4-Amino-7-(2-de­oxy-2-fluoro-β-D-arabinofuranos­yl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine: a bis-fluorinated analogue of 2′-deoxy­tubercidin

The title compound, C₁₁H₁₂F₂N₄O₃, exhibits an anti glycosylic bond conformation, with a torsion angle χ = −117.8 (2)°. The sugar pucker is N-type (C4′-exo, between ³T₄ and E₄, with P = 45.3° and τ_m = 41.3°). The conformation around the exocyclic C—C bond is −ap (trans), with a torsion angle γ = −177.46 (15)°. The nucleobases are stacked head-to-head. The crystal structure is characterized by a three-dimensional hydrogen-bond network involving N—H...O, O—H...O and O—H...N hydrogen bonds.

S1. Comment

7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides are a class of compounds with significant biological activity. Among them are the nucleoside antibiotics tubercidin, toyocamycin and sangivamycin, which all show antitumour activity (Rao & Renn, 1963; Tolman et al., 1969). A series of 7-substituted tubercidin analogues (purine numbering is used throughout the discussion) exhibit antiviral activity against various RNA and DNA viruses, including herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) (Bergstrom et al., 1984; De Clercq et al., 1986). The extraordinary activity of pyrrolo[2,3-d]pyrimidine nucleosides against the hepatitis C virus is a subject of current investigation (Eldrup et al., 2004). Among the base- and sugar-modified nucleosides, those with an F atom in the 2'-up (arabino) configuration make purine nucleosides stable towards acids (Marquez et al., 1990, 1987) and more resistant towards hydrolysis by adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) (Hitchcock et al., 1990). Recently, the synthesis and properties of the 7-fluoro analogue of tubercidin, which exhibits less cytotoxicity than the parent tubercidin, have been reported (Wang et al., 2004). In an effort to correlate the structural characteristics with biological activity, we have synthesized the bis-fluorinated 2'-deoxytubercidin analogue, (I), and subjected it to single-crystal X-ray analysis.

The orientation of the nucleobase relative to the sugar moiety (syn/anti) of purine nucleosides is defined by the torsion angle χ (O4'—C1'—N9—C4) (IUPAC–IUB Joint Commission on Biochemical Nomenclature, 1983). The natural 2'-deoxyribonucleosides usually adopt an anti conformation. From the crystal structure of (I), the glycosylic bond torsion angle was determined to be in the anti range, with a χ value of −117.8 (2)° (Fig. 1 and Table 1). The conformation of the nucleoside (II), lacking the 2'-fluoro substituent, falls into a range between anti and high-anti conformation [χ = −101.1 (3)°; ????Seela, Xu & Eickmeier, 2005], which is similar to that of natural 2'-deoxytubercidin (III) [χ = −104.(4)°; Zabel et al., 1987]. The related pyrimidine nucleoside (IV) exhibits an anti orientation with a χ value of −158.6 (3)° (Hempel et al., 1999).

The sugar moiety of nucleoside (I) shows an N-conformation (C4'-exo; ³T₄/E₄) with a pseudorotation phase angle, P (Rao et al., 1981), of 45.3° and an amplitude, τ_m, of 41.3°, while compound (II) exhibits an S-conformation [C2'-endo; ²E; P = 164.7 (3)° and τ_m = 40.1 (2)°]. An S-conformation was observed for the non-fluorinated 2'-deoxytubercidin (III) [C3'-exo; ²T₃; P = 186.6 (2)°]. The fluorinated pyrimidine nucleoside (IV), with the same sugar moiety as (I), adopts an S-conformation (⁰T₁) with a pseudorotation phase angle of 101.6 (2)° and an amplitude of 43.2 (1)°.

The conformation around the C4'—C5' bond, which is defined by the torsion angle γ(O5'—C5'—C4'—C3'), is −177.46 (15)° for compound (I), representing an antiperiplanar (trans) conformation. The length of the N9—C1' glycosylic bond is 1.436 (3) Å, which is close to that in (II) [1.444 (4) Å]. The F2'—C2' distance is 1.379 (3) Å, similar to C—F bonds found in other 2'-fluoroarabino nucleosides (Birnbaum et al., 1982) and also in 2'-fluoro ribonucleosides (Suck et al., 1974; Hakoshima et al., 1981).

The sugar conformations of the 7-deazapurine nucleosides have been also determined in D₂O solution. The conformational analysis of nucleoside (I) was determined on the basis of ³J_H,H and ³J_H,F coupling constants obtained from ¹H NMR spectra measured in D₂O by applying PSEUDOROT6.3 (Van Wijk et al., 1999). Compound (I) has two populations (67% S and 33% N). The sugar pucker is similar to that of related 2'-deoxyribonucleosides (II) (70% S) and (III) (69% S).

In the close-packed network of (I), both the nucleobases and the sugar residues are stacked. The bases are arranged head-to-head. The structure is stabilized by several hydrogen bonds (Fig. 2 and Table 2). Three hydrogen bonds combine to form highly corrugated layers with an overall position parallel to the xy plane. A fourth hydrogen bond (O5'—H5'···O3') connects the layers. A intramolecular hydrogen bond is also observed (N6—H6B···F7); it forms one component of a three-centre system at H6B.

S2. Experimental

Compound (I) was prepared according to the method described by (Seela, Chittepu et al., 2005) and crystallized from methanol as colourless needles (m.p. 470—473 K).

S3. Refinement

In the absence of suitable anomalous scattering, refinement of the Flack (1983) parameter led to inconclusive values (Flack & Bernardinelli, 2000); Friedel equivalents were therefore merged before the final refinement. The known configuration of the parent molecule was used to define the enantiomer employed in the refined model. All H atoms were found in a difference Fourier synthesis. In order to maximize the data/parameter ratio, H atoms were placed in geometrically idealized positions (C—H = 0.93–0.98 Å and N—H = 0.86 Å) and constrained to ride on their parent atoms with U_iso(H) = 1.2U_eq(C,N). The OH groups were refined as rigid groups allowed to rotate but not tip, with O—H= 0.82 Å and U_iso(H) = 1.5U_eq(O).

Computing details

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: SHELXTL (Sheldrick, 1997); program(s) used to solve structure: SHELXTL; program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 1999).

Figures

	Fig. 1. A perspective view of nucleoside (I). Displacement ellipsoids for non-H atoms are drawn at the 50% probability level.
	Fig. 2. The crystal packing of (I), showing the intermolecular hydrogen-bonding network (projection parallel to the a axis).

4-Amino-7-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro- 7H-pyrrolo[2,3-d]pyrimidine

Crystal data

C11H12F2N4O3	F(000) = 296
Mr = 286.25	Dx = 1.554 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 54 reflections
a = 5.7355 (6) Å	θ = 5.5–12.5°
b = 9.8374 (13) Å	µ = 0.14 mm^−1
c = 10.9428 (13) Å	T = 293 K
β = 97.856 (9)°	Block, colourless
V = 611.62 (13) Å^3	0.5 × 0.3 × 0.2 mm
Z = 2

Data collection

Bruker P4 diffractometer	Rint = 0.027
Radiation source: fine-focus sealed tube	θmax = 31.0°, θmin = 1.9°
Graphite monochromator	h = −8→1
2θ/ω scans	k = −14→1
2846 measured reflections	l = −15→15
2056 independent reflections	3 standard reflections every 97 reflections
1809 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.039	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.102	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0515P)^2 + 0.0481P] where P = (Fo^2 + 2Fc^2)/3
2056 reflections	(Δ/σ)max < 0.001
188 parameters	Δρmax = 0.32 e Å^−3
3 restraints	Δρmin = −0.21 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
N1	0.5981 (3)	0.9121 (2)	0.26365 (14)	0.0376 (4)
C2	0.4549 (5)	0.9870 (3)	0.32462 (18)	0.0402 (5)
H2	0.3428	1.0388	0.2757	0.048*
N3	0.4528 (4)	0.9966 (2)	0.44545 (15)	0.0364 (4)
C4	0.6171 (3)	0.9177 (2)	0.50863 (15)	0.0280 (4)
C5	0.7753 (4)	0.8333 (2)	0.45896 (16)	0.0309 (4)
C6	0.7613 (4)	0.8336 (2)	0.32917 (17)	0.0333 (4)
N6	0.9026 (4)	0.7559 (3)	0.26887 (19)	0.0505 (6)
H6A	0.8873	0.7572	0.1896	0.061*
H6B	1.0078	0.7052	0.3097	0.061*
C7	0.9142 (4)	0.7713 (3)	0.5617 (2)	0.0382 (5)
F7	1.0868 (3)	0.6806 (2)	0.55244 (16)	0.0637 (5)
C8	0.8439 (4)	0.8166 (3)	0.66739 (19)	0.0364 (4)
H8	0.9066	0.7915	0.7471	0.044*
N9	0.6595 (3)	0.9083 (2)	0.63497 (13)	0.0305 (3)
C1'	0.5435 (4)	0.9910 (2)	0.71657 (16)	0.0313 (4)
H1'	0.4312	1.0513	0.6676	0.038*
C2'	0.4155 (4)	0.9118 (2)	0.80942 (16)	0.0309 (4)
H2'	0.2558	0.9482	0.8071	0.037*
F2'	0.4021 (3)	0.77445 (17)	0.78432 (14)	0.0533 (4)
O3'	0.4053 (3)	0.93855 (18)	1.02730 (11)	0.0338 (3)
H3'	0.486 (4)	0.927 (4)	1.0944 (13)	0.051*
C3'	0.5540 (3)	0.94184 (19)	0.93427 (15)	0.0246 (3)
H3'1	0.6820	0.8759	0.9528	0.029*
C4'	0.6543 (3)	1.0824 (2)	0.91300 (15)	0.0257 (3)
H4'	0.5325	1.1519	0.9149	0.031*
O4'	0.7188 (3)	1.07168 (19)	0.79053 (13)	0.0426 (4)
O5'	0.9562 (3)	1.25163 (15)	0.98599 (16)	0.0374 (4)
H5'	0.848 (4)	1.307 (3)	0.974 (3)	0.056*
C5'	0.8694 (3)	1.1182 (2)	1.00292 (18)	0.0301 (4)
H5'1	0.8310	1.1104	1.0862	0.036*
H5'2	0.9929	1.0530	0.9941	0.036*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0480 (10)	0.0471 (10)	0.0186 (6)	0.0027 (10)	0.0082 (6)	−0.0020 (7)
C2	0.0506 (12)	0.0481 (12)	0.0218 (8)	0.0106 (11)	0.0042 (8)	0.0030 (9)
N3	0.0456 (10)	0.0430 (10)	0.0212 (6)	0.0102 (9)	0.0064 (7)	0.0004 (7)
C4	0.0330 (8)	0.0340 (9)	0.0173 (6)	0.0002 (8)	0.0051 (6)	−0.0013 (7)
C5	0.0337 (9)	0.0374 (10)	0.0225 (7)	0.0033 (8)	0.0074 (7)	−0.0028 (8)
C6	0.0385 (9)	0.0390 (11)	0.0239 (8)	−0.0029 (9)	0.0097 (7)	−0.0061 (8)
N6	0.0551 (12)	0.0659 (15)	0.0336 (9)	0.0138 (12)	0.0167 (8)	−0.0094 (10)
C7	0.0356 (10)	0.0440 (12)	0.0345 (9)	0.0085 (10)	0.0032 (8)	−0.0016 (9)
F7	0.0560 (9)	0.0775 (13)	0.0558 (9)	0.0359 (10)	0.0008 (7)	−0.0057 (9)
C8	0.0371 (9)	0.0454 (12)	0.0252 (8)	0.0033 (10)	−0.0009 (7)	0.0017 (8)
N9	0.0355 (8)	0.0396 (9)	0.0162 (6)	0.0027 (8)	0.0034 (5)	0.0008 (6)
C1'	0.0402 (10)	0.0367 (10)	0.0179 (7)	−0.0039 (9)	0.0073 (7)	−0.0017 (7)
C2'	0.0346 (9)	0.0389 (10)	0.0196 (7)	−0.0097 (9)	0.0056 (6)	−0.0065 (7)
F2'	0.0801 (11)	0.0436 (8)	0.0400 (7)	−0.0277 (8)	0.0214 (7)	−0.0149 (6)
O3'	0.0349 (7)	0.0497 (9)	0.0181 (5)	−0.0051 (7)	0.0089 (5)	−0.0002 (6)
C3'	0.0276 (8)	0.0289 (8)	0.0182 (6)	−0.0021 (7)	0.0065 (6)	−0.0014 (6)
C4'	0.0314 (8)	0.0279 (8)	0.0182 (6)	−0.0020 (7)	0.0053 (6)	−0.0025 (6)
O4'	0.0595 (10)	0.0500 (10)	0.0211 (6)	−0.0260 (9)	0.0150 (6)	−0.0079 (6)
O5'	0.0303 (7)	0.0356 (8)	0.0476 (9)	−0.0076 (7)	0.0098 (6)	−0.0072 (7)
C5'	0.0287 (9)	0.0318 (9)	0.0295 (8)	−0.0011 (8)	0.0033 (7)	−0.0031 (7)

Geometric parameters (Å, º)

N1—C6	1.343 (3)	C1'—O4'	1.440 (3)
N1—C2	1.346 (3)	C1'—C2'	1.543 (3)
C2—N3	1.327 (2)	C1'—H1'	0.9800
C2—H2	0.9300	C2'—F2'	1.379 (3)
N3—C4	1.338 (3)	C2'—C3'	1.513 (2)
C4—N9	1.374 (2)	C2'—H2'	0.9800
C4—C5	1.394 (3)	O3'—C3'	1.415 (2)
C5—C6	1.412 (2)	O3'—H3'	0.821 (17)
C5—C7	1.423 (3)	C3'—C4'	1.527 (3)
C6—N6	1.350 (3)	C3'—H3'1	0.9800
N6—H6A	0.8600	C4'—O4'	1.442 (2)
N6—H6B	0.8600	C4'—C5'	1.511 (3)
C7—F7	1.346 (3)	C4'—H4'	0.9800
C7—C8	1.352 (3)	O5'—C5'	1.425 (3)
C8—N9	1.398 (3)	O5'—H5'	0.82 (3)
C8—H8	0.9300	C5'—H5'1	0.9700
N9—C1'	1.436 (3)	C5'—H5'2	0.9700
C6—N1—C2	118.58 (17)	O4'—C1'—H1'	109.2
N3—C2—N1	128.4 (2)	C2'—C1'—H1'	109.2
N3—C2—H2	115.8	F2'—C2'—C3'	112.28 (18)
N1—C2—H2	115.8	F2'—C2'—C1'	112.44 (16)
C2—N3—C4	111.85 (18)	C3'—C2'—C1'	104.93 (15)
N3—C4—N9	125.06 (17)	F2'—C2'—H2'	109.0
N3—C4—C5	126.44 (16)	C3'—C2'—H2'	109.0
N9—C4—C5	108.49 (17)	C1'—C2'—H2'	109.0
C4—C5—C6	116.14 (18)	C3'—O3'—H3'	109 (2)
C4—C5—C7	105.73 (16)	O3'—C3'—C2'	110.56 (15)
C6—C5—C7	138.1 (2)	O3'—C3'—C4'	114.01 (15)
N1—C6—N6	119.07 (19)	C2'—C3'—C4'	101.61 (15)
N1—C6—C5	118.55 (18)	O3'—C3'—H3'1	110.1
N6—C6—C5	122.4 (2)	C2'—C3'—H3'1	110.1
C6—N6—H6A	120.0	C4'—C3'—H3'1	110.1
C6—N6—H6B	120.0	O4'—C4'—C5'	109.37 (15)
H6A—N6—H6B	120.0	O4'—C4'—C3'	103.02 (14)
F7—C7—C8	126.3 (2)	C5'—C4'—C3'	113.75 (15)
F7—C7—C5	124.21 (19)	O4'—C4'—H4'	110.2
C8—C7—C5	109.5 (2)	C5'—C4'—H4'	110.2
C7—C8—N9	107.43 (18)	C3'—C4'—H4'	110.2
C7—C8—H8	126.3	C1'—O4'—C4'	108.33 (14)
N9—C8—H8	126.3	C5'—O5'—H5'	111 (2)
C4—N9—C8	108.81 (16)	O5'—C5'—C4'	113.51 (17)
C4—N9—C1'	123.65 (17)	O5'—C5'—H5'1	108.9
C8—N9—C1'	127.29 (16)	C4'—C5'—H5'1	108.9
N9—C1'—O4'	108.33 (17)	O5'—C5'—H5'2	108.9
N9—C1'—C2'	115.22 (19)	C4'—C5'—H5'2	108.9
O4'—C1'—C2'	105.46 (14)	H5'1—C5'—H5'2	107.7
N9—C1'—H1'	109.2
C6—N1—C2—N3	1.0 (4)	C7—C8—N9—C4	0.4 (3)
N1—C2—N3—C4	−0.8 (4)	C7—C8—N9—C1'	−174.0 (2)
C2—N3—C4—N9	178.8 (2)	C4—N9—C1'—O4'	−117.8 (2)
C2—N3—C4—C5	−0.3 (3)	C8—N9—C1'—O4'	55.9 (3)
N3—C4—C5—C6	1.1 (3)	C4—N9—C1'—C2'	124.4 (2)
N9—C4—C5—C6	−178.11 (19)	C8—N9—C1'—C2'	−61.9 (3)
N3—C4—C5—C7	179.7 (2)	N9—C1'—C2'—F2'	−10.0 (3)
N9—C4—C5—C7	0.5 (2)	O4'—C1'—C2'—F2'	−129.45 (19)
C2—N1—C6—N6	178.6 (2)	N9—C1'—C2'—C3'	112.27 (19)
C2—N1—C6—C5	0.0 (3)	O4'—C1'—C2'—C3'	−7.1 (2)
C4—C5—C6—N1	−0.9 (3)	F2'—C2'—C3'—O3'	−87.7 (2)
C7—C5—C6—N1	−178.9 (3)	C1'—C2'—C3'—O3'	149.88 (17)
C4—C5—C6—N6	−179.5 (2)	F2'—C2'—C3'—C4'	150.92 (17)
C7—C5—C6—N6	2.5 (4)	C1'—C2'—C3'—C4'	28.5 (2)
C4—C5—C7—F7	179.1 (2)	O3'—C3'—C4'—O4'	−159.14 (15)
C6—C5—C7—F7	−2.7 (5)	C2'—C3'—C4'—O4'	−40.19 (18)
C4—C5—C7—C8	−0.3 (3)	O3'—C3'—C4'—C5'	82.58 (19)
C6—C5—C7—C8	177.9 (3)	C2'—C3'—C4'—C5'	−158.47 (16)
F7—C7—C8—N9	−179.4 (2)	N9—C1'—O4'—C4'	−142.98 (18)
C5—C7—C8—N9	−0.1 (3)	C2'—C1'—O4'—C4'	−19.1 (2)
N3—C4—N9—C8	−179.8 (2)	C5'—C4'—O4'—C1'	158.90 (18)
C5—C4—N9—C8	−0.6 (2)	C3'—C4'—O4'—C1'	37.6 (2)
N3—C4—N9—C1'	−5.1 (3)	O4'—C4'—C5'—O5'	68.0 (2)
C5—C4—N9—C1'	174.12 (19)	C3'—C4'—C5'—O5'	−177.46 (15)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H6A···O5′^i	0.86	2.23	3.009 (3)	151
N6—H6B···O4′^i	0.86	2.42	2.968 (3)	122
O3′—H3′···N1^ii	0.82 (2)	1.88 (2)	2.683 (2)	165 (3)
O5′—H5′···O3′^iii	0.82 (3)	1.94 (3)	2.760 (2)	171 (3)
N6—H6B···F7	0.86	2.64	3.225 (3)	126

Symmetry codes: (i) −x+2, y−1/2, −z+1; (ii) x, y, z+1; (iii) −x+1, y+1/2, −z+2.