1-(2′,3′-An­hydro-5′-O-benzoyl-β-D-lyxo­furan­soyl)-5-fluoro­uracil

The crystal structure of the title compound, C₁₆H₁₃FN₂O₆, was determined in order to establish the relative stereochemistry between the nucleoside base and the epoxide ring oxy­gen. This analysis allowed us to establish that the relationship of these two groups is cis. The furan­ose ring adopts an envelope conformation in which the oxy­gen is displaced above the plane (°E). The pseudorotational phase angle (P) is 88.5° and the puckering amplitude (τ_m) is 29.8°. The conformation about the C4—C5 bond is gauche–trans (ap) and the nucleoside base adopts the anti orientation.

Key indicators

• Single-crystal X-ray study
• T = 298 K
• Mean [sigma](C-C) = 0.010 Å
• R factor = 0.052
• wR factor = 0.151
• Data-to-parameter ratio = 8.1

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level C:



ABSTM_02  Alert C The ratio of expected to reported Tmax/Tmin(RR') is < 0.90
          Tmin and Tmax reported:      0.834     0.981
          Tmin' and Tmax expected:      0.960     0.991
          RR' =      0.878
          Please check that your absorption correction is appropriate.

REFLT_03
         From the CIF: _diffrn_reflns_theta_max           27.48
         From the CIF: _reflns_number_total               1839
         TEST2: Reflns within _diffrn_reflns_theta_max
         Count of symmetry unique reflns         1939
         Completeness (_total/calc)             94.84%
          Alert C: < 95% complete

General Notes



REFLT_03
         From the CIF: _diffrn_reflns_theta_max           27.48
         From the CIF: _reflns_number_total               1839
         Count of symmetry unique reflns         1939
         Completeness (_total/calc)             94.84%
         TEST3: Check Friedels for noncentro structure
         Estimate of Friedel pairs measured         0
         Fraction of Friedel pairs measured     0.000
         Are heavy atom types Z>Si present           no
          Please check that the estimate of the number of Friedel pairs is
          correct. If it is not, please give the correct count in the
          _publ_section_exptl_refinement section of the submitted CIF.


 0 Alert Level A = Potentially serious problem

 0 Alert Level B = Potential problem

 2 Alert Level C = Please check

---

S1. Comment

2',3'-Anhydro-β-D-lyxofuranosyl nucleosides are important intermediates in the synthesis of nucleoside derivatives. Modification of these structures can be readily done through reactions involving the epoxide moiety (Huryn & Okabe, 1992; Roussev et al., 1997; Miah et al., 1998; Hirota et al., 1999; Hirota et al., 2000). Because nucleophilic opening of the epoxide ring in these compounds usually proceeds such that the nucleophile attacks regioselectively at C3', they have found particular application in the synthesis of β-arabinofuranosyl nucleosides (Codington et al., 1962; Hollenberg et al., 1977). Some 2',3'-anhydro-β-D-lyxofuranosyl nucleosides, or their corresponding 5' triphosphates, have also been shown to possess antiviral activity (Krayevsky et al., 1988; Dimoglo et al., 1997; Webb et al., 1988).

We have recently developed a highly convergent method for the synthesis of 2',3'-anhydro-β-D-lyxofuranosyl nucleosides that proceeds via the coupling of glycosyl sulfoxide (II) and a silylated nucleoside base, e.g. (III), mediated by trifluoromethanesulfonic acid anhydride (Callam et al., 2003). This approach is significantly more efficient than previously developed methods for the synthesis of compounds of this type, of which all have involved the installation of the epoxide ring on a preformed nucleoside. However, unambiguously determining the stereochemistry at the anomeric center in (I) was not possible using NMR spectroscopy and we therefore crystallized this compound so that the structure could be proven. The key issue was the relative stereochemistry between the epoxide oxygen and the nucleoside base.

The structure of (I) in the crystal is given in Fig. 1 and it is clear that there is a cis relationship between the nucleoside base and the epoxide oxygen. This is the relative stereochemistry that would have been predicted for a product formed by condensation of (II) and (III), given previous results on the glycosylation of alcohols by (II) (Gadikota et al., 2003). Note also that the absolute configuration for the structure was assigned on the basis of the known configuration of (II), which was synthesized from D-arabinose (Gadikota et al., 2003). The furanose ring in (I) adopts an envelope conformation, in which the ring oxygen is displaced above the plane (°E). The pseudorotational phase angle (P) is 88.5° and the puckering amplitude (τ_m) is 29.8° (Altona & Sundaralingam, 1972). In this regard, the structure is similar to other 2',3'-anhydro-β-D-lyxofuranosyl nucleotides for which crystal structures have been determined, e.g. (IV) and (V) (Gurskaya et al., 1990, 1996) or for which molecular-mechanics calculations have been carried out, e.g. (IV), (VI) and (VII) (Koole et al., 1991). In these compounds, the furanose and epoxide O atoms are on the same side of the furanose ring, resulting in a boat-like structure. In addition, the five-membered rings in these systems are generally less puckered than other nucleoside derivatives, which typically have τ_m magnitudes in the range 34–40° (Sanger, 1984). Similar structural features have been observed in ab initio and density functional theory calculations on 2,3-anhydro-β-D-lyxofuranosyl glycosides (Callam et al., 2001) and in the crystal structure of a 2,3-anhydro-α-D-lyxofuranosyl thioglycoside (Gallucci et al., 2000).

The orientation about the C4—C5 bond in (I) is gauche–trans (ap) (Sanger, 1984). This bond adopts the same orientation in the crystal structure of (IV) and in low-energy geometries obtained from molecular mechanics calculations of (IV), (VI) and (VII), thus indicating that the presence of the benozate ester on O3 in (I) does not alter the favored rotamer around the C4–C5 bond, as compared to the unprotected nucleosides. In the crystal structure of (V), however, the orientation of this bond differs from that in (I), (IV), (VI) and (VII), which is likely due to the presence of the additional hydroxymethyl group substituent at C4. Finally, in (I) the nucleoside base adopts the anti-conformation, which is the same as in compounds (IV)–(VII).

S2. Experimental

Sulfoxide (II) (0.5 mmol), 2,6-di-tert-butyl-4-methyl pyridine (2.5 mmol), and 4 Å molecular sieves (0.1 g) were dried for 3 h under vacuum in the presence of P₂O₅. To this mixture was added CH₂Cl₂ (10 ml) and the reaction mixture was cooled to 195 K. Triflic anhydride (0.6 mmol) was added and the mixture was stirred for 10 min before a solution of the persilylated nucleoside [(III), 0.6 mmol; Nishimura & Iwai, 1964] in CH₂Cl₂ (1.0 ml) was added dropwise by syringe over 2 min. After 15 min, the reaction mixture turned dark brown–green and a saturated aqueous solution of NaHCO₃ was added, before the solution was allowed to warm to room temperature. The resulting solution was filtered through Celite, dried, filtered, and concentrated, to yield a crude oil that was purified by chromatography (2:1, hexanes/EtOAc), yielding (I) (0.35 mmol, 70%) as an oil. The product was recrystallized from 10:1 dichloromethane–hexane (m.p.: 366–367 K).

S3. Refinement

All H atoms were refined using a riding model, with bond lengths of 0.86 (N—-H), 0.93 (aryl H), 0.97 (CH₂), and 0.98 Å (epoxide ring H). For all H atoms, U_iso(H) = 1.2U_eq(parent). Friedel pair reflections were merged prior to final refinement, as the refined Flack (1983) parameter was meaningless.

Computing details

Data collection: XSCANS (Bruker, 1996); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP (Bruker, 2001); software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. A plot of the molecular structure of (I) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small circles of an arbitrary radius.

1-(2',3'-Anhydro-5'-O-benzoyl-β-D-lyxofuranoyl)-5-fluorouracil

Crystal data

C16H13FN2O6	F(000) = 360
Mr = 348.28	Dx = 1.506 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 96 reflections
a = 7.3537 (8) Å	θ = 2.8–25.3°
b = 5.5149 (8) Å	µ = 0.12 mm^−1
c = 19.290 (2) Å	T = 298 K
β = 100.928 (9)°	Plate, colorless
V = 768.13 (17) Å^3	0.32 × 0.20 × 0.07 mm
Z = 2

Data collection

Bruker P4 diffractometer	980 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.048
Graphite monochromator	θmax = 27.5°, θmin = 2.8°
θ/2θ scans	h = −9→9
Absorption correction: ψ scan (XPREP; Bruker, 2001)	k = −7→7
Tmin = 0.834, Tmax = 0.981	l = −25→25
3910 measured reflections	3 standard reflections every 97 reflections
1839 independent reflections	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)] = 0.052	H-atom parameters constrained
wR(F^2) = 0.151	w = 1/[σ^2(Fo^2) + (0.0707P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
1839 reflections	Δρmax = 0.27 e Å^−3
227 parameters	Δρmin = −0.27 e Å^−3
1 restraint	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.039 (8)

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
F1	0.8732 (4)	−0.4285 (7)	0.19297 (15)	0.0615 (9)
O1	0.5109 (4)	0.3444 (7)	0.18779 (16)	0.0470 (9)
O2	0.2866 (5)	−0.0274 (7)	0.1889 (2)	0.0594 (11)
O3	0.5312 (6)	0.5828 (10)	0.3127 (2)	0.0737 (13)
O4	0.4104 (8)	0.6893 (13)	0.4046 (3)	0.123 (2)
O5	1.0030 (5)	−0.3851 (8)	0.06968 (17)	0.0545 (10)
O6	0.6325 (5)	0.2691 (8)	0.00678 (18)	0.0598 (11)
N1	0.6133 (5)	0.0793 (8)	0.11036 (18)	0.0387 (9)
N2	0.8221 (5)	−0.0490 (8)	0.0413 (2)	0.0451 (11)
H2	0.8733	−0.0263	0.0053	0.054*
C1	0.4609 (6)	0.2329 (10)	0.1215 (2)	0.0415 (11)
H1	0.4393	0.3581	0.0848	0.050*
C2	0.2817 (6)	0.1024 (11)	0.1230 (3)	0.0514 (13)
H2A	0.1991	0.0519	0.0794	0.062*
C3	0.2094 (7)	0.2134 (10)	0.1808 (3)	0.0494 (13)
H3	0.0759	0.2381	0.1769	0.059*
C4	0.3443 (7)	0.4048 (10)	0.2140 (3)	0.0482 (13)
H4	0.2998	0.5653	0.1967	0.058*
C5	0.3866 (8)	0.4056 (13)	0.2916 (3)	0.0682 (17)
H5A	0.2773	0.4485	0.3102	0.082*
H5B	0.4281	0.2464	0.3092	0.082*
C6	0.5287 (10)	0.7106 (14)	0.3701 (3)	0.0715 (18)
C7	0.6879 (10)	0.8800 (13)	0.3863 (3)	0.0686 (17)
C8	0.6836 (12)	1.0581 (15)	0.4361 (3)	0.089 (2)
H8	0.5856	1.0650	0.4602	0.107*
C9	0.8265 (16)	1.2282 (19)	0.4504 (5)	0.114 (3)
H9	0.8222	1.3514	0.4829	0.136*
C10	0.9705 (15)	1.213 (2)	0.4168 (5)	0.117 (3)
H10	1.0666	1.3244	0.4270	0.140*
C11	0.9779 (11)	1.0343 (17)	0.3675 (4)	0.099 (3)
H11	1.0781	1.0268	0.3445	0.118*
C12	0.8366 (10)	0.8664 (15)	0.3522 (3)	0.0764 (19)
H12	0.8415	0.7450	0.3191	0.092*
C13	0.6756 (6)	−0.1014 (10)	0.1576 (2)	0.0416 (11)
H13	0.6256	−0.1180	0.1982	0.050*
C14	0.8082 (6)	−0.2546 (10)	0.1459 (2)	0.0413 (11)
C15	0.8867 (6)	−0.2409 (10)	0.0842 (2)	0.0411 (11)
C16	0.6836 (6)	0.1120 (10)	0.0497 (2)	0.0412 (11)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.0523 (18)	0.065 (2)	0.0735 (19)	0.0231 (18)	0.0278 (14)	0.0224 (19)
O1	0.0360 (17)	0.050 (2)	0.0567 (19)	−0.0027 (17)	0.0123 (14)	−0.0085 (17)
O2	0.049 (2)	0.0325 (19)	0.103 (3)	0.0025 (18)	0.031 (2)	0.006 (2)
O3	0.077 (3)	0.082 (3)	0.066 (2)	−0.012 (3)	0.023 (2)	−0.029 (3)
O4	0.123 (4)	0.152 (6)	0.112 (4)	−0.020 (5)	0.066 (3)	−0.052 (4)
O5	0.0420 (19)	0.060 (2)	0.066 (2)	0.006 (2)	0.0232 (16)	−0.005 (2)
O6	0.049 (2)	0.068 (3)	0.065 (2)	0.007 (2)	0.0185 (17)	0.023 (2)
N1	0.0327 (19)	0.043 (2)	0.0426 (19)	0.005 (2)	0.0116 (16)	0.004 (2)
N2	0.038 (2)	0.056 (3)	0.045 (2)	−0.001 (2)	0.0169 (17)	0.003 (2)
C1	0.035 (2)	0.037 (3)	0.053 (3)	0.001 (2)	0.008 (2)	−0.008 (2)
C2	0.038 (3)	0.046 (3)	0.070 (3)	0.001 (3)	0.010 (2)	−0.009 (3)
C3	0.034 (2)	0.036 (3)	0.080 (4)	0.004 (2)	0.016 (2)	−0.005 (3)
C4	0.043 (3)	0.035 (3)	0.069 (3)	0.009 (2)	0.019 (2)	−0.002 (3)
C5	0.070 (4)	0.068 (4)	0.073 (4)	−0.010 (4)	0.029 (3)	−0.018 (4)
C6	0.086 (5)	0.070 (4)	0.059 (3)	0.010 (4)	0.016 (3)	−0.015 (4)
C7	0.086 (4)	0.064 (4)	0.051 (3)	0.007 (4)	0.002 (3)	−0.006 (3)
C8	0.120 (6)	0.074 (5)	0.067 (4)	0.019 (5)	0.004 (4)	−0.017 (4)
C9	0.162 (10)	0.078 (6)	0.083 (5)	−0.003 (8)	−0.023 (6)	−0.019 (5)
C10	0.129 (9)	0.089 (7)	0.108 (7)	−0.027 (7)	−0.037 (6)	−0.003 (7)
C11	0.090 (5)	0.096 (7)	0.101 (5)	−0.020 (6)	−0.005 (4)	0.005 (5)
C12	0.080 (5)	0.075 (5)	0.071 (4)	−0.002 (4)	0.008 (3)	−0.005 (4)
C13	0.036 (2)	0.044 (3)	0.048 (2)	0.008 (2)	0.017 (2)	0.006 (2)
C14	0.036 (2)	0.043 (3)	0.047 (2)	0.007 (3)	0.014 (2)	0.010 (3)
C15	0.033 (2)	0.043 (3)	0.049 (3)	0.000 (3)	0.011 (2)	−0.003 (3)
C16	0.030 (2)	0.045 (3)	0.048 (3)	−0.002 (2)	0.006 (2)	0.004 (3)

Geometric parameters (Å, º)

F1—C14	1.344 (6)	C3—H3	0.980
O1—C1	1.404 (5)	C4—C5	1.469 (7)
O1—C4	1.450 (6)	C4—H4	0.980
O2—C3	1.441 (6)	C5—H5A	0.970
O2—C2	1.452 (7)	C5—H5B	0.970
O3—C6	1.315 (7)	C6—C7	1.484 (10)
O3—C5	1.445 (8)	C7—C8	1.378 (9)
O4—C6	1.197 (8)	C7—C12	1.382 (9)
O5—C15	1.238 (6)	C8—C9	1.396 (12)
O6—C16	1.208 (6)	C8—H8	0.930
N1—C13	1.370 (6)	C9—C10	1.345 (12)
N1—C16	1.377 (6)	C9—H9	0.930
N1—C1	1.453 (6)	C10—C11	1.377 (13)
N2—C15	1.372 (6)	C10—H10	0.930
N2—C16	1.384 (6)	C11—C12	1.381 (10)
N2—H2	0.860	C11—H11	0.930
C1—C2	1.507 (7)	C12—H12	0.930
C1—H1	0.980	C13—C14	1.341 (7)
C2—C3	1.457 (7)	C13—H13	0.930
C2—H2A	0.980	C14—C15	1.420 (6)
C3—C4	1.506 (8)
C1—O1—C4	109.0 (3)	O3—C5—H5B	110.3
C3—O2—C2	60.5 (3)	C4—C5—H5B	110.3
C6—O3—C5	118.3 (5)	H5A—C5—H5B	108.6
C13—N1—C16	121.9 (4)	O4—C6—O3	122.9 (7)
C13—N1—C1	119.7 (4)	O4—C6—C7	124.9 (6)
C16—N1—C1	118.2 (4)	O3—C6—C7	112.2 (5)
C15—N2—C16	127.1 (4)	C8—C7—C12	119.7 (7)
C15—N2—H2	116.5	C8—C7—C6	118.3 (7)
C16—N2—H2	116.5	C12—C7—C6	122.0 (6)
O1—C1—N1	108.3 (3)	C7—C8—C9	120.0 (8)
O1—C1—C2	105.7 (4)	C7—C8—H8	120.0
N1—C1—C2	115.2 (4)	C9—C8—H8	120.0
O1—C1—H1	109.2	C10—C9—C8	119.6 (9)
N1—C1—H1	109.2	C10—C9—H9	120.2
C2—C1—H1	109.2	C8—C9—H9	120.2
O2—C2—C3	59.4 (3)	C9—C10—C11	121.1 (10)
O2—C2—C1	112.1 (4)	C9—C10—H10	119.5
C3—C2—C1	105.2 (4)	C11—C10—H10	119.5
O2—C2—H2A	121.3	C10—C11—C12	120.0 (9)
C3—C2—H2A	121.3	C10—C11—H11	120.0
C1—C2—H2A	121.3	C12—C11—H11	120.0
O2—C3—C2	60.1 (4)	C11—C12—C7	119.6 (7)
O2—C3—C4	112.7 (4)	C11—C12—H12	120.2
C2—C3—C4	108.3 (4)	C7—C12—H12	120.2
O2—C3—H3	120.3	C14—C13—N1	120.6 (4)
C2—C3—H3	120.3	C14—C13—H13	119.7
C4—C3—H3	120.3	N1—C13—H13	119.7
O1—C4—C5	109.0 (4)	C13—C14—F1	120.8 (4)
O1—C4—C3	102.8 (4)	C13—C14—C15	122.1 (4)
C5—C4—C3	115.5 (5)	F1—C14—C15	117.1 (4)
O1—C4—H4	109.7	O5—C15—N2	122.3 (4)
C5—C4—H4	109.7	O5—C15—C14	124.3 (5)
C3—C4—H4	109.7	N2—C15—C14	113.4 (4)
O3—C5—C4	107.0 (5)	O6—C16—N1	124.0 (5)
O3—C5—H5A	110.3	O6—C16—N2	121.3 (4)
C4—C5—H5A	110.3	N1—C16—N2	114.7 (4)
C4—O1—C1—N1	−154.4 (4)	O3—C6—C7—C8	167.2 (6)
C4—O1—C1—C2	−30.4 (5)	O4—C6—C7—C12	168.3 (8)
C13—N1—C1—O1	57.7 (5)	O3—C6—C7—C12	−11.5 (9)
C16—N1—C1—O1	−126.0 (5)	C12—C7—C8—C9	1.9 (10)
C13—N1—C1—C2	−60.3 (5)	C6—C7—C8—C9	−176.9 (7)
C16—N1—C1—C2	115.9 (5)	C7—C8—C9—C10	−1.9 (13)
C3—O2—C2—C1	95.1 (5)	C8—C9—C10—C11	1.2 (15)
O1—C1—C2—O2	−44.1 (5)	C9—C10—C11—C12	−0.4 (14)
N1—C1—C2—O2	75.4 (5)	C10—C11—C12—C7	0.4 (11)
O1—C1—C2—C3	18.6 (5)	C8—C7—C12—C11	−1.1 (10)
N1—C1—C2—C3	138.1 (4)	C6—C7—C12—C11	177.6 (6)
C2—O2—C3—C4	−98.7 (5)	C16—N1—C13—C14	−0.3 (7)
C1—C2—C3—O2	−107.0 (4)	C1—N1—C13—C14	175.8 (5)
O2—C2—C3—C4	106.2 (4)	N1—C13—C14—F1	178.3 (4)
C1—C2—C3—C4	−0.8 (6)	N1—C13—C14—C15	−1.3 (8)
C1—O1—C4—C5	152.3 (5)	C16—N2—C15—O5	175.0 (5)
C1—O1—C4—C3	29.2 (5)	C16—N2—C15—C14	−5.4 (7)
O2—C3—C4—O1	48.0 (5)	C13—C14—C15—O5	−176.5 (5)
C2—C3—C4—O1	−16.5 (5)	F1—C14—C15—O5	3.8 (7)
O2—C3—C4—C5	−70.6 (6)	C13—C14—C15—N2	3.9 (7)
C2—C3—C4—C5	−135.1 (5)	F1—C14—C15—N2	−175.8 (4)
C6—O3—C5—C4	144.5 (5)	C13—N1—C16—O6	−180.0 (5)
O1—C4—C5—O3	58.9 (6)	C1—N1—C16—O6	3.9 (7)
C3—C4—C5—O3	174.1 (5)	C13—N1—C16—N2	−0.8 (6)
C5—O3—C6—O4	−1.3 (10)	C1—N1—C16—N2	−176.9 (4)
C5—O3—C6—C7	178.5 (6)	C15—N2—C16—O6	−176.8 (5)
O4—C6—C7—C8	−13.0 (11)	C15—N2—C16—N1	3.9 (7)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2···O5^i	0.86	2.01	2.846 (5)	165

Symmetry code: (i) −x+2, y+1/2, −z.