Å with U iso (H) = 1.2U eq (C) or 1.5U eq (C) (for methyl C) of their parent atom. Specific variations were: (I) Data at resolution less than 1.12 Å was not significantly above the noise level and was excluded from the refinement. One other reflection (1,0,9) was OMITted as an outlier. Data analysis shows that there are many data in the resolution range 1.40-1.12 Å that are in poor agreement reflecting crystal quality.
There was conformational disorder in the chloroacetoxy (atoms C28, C29, O9 and Cl1) and the methoxycarbonyloxy (atoms C37, C37 and O12) groups which was modelled as two (A and B) groups. Because of proximity, and poor data quality, these atoms were unable to be refined with anisotropic  Table 3 Hydrogen-bond geometry (Å , ) for OZTF.