In the title compound, 2-(2-deoxy-2-fluoro-
-
D-arabinofuranosyl)-1,2,4-triazine-3,5(2
H,4
H)-dione, C
8H
10FN
3O
5, the torsion angle of the N-glycosylic bond is
anti [
= -125.37 (13)°]. The furanose moiety adopts the N-type sugar pucker (
3T2), with
P = 359.2° and
m = 31.4°. The conformation around the C4'-C5' bond is antiperiplanar (
trans), with a torsion angle
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.
Supporting information
CCDC reference: 259044
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.
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 Uiso(H) = 1.2Ueq(C). The positions of the H atoms on O and N atoms were refined and their Uiso(H) values were constrained to 1.2Ueq(N,O). Please check added text.
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.
2-(2-deoxy-2-fluoro-
β-
D-arabinofuranosyl)-1,2,4-triazine-3,5(2
H,4H)-dione
top
Crystal data top
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) Å3 | 0.4 × 0.3 × 0.3 mm |
Z = 2 | |
Data collection top
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 top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.034 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.094 | w = 1/[σ2(Fo2) + (0.0646P)2 + 0.023P] where P = (Fo2 + 2Fc2)/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+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.083 (12) |
Crystal data top
C8H10FN3O5 | V = 505.65 (16) Å3 |
Mr = 247.19 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 4.9302 (9) Å | µ = 0.15 mm−1 |
b = 10.993 (2) Å | T = 293 K |
c = 9.4360 (16) Å | 0.4 × 0.3 × 0.3 mm |
β = 98.62 (2)° | |
Data collection top
Bruker P4 diffractometer | Rint = 0.022 |
2574 measured reflections | 3 standard reflections every 97 reflections |
1832 independent reflections | intensity decay: none |
1769 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.034 | 4 restraints |
wR(F2) = 0.094 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | Δρmax = 0.29 e Å−3 |
1832 reflections | Δρmin = −0.26 e Å−3 |
164 parameters | |
Special details top
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 (Å2) top | 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 (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
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) top
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) top
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′···O2iii | 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. |
Experimental details
Crystal data |
Chemical formula | C8H10FN3O5 |
Mr | 247.19 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 293 |
a, b, c (Å) | 4.9302 (9), 10.993 (2), 9.4360 (16) |
β (°) | 98.62 (2) |
V (Å3) | 505.65 (16) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.15 |
Crystal size (mm) | 0.4 × 0.3 × 0.3 |
|
Data collection |
Diffractometer | Bruker P4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 2574, 1832, 1769 |
Rint | 0.022 |
(sin θ/λ)max (Å−1) | 0.746 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.034, 0.094, 1.05 |
No. of reflections | 1832 |
No. of parameters | 164 |
No. of restraints | 4 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.29, −0.26 |
Selected geometric parameters (Å, º) topN1—C2 | 1.3793 (15) | C4—C5 | 1.4645 (19) |
N1—C1' | 1.4649 (16) | C5—N6 | 1.2829 (17) |
F1—C2' | 1.3929 (16) | C1'—O4' | 1.4058 (18) |
N3—C4 | 1.376 (2) | O4'—C4' | 1.4486 (14) |
| | | |
O4'—C1'—C2' | 105.34 (10) | F1—C2'—C1' | 111.73 (10) |
F1—C2'—C3' | 112.82 (10) | C3'—C2'—C1' | 105.11 (11) |
| | | |
N6—N1—C2—O2 | 179.01 (15) | F1—C2'—C3'—O3' | −84.17 (14) |
N1—C2—N3—C4 | 2.9 (2) | N1—C1'—O4'—C4' | −111.35 (11) |
N3—C4—C5—N6 | 0.0 (2) | C2'—C1'—O4'—C4' | 10.18 (13) |
C4—C5—N6—N1 | 1.1 (2) | C1'—O4'—C4'—C3' | 9.68 (13) |
C2—N1—N6—C5 | −0.2 (2) | C2'—C3'—C4'—O4' | −25.17 (12) |
C2—N1—C1'—O4' | −125.48 (13) | O3'—C3'—C4'—C5' | 92.60 (14) |
O4'—C1'—C2'—F1 | −148.96 (11) | O4'—C4'—C5'—O5' | 58.56 (15) |
N1—C1'—C2'—F1 | −29.03 (16) | C3'—C4'—C5'—O5' | 176.95 (11) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N3—H3···O3'i | 0.861 (13) | 2.027 (13) | 2.8817 (16) | 172 (2) |
O3'—H3'···O5'ii | 0.82 (2) | 1.94 (2) | 2.7330 (18) | 163 (3) |
O5'—H5'···O2iii | 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. |
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 τm = 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 τm = 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 3JH,H and two 3JH,F experimental coupling constants to the five conformational parameters, namely the phase angles (PS and PN) and puckering amplitudes (ψS and ψN) of the S– and N-conformers, and the population of the S-type conformer (XS; XS + XN = 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 - PN = 14.8° (3E, C3'-endo), 77%; 2 - PN = 288.0° (1OT, 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.