The title compound [systematic name: 4-amino-5-fluoro-7-(β-
D-ribofuranosyl)-7
H-pyrrolo[2,3-
d]pyrimidine], C
11H
13FN
4O
4, exhibits an
anti glycosylic bond conformation, with a χ torsion angle of −124.7 (3)°. The furanose moiety shows a twisted C2′
-endo sugar pucker (
S-type), with
P = 169.8 (3)° and τ
m = 38.7 (2)°. The orientation of the exocyclic C4′—C5′ bond is +
sc (
gauche, gauche), with a γ torsion angle of 59.3 (3)°. The nucleobases are stacked head-to-head. The extended crystal structure is a three-dimensional hydrogen-bond network involving O—H
O, O—H
N and N—H
O hydrogen bonds. The crystal structure of the title nucleoside demonstrates that the C—C bonds nearest the F atom of the pyrrole system are significantly shortened by the electronegative halogen atom.
Supporting information
CCDC reference: 690203
Compound (I) was synthesized according to the `one-pot' Vorbrüggen
glycosylation protocol recently reported by Wang et al. (2004)
and was
crystallized from methanol as colorless needles (m.p. 494–495 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 refinements. The known configuration of the
parent molecule was used to define the enantiomer of the final model. All H
atoms were initially found in a difference Fourier synthesis. In order to
maximize the data/parameter ratio, the H atoms were placed in geometrically
idealized positions (C—H = 0.93–0.98Å, O—H = 0.82Å and N—H =
0.86Å) and constrained to ride on their parent atoms [Uiso(H)=
1.2Ueq(C) = Ueq(N) and 1.5Ueq(O).
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).
4-amino-5-fluoro-7-(
β-D-ribofuranosyl)-7
H-
pyrrolo[2,3-
d]pyrimidine
top
Crystal data top
C11H13FN4O4 | F(000) = 592 |
Mr = 284.25 | Dx = 1.549 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 52 reflections |
a = 4.9394 (13) Å | θ = 2.4–22.4° |
b = 14.6718 (19) Å | µ = 0.13 mm−1 |
c = 16.8181 (16) Å | T = 293 K |
V = 1218.8 (4) Å3 | Needle, colourless |
Z = 4 | 0.5 × 0.3 × 0.2 mm |
Data collection top
Bruker P4 diffractometer | Rint = 0.025 |
Radiation source: fine-focus sealed tube | θmax = 27.0°, θmin = 1.8° |
Graphite monochromator | h = −6→1 |
2θ/ω scans | k = −18→1 |
2181 measured reflections | l = −1→21 |
1580 independent reflections | 3 standard reflections every 97 reflections |
1438 reflections with I > 2σ(I) | intensity decay: none |
Refinement top
Refinement on F2 | Hydrogen site location: inferred from neighbouring sites |
Least-squares matrix: full | H-atom parameters constrained |
R[F2 > 2σ(F2)] = 0.039 | w = 1/[σ2(Fo2) + (0.0475P)2 + 0.4749P] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.107 | (Δ/σ)max < 0.001 |
S = 1.10 | Δρmax = 0.22 e Å−3 |
1580 reflections | Δρmin = −0.20 e Å−3 |
185 parameters | Extinction correction: SHELXTL (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
0 restraints | Extinction coefficient: 0.014 (3) |
Primary atom site location: structure-invariant direct methods | Absolute structure: establisched by known chemical absolute configuration |
Secondary atom site location: difference Fourier map | |
Crystal data top
C11H13FN4O4 | V = 1218.8 (4) Å3 |
Mr = 284.25 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 4.9394 (13) Å | µ = 0.13 mm−1 |
b = 14.6718 (19) Å | T = 293 K |
c = 16.8181 (16) Å | 0.5 × 0.3 × 0.2 mm |
Data collection top
Bruker P4 diffractometer | Rint = 0.025 |
2181 measured reflections | 3 standard reflections every 97 reflections |
1580 independent reflections | intensity decay: none |
1438 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.039 | 0 restraints |
wR(F2) = 0.107 | H-atom parameters constrained |
S = 1.10 | Δρmax = 0.22 e Å−3 |
1580 reflections | Δρmin = −0.20 e Å−3 |
185 parameters | Absolute structure: establisched by known chemical absolute configuration |
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 | 0.2075 (6) | 0.23532 (15) | 0.25078 (14) | 0.0352 (6) | |
C2 | 0.1758 (6) | 0.14486 (18) | 0.25525 (16) | 0.0327 (6) | |
H2 | 0.0488 | 0.1202 | 0.2205 | 0.039* | |
N3 | 0.2996 (5) | 0.08544 (14) | 0.30212 (13) | 0.0300 (5) | |
C4 | 0.4782 (6) | 0.12533 (17) | 0.35141 (14) | 0.0260 (5) | |
C5 | 0.5333 (6) | 0.21937 (16) | 0.35384 (14) | 0.0281 (5) | |
C6 | 0.3855 (6) | 0.27452 (17) | 0.30116 (15) | 0.0302 (6) | |
N6 | 0.4134 (6) | 0.36538 (15) | 0.29766 (15) | 0.0413 (7) | |
H6A | 0.3196 | 0.3964 | 0.2642 | 0.050* | |
H6B | 0.5251 | 0.3926 | 0.3289 | 0.050* | |
C7 | 0.7356 (6) | 0.22930 (17) | 0.41226 (16) | 0.0310 (6) | |
F7 | 0.8474 (4) | 0.31034 (11) | 0.43370 (12) | 0.0486 (5) | |
C8 | 0.7976 (6) | 0.14735 (17) | 0.44374 (17) | 0.0326 (6) | |
H8 | 0.9254 | 0.1362 | 0.4832 | 0.039* | |
N9 | 0.6354 (5) | 0.08245 (14) | 0.40646 (13) | 0.0285 (5) | |
C1' | 0.6578 (6) | −0.01487 (16) | 0.41729 (15) | 0.0262 (5) | |
H1' | 0.5292 | −0.0455 | 0.3818 | 0.031* | |
C2' | 0.9388 (5) | −0.05223 (16) | 0.40231 (14) | 0.0244 (5) | |
H2'1 | 1.0740 | −0.0100 | 0.4238 | 0.029* | |
O2' | 0.9889 (5) | −0.06665 (12) | 0.32045 (10) | 0.0335 (5) | |
H2' | 1.0963 | −0.0283 | 0.3043 | 0.050* | |
C3' | 0.9395 (6) | −0.13988 (16) | 0.45067 (15) | 0.0288 (6) | |
H3'1 | 1.1237 | −0.1587 | 0.4648 | 0.035* | |
O3' | 0.7967 (5) | −0.21047 (12) | 0.41137 (12) | 0.0408 (5) | |
H3' | 0.8474 | −0.2137 | 0.3650 | 0.061* | |
C4' | 0.7767 (6) | −0.11186 (17) | 0.52391 (15) | 0.0302 (6) | |
H4' | 0.6652 | −0.1638 | 0.5404 | 0.036* | |
O4' | 0.5963 (4) | −0.03845 (13) | 0.49768 (11) | 0.0339 (5) | |
C5' | 0.9376 (7) | −0.07980 (19) | 0.59485 (16) | 0.0366 (6) | |
H5'1 | 0.8127 | −0.0651 | 0.6375 | 0.044* | |
H5'2 | 1.0511 | −0.1296 | 0.6130 | 0.044* | |
O5' | 1.1047 (5) | −0.00242 (14) | 0.58021 (13) | 0.0400 (5) | |
H5' | 1.2411 | −0.0184 | 0.5562 | 0.060* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
N1 | 0.0427 (14) | 0.0299 (11) | 0.0330 (11) | 0.0007 (12) | −0.0081 (12) | 0.0049 (9) |
C2 | 0.0344 (15) | 0.0313 (12) | 0.0325 (12) | −0.0051 (13) | −0.0074 (13) | 0.0026 (10) |
N3 | 0.0314 (11) | 0.0276 (10) | 0.0309 (11) | −0.0047 (10) | −0.0031 (10) | 0.0035 (9) |
C4 | 0.0271 (12) | 0.0243 (11) | 0.0265 (11) | 0.0006 (11) | 0.0032 (11) | 0.0024 (9) |
C5 | 0.0324 (13) | 0.0242 (11) | 0.0276 (11) | −0.0010 (11) | 0.0010 (12) | −0.0010 (9) |
C6 | 0.0365 (14) | 0.0246 (11) | 0.0294 (12) | 0.0007 (11) | 0.0010 (13) | 0.0012 (10) |
N6 | 0.0555 (17) | 0.0236 (10) | 0.0448 (13) | 0.0022 (12) | −0.0147 (14) | 0.0048 (10) |
C7 | 0.0321 (14) | 0.0243 (11) | 0.0366 (14) | 0.0009 (11) | −0.0072 (13) | −0.0045 (10) |
F7 | 0.0583 (12) | 0.0267 (8) | 0.0609 (11) | −0.0015 (9) | −0.0255 (10) | −0.0064 (7) |
C8 | 0.0343 (14) | 0.0274 (12) | 0.0362 (13) | 0.0054 (12) | −0.0099 (13) | −0.0037 (10) |
N9 | 0.0294 (11) | 0.0228 (10) | 0.0332 (10) | 0.0019 (9) | −0.0050 (11) | 0.0016 (8) |
C1' | 0.0268 (12) | 0.0219 (11) | 0.0299 (12) | −0.0022 (10) | −0.0020 (12) | 0.0035 (9) |
C2' | 0.0258 (12) | 0.0206 (10) | 0.0267 (11) | −0.0021 (10) | −0.0002 (11) | −0.0011 (9) |
O2' | 0.0413 (12) | 0.0314 (9) | 0.0279 (8) | −0.0099 (9) | 0.0065 (9) | −0.0022 (7) |
C3' | 0.0342 (14) | 0.0203 (10) | 0.0318 (12) | −0.0010 (11) | −0.0035 (12) | −0.0009 (9) |
O3' | 0.0627 (14) | 0.0247 (9) | 0.0350 (10) | −0.0122 (10) | −0.0016 (11) | −0.0015 (8) |
C4' | 0.0375 (15) | 0.0225 (11) | 0.0307 (12) | −0.0002 (11) | 0.0006 (12) | 0.0061 (9) |
O4' | 0.0310 (10) | 0.0355 (10) | 0.0354 (10) | 0.0057 (9) | 0.0083 (10) | 0.0091 (8) |
C5' | 0.0436 (16) | 0.0338 (13) | 0.0323 (12) | 0.0018 (14) | −0.0026 (14) | −0.0006 (11) |
O5' | 0.0351 (11) | 0.0389 (11) | 0.0461 (11) | −0.0043 (10) | 0.0027 (11) | −0.0128 (9) |
Geometric parameters (Å, º) top
N1—C2 | 1.339 (3) | C1'—C2' | 1.513 (4) |
N1—C6 | 1.350 (4) | C1'—H1' | 0.9800 |
C2—N3 | 1.325 (3) | C2'—O2' | 1.415 (3) |
C2—H2 | 0.9300 | C2'—C3' | 1.522 (3) |
N3—C4 | 1.345 (4) | C2'—H2'1 | 0.9800 |
C4—N9 | 1.362 (3) | O2'—H2' | 0.8200 |
C4—C5 | 1.407 (3) | C3'—O3' | 1.417 (3) |
C5—C6 | 1.405 (4) | C3'—C4' | 1.527 (4) |
C5—C7 | 1.409 (4) | C3'—H3'1 | 0.9800 |
C6—N6 | 1.341 (3) | O3'—H3' | 0.8200 |
N6—H6A | 0.8600 | C4'—O4' | 1.466 (3) |
N6—H6B | 0.8600 | C4'—C5' | 1.509 (4) |
C7—C8 | 1.349 (4) | C4'—H4' | 0.9800 |
C7—F7 | 1.360 (3) | C5'—O5' | 1.425 (4) |
C8—N9 | 1.394 (4) | C5'—H5'1 | 0.9700 |
C8—H8 | 0.9300 | C5'—H5'2 | 0.9700 |
N9—C1' | 1.444 (3) | O5'—H5' | 0.8200 |
C1'—O4' | 1.428 (3) | | |
| | | |
C2—N1—C6 | 117.6 (2) | N9—C1'—H1' | 109.1 |
N3—C2—N1 | 129.2 (3) | C2'—C1'—H1' | 109.1 |
N3—C2—H2 | 115.4 | O2'—C2'—C1' | 112.1 (2) |
N1—C2—H2 | 115.4 | O2'—C2'—C3' | 113.2 (2) |
C2—N3—C4 | 112.5 (2) | C1'—C2'—C3' | 102.7 (2) |
N3—C4—N9 | 126.3 (2) | O2'—C2'—H2'1 | 109.6 |
N3—C4—C5 | 124.9 (2) | C1'—C2'—H2'1 | 109.6 |
N9—C4—C5 | 108.8 (2) | C3'—C2'—H2'1 | 109.6 |
C6—C5—C4 | 116.5 (2) | C2'—O2'—H2' | 109.5 |
C6—C5—C7 | 138.5 (2) | O3'—C3'—C2' | 111.6 (2) |
C4—C5—C7 | 105.0 (2) | O3'—C3'—C4' | 108.1 (2) |
N6—C6—N1 | 117.6 (3) | C2'—C3'—C4' | 101.7 (2) |
N6—C6—C5 | 123.1 (3) | O3'—C3'—H3'1 | 111.7 |
N1—C6—C5 | 119.3 (2) | C2'—C3'—H3'1 | 111.7 |
C6—N6—H6A | 120.0 | C4'—C3'—H3'1 | 111.7 |
C6—N6—H6B | 120.0 | C3'—O3'—H3' | 109.5 |
H6A—N6—H6B | 120.0 | O4'—C4'—C5' | 109.2 (2) |
C8—C7—F7 | 125.7 (2) | O4'—C4'—C3' | 105.96 (19) |
C8—C7—C5 | 110.0 (2) | C5'—C4'—C3' | 116.4 (2) |
F7—C7—C5 | 124.3 (2) | O4'—C4'—H4' | 108.3 |
C7—C8—N9 | 107.6 (2) | C5'—C4'—H4' | 108.3 |
C7—C8—H8 | 126.2 | C3'—C4'—H4' | 108.3 |
N9—C8—H8 | 126.2 | C1'—O4'—C4' | 109.5 (2) |
C4—N9—C8 | 108.5 (2) | O5'—C5'—C4' | 114.6 (2) |
C4—N9—C1' | 125.9 (2) | O5'—C5'—H5'1 | 108.6 |
C8—N9—C1' | 125.1 (2) | C4'—C5'—H5'1 | 108.6 |
O4'—C1'—N9 | 110.0 (2) | O5'—C5'—H5'2 | 108.6 |
O4'—C1'—C2' | 105.4 (2) | C4'—C5'—H5'2 | 108.6 |
N9—C1'—C2' | 114.0 (2) | H5'1—C5'—H5'2 | 107.6 |
O4'—C1'—H1' | 109.1 | C5'—O5'—H5' | 109.5 |
| | | |
C6—N1—C2—N3 | −1.3 (5) | C7—C8—N9—C4 | 1.0 (3) |
N1—C2—N3—C4 | 0.7 (5) | C7—C8—N9—C1' | 173.4 (3) |
C2—N3—C4—N9 | 179.8 (3) | C4—N9—C1'—O4' | −124.7 (3) |
C2—N3—C4—C5 | −0.5 (4) | C8—N9—C1'—O4' | 64.2 (4) |
N3—C4—C5—C6 | 1.0 (4) | C4—N9—C1'—C2' | 117.2 (3) |
N9—C4—C5—C6 | −179.3 (2) | C8—N9—C1'—C2' | −54.0 (4) |
N3—C4—C5—C7 | −178.6 (3) | O4'—C1'—C2'—O2' | 157.02 (19) |
N9—C4—C5—C7 | 1.1 (3) | N9—C1'—C2'—O2' | −82.2 (3) |
C2—N1—C6—N6 | −178.8 (3) | O4'—C1'—C2'—C3' | 35.3 (2) |
C2—N1—C6—C5 | 1.7 (4) | N9—C1'—C2'—C3' | 156.0 (2) |
C4—C5—C6—N6 | 178.9 (3) | O2'—C2'—C3'—O3' | −43.4 (3) |
C7—C5—C6—N6 | −1.6 (6) | C1'—C2'—C3'—O3' | 77.6 (3) |
C4—C5—C6—N1 | −1.6 (4) | O2'—C2'—C3'—C4' | −158.5 (2) |
C7—C5—C6—N1 | 177.8 (3) | C1'—C2'—C3'—C4' | −37.4 (2) |
C6—C5—C7—C8 | −180.0 (3) | O3'—C3'—C4'—O4' | −90.5 (2) |
C4—C5—C7—C8 | −0.5 (3) | C2'—C3'—C4'—O4' | 27.0 (3) |
C6—C5—C7—F7 | 0.7 (6) | O3'—C3'—C4'—C5' | 147.9 (2) |
C4—C5—C7—F7 | −179.8 (3) | C2'—C3'—C4'—C5' | −94.6 (3) |
F7—C7—C8—N9 | 179.0 (3) | N9—C1'—O4'—C4' | −141.9 (2) |
C5—C7—C8—N9 | −0.3 (3) | C2'—C1'—O4'—C4' | −18.5 (3) |
N3—C4—N9—C8 | 178.4 (3) | C5'—C4'—O4'—C1' | 120.4 (2) |
C5—C4—N9—C8 | −1.3 (3) | C3'—C4'—O4'—C1' | −5.6 (3) |
N3—C4—N9—C1' | 6.0 (4) | O4'—C4'—C5'—O5' | −60.5 (3) |
C5—C4—N9—C1' | −173.7 (3) | C3'—C4'—C5'—O5' | 59.3 (3) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N6—H6A···O2′i | 0.86 | 2.15 | 2.982 (3) | 161 |
N6—H6B···O5′ii | 0.86 | 2.26 | 3.026 (3) | 149 |
O2′—H2′···N3iii | 0.82 | 1.95 | 2.726 (3) | 158 |
O3′—H3′···N1iv | 0.82 | 2.10 | 2.841 (3) | 149 |
O5′—H5′···O4′iii | 0.82 | 2.03 | 2.846 (3) | 172 |
Symmetry codes: (i) −x+1, y+1/2, −z+1/2; (ii) x−1/2, −y+1/2, −z+1; (iii) x+1, y, z; (iv) −x+1, y−1/2, −z+1/2. |
Experimental details
Crystal data |
Chemical formula | C11H13FN4O4 |
Mr | 284.25 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 293 |
a, b, c (Å) | 4.9394 (13), 14.6718 (19), 16.8181 (16) |
V (Å3) | 1218.8 (4) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.13 |
Crystal size (mm) | 0.5 × 0.3 × 0.2 |
|
Data collection |
Diffractometer | Bruker P4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 2181, 1580, 1438 |
Rint | 0.025 |
(sin θ/λ)max (Å−1) | 0.639 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.039, 0.107, 1.10 |
No. of reflections | 1580 |
No. of parameters | 185 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.22, −0.20 |
Absolute structure | Establisched by known chemical absolute configuration |
Selected geometric parameters (Å, º) topC5—C7 | 1.409 (4) | C7—F7 | 1.360 (3) |
C7—C8 | 1.349 (4) | N9—C1' | 1.444 (3) |
| | | |
C8—C7—F7 | 125.7 (2) | F7—C7—C5 | 124.3 (2) |
C8—C7—C5 | 110.0 (2) | | |
| | | |
C2—N1—C6—N6 | −178.8 (3) | F7—C7—C8—N9 | 179.0 (3) |
C4—C5—C6—N6 | 178.9 (3) | C4—N9—C1'—O4' | −124.7 (3) |
C7—C5—C6—N6 | −1.6 (6) | C8—N9—C1'—O4' | 64.2 (4) |
C6—C5—C7—F7 | 0.7 (6) | O4'—C4'—C5'—O5' | −60.5 (3) |
C4—C5—C7—F7 | −179.8 (3) | C3'—C4'—C5'—O5' | 59.3 (3) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N6—H6A···O2'i | 0.86 | 2.15 | 2.982 (3) | 161.2 |
N6—H6B···O5'ii | 0.86 | 2.26 | 3.026 (3) | 149.0 |
O2'—H2'···N3iii | 0.82 | 1.95 | 2.726 (3) | 158.1 |
O3'—H3'···N1iv | 0.82 | 2.10 | 2.841 (3) | 149.4 |
O5'—H5'···O4'iii | 0.82 | 2.03 | 2.846 (3) | 171.5 |
Symmetry codes: (i) −x+1, y+1/2, −z+1/2; (ii) x−1/2, −y+1/2, −z+1; (iii) x+1, y, z; (iv) −x+1, y−1/2, −z+1/2. |
The naturally occurring nucleoside antibiotic tubercidin is a close structural analogue of adenosine and shows significant biological activities (Suhadolnik, 1970, and references therein). 50 years ago, tubercidin was isolated from Streptomyces tubercidicus (Anzai et al., 1957), while its crystal structure was reported by Stroud and Abola & Sundaralingam in 1973 (Stroud, 1973; Abola & Sundaralingam, 1973). A series of 7-substituted tubercidin derivatives (purine numbering is used throughout this 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). Moreover, 2'-C-methyltubercidin, as well as its 7-fluoro derivative, are potent and selective inhibitors of hepatitis C virus (HCV) RNA replication (Olsen et al., 2004; Eldrup et al., 2004).
The introduction of an F atom as a substituent of the sugar residue or of the heterocyclic ring moiety of nucleosides has a positive effect on the biological activity. A number of fluorine-substituted analogues of nucleic acid components were established as antiviral, anticancer and antifungal agents (Pankiewicz, 2000). Recently, Wang et al. (2004) reported the synthesis and characteristics of 7-fluorotubercidin, (I), which exhibits reduced cytotoxicity compared to its parent derivative tubercidin.
Due to the favorable biological activity of 7-fluorotubercidin, (I), we became interested in performing a single-crystal X-ray analysis of (I) and comparing the solid-state structure with closely related nucleosides. The parent tubercidin, (IIa) (Stroud, 1973; Abola & Sundaralingam, 1973), 2'-deoxytubercidin, (IIb) (Zabel et al., 1987), 7-fluoro-2'-deoxytubercidin, (IIc) (Seela et al., 2005), 2'-deoxy-2-fluorotubercidin, (III) (Seela et al., 2007), as well as the difluorinated tubercidin analogue (IV) (Seela et al., 2006), were selected for comparison.
Compound (I) was synthesized according to the `one-pot' Vorbrüggen glycosylation protocol recently reported by Wang et al. (2004) and was crystallized from methanol as colorless needles. The three-dimensional structure of (I) is shown in Fig. 1 and selected geometric parameters are listed in Table 1.
From the crystal structure of (I), the orientation of the nucleobase relative to the sugar moiety was determined to be in the anti range, with χ (O4'—C1'–N9—C4) = -124.7 (3)° according to IUPAC–IUB (Joint Commission on Biochemical Nomenclature, 1983). The glycosylic bond conformation of the parent unsubstituted compound, (IIa), as well as that of the difluorinated nucleoside (IV) adopt, χ values within the same anti range, with χ values of -112.8 (4)° for (IIa) (Abola & Sundaralingam, 1973) and -117.8 (2)° for (IV) (Seela et al., 2006). For comparison, the conformation of the 2'-deoxyribonucleoside analogues (IIb), (IIc) and (III) fall into the range between anti and high-anti [χ values of -104.4 (2)° for (IIb) (Zabel et al., 1987), -101.1 (3)° for (IIc) (Seela et al., 2005) and -110.2 (3)° for (III) (Seela et al., 2007)]. The glycosylic bond length (N9—C1') in (I) is 1.444 (3)Å, which is identical to that in (IIc) [1.444 (4)Å; Seela et al., 2005].
The most frequently observed sugar ring conformations of nucleosides are C2'-endo (`south') and C3'-endo (`north') (Arnott & Hukins, 1972). The sugar moiety of nucleoside (I) shows an S conformation with an unsymmetrical twist of C2'-endo–C3'-exo (2T3), a pseudorotation phase angle, P (Rao et al., 1981), of 169.8 (3)° with the maximum amplitude of pucker, τm, of 38.7 (2)°. This is very similar to compound (IIc) which also has a 2T3 sugar conformation (P = 164.7 (3)°; Seela et al., 2005). In the case of the parent unsubstituted compound, (IIa), and closely related (IIb), the sugar ring conformation is C2'-endo–C1'-exo (2T1; S conformation), with P = 149.3° and P = 186.6 (2)° (Abola & Sundaralingam, 1973; Zabel et al., 1987). In contrast, an N conformation was observed for difluorinated compound (IV) (C4'-exo, between 3T4 and E4, with P = 45.3°; Seela et al., 2006) and nucleoside (III) (C3'-endo–C4'-exo, with P = 40.3°; Seela et al., 2007). From the examples mentioned above, it can be seen that the sugar conformation obtained for nucleosides in the solid state do not reflect the sugar conformations found in DNA or RNA. The S conformation of the sugar moiety of ribonucleoside (I) is in contrast to the N sugar conformation of RNA.
The sugar conformation of nucleoside (I) was also determined in solution and compared to the conformation of the parent tubercidin (IIa). In solution, both compounds show a predominantly S conformation [85% S for (I) and 88% S for (IIa)], which is consistent with their sugar conformation in solid state. The conformation analysis was performed on the basis of the vicinal 3J(H,H) coupling constants of 1H NMR spectra measured in D2O, applying the program PSEUROT6.3 (Van Wijk et al., 1999).
The conformation about the exocyclic C4'—C5' bond, which is defined by the torsion angle γ (O5'—C5'—C4'—C3'), is 59.3 (3)° for (I), representing a +sc (gauche, gauche) conformation, whereas in the parent (IIa) and in compound (IIb), the C4'—C5' bond shows an ap (gauche, trans) conformation [(IIa): γ = -178.3 (4)°; (IIb): γ = -179.6 (2)°] (Abola & Sundaralingam, 1973; Zabel et al., 1987).
The 7-deazapurine ring system is nearly planar. The r.m.s. deviation of the ring atoms from their calculated least-squares planes is 0.0103Å, with a maximum deviation of 0.0159 (2)Å for atom C6. The F7 substituent of (I) lies -0.0142 (8)Å below and atom N6 of the amino group lies 0.0379 (3)Å above this plane. The C5—C7 [1.409 (4)Å] and C7—C8 [1.349 (4)Å] bond lengths in (I) are shorter than those in the parent (IIa) [C5—C7 = 1.433 (4)Å and C7—C8 = 1.359 (5)Å; Abola & Sundaralingam, 1973]. This might be caused by the strong electron-withdrawing effect of the 7-fluoro substituent.
In the close-packed network of (I), both the nucleobases and sugar residues are stacked. The bases are arranged head-to-head. The structure is stabilized by several hydrogen bonds, leading to a three-dimensional layered network (Fig. 2 and Table 2). In the solid-state structure of nucleoside (I), the distance of each atom between neighboring sheets is 3.264Å, which is less than the average base-pair stacking distance in B-DNA (3.5Å). Hydrogen bonds are mainly formed between adjacent nucleobases and sugar moieties. N6—H6A···O2' and O3'—H3'···N1 hydrogen bonds are formed within each sheet, while N6—H6B···O5', O2'—H2'···N3 and O5'—H5'A···O4' hydrogen bonds connect neighboring sheets. Contrary to nucleoside (IIc), the 7-fluoro substituent does not take part in hydrogen-bond formation (Seela et al., 2005).