5-Ethyl-2'-deoxy-4'-thiouridine (R)-S-oxide monohydrate

The pyrimidine ring of the title compound, C₁₁H₁₆N₂O₅S·H₂O, is planar to within 0.026 (1) Å and makes an angle of 77.73 (8)° with the mean plane of the thiosugar ring. In terms of standard nucleoside nomenclature, this ring has a C1'-exo,C2'-endo conformation. The O5'-C5'-C4'-C3' torsion angle is -167.4 (2)° and the glycosidic S4'-C1'-N1-C2 torsion angle is -101.8 (2)° (anti).

S1. Comment

5-Substituted 2'-deoxy-4'-thiouridines possess significant antiviral activity (Dyson et al., 1991; Rahim et al., 1996). In order to provide data for structure–activity relationships, the crystal structure of the title compound, (I), synthesized by Macculloch (1998), is presented here. \sch

Bond lengths in (I) are normal. The C1'—S4' and C4'—S4' bonds are 1.847 (2) and 1.837 (2) Å, respectively, slightly longer than the mean length of 1.818 Å measured in a 6-aza-2'-deoxy-4'-thiouridine (Basnak et al., 1998), but in good agreement with the values found in 4'-thiothymidine (Koole et al., 1992; Uenischi et al., 1993) and 5-(2-bromovinyl)-2'-deoxy-4'-thiouridine (Koole et al., 1992) which were in the range 1.83–1.85 Å. The thiosugar has the C1'-exo,C2'-endo (₁T²) conformation (south), a pseudo-rotation phase angle (P) of 135.7° and a degree of pucker of 49.9°. These two atoms are displaced by 0.648 (5) and 0.134 (6) Å, respectively, on opposite sides of the C3'/C4'/S4' plane. This appears to be an unusual conformation for sugar rings of this type. The conformation about C4'—C5' is trans [O5'—C5'—C4—C3' −167.4 (2)°]. The glycosidic torsion angle, defined as S4'—C1'—N1—C2 (IUPAC-IUB Joint Commission on Biochemical Nomenclature, 1983) is −101.8 (2)°, similar to that found in the crystal structure of the sulfone of 4'-thiothymidine (−99.8°; Hancox et al., 1994) and in some 6-aza-2'-deoxyuridines (Basnak et al., 1998), but different from the angles between −121 and −146° found in other thiouridines (Bobek et al., 1975; Koole et al., 1992; Uenische et al., 1993). The steeper inclination of the pyrimidine ring with respect to the sugar ring in both the sulfoxide and the sulfone is presumably due to steric interactions between these O atoms and the pyrimidine ring, specifically, C6 and H6; O4''···C6 is 3.142 (3) Å and O4''···H6 is 2.77 Å in the title compound. In the 6-aza-nucleosides, repulsion between the N atom in the 6-position of the pyrimidine ring and the 4'-O or 4'-S atom of the sugar may affect the glycosidic torsion angle in a similar manner.

In the crystal (Fig. 1), nucleoside and water molecules are linked through a three-dimensional network of hydrogen bonds. Atoms N3, O3' and O5' each donate a proton, forming bonds with, repectively, the water molecule, the O5' atom and the O2 atom of neighbouring nucleoside molecules. The water molecule, in turn, forms hydrogen bonds with O5' and the sulfone O atom of two different molecules (Table 2). All H atoms attached to electronegative atoms take part in hydrogen bonding consistent with the principle of maximum hydrogen bonding (Robertson, 1953).

S2. Experimental

The title compound was recrystallized was from MeOH–H₂O solution.

S3. Refinement

H atoms were placed in calculated positions, except for those bonded to O3' and O5', and those of the water molecule, which were located from difference maps and refined with isotropic displacement parameters.

Computing details

Data collection: R-AXIS II Software (Rigaku, 1994); cell refinement: R-AXIS II Software; data reduction: TEXSAN (Molecular Structure Corporation, 1993); program(s) used to solve structure: TEXSAN; program(s) used to refine structure: SHELXL93 (Sheldrick, 1993); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL93.

Figures

Fig. 1. The molecular structure of (I) showing 50% probability displacement ellipsoids (ORTEPII; Johnson, 1976).

5-Ethyl-4'-thio-2'-deoxyuridine sulfoxide monohydrate

Crystal data

C11H16N2O5S·H2O	Dx = 1.541 Mg m^−3
Mr = 306.33	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 7338 reflections (post-refined using complete data set) reflections
a = 9.343 (4) Å	θ = 1.9–25.2°
b = 21.922 (8) Å	µ = 0.27 mm^−1
c = 6.447 (3) Å	T = 293 K
V = 1320.5 (10) Å^3	Rod, colourless
Z = 4	0.40 × 0.25 × 0.25 mm
F(000) = 648

Data collection

Rigaku R-AXIS II area-detector diffractometer	2169 reflections with I > 2σ(I)
Radiation source: rotating anode	Rint = 0.040
Graphite monochromator	θmax = 25.2°, θmin = 1.9°
image–plate scans	h = −10→11
7338 measured reflections	k = −26→26
2184 independent reflections	l = −7→7

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.031	w = 1/[σ^2(Fo^2) + (0.0329P)^2 + 0.5503P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.077	(Δ/σ)max = 0.001
S = 1.07	Δρmax = 0.19 e Å^−3
2184 reflections	Δρmin = −0.16 e Å^−3
197 parameters	Absolute structure: Flack (1983)
0 restraints	Absolute structure parameter: 0.00 (8)
Primary atom site location: structure-invariant direct methods

Special details

Experimental. Image plates were scanned in 5° frames covering 180° of rotation about one setting, with crystal–detector distance 80 mm and exposure time 10 min per frame. Reflections with I < σ(I) were discarded. Data includes 1062 Friedel pairs.

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 on F² for reflections with I > σ(I). Weighted R-factors wR and all goodnesses of fit S are based on F², conventional R-factors R are based on F. The observed criterion of F² > 2σ(F²) is used only for calculating the R factor for observed reflections 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
S4'	−0.76997 (6)	−0.21012 (2)	−0.88146 (8)	0.0330 (2)
O2	−0.5095 (2)	−0.09395 (7)	−0.6681 (3)	0.0392 (4)
O3'	−0.6729 (2)	−0.29336 (9)	−0.4086 (3)	0.0507 (5)
O4''	−0.9216 (2)	−0.19426 (7)	−0.9345 (3)	0.0426 (4)
O4	−0.7933 (2)	0.07456 (6)	−0.6420 (3)	0.0465 (4)
O5'	−0.8258 (2)	−0.34256 (8)	−1.0481 (3)	0.0519 (5)
O6	−1.0463 (2)	−0.08973 (8)	−1.1273 (3)	0.0490 (5)
N1	−0.7522 (2)	−0.10763 (7)	−0.6403 (3)	0.0276 (4)
N3	−0.6552 (2)	−0.01055 (8)	−0.6500 (3)	0.0325 (4)
H3	−0.5809 (2)	0.01258 (8)	−0.6501 (3)	0.039*
C1'	−0.7333 (2)	−0.17334 (8)	−0.6293 (3)	0.0281 (4)
H1'	−0.6335 (2)	−0.18165 (8)	−0.5919 (3)	0.034*
C2'	−0.8290 (3)	−0.20670 (9)	−0.4770 (3)	0.0353 (5)
H2'1	−0.9289 (3)	−0.19742 (9)	−0.5031 (3)	0.042*
H2'2	−0.8060 (3)	−0.19530 (9)	−0.3355 (3)	0.042*
C2	−0.6309 (2)	−0.07208 (9)	−0.6550 (3)	0.0296 (5)
C3'	−0.7990 (3)	−0.27402 (9)	−0.5133 (3)	0.0323 (5)
H3'	−0.8810 (3)	−0.29851 (9)	−0.4679 (3)	0.039*
C4	−0.7880 (3)	0.01865 (9)	−0.6448 (3)	0.0331 (5)
C4'	−0.7719 (2)	−0.28406 (8)	−0.7473 (3)	0.0309 (5)
H4'	−0.6767 (2)	−0.30234 (8)	−0.7626 (3)	0.037*
C5	−0.9105 (2)	−0.02172 (8)	−0.6404 (4)	0.0293 (4)
C5'	−0.8783 (3)	−0.32623 (9)	−0.8484 (4)	0.0403 (6)
H5'1	−0.8910 (3)	−0.36250 (9)	−0.7643 (4)	0.048*
H5'2	−0.9702 (3)	−0.30601 (9)	−0.8615 (4)	0.048*
C6	−0.8875 (2)	−0.08200 (8)	−0.6356 (4)	0.0294 (4)
H6	−0.9663 (2)	−0.10788 (8)	−0.6287 (4)	0.035*
C7	−1.0574 (2)	0.00692 (9)	−0.6384 (4)	0.0396 (6)
H7A	−1.0612 (2)	0.03610 (9)	−0.5254 (4)	0.047*
H7B	−1.0699 (2)	0.02948 (9)	−0.7665 (4)	0.047*
C8	−1.1815 (3)	−0.03652 (11)	−0.6152 (5)	0.0466 (6)
H8A	−1.2697 (3)	−0.01406 (11)	−0.6187 (5)	0.070*
H8B	−1.1737 (3)	−0.05767 (11)	−0.4853 (5)	0.070*
H8C	−1.1801 (3)	−0.06551 (11)	−0.7268 (5)	0.070*
HO3'	−0.712 (4)	−0.3023 (18)	−0.284 (7)	0.103 (14)*
HO5'	−0.904 (5)	−0.3614 (19)	−1.131 (7)	0.132 (16)*
HW1	−0.979 (4)	−0.1159 (14)	−1.095 (5)	0.071 (10)*
HW2	−1.134 (4)	−0.0980 (15)	−1.073 (6)	0.085 (12)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S4'	0.0446 (3)	0.0242 (2)	0.0303 (3)	−0.0034 (2)	0.0068 (2)	−0.0020 (2)
O2	0.0291 (9)	0.0394 (8)	0.0492 (11)	−0.0012 (7)	0.0044 (7)	−0.0036 (7)
O3'	0.0542 (12)	0.0524 (10)	0.0454 (11)	0.0168 (8)	−0.0110 (9)	0.0092 (9)
O4''	0.0527 (11)	0.0344 (8)	0.0406 (10)	0.0026 (7)	−0.0148 (8)	0.0046 (7)
O4	0.0595 (12)	0.0237 (7)	0.0564 (10)	−0.0034 (7)	0.0006 (10)	0.0001 (7)
O5'	0.0664 (13)	0.0479 (10)	0.0414 (10)	−0.0187 (9)	0.0010 (9)	−0.0130 (8)
O6	0.0455 (12)	0.0380 (9)	0.0636 (13)	−0.0046 (8)	−0.0082 (11)	0.0097 (9)
N1	0.0265 (9)	0.0220 (7)	0.0344 (9)	0.0000 (6)	−0.0024 (8)	−0.0032 (6)
N3	0.0355 (10)	0.0270 (8)	0.0349 (11)	−0.0071 (7)	0.0011 (8)	−0.0018 (8)
C1'	0.0251 (11)	0.0241 (9)	0.0353 (11)	0.0007 (7)	0.0004 (10)	−0.0006 (8)
C2'	0.0463 (14)	0.0309 (10)	0.0288 (11)	0.0053 (10)	0.0037 (9)	0.0019 (9)
C2	0.0324 (13)	0.0290 (10)	0.0273 (12)	−0.0036 (8)	−0.0014 (9)	−0.0023 (8)
C3'	0.0318 (13)	0.0292 (10)	0.0360 (12)	0.0002 (8)	−0.0017 (10)	0.0055 (8)
C4	0.0460 (14)	0.0257 (10)	0.0276 (11)	−0.0025 (8)	−0.0023 (11)	−0.0002 (8)
C4'	0.0320 (12)	0.0239 (9)	0.0368 (12)	0.0003 (8)	0.0006 (9)	−0.0027 (8)
C5	0.0331 (12)	0.0241 (9)	0.0305 (11)	0.0024 (8)	−0.0050 (10)	−0.0025 (8)
C5'	0.0451 (14)	0.0304 (10)	0.0456 (14)	−0.0080 (9)	0.0009 (12)	−0.0040 (10)
C6	0.0285 (12)	0.0255 (9)	0.0342 (11)	−0.0002 (8)	−0.0027 (10)	−0.0048 (9)
C7	0.0399 (13)	0.0285 (10)	0.0503 (15)	0.0091 (9)	−0.0072 (12)	−0.0056 (10)
C8	0.0367 (14)	0.0449 (13)	0.058 (2)	0.0079 (10)	0.0005 (13)	−0.0047 (12)

Geometric parameters (Å, º)

S4'—O4''	1.498 (2)	N3—C2	1.368 (3)
S4'—C4'	1.837 (2)	N3—C4	1.396 (3)
S4'—C1'	1.847 (2)	C1'—C2'	1.516 (3)
O2—C2	1.234 (3)	C2'—C3'	1.520 (3)
O3'—C3'	1.423 (3)	C3'—C4'	1.546 (3)
O4—C4	1.227 (3)	C4—C5	1.447 (3)
O5'—C5'	1.423 (3)	C4'—C5'	1.506 (3)
N1—C2	1.379 (3)	C5—C6	1.339 (3)
N1—C6	1.383 (3)	C5—C7	1.509 (3)
N1—C1'	1.453 (2)	C7—C8	1.508 (3)
O4''—S4'—C4'	107.64 (10)	O3'—C3'—C4'	106.5 (2)
O4''—S4'—C1'	105.97 (9)	C2'—C3'—C4'	108.6 (2)
C4'—S4'—C1'	88.44 (9)	O4—C4—N3	119.6 (2)
C2—N1—C6	121.5 (2)	O4—C4—C5	125.4 (2)
C2—N1—C1'	117.6 (2)	N3—C4—C5	115.0 (2)
C6—N1—C1'	120.9 (2)	C5'—C4'—C3'	113.7 (2)
C2—N3—C4	126.9 (2)	C5'—C4'—S4'	110.1 (2)
N1—C1'—C2'	116.0 (2)	C3'—C4'—S4'	109.59 (13)
N1—C1'—S4'	111.53 (14)	C6—C5—C4	118.5 (2)
C2'—C1'—S4'	104.47 (14)	C6—C5—C7	123.8 (2)
C1'—C2'—C3'	105.0 (2)	C4—C5—C7	117.7 (2)
O2—C2—N3	122.5 (2)	O5'—C5'—C4'	108.6 (2)
O2—C2—N1	122.7 (2)	C5—C6—N1	123.1 (2)
N3—C2—N1	114.8 (2)	C8—C7—C5	115.9 (2)
O3'—C3'—C2'	111.6 (2)
C2—N1—C1'—C2'	138.8 (2)	O3'—C3'—C4'—C5'	121.2 (2)
C6—N1—C1'—C2'	−41.0 (3)	C2'—C3'—C4'—C5'	−118.4 (2)
C2—N1—C1'—S4'	−101.8 (2)	O3'—C3'—C4'—S4'	−115.1 (2)
C6—N1—C1'—S4'	78.4 (2)	C2'—C3'—C4'—S4'	5.3 (2)
O4''—S4'—C1'—N1	−59.2 (2)	O4''—S4'—C4'—C5'	40.0 (2)
C4'—S4'—C1'—N1	−167.13 (15)	C1'—S4'—C4'—C5'	146.3 (2)
O4''—S4'—C1'—C2'	66.78 (15)	O4''—S4'—C4'—C3'	−85.7 (2)
C4'—S4'—C1'—C2'	−41.13 (15)	C1'—S4'—C4'—C3'	20.6 (2)
N1—C1'—C2'—C3'	174.1 (2)	O4—C4—C5—C6	−177.3 (2)
S4'—C1'—C2'—C3'	50.9 (2)	N3—C4—C5—C6	1.9 (3)
C4—N3—C2—O2	176.9 (2)	O4—C4—C5—C7	1.9 (3)
C4—N3—C2—N1	−4.2 (3)	N3—C4—C5—C7	−179.0 (2)
C6—N1—C2—O2	−176.9 (2)	C3'—C4'—C5'—O5'	−167.4 (2)
C1'—N1—C2—O2	3.3 (3)	S4'—C4'—C5'—O5'	69.2 (2)
C6—N1—C2—N3	4.2 (3)	C4—C5—C6—N1	−1.8 (4)
C1'—N1—C2—N3	−175.6 (2)	C7—C5—C6—N1	179.1 (2)
C1'—C2'—C3'—O3'	81.4 (2)	C2—N1—C6—C5	−1.4 (3)
C1'—C2'—C3'—C4'	−35.7 (2)	C1'—N1—C6—C5	178.4 (2)
C2—N3—C4—O4	−179.5 (2)	C6—C5—C7—C8	4.1 (4)
C2—N3—C4—C5	1.3 (3)	C4—C5—C7—C8	−174.9 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O6^i	0.86	2.07	2.898 (3)	161
O3′—HO3′···O5′^ii	0.90 (2)	2.06 (2)	2.934 (2)	164 (2)
O5′—HO5′···O2^iii	1.00 (2)	1.90 (3)	2.869 (2)	164 (3)
O6—HW1···O4′′	0.87 (3)	2.08 (2)	2.855 (3)	148 (2)
O6—HW2···O5′^iii	0.91 (3)	2.35 (2)	3.210 (3)	158 (2)

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