6-Aza-2'-deoxy-2'-arabino­fluoro­uridine, a 2'-deoxy­ribonucleoside with an N-sugar conformation in the solid state and in solution

In the title compound, 2-(2-deoxy-2-fluoro-[beta]-D-arabino­fur­anosyl)-1,2,4-triazine-3,5(2H,4H)-dione, C₈H₁₀FN₃O₅, the torsion angle of the N-gly­cosylic bond is anti [[chi] = -125.37 (13)°]. The furan­ose moiety adopts the N-type sugar pucker (³T₂), with P = 359.2° and [tau]_m = 31.4°. The conformation around the C4'-C5' bond is antiperiplanar (trans), with a torsion angle [gamma] of 177.00 (11)°. A network is formed via hydrogen bonds from the nucleobases to the sugar residues, as well as through hydrogen bonds between the sugar moieties.

S1. Comment

About 0.07% of the Earth's crust consists of fluorine. Very few naturally occurring organo-fluorine compounds are known to exist and only 13 have been discovered, including molecules like fluorothreonine (Sanda et al., 1986) and nucleocidin (Morton, et al., 1969; Thomas et al., 1956). Recently, 5-fluorouracil derivatives were isolated from the sponge Phakellia fusca (Xu et al., 2003).

Fluorine-substituted analogues of the components of nucleic acid have become established as antiviral, antitumour and antifungal agents. Compounds of this class contain an F atom at the C2' position of the sugar moiety. This modification strongly influences physical, chemical and biological properties without perturbing the molecular geometry. Thus, the compounds 2'-fluoro-5-methyl-1-β-D-arabinofuranosyluracil, FMAU (Watanabe et al., 1979), and 2'-fluoro-5-iodo-1-β-D-arabinofuranosyluracil, FIAU, and 2'-fluoro-5-iodo-1-β-D-arabinofuranosylcytosine, FIAC (Watanabe et al., 1983, 1984), are potent and selective inhibitors of herpes simplex virus types 1 and 2, varicella zoster virus and cytomegalovirus, while 2',2'-difluorocytidine gem-citabine (Hertel et al., 1988) shows anticancer activity. The 2'-fluoro substituent also shifts the conformational equilibrium of the sugar moiety of a nucleoside, based on its configuration (Guschlbauer & Jankowski, 1980; Berger et al., 1998; Ikeda et al., 1998; Thibaudeau et al., 1998). The incorporation of 2'-fluoroarabino nucleosides into oligonucleotide duplexes enhances their susceptibility to RNase H cleavage, which makes them useful for antisense therapeutics (Damha et al., 1998; Ikeda et al., 1998; Yazbeck et al., 2002). Here, we report the single-crystal X-ray structure of the title compound, (I). The absolute configuration of this molecule is β-D, established from the absolute configuration of the sugar moiety used in the synthesis. The synthesis will be described elsewhere (Seela et al., 2004). \sch

From the crystal structure of (I), it can be established that the torsion angle of the glycosylic bond is in the anti range, with χ = −125.37 (13)° (Fig. 1 and Table 1). Compound (III) has an anti orientation of the base with respect to the sugar ring [χ = −158.6 (3)°; Hempel et al., 1999], while nucleoside (II), without a 2'-fluoro substituent, adopts an anti conformation which is very close to syn [χ = −93.9 (3)°; Seela & Chittepu, 2004]. The intramolecular repulsion between the 2'-fluoro substituent and the ring N atom adjacent to the glycosylation position (N2 Please clarify - there is no atom labelled N2. Should it be N1?) is responsible for a significant change in the conformation of (I) compared with (II).

The sugar moiety of (I) shows pseudorotation parameters (Rao et al., 1981) of P = 359.2° and τ_m = 31.4° with an N-type sugar pucker (C2'-exo and C3'-endo, ³T₂), while (III) adopts a twisted conformation (^OT₁) with a pseudorotation phase angle P = 101.6 (2) and an amplitude τ_m = 43.2 (1)°. The sugar conformation of nucleoside (II) is C2'-endo-C3'-exo (²T₃) (S-type sugar). The orientation around the C4'-C5' bond of (I) is anti-periplanar (trans), with a torsion angle γ (O5'-C5'-C4'-C3') of 177.00 (11)°. The presence of the 2'-fluoro substituent effects the sugar ring bond lengths and angles when compared with those of (II). The C1'-O4' bond length in (I) is about 0.04 Å shorter than the C4'-O4' bond. The F2'-C2' distance is similar to the C—F bonds found in other 2'-fluoroarabinonucleosides (Birnbaum et al., 1982) and 2'-fluororibonucleosides (Suck et al., 1974; Hakoshima et al., 1981).

The sugar conformation of (I) in aqueous solution was also determined, from the ¹H NMR coupling constants measured in D₂O, using the program PSEUROT6.3 (Van Wijk et al., 1999). This program calculates the best fits of three ³J_H,H and two ³J_H,F experimental coupling constants to the five conformational parameters, namely the phase angles (P_S and P_N) and puckering amplitudes (ψ_S and ψ_N) of the S– and N-conformers, and the population of the S-type conformer (X_S; X_S + X_N = 1). The input contained the following coupling constants: ³J(H1',H2'), J(H2',H3'), J(H3',H4'), J(H1',F), J(H3',F). The program reveals that (I) exists as 100% N-type with two regions [1 - P_N = 14.8° (³E, C3'-endo), 77%; 2 - P_N = 288.0° (¹_OT, C1'-endo-O4'-exo), 23%], very different from the non-fluorinated nucleoside, (II), for which the solution conformation is only 58% N-type. This unusual N-conformation of (I) is due to the combined influence of the gauche effect of the 2'-F atom and the anomeric effect of the nucleobase with the N atom next to the glycosylation site.

The structure of (I) is stabilized by several intermolecular hydrogen bonds (N3—H3···O3', O3'-H3'···O5' and O5'-H5'···O2; Table 2), as well as by a stacking interaction of the bases (nucleobase distance = 4.93 Å; Fig. 2).

The (100% N-type) sugar conformation observed for (I) has been previously reported for 8-aza-7-deazapurine 2'-deoxy 2'-fluoroarabinonucleosides (He et al., 2003). These unusual conformational properties of the sugar moiety are the result of the F atom in the arabino configuration and a nucleobase N atom next to the glycosylation site. The non-fluorinated compound, (II), exhibits the S-conformation in the solid state and an almost equal population of N– and S-conformers in solution.

S2. Experimental

Nucleoside (I) was synthesized as described by Seela et al. (2004). Suitable crystals were grown from a solution in dichloromethane-methanol (9:1) (m.p. 438 K). For the diffraction experiment, a single-crystal was fixed at the top of a Lindemann capillary with epoxy resin.

S3. Refinement

In the absence of suitable anomalous scattering, Friedel equivalents could not be used to determine the absolute structure. Therefore, Friedel equivalents were merged before the final refinement. The known configuration of the parent molecule was used to define the enantiomer of the final nucleoside. All H atoms were initially found in a difference Fourier synthesis. In order to maximize the data:parameter ratio, H atoms bonded to C atoms were placed in geometrically idealized positions (C—H = 0.93–0.98 Å) and constrained to ride on their parent atoms, with U_iso(H) = 1.2U_eq(C). The positions of the H atoms on O and N atoms were refined and their U_iso(H) values were constrained to 1.2U_eq(N,O). Please check added text.

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.

Figures

	Fig. 1. A perspective view of the nucleoside moiety of (I). Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary size.
	Fig. 2. The crystal packing of (I), showing the intermolecular hydrogen-bonding network.

2-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-1,2,4-triazine-3,5(2H,4H)-dione

Crystal data

C8H10FN3O5	F(000) = 256
Mr = 247.19	Dx = 1.624 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 47 reflections
a = 4.9302 (9) Å	θ = 5.3–17.3°
b = 10.993 (2) Å	µ = 0.15 mm^−1
c = 9.4360 (16) Å	T = 293 K
β = 98.62 (2)°	Block, colourless
V = 505.65 (16) Å^3	0.4 × 0.3 × 0.3 mm
Z = 2

Data collection

Bruker P4 diffractometer	Rint = 0.022
Radiation source: fine-focus sealed tube	θmax = 32.0°, θmin = 2.2°
Graphite monochromator	h = −7→1
2θ/ω scans	k = −16→1
2574 measured reflections	l = −14→14
1832 independent reflections	3 standard reflections every 97 reflections
1769 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.034	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.094	w = 1/[σ^2(Fo^2) + (0.0646P)^2 + 0.023P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
1832 reflections	Δρmax = 0.29 e Å^−3
164 parameters	Δρmin = −0.26 e Å^−3
4 restraints	Extinction correction: SHELXTL (Sheldrick, 1997), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.083 (12)

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	0.6366 (2)	0.07966 (12)	0.53089 (11)	0.0292 (2)
F1	0.4588 (2)	0.25051 (11)	0.70003 (12)	0.0431 (2)
O2	0.8420 (3)	0.19456 (14)	0.37620 (11)	0.0418 (3)
C2	0.6635 (3)	0.12239 (13)	0.39626 (13)	0.0290 (2)
N3	0.4753 (3)	0.07604 (13)	0.28782 (12)	0.0342 (3)
H3	0.499 (4)	0.100 (2)	0.2037 (11)	0.041*
O4	0.0992 (3)	−0.03853 (15)	0.20632 (13)	0.0476 (3)
C4	0.2654 (3)	−0.00228 (14)	0.30573 (13)	0.0320 (3)
C5	0.2633 (3)	−0.03758 (15)	0.45521 (15)	0.0327 (3)
H5	0.1270	−0.0905	0.4755	0.039*
N6	0.4395 (2)	0.00068 (13)	0.55962 (11)	0.0312 (2)
C1'	0.8291 (2)	0.11687 (13)	0.65702 (12)	0.0276 (2)
H1'	0.9749	0.1669	0.6270	0.033*
C2'	0.6884 (3)	0.18738 (13)	0.76610 (13)	0.0276 (2)
H2'	0.8192	0.2454	0.8169	0.033*
O3'	0.6008 (2)	0.13989 (11)	1.00863 (11)	0.0360 (2)
H3'	0.732 (4)	0.186 (2)	1.027 (3)	0.054*
C3'	0.6187 (2)	0.09236 (12)	0.87123 (12)	0.0247 (2)
H3'1	0.4437	0.0540	0.8327	0.030*
O4'	0.94466 (19)	0.01379 (11)	0.73097 (10)	0.0313 (2)
C4'	0.8511 (2)	0.00009 (13)	0.86849 (12)	0.0253 (2)
H4'	1.0020	0.0193	0.9452	0.030*
O5'	0.9760 (4)	−0.21389 (14)	0.87416 (13)	0.0495 (4)
H5'	1.036 (7)	−0.215 (4)	0.7978 (19)	0.074*
C5'	0.7621 (3)	−0.12968 (15)	0.88436 (17)	0.0358 (3)
H5'1	0.7001	−0.1393	0.9766	0.043*
H5'2	0.6085	−0.1475	0.8104	0.043*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0310 (4)	0.0417 (6)	0.0149 (4)	−0.0074 (4)	0.0031 (3)	0.0029 (4)
F1	0.0470 (5)	0.0404 (5)	0.0398 (5)	0.0107 (4)	−0.0001 (4)	0.0085 (4)
O2	0.0545 (6)	0.0490 (7)	0.0234 (4)	−0.0129 (6)	0.0110 (4)	0.0058 (5)
C2	0.0373 (5)	0.0337 (6)	0.0163 (4)	0.0021 (5)	0.0052 (4)	0.0028 (4)
N3	0.0471 (6)	0.0393 (6)	0.0154 (4)	−0.0005 (5)	0.0017 (4)	0.0020 (4)
O4	0.0608 (7)	0.0463 (7)	0.0289 (5)	−0.0039 (6)	−0.0151 (5)	−0.0033 (5)
C4	0.0415 (6)	0.0309 (6)	0.0210 (5)	0.0050 (5)	−0.0033 (4)	−0.0023 (5)
C5	0.0341 (6)	0.0378 (7)	0.0255 (5)	−0.0033 (5)	0.0016 (4)	−0.0022 (5)
N6	0.0329 (5)	0.0413 (6)	0.0196 (4)	−0.0075 (5)	0.0049 (3)	0.0021 (4)
C1'	0.0279 (4)	0.0385 (6)	0.0166 (4)	−0.0063 (5)	0.0035 (3)	0.0033 (4)
C2'	0.0322 (5)	0.0280 (5)	0.0220 (5)	−0.0025 (4)	0.0015 (4)	0.0015 (4)
O3'	0.0444 (5)	0.0442 (6)	0.0217 (4)	−0.0038 (4)	0.0121 (4)	−0.0084 (4)
C3'	0.0277 (4)	0.0297 (5)	0.0172 (4)	−0.0013 (4)	0.0048 (3)	−0.0014 (4)
O4'	0.0304 (4)	0.0451 (6)	0.0199 (4)	0.0065 (4)	0.0082 (3)	0.0042 (4)
C4'	0.0276 (4)	0.0322 (5)	0.0158 (4)	0.0017 (4)	0.0026 (3)	0.0022 (4)
O5'	0.0761 (9)	0.0452 (7)	0.0291 (5)	0.0270 (6)	0.0135 (6)	0.0065 (5)
C5'	0.0458 (7)	0.0297 (6)	0.0335 (6)	0.0040 (5)	0.0108 (5)	0.0041 (5)

Geometric parameters (Å, º)

N1—N6	1.3604 (16)	C1'—H1'	0.9800
N1—C2	1.3793 (15)	C2'—C3'	1.5150 (18)
N1—C1'	1.4649 (16)	C2'—H2'	0.9800
F1—C2'	1.3929 (16)	O3'—C3'	1.4127 (14)
O2—C2	1.2205 (19)	O3'—H3'	0.82 (2)
C2—N3	1.3722 (18)	C3'—C4'	1.5336 (18)
N3—C4	1.376 (2)	C3'—H3'1	0.9800
N3—H3	0.861 (13)	O4'—C4'	1.4486 (14)
O4—C4	1.2165 (16)	C4'—C5'	1.507 (2)
C4—C5	1.4645 (19)	C4'—H4'	0.9800
C5—N6	1.2829 (17)	O5'—C5'	1.417 (2)
C5—H5	0.9300	O5'—H5'	0.82 (2)
C1'—O4'	1.4058 (18)	C5'—H5'1	0.9700
C1'—C2'	1.5348 (19)	C5'—H5'2	0.9700
N6—N1—C2	124.81 (11)	F1—C2'—H2'	109.0
N6—N1—C1'	114.30 (9)	C3'—C2'—H2'	109.0
C2—N1—C1'	120.88 (11)	C1'—C2'—H2'	109.0
O2—C2—N3	123.26 (12)	C3'—O3'—H3'	105 (2)
O2—C2—N1	122.36 (12)	O3'—C3'—C2'	113.41 (11)
N3—C2—N1	114.38 (12)	O3'—C3'—C4'	114.18 (10)
C2—N3—C4	125.29 (11)	C2'—C3'—C4'	101.63 (10)
C2—N3—H3	113.9 (16)	O3'—C3'—H3'1	109.1
C4—N3—H3	120.8 (16)	C2'—C3'—H3'1	109.1
O4—C4—N3	122.84 (14)	C4'—C3'—H3'1	109.1
O4—C4—C5	123.69 (15)	C1'—O4'—C4'	111.64 (10)
N3—C4—C5	113.47 (11)	O4'—C4'—C5'	108.91 (11)
N6—C5—C4	123.43 (14)	O4'—C4'—C3'	106.58 (10)
N6—C5—H5	118.3	C5'—C4'—C3'	113.26 (10)
C4—C5—H5	118.3	O4'—C4'—H4'	109.3
C5—N6—N1	118.56 (11)	C5'—C4'—H4'	109.3
O4'—C1'—N1	110.07 (12)	C3'—C4'—H4'	109.3
O4'—C1'—C2'	105.34 (10)	C5'—O5'—H5'	116 (3)
N1—C1'—C2'	112.51 (10)	O5'—C5'—C4'	112.38 (13)
O4'—C1'—H1'	109.6	O5'—C5'—H5'1	109.1
N1—C1'—H1'	109.6	C4'—C5'—H5'1	109.1
C2'—C1'—H1'	109.6	O5'—C5'—H5'2	109.1
F1—C2'—C3'	112.82 (10)	C4'—C5'—H5'2	109.1
F1—C2'—C1'	111.73 (10)	H5'1—C5'—H5'2	107.9
C3'—C2'—C1'	105.11 (11)
N6—N1—C2—O2	179.01 (15)	N1—C1'—C2'—F1	−29.03 (16)
C1'—N1—C2—O2	−1.8 (2)	O4'—C1'—C2'—C3'	−26.27 (12)
N6—N1—C2—N3	−1.6 (2)	N1—C1'—C2'—C3'	93.66 (12)
C1'—N1—C2—N3	177.53 (12)	F1—C2'—C3'—O3'	−84.17 (14)
O2—C2—N3—C4	−177.77 (16)	C1'—C2'—C3'—O3'	153.85 (10)
N1—C2—N3—C4	2.9 (2)	F1—C2'—C3'—C4'	152.81 (11)
C2—N3—C4—O4	178.09 (16)	C1'—C2'—C3'—C4'	30.83 (11)
C2—N3—C4—C5	−2.1 (2)	N1—C1'—O4'—C4'	−111.35 (11)
O4—C4—C5—N6	179.81 (16)	C2'—C1'—O4'—C4'	10.18 (13)
N3—C4—C5—N6	0.0 (2)	C1'—O4'—C4'—C5'	132.19 (11)
C4—C5—N6—N1	1.1 (2)	C1'—O4'—C4'—C3'	9.68 (13)
C2—N1—N6—C5	−0.2 (2)	O3'—C3'—C4'—O4'	−147.67 (11)
C1'—N1—N6—C5	−179.44 (14)	C2'—C3'—C4'—O4'	−25.17 (12)
N6—N1—C1'—O4'	53.76 (15)	O3'—C3'—C4'—C5'	92.60 (14)
C2—N1—C1'—O4'	−125.48 (13)	C2'—C3'—C4'—C5'	−144.91 (11)
N6—N1—C1'—C2'	−63.39 (16)	O4'—C4'—C5'—O5'	58.56 (15)
C2—N1—C1'—C2'	117.38 (14)	C3'—C4'—C5'—O5'	176.95 (11)
O4'—C1'—C2'—F1	−148.96 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O3′^i	0.86 (1)	2.03 (1)	2.8817 (16)	172 (2)
O3′—H3′···O5′^ii	0.82 (2)	1.94 (2)	2.7330 (18)	163 (3)
O5′—H5′···O2^iii	0.82 (2)	2.08 (2)	2.8344 (16)	153 (4)

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