2-Acetamido-N-benzyl-1,4-imino-1,2,4-tride­oxy-l-xylitol (N-benzyl-l-XYLNAc)

Sarah F Jenkinson; Elizabeth V Crabtree; Andreas F G Glawar; Terry D Butters; George W J Fleet; David J Watkin

doi:10.1107/S1600536810014145

. 2010 Apr 24;66(Pt 5):o1147–o1148. doi: 10.1107/S1600536810014145

2-Acetamido-N-benzyl-1,4-imino-1,2,4-trideoxy-l-xylitol (N-benzyl-l-XYLNAc)

Sarah F Jenkinson ^a,^*, Elizabeth V Crabtree ^a, Andreas F G Glawar ^a, Terry D Butters ^b, George W J Fleet ^a, David J Watkin ^c

PMCID: PMC2979175 PMID: 21579195

Abstract

X-ray crystallography defines the relative configuration at the three-stereogenic centres in the title compound N-benzyl-l-XYLNAc, C₁₄H₂₀N₂O₃. The five-membered pyrrolidine ring adopts an envelope conformation with the N atom lying out of the plane of the other four atoms. In the crystal structure, intermolecular O—H⋯O, N—H⋯O and O—H⋯N hydrogen bonds link the molecules into chains along [100]. The carbonyl group O atom acts as an acceptor for a bifurcated hydrogen bond. The absolute configuration is determined by the use of l-glucuronolactone as the starting material for the synthesis.

Related literature

For iminosugars see: Asano et al. (2000 ▶); Watson et al. (2001 ▶). For the inhibition of hexosaminidases, see: Liu, Numa et al. (2004 ▶); Reese et al. (2007 ▶); Liu, Iqbal et al. (2004 ▶); Woynarowska et al. (1992 ▶). For piperidine hexosaminidase inhibitors, see: Tatsuta et al. (1997 ▶); Fleet et al. (1986 ▶, 1987 ▶); Steiner et al. (2009 ▶); Ho et al. (2010 ▶); For furanose hexosaminidase inhibitors, see: Usuki et al. (2009 ▶); Rountree et al. (2007 ▶, 2009 ▶); Boomkamp et al. (2010 ▶). For strategies for cancer treatment, see: Kato et al. (2010 ▶); Greco et al. (2009 ▶). For the use of glucuronolactone as a starting material for the synthesis of iminosugars, see: Best, Wang et al. (2010 ▶); Best, Chairatana et al. (2010 ▶).

Experimental

Crystal data

C₁₄H₂₀N₂O₃
M _r = 264.32
Orthorhombic,
a = 4.9731 (1) Å
b = 10.0145 (3) Å
c = 26.9297 (7) Å
V = 1341.18 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 150 K
0.50 × 0.15 × 0.05 mm

Data collection

Nonius KappaCCD area-detector diffractometer
Absorption correction: multi-scan (DENZO/SCALEPACK; Otwinowski & Minor, 1997 ▶) T _min = 0.77, T _max = 1.00
7494 measured reflections
1788 independent reflections
1471 reflections with I > 2σ(I)
R _int = 0.040

Refinement

R[F ² > 2σ(F ²)] = 0.051
wR(F ²) = 0.130
S = 0.95
1788 reflections
172 parameters
H-atom parameters constrained
Δρ_max = 0.33 e Å⁻³
Δρ_min = −0.46 e Å⁻³

Data collection: COLLECT (Nonius, 2001 ▶); cell refinement: DENZO/SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO/SCALEPACK and Görbitz (1999 ▶); program(s) used to solve structure: SIR92 (Altomare et al., 1994 ▶); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003 ▶); molecular graphics: CAMERON (Watkin et al., 1996 ▶); software used to prepare material for publication: CRYSTALS.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810014145/lh5029sup1.cif

e-66-o1147-sup1.cif^{(16.5KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810014145/lh5029Isup2.hkl

e-66-o1147-Isup2.hkl^{(89.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O15—H151⋯O19ⁱ	0.85	1.94	2.790 (4)	173
N16—H161⋯O19ⁱⁱ	0.89	2.19	3.041 (4)	159
O1—H11⋯N4ⁱⁱ	0.85	2.29	3.121 (4)	167

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Symmetry codes: (i) Inline graphic ; (ii) .

supplementary crystallographic information

Comment

Iminosugars in which the oxygen of a sugar ring is replaced by nitrogen comprise a large family of inhibitors of carbohydrate processing enzymes (Asano et al., 2000; Watson et al., 2001). Specific inhibition of individual hexosaminidases may allow the investigation of a number of diseases including osteoarthritis (Liu, Numa et al., 2004), allergy (Reese et al., 2007), Alzheimer's disease (Liu, Iqbal et al., 2004), and cancer (Woynarowska et al., 1992). Inhibition of N-acetylgalactosaminyltransferases (Kato et al., 2010) and protection of macrophage activating factor (Greco et al., 2009) may provide new strategies for the treatment of cancer. There are many piperidine hexosaminidase inhibitors, such as naturally occurring nagstatin (Tatsuta et al., 1997) and DNJNAc (Fleet et al., 1986; Fleet et al., 1987; Steiner et al., 2009), some with picomolar inhibition (Ho et al., 2010). Until very recently, potent furanose analogue inhibitors of hexosaminidases have been unknown. The first pyrrolizidine β-hexosaminidase inhibitor, pochonicine 1 (Fig. 1) [or its enantiomer], has been isolated from a fungal strain (Usuki et al., 2009). A rare example of a pyrrolidine potent hexosaminidase inhibitor is the iminoarabinitol LABNAc 2 (Rountree et al., 2007; Rountree et al., 2009) which has promise for the study of lysosomal storage of oligosaccharide and glycosphingolipid in iminosugar treated cells (Boomkamp et al., 2010).

In a study of the hexosaminidase inhibition of diastereomers of LABNAc 2 (Fig. 1), the L-xylo-epimer L-XYLNAc 4 has been prepared from L-glucuronolactone 6, a common constituent of the chiral pool for the preparation of imino sugars (Best, Wang et al., 2010). The lactone 6 may be efficiently converted to the diol 5 (Best, Chairatana et al., 2010) which has been further transformed to 4via the N-benzyl L-XYLNAc 3 of L-XYLNAc. This paper reports the crystal structure of 3 which establishes the relative configuration and will allow modelling studies to rationalize enzyme inhibition by the diastereomeric 2-acetamido-pyrrolidine sugar mimics; the absolute configuration is determined by the use of L-glucuronolactone 6 as the starting material.

The pyrrolidine ring of the title compound adopts an envelope conformation with the nitrogen lying out of the plane (Fig. 2). The compound exists as chains of hydrogen-bonded molecules lying parallel to the a-axis (Fig. 3). Each molecule is a donor and acceptor for 3 hydrogen bonds and the hydrogen bond involving O19 is bifurcated. Only classical hydrogen bonding is considered.

Experimental

N-Benzyl-L-XYLNAc 3 was crystallized from acetonitrile: m.p. 396-399 K; [α]_D²⁵ +39.9 (c, 0.99 in MeOH).