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Acta Crystallogr Sect E Struct Rep Online. 2010 June 1; 66(Pt 6): o1317.
Published online 2010 May 12. doi:  10.1107/S1600536810016065
PMCID: PMC2979416

5-Fluoro-1-[(4S,5R)-5-(2-hydroxy­ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrimidine-2,4(1H,3H)-dione

Abstract

In the title compound, C11H15FN2O5, the five-membered ring has an envelope conformation, while the six-membered ring is essentially planar, with a maximum deviation of 0.032 (2) Å from the mean plane. The crystal packing is stabilized by inter­molecular N—H(...)O and O—H(...)O hydrogen bonds, generating a layer structure parallel to (001).

Related literature

For applications of modified nucleosides in medical chemistry, see: Huryn & Okabe (1992 [triangle]); Minuk et al. (1992 [triangle]); Luscombe et al. (1996 [triangle]); Korba & Boyd (1996 [triangle]). For the synthesis, see: Valdivia et al. (2005 [triangle]); Xie et al. (1996 [triangle]). For ring conformation analysis, see: Cremer & Pople (1975 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o1317-scheme1.jpg

Experimental

Crystal data

  • C11H15FN2O5
  • M r = 274.25
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1317-efi1.jpg
  • a = 20.8905 (8) Å
  • b = 5.5751 (1) Å
  • c = 13.5639 (5) Å
  • β = 126.297 (6)°
  • V = 1273.21 (12) Å3
  • Z = 4
  • Cu Kα radiation
  • μ = 1.06 mm−1
  • T = 298 K
  • 0.40 × 0.12 × 0.08 mm

Data collection

  • Oxford Diffraction Gemini Atlas CCD diffractometer
  • Absorption correction: analytical (CrysAlis RED; Oxford Diffraction, 2009 [triangle]) T min = 0.885, T max = 0.964
  • 4606 measured reflections
  • 1786 independent reflections
  • 1732 reflections with I > 2σ(I)
  • R int = 0.013

Refinement

  • R[F 2 > 2σ(F 2)] = 0.027
  • wR(F 2) = 0.071
  • S = 1.04
  • 1786 reflections
  • 181 parameters
  • 1 restraint
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.23 e Å−3
  • Δρmin = −0.20 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 498 Friedel pairs
  • Flack parameter: 0.0 (2)

Data collection: CrysAlis CCD (Oxford Diffraction, 2009 [triangle]); cell refinement: CrysAlis RED (Oxford Diffraction, 2009 [triangle]); data reduction: CrysAlis RED; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 [triangle]); software used to prepare material for publication: WinGX (Farrugia, 1999 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810016065/is2543sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810016065/is2543Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

Special thanks to BUAP for financial support.

supplementary crystallographic information

Comment

For many years, design of modified nucleosides has been a focal point of research in medicinal chemistry (Huryn & Okabe, 1992). Modified nucleosides have acquired an important role as therapeutic agents for the treatment of patients with devastating infections with viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and herpes viruses. A class of nucleoside analogues for antiviral chemotherapy is that where cyclic carbohydrate moiety is replaced with open-chain "acyclic" sugar moieties. Among purine acyclic nucleosides, are Acyclovir, Ganciclovir and Penciclovir (Minuk et al., 1992; Luscombe et al., 1996; Korba & Boyd, 1996).

In this context and as result of our continuing investigations on the synthesis of nucleoside analogues, we report a new compound 1 (Scheme 1). This new analogue might present a similarity with a number of acyclic nucleosides, which showed remarkable antiviral properties.

In the present paper, we report the structure of title compound 1. In the [(1'S, 2'R)-(1', 2'-O-isopropylidene-4'-hydroxy-1-butyl)], the five member ring (C5/C6/O3/O4/C9) shows an envelope conformation on atom C6 with puckering parameters (Cremer & Pople, 1975) q2 = 0.238 (2) Å and [var phi]2 = 69.8 (6)°. For the six member ring uracil, shows a planar configuration with torsion angle (N1—C4—N2—C3) of 4.8 (3)°, and C1—C2 = 1.325 (3) Å and N2—C4 = 1.384 (2) Å (double bond). The crystal packing is stabilized by two intermolecular hydrogen bonds [O5···O2 = 2.828 (2) Å and N2···O5 = 2.876 (2) Å], generating a layer parallel to the (001) plane.

Experimental

Deshomologation of previos nucleoside analogue, 1-[(1'S,2'R,4'S)-(1',2'-O-isopropylidene-4',5'-dihydroxy-1'-pentyl)]-5-fluorouracil, was achieved following non-aqueous protocol (Valdivia et al., 2005; Xie et al., 1996). Reaction was carried out by two steps: a) periodic acid/ethyl acetate, 30 min, b) EtOH/H2O/ NaBH4, 20 min, rt. Final purification of compound 1 was achieved by crystallization from hexane. Yield 80%, white solid, m.p. 184 °C; [α]D -18.51 (c 1.0, CH3OH). 1H NMR (300 MHz, CDCl3/TMS) 1.53 (s, 3H), 1.57 (s, 3H), 1.95 (m, 1H), 2.11 (m, 1H), 3.80 (m, 2H), 4.21 (m, 1H), 5.90 (d, 1H, J = 5.1 Hz), 7.3 (s, 1H). 13C MNR (75 MHz, CDCl3/TMS) 26.9, 27.9, 34.9, 55.8, 58.9, 79.4, 86.8, 111.6, 142.2, 149.5, 157.5.

Refinement

H atoms bonded to N2 and O5 atoms were located in a difference Fourier map and refined with free coordinates and isotropic U parameters. H atoms linked to C atoms were placed in geometrical idealized positions and refined as riding on their parent atoms, with C—H = 0.93–0.98 Å, and with Uiso(H) = 1.2Ueq(C) or 1.5Ueq(C) for methyl groups.

Figures

Fig. 1.
The molecular structure of compound 1, with atom labels and 50% probability displacement ellipsoids for non-H atoms.
Fig. 2.
The packing of compound 1, viewed down the b axis, showing one layer of molecules connected by O5—H···O2 and N2—H···O5 hydrogen bonds (dashed lines).

Crystal data

C11H15FN2O5F(000) = 576
Mr = 274.25Dx = 1.431 Mg m3
Monoclinic, C2Cu Kα radiation, λ = 1.54184 Å
Hall symbol: C 2yCell parameters from 4215 reflections
a = 20.8905 (8) Åθ = 4.0–68.0°
b = 5.5751 (1) ŵ = 1.06 mm1
c = 13.5639 (5) ÅT = 298 K
β = 126.297 (6)°Prism, colorless
V = 1273.21 (12) Å30.40 × 0.12 × 0.08 mm
Z = 4

Data collection

Oxford Diffraction Gemini Atlas CCD diffractometer1786 independent reflections
Radiation source: fine-focus sealed tube1732 reflections with I > 2σ(I)
graphiteRint = 0.013
Detector resolution: 10.4685 pixels mm-1θmax = 68.1°, θmin = 4.0°
ω scansh = −22→24
Absorption correction: analytical (CrysAlis RED; Oxford Diffraction, 2009)k = −4→6
Tmin = 0.885, Tmax = 0.964l = −16→16
4606 measured reflections

Refinement

Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.027w = 1/[σ2(Fo2) + (0.038P)2 + 0.4768P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.071(Δ/σ)max < 0.001
S = 1.04Δρmax = 0.23 e Å3
1786 reflectionsΔρmin = −0.19 e Å3
181 parametersExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
1 restraintExtinction coefficient: 0.0075 (4)
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), 498 Friedel pairs
Secondary atom site location: difference Fourier mapFlack parameter: 0.0 (2)

Special details

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'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 > 2σ(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)

xyzUiso*/Ueq
O10.69200 (8)0.0051 (3)0.95722 (12)0.0519 (4)
N10.66380 (8)0.2920 (3)0.81679 (12)0.0339 (3)
O40.72382 (7)0.3751 (3)0.65042 (11)0.0438 (3)
F10.52029 (9)0.7673 (3)0.69645 (15)0.0816 (5)
O50.90402 (9)0.7069 (3)0.88915 (13)0.0478 (4)
O20.49424 (9)0.5250 (3)0.84757 (15)0.0627 (5)
C50.72230 (11)0.1894 (4)0.80156 (17)0.0403 (4)
H50.76090.09500.87450.048*
N20.59707 (9)0.2801 (4)0.90550 (15)0.0434 (4)
C10.61955 (10)0.4901 (4)0.75175 (16)0.0418 (4)
H10.62910.56730.70090.050*
O30.68552 (11)0.0402 (3)0.69943 (16)0.0681 (5)
C40.65428 (10)0.1784 (4)0.89752 (15)0.0362 (4)
C60.76688 (9)0.3754 (4)0.78102 (14)0.0350 (4)
H60.76250.53320.80840.042*
C20.56349 (11)0.5732 (4)0.76007 (18)0.0466 (5)
C30.54650 (10)0.4653 (4)0.83818 (17)0.0435 (5)
C80.89973 (11)0.4915 (4)0.83002 (18)0.0469 (5)
H8A0.95280.43180.86490.056*
H8B0.87330.52060.74350.056*
C70.85368 (10)0.3099 (4)0.84748 (17)0.0437 (5)
H7A0.87790.29480.93420.052*
H7B0.85720.15510.81840.052*
C90.68429 (13)0.1521 (4)0.60232 (19)0.0533 (6)
C100.72705 (17)−0.0147 (5)0.5721 (2)0.0689 (7)
H10A0.6979−0.16210.54000.103*
H10B0.7793−0.04730.64480.103*
H10C0.73130.05880.51210.103*
C110.60061 (17)0.2034 (8)0.4934 (3)0.1094 (13)
H11A0.57250.05500.45920.164*
H11B0.60160.28930.43300.164*
H11C0.57430.29860.51850.164*
H1N0.5950 (12)0.236 (5)0.9622 (19)0.048 (6)*
H1O0.9348 (15)0.789 (6)0.896 (2)0.072 (9)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O10.0606 (7)0.0506 (9)0.0586 (7)0.0216 (7)0.0430 (7)0.0239 (8)
N10.0336 (6)0.0365 (9)0.0345 (7)0.0036 (7)0.0218 (6)0.0044 (6)
O40.0520 (7)0.0397 (8)0.0390 (6)−0.0028 (6)0.0265 (5)0.0009 (6)
F10.0799 (8)0.0748 (11)0.1109 (11)0.0463 (8)0.0678 (8)0.0532 (10)
O50.0529 (8)0.0445 (10)0.0622 (8)−0.0061 (7)0.0430 (7)−0.0071 (7)
O20.0621 (8)0.0584 (11)0.0954 (11)0.0167 (8)0.0619 (8)0.0137 (10)
C50.0465 (9)0.0352 (11)0.0509 (9)0.0048 (9)0.0353 (8)0.0038 (9)
N20.0502 (8)0.0455 (10)0.0498 (8)0.0083 (8)0.0381 (7)0.0092 (8)
C10.0410 (8)0.0437 (12)0.0447 (9)0.0064 (9)0.0275 (7)0.0138 (9)
O30.1087 (12)0.0487 (10)0.0938 (11)−0.0334 (9)0.0857 (10)−0.0292 (9)
C40.0368 (8)0.0390 (11)0.0359 (8)0.0011 (8)0.0232 (7)0.0018 (8)
C60.0397 (8)0.0320 (10)0.0388 (8)0.0022 (8)0.0263 (7)0.0006 (8)
C20.0444 (9)0.0382 (12)0.0563 (11)0.0122 (9)0.0294 (9)0.0139 (9)
C30.0417 (8)0.0401 (12)0.0557 (10)0.0025 (9)0.0326 (8)0.0013 (9)
C80.0430 (9)0.0492 (13)0.0608 (11)0.0008 (10)0.0374 (9)−0.0079 (11)
C70.0400 (9)0.0402 (12)0.0531 (10)0.0056 (9)0.0288 (8)0.0001 (9)
C90.0641 (12)0.0483 (14)0.0551 (11)−0.0145 (11)0.0394 (10)−0.0142 (10)
C100.1132 (18)0.0523 (16)0.0761 (14)−0.0072 (15)0.0752 (15)−0.0113 (13)
C110.0695 (16)0.110 (3)0.086 (2)−0.0123 (19)0.0121 (15)−0.043 (2)

Geometric parameters (Å, °)

O1—C41.206 (2)O3—C91.444 (3)
N1—C11.373 (3)C6—C71.516 (2)
N1—C41.378 (2)C6—H60.9800
N1—C51.471 (2)C2—C31.434 (3)
O4—C91.419 (3)C8—C71.509 (3)
O4—C61.435 (2)C8—H8A0.9700
F1—C21.345 (2)C8—H8B0.9700
O5—C81.417 (3)C7—H7A0.9700
O5—H1O0.75 (3)C7—H7B0.9700
O2—C31.218 (2)C9—C111.504 (4)
C5—O31.393 (3)C9—C101.505 (3)
C5—C61.526 (3)C10—H10A0.9600
C5—H50.9800C10—H10B0.9600
N2—C31.369 (3)C10—H10C0.9600
N2—C41.384 (2)C11—H11A0.9600
N2—H1N0.83 (2)C11—H11B0.9600
C1—C21.325 (3)C11—H11C0.9600
C1—H10.9300
C1—N1—C4121.43 (14)N2—C3—C2112.25 (16)
C1—N1—C5121.47 (14)O5—C8—C7108.20 (15)
C4—N1—C5117.10 (15)O5—C8—H8A110.1
C9—O4—C6109.72 (14)C7—C8—H8A110.1
C8—O5—H1O110 (2)O5—C8—H8B110.1
O3—C5—N1110.92 (16)C7—C8—H8B110.1
O3—C5—C6105.14 (14)H8A—C8—H8B108.4
N1—C5—C6114.14 (16)C8—C7—C6113.23 (17)
O3—C5—H5108.8C8—C7—H7A108.9
N1—C5—H5108.8C6—C7—H7A108.9
C6—C5—H5108.8C8—C7—H7B108.9
C3—N2—C4128.17 (16)C6—C7—H7B108.9
C3—N2—H1N113.4 (16)H7A—C7—H7B107.7
C4—N2—H1N118.1 (16)O4—C9—O3105.54 (16)
C2—C1—N1121.28 (17)O4—C9—C11107.9 (2)
C2—C1—H1119.4O3—C9—C11111.2 (2)
N1—C1—H1119.4O4—C9—C10112.88 (19)
C5—O3—C9110.51 (16)O3—C9—C10106.8 (2)
O1—C4—N1123.91 (16)C11—C9—C10112.5 (2)
O1—C4—N2121.80 (16)C9—C10—H10A109.5
N1—C4—N2114.29 (16)C9—C10—H10B109.5
O4—C6—C7112.88 (14)H10A—C10—H10B109.5
O4—C6—C5102.72 (13)C9—C10—H10C109.5
C7—C6—C5111.86 (15)H10A—C10—H10C109.5
O4—C6—H6109.7H10B—C10—H10C109.5
C7—C6—H6109.7C9—C11—H11A109.5
C5—C6—H6109.7C9—C11—H11B109.5
C1—C2—F1121.20 (18)H11A—C11—H11B109.5
C1—C2—C3122.28 (19)C9—C11—H11C109.5
F1—C2—C3116.51 (17)H11A—C11—H11C109.5
O2—C3—N2121.46 (18)H11B—C11—H11C109.5
O2—C3—C2126.3 (2)
C1—N1—C5—O3−82.0 (2)N1—C5—C6—C7141.06 (16)
C4—N1—C5—O396.83 (19)N1—C1—C2—F1179.91 (19)
C1—N1—C5—C636.5 (2)N1—C1—C2—C31.0 (3)
C4—N1—C5—C6−144.63 (16)C4—N2—C3—O2173.9 (2)
C4—N1—C1—C2−3.0 (3)C4—N2—C3—C2−6.5 (3)
C5—N1—C1—C2175.8 (2)C1—C2—C3—O2−177.1 (2)
N1—C5—O3—C9107.78 (18)F1—C2—C3—O24.0 (3)
C6—C5—O3—C9−16.1 (2)C1—C2—C3—N23.3 (3)
C1—N1—C4—O1−179.53 (18)F1—C2—C3—N2−175.64 (18)
C5—N1—C4—O11.6 (3)O5—C8—C7—C667.2 (2)
C1—N1—C4—N20.4 (3)O4—C6—C7—C865.3 (2)
C5—N1—C4—N2−178.50 (15)C5—C6—C7—C8−179.47 (16)
C3—N2—C4—O1−175.3 (2)C6—O4—C9—O315.2 (2)
C3—N2—C4—N14.8 (3)C6—O4—C9—C11134.1 (2)
C9—O4—C6—C796.42 (19)C6—O4—C9—C10−101.1 (2)
C9—O4—C6—C5−24.21 (19)C5—O3—C9—O41.4 (2)
O3—C5—C6—O424.16 (19)C5—O3—C9—C11−115.3 (2)
N1—C5—C6—O4−97.61 (16)C5—O3—C9—C10121.8 (2)
O3—C5—C6—C7−97.17 (18)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N2—H1N···O5i0.83 (2)2.01 (2)2.828 (2)167 (3)
O5—H1O···O2ii0.75 (3)2.16 (3)2.876 (2)160 (3)

Symmetry codes: (i) −x+3/2, y−1/2, −z+2; (ii) x+1/2, y+1/2, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: IS2543).

References

  • Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc.97, 1354–1358.
  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Farrugia, L. J. (1999). J. Appl. Cryst.32, 837–838.
  • Flack, H. D. (1983). Acta Cryst. A39, 876–881.
  • Huryn, D. M. & Okabe, M. (1992). Chem. Rev.92, 1745–1768.
  • Korba, B. E. & Boyd, M. R. (1996). Antimicrob. Agents Chemother.40, 1282–1284. [PMC free article] [PubMed]
  • Luscombe, C., Pedersen, J., Uren, E. & Locarnini, S. (1996). Hepatology24, 766–773. [PubMed]
  • Minuk, G. Y., German, G. B., Bernstein, C., Benarroch, A., Gauthiar, T. & Sekla, L. (1992). Clin. Invest. Med.15, 506–512. [PubMed]
  • Oxford Diffraction (2009). CrysAlis CCD and CrysAlis RED Oxford Diffraction Ltd, Yarnton, England.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Valdivia, V., Hernández, A., Rivera, A., Sartillo-Piscil, F., Loukaci, A., Fourrey, J.-L. & Quintero, L. (2005). Tetrahedron Lett.46, 6511–6514.
  • Xie, M., Berges, D. A. & Robins, M. (1996). J. Org. Chem.61, 5178–5179.

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