Date Published: June 01, 2015
Publisher: International Union of Crystallography
Author(s): Graeme J. Gainsford, Ralf Schwörer, Peter C. Tyler, Olga V. Zubkova.
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.
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 β-secretase (BACE1) inhibitors might have an application as novel therapeutics for Alzheimer’s disease (Schwörer et al., 2013 ▸; Scholefield et al., 2003 ▸).
4-Methoxyphenyl 4-O-[6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-4-O-(9-fluorenylmethyloxycarbonyl)-α-D-glucopyranosyl]-2-O-benzoyl-3-O-benzyl-6-O-chloroacetyl-α-l-idopyranoside, (I) (hereafter OZTF)
The crystal packing in (I) is provided by weak C—H⋯O(ether), C—H⋯O (carbonyl) hydrogen bonds and one C—H⋯π interaction (Table 3 ▸). These interactions form a three-dimensional network in which the base motifs are C(8), C(12) and C(20) (Bernstein et al., 1995 ▸; Fig. 5 ▸). Given the unusual pseudo-dimeric nature of the hydrogen bonding in the glucopyranoside crystal (Gainsford et al., 2013 ▸) and the chloroacetoxy group disorder, it is not surprising that there is only one common C—H⋯O(carbonyl) interaction involving the C1—H1 atoms. In the isostructural compound (II), the same interactions are observed plus one additional methylene-H⋯O(ether) (C29—H29⋯O12A) interaction (Table 4 ▸); this is only possible in (II) with the difference in composition of the two molecules (the chloroacetyl being replaced by the methoxyacetyl group).
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 θ criteria (Cremer & Pople, 1975 ▸).
The title compounds were prepared as described in Schwörer 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).
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 Uiso(H) = 1.5Ueq(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 Uiso(H) = 1.2Ueq(C) or 1.5Ueq(C) (for methyl C) of their parent atom. Specific variations were: