2,6-Di­chloro-9-(2′,3′,5′-tri-O-acetyl-β-d-ribo­furanos­yl)-9H-purine

Irina Novosjolova; Dmitrijs Stepanovs; Ērika Bizdēna; Anatoly Mishnev; Māris Turks

doi:10.1107/S1600536813034521

. 2014 Jan 4;70(Pt 2):o108–o109. doi: 10.1107/S1600536813034521

2,6-Dichloro-9-(2′,3′,5′-tri-O-acetyl-β-d-ribofuranosyl)-9H-purine

Irina Novosjolova ^a,^*, Dmitrijs Stepanovs ^b, Ērika Bizdēna ^a, Anatoly Mishnev ^b, Māris Turks ^a

PMCID: PMC3998279 PMID: 24764840

Abstract

The title synthetic analog of purine nucleosides, C₁₆H₁₆Cl₂N₄O₇, has its acetylated β-furanose ring in a 3′β-envelope conformation, with the corresponding C atom deviating by 0.602 (5) Å from the rest of the ring. The planar part of the furanose ring forms a dihedral angle of 65.0 (1)° with the mean plane of the purine bicycle. In the crystal, molecules form a three-dimensional network through multiple C—H⋯O and C—H⋯N hydrogen bonds and C—H⋯π interactions.

Related literature

For applications of 9-(2′,3′,5′-tri-O-acetyl-β-d-ribofuranosyl)-2,6-dichloro-9H-purine in synthesis, see: Caner & Vilarrasa (2010 ▶); Korboukh et al. (2012 ▶). For the synthesis, see: Vorbrüggen (1995 ▶); Robins & Uznański (1981 ▶); Nair & Richardson (1982 ▶); Francom et al. (2002 ▶); Francom & Robins (2003 ▶); Gerster & Robins (1966 ▶). The conditions were improved by using our previous studies (Kovalovs et al., 2013 ▶; Novosjolova et al., 2013 ▶). For the biological activity of purine nucleosides, their anticancer and antiviral activity and use as agonists and antagonists of adenosine receptors, see: Lech-Maranda et al. (2006 ▶); Robak et al. (2009 ▶); Gumina et al. (2003 ▶); Fredholm et al. (2011 ▶); Elzein & Zablocki (2008 ▶). For the structure of another 2,6-dichloropurine ribonucleoside, 9-(2′-deoxy-3′,5′-di-O-4-methoxybenzoyl-β-d-ribofuranosyl)-2,6-dichloro-9H-purine, see:Yang et al. (2012 ▶). The purine heterocycle is known to form π–π stacking interactions in related structures, see: Sternglanz & Bugg (1975 ▶). For standard bond lengths, see: Allen et al. (1987 ▶). The nature of hydrogen bonding is described by Gilli (2002 ▶). For a description of the Cambridge Structural Database, see: Allen (2002 ▶).

Experimental

Crystal data

C₁₆H₁₆Cl₂N₄O₇
M _r = 447.23
Monoclinic,
a = 10.1324 (2) Å
b = 9.6887 (3) Å
c = 10.5399 (2) Å
β = 106.537 (2)°
V = 991.90 (4) Å³
Z = 2
Mo Kα radiation
μ = 0.37 mm⁻¹
T = 296 K
0.38 × 0.32 × 0.15 mm

Data collection

Nonius KappaCCD diffractometer
3898 measured reflections
3898 independent reflections
2846 reflections with I > 2σ(I)

Refinement

R[F ² > 2σ(F ²)] = 0.046
wR(F ²) = 0.107
S = 1.02
3898 reflections
265 parameters
H-atom parameters constrained
Δρ_max = 0.22 e Å⁻³
Δρ_min = −0.20 e Å⁻³
Absolute structure: Flack (1983 ▶), 1518 Friedel pairs
Absolute structure parameter: 0.00 (7)

Data collection: KappaCCD Server Software (Nonius, 1997 ▶); cell refinement: SCALEPACK (Otwinovski & Minor, 1997 ▶); data reduction: DENZO (Otwinovski & Minor, 1997 ▶) and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXL97, PLATON (Spek, 2009 ▶) and publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S1600536813034521/ld2116sup1.cif

e-70-0o108-sup1.cif^{(28.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813034521/ld2116Isup2.hkl

e-70-0o108-Isup2.hkl^{(191.1KB, hkl)}

CCDC reference: http://scripts.iucr.org/cgi-bin/cr.cgi?rm=csd&csdid=968101

Additional supporting information: crystallographic information; 3D view; checkCIF report

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

Cg is the centroid of the C4/C5/N7/C8/N9 imidazole ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C8—H8⋯O15′	0.93	2.52	3.265 (4)	137
C8—H8⋯O14′ⁱ	0.93	2.56	3.350 (4)	143
C1′—H1⋯N1ⁱⁱ	0.98	2.48	3.355 (5)	148
C9′—H9B⋯O18′ⁱⁱⁱ	0.96	2.51	3.434 (4)	161
C13′—H13B⋯N7^iv	0.96	2.54	3.502 (5)	175
C5′—H5A⋯Cg ⁱ	0.97	2.69	3.454	136

Open in a new tab

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

Acknowledgments

IN thanks the European Social Fund within the project ‘Support for the implementation of doctoral studies at Riga Technical University’ for a scholarship and ERDF project 2DP/2.1.1.2.0/10/APIA/VI4AA/003 for the opportunity to present this work at the 14th Tetrahedron Symposium.

supplementary crystallographic information

1. 1. Comment

Purine nucleosides are well known of their biological activity: anticancer and antiviral activities, and as agonists and antagonists of adenosine receptors (Lech-Maranda et al. (2006), Robak et al. (2009), Gumina et al. (2003), Fredholm et al. (2011), Elzein & Zablocki (2008).

There is only one example of similar crystal structure of 2,6-dichloropurine ribonucleoside (9-(2'-deoxy-3',5'-di-O-4-methoxybenzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine) in literature (Yang et al., 2012, CSD refcode KEBWOF). Search of the Cambridge Structural Database (CSD, Version 1.15; Allen, 2002) indicated that there are only 4 (CSD refcodes: CLPURB, JEMHUF, PUPZAC, ZEXWEE) entries of 2- or 6-chloro substituted derivatives from over 300 crystal structures of 9-(ribofuranosyl)-9H-purines. The bond lengths (Allen et al., 1987) and angles in the molecule of are close to standard values. The furanose cycle adopts an envelope conformation. Atoms C2', C1', O6' and C4' of furanose lie in same plane (denoted as plane A), 2'- and 5'-O-acetyl groups are on opposite sides of the A plane, while 3'-O-acetyl group lies close to the A plane. The C3' deviates from the A by 0.602 (5) Å. The dihedral angle between the least-square planes of the purine system and four planar atoms (C2', C1', O6' and C4') of furanose cycle is 65.0 (1)°. The main torsion angles describing the location of purine system in respect to furanose ring are: C8—N9—C1'—O6' (6.9 (4)°); C8—N9—C1'—C2' (-111.1 (3)°); C4—N9—C1'—O6' (-168.8 (3)°); C4—N9—C1'—C2' (73.2 (4)°). Regardless of the fact that purine heterocycle is known to form π–π stacking interactions in related structures (Sternglanz & Bugg, 1975), such interaction was not observed in the crystals of the title compound. Moderate hydrogen bonds type C—H···O and C— H···N are present to form and stabilize three-dimensional architecture (Table 1).

The 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine 1 was synthesized by method of Vorbrüggen glycosylation of 2,6-dichloropurine (Vorbrüggen, 1995). The conditions were improved by using our previous studies (Kovalovs et al., 2013; Novosjolova et al., 2013).

2. 2. Experimental

Single crystals of 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine were grown from an ethanol solution by slow evaporation in ambient temperature. ¹H-NMR and ¹³C-NMR spectra were recorded at 300 MHz and at 75.5 MHz, respectively. The proton signals for residual non-deuterated solvents (δ 7.26 for CDCl₃) and carbon signals (δ 77.1 for CDCl₃) were used as an internal references for ¹H-NMR and ¹³C-NMR spectra, respectively. Coupling constants are reported in Hz. Analytical thin layer chromatography (TLC) was performed on Kieselgel 60 F254 glass plates precoated with a 0.25 mm thickness of silica gel. Dry MeCN was obtained by distillation over CaH₂. Commercial reagents were used as received.

9-(2',3',5'-Tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (3). N,O-Bis(trimethylsilyl)acetamide (5.60 mL, 22.7 mmol) was added to a stirred suspension of 2,6-dichloropurine (2) (4.02 g, 21.2 mmol) in dry acetonitrile (50 mL). The resulting mixture was stirred at 40 °C for 30 min until a clear solution was obtained. Solution of tetra-O-acetyl-D-ribofuranose (1) (6.77 g, 21.3 mmol) in dry acetonitrile (35 mL) was then added, followed by TMSOTf (0.80 mL, 4.4 mmol). The resulting reaction mixture was stirred at 75-80 °C for 2.5-3 h (TLC control). Then it was cooled to ambient temperature and ethanol (1 mL) was added and the mixture was stirred for 15 min at the same temperature followed by evaporation under reduced pressure. The residue was dissolved in CH₂Cl₂ (100 mL) washed with saturated aqueous solution of NaHCO₃ (3 × 25 mL) and water (1 × 25 mL), dried over anh. Na₂SO₄. Evaporation under reduced pressure provided product 3 (8.95 g, 95%) as a slightly yellow powder. The title compound was crystallized from ethanol, mp 158-160 °C [lit.: 159-161 °C (Gerster & Robins, 1966)]. The other analytical data of 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine are consistent with those reported earlier (Francom et al., 2002; Caner & Vilarrasa, 2010). R_f=0.45 (Toluene/EtOAc 1:2), IR (KBr), ν, cm^-1: 2976, 2924, 1773, 1742, 1593, 1560, 1381, 1367, 1245, 1229, 1200, 1137, 1100, 1061; ¹H-NMR (300 MHz, CDCl₃) δ (ppm): 8.29 (s, 1H, H—C(8)), 6.21 (d, 1H, ³J_1'-2' = 5.6 Hz, H—C(1')), 5.79 (t, 1H, ³J_1'-2' = ³J_2'-3' = 5.6 Hz, H—C(2')), 5.57 (dd, 1H, ³J_2'-3' = 5.6 Hz, ³J_3'-4' = 4.4 Hz, H—C(3')), 4.47 (quartet, 1H, ³J_3'-4' = ³J_4'-5' = 4.4 Hz, H—C(4')), 4.41 (d, 2H, ³J_4'-5' = 4.4 Hz, H—C(5')), 2.16, 2.14, 2.09 (3s, 9H, H₃COOC-C(2',3',5')); ¹³C-NMR (75.5 MHz, CDCl₃) δ (ppm): 170.2, 169.5, 169.4, 153.3, 152.6, 152.2, 143.9, 131.3, 86.5, 80.8, 73.2, 70.5, 62.8, 20.7, 20.5, 20.3.

2.1. 3. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were positioned geometrically with C—H distances ranging from 0.93 Å to 0.98 Å and refined as riding on their parent atoms with U_iso (H) = 1.5U_eq (C) for methyl groups and U_iso (H) = 1.2U_eq (C) for others.