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

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.

Partial Text

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: