5-Methyl-2′-deoxy-4′-thio-α-uridine (R)-­S-oxide

The pyrimidine ring of the title compound, C₁₀H₁₄N₂O₅S, is planar to within 0.024 (1) Å and makes an angle of 75.46 (10)° with the mean plane of the thio­sugar ring. In terms of standard nucleoside nomenclature, this ring has the C3′-endo conformation. The O5′—C5′—C4′—C3′ torsion angle is 166.5 (3)° and the glycosidic torsion angle S4′—C1′—N1—C2 is −52.1 (2)° (syn).

S1. Comment

5-Substituted 2'-deoxy-4'-thio-β-uridines possess significant antiviral activity (Rahim et al., 1996). The α-anomers, however, are inactive. In order to provide data for structure-activity relationships in both anomeric series, the crystal structure of the title compound, (I), synthesized by Macculloch (1998), is presented here. Bond lengths in (I) (Fig. 1) are normal (Table 1). The C1'—S4' and C4'—S4' bonds are 1.870 (2) and 1.819 (3) Å, respectively, averaging a little larger than the values found in the crystal structures of 4'-thiothymidine (Koole et al., 1992; Uenischi et al., 1993), 5-(2-bromovinyl)-2'-deoxy-4'-thiouridine (Koole et al., 1992), the sulfone of 4'-thiothymidine (Hancox et al., 1994), α-5-adamantyl-4'-thio-2'-deoxyuridine (Sun et al., 1996), 5-(2-thienyl)-6-aza-4'-thio-2'-deoxyuridine (Basnak et al., 1998) and 5-ethyl-2'-deoxy-4'-thiouridine(R)—S-oxide (Sun et al., 2000) at 1.80–1.85 Å. Interestingly, in the sulfoxide and the sulfone, C1'—S4' > C4'—S4' (mean lengths, excluding present work, 1.842 and 1.819 Å, respectively), whereas in the unoxygenated thionucleosides C1'—S4' tends to be slightly shorter than C4'—S4' (mean lengths 1.828 and 1.833 Å, respectively). \sch

The thiosugar has the C3'-endo (³E) conformation with C3' displaced by 0.645 (3) Å from the accurately planar C1'/C2'/C4'/S4' moiety (r.m.s. deviation 0.002 Å). The pseudo-rotation phase angle (P) is 17.9° and the degree of pucker is 48.9°. The conformation about C4'—C5' is trans [O5'—C5'—C4—C3' 166.5 (3)°]. The glycosidic torsion angle, defined as S4'—C1'—N1—C2 (IUPAC-IUB Joint Commission on Biochemical Nomenclature, 1983) is −52.1 (2)° (syn), differing by some 145° from this angle in α-5-adamantyl-4'-thio-2'-deoxyuridine (Sun et al., 1996) and α-5-acetyl-2'-deoxyuridine (Hamor et al., 1977). Thus as in these other α-nucleosides, the pyrimidine ring is steeply inclined with respect to the sugar, but is essentially flipped over.

The structure discussed above accounts for 60.4 (6)% of the molecules in the crystal. The remaining molecules differ in the orientation about the C4'—C5' bond, resulting in an alternative position for O5' (denoted O5'B), the torsion angle O5'B—C5'—C4'—C3' being 32.6 (6)° (gauche).

In the crystal, nucleoside molecules are linked through a network of hydrogen bonds. Atoms N3, O3' and O5' each donate a hydrogen atom, forming bonds with, respectively, the sulfoxide O atom O4" and the ketonic O atoms, O4 and O2, of neighbouring molecules (Table 2). In the minor conformer, O5'B appears to form a hydrogen bond with O2 of a different molecule. The hydrogen atom associated with O5'B could not be located and was not included in the calculations. A short contact of 2.373 (7) Å apparently occurs between O5' of the major conformer and O5'B of the minor conformer related by the twofold screw axis parallel to c (Table 2). We consider that this contact is not real, and that molecules related in this way are either all major conformer, or all minor conformer, so avoiding the occurrence of this short contact.

S2. Experimental

Recrystallization was from a 1:1 mixture of methanol and water.

S3. Refinement

Data includes 1034 independent reflections plus 912 Friedel-related reflections. Coordinates and anisotropic displacement parameters were refined for non-H atoms. H atoms were located from difference maps but their parameters were not refined. The H atoms bonded to C5' were placed in calculated positions

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 the major conformer of (I) showing 50% probability displacement ellipsoids (ORTEPII; Johnson, 1976).

4'-Thio-α-thymidine(R)—S-oxide

Crystal data

C10H14N2O5S	Dx = 1.527 Mg m^−3
Mr = 274.29	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 6670 (post-refined using complete data set) reflections
a = 8.018 (8) Å	θ = 3.4–25.2°
b = 20.134 (13) Å	µ = 0.29 mm^−1
c = 7.389 (8) Å	T = 293 K
V = 1192.8 (19) Å^3	Rod, colourless
Z = 4	0.5 × 0.3 × 0.25 mm
F(000) = 576

Data collection

Rigaku R-Axis II area detector diffractometer	1941 reflections with I > 2σ(I)
Radiation source: rotating anode	Rint = 0.021
Graphite monochromator	θmax = 25.2°, θmin = 3.4°
image–plate scans	h = −9→9
6670 measured reflections	k = −23→23
1946 independent reflections	l = −8→7

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difmap, except those bonded to C5' from geom
R[F^2 > 2σ(F^2)] = 0.030	H-atom parameters not refined
wR(F^2) = 0.082	Weighting scheme based on measured s.u.'s w = 1/[σ^2(Fo^2) + (0.0458P)^2 + 0.401P] where P = (Fo^2 + 2Fc^2)/3
S = 1.09	(Δ/σ)max = −0.001
1946 reflections	Δρmax = 0.27 e Å^−3
173 parameters	Δρmin = −0.15 e Å^−3
0 restraints	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.02 (9)

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 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 > σ(F²) is used only for calculating Robs 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.

37 frames of data were collected in 5° oscillations at a crystal–detector distance of 80 mm and exposure time 10 min per frame. Reflections with I < σ(I) were discarded.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
S4'	−0.09108 (7)	−0.04531 (2)	0.02039 (7)	0.0326 (2)
O2	−0.0398 (2)	−0.08303 (8)	0.3899 (2)	0.0412 (4)
O3'	0.2487 (2)	−0.18600 (9)	−0.0625 (3)	0.0495 (5)
O4	−0.4762 (2)	−0.14864 (10)	0.7352 (3)	0.0510 (5)
O4"	−0.1605 (2)	−0.03169 (8)	−0.1664 (2)	0.0490 (5)
O5'	0.1914 (5)	0.0341 (2)	−0.1148 (6)	0.082 (2)	0.604 (6)
O5'B	0.1902 (9)	−0.0467 (4)	−0.3225 (8)	0.084 (3)	0.396 (6)
N1	−0.2588 (2)	−0.13233 (9)	0.2488 (3)	0.0314 (4)
N3	−0.2657 (2)	−0.11279 (9)	0.5573 (2)	0.0329 (4)
C1'	−0.1712 (3)	−0.13021 (10)	0.0748 (3)	0.0327 (5)
C2	−0.1787 (3)	−0.10736 (10)	0.3987 (3)	0.0305 (4)
C2'	−0.0262 (3)	−0.17888 (10)	0.0589 (3)	0.0384 (6)
C3'	0.0974 (3)	−0.14952 (9)	−0.0729 (3)	0.0335 (5)
C4	−0.4183 (3)	−0.14426 (10)	0.5807 (3)	0.0356 (5)
C4'	0.1186 (3)	−0.07686 (10)	−0.0170 (3)	0.0348 (5)
C5	−0.4948 (3)	−0.16964 (11)	0.4187 (3)	0.0363 (5)
C5'	0.2085 (4)	−0.03363 (13)	−0.1531 (5)	0.0627 (9)
C6	−0.4142 (3)	−0.16190 (10)	0.2608 (3)	0.0339 (4)
C7	−0.6622 (3)	−0.2024 (2)	0.4333 (4)	0.0592 (8)
H1'	−0.2600	−0.1378	−0.0291	0.039*
H2'A	0.0400	−0.1827	0.1816	0.046*
H2'B	−0.0600	−0.2231	0.0226	0.046*
H3	−0.2200	−0.0916	0.6623	0.040*
H3'	0.0400	−0.1540	−0.2054	0.040*
HO3'	0.3200	−0.1654	−0.1408	0.060*
H4'	0.1800	−0.0747	0.1025	0.042*
HO5'	0.3000	0.0580	−0.0990	0.098*	0.604
H5'1	0.3260	−0.0450	−0.1550	0.075*	0.604
H5'2	0.1640	−0.0420	−0.2730	0.075*	0.604
H5'3	0.1740	0.0120	−0.1340	0.075*	0.396
H5'4	0.3270	−0.0360	−0.1280	0.075*	0.396
H6	−0.4600	−0.1765	0.1424	0.041*
H7A	−0.7400	−0.1676	0.4992	0.089*
H7B	−0.6800	−0.2366	0.5218	0.089*
H7C	−0.7000	−0.2262	0.3313	0.089*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S4'	0.0422 (3)	0.0295 (2)	0.0261 (3)	0.0031 (2)	0.0020 (2)	−0.0013 (2)
O2	0.0295 (8)	0.0589 (10)	0.0353 (9)	−0.0126 (7)	0.0016 (6)	−0.0017 (7)
O3'	0.0411 (9)	0.0480 (9)	0.0594 (12)	0.0140 (7)	0.0216 (8)	0.0145 (8)
O4	0.0427 (9)	0.0767 (12)	0.0337 (11)	−0.0084 (8)	0.0138 (8)	0.0058 (8)
O4"	0.0711 (12)	0.0457 (9)	0.0303 (10)	0.0109 (8)	−0.0093 (8)	0.0044 (7)
O5'	0.102 (3)	0.042 (2)	0.103 (3)	−0.020 (2)	0.044 (3)	0.003 (2)
O5'B	0.108 (5)	0.107 (5)	0.038 (4)	−0.047 (4)	0.007 (3)	0.016 (3)
N1	0.0275 (8)	0.0404 (9)	0.0265 (10)	−0.0041 (7)	0.0052 (8)	−0.0029 (7)
N3	0.0308 (9)	0.0405 (9)	0.0276 (10)	−0.0035 (7)	0.0037 (7)	0.0007 (7)
C1'	0.0333 (10)	0.0363 (10)	0.0287 (13)	−0.0037 (8)	0.0060 (9)	−0.0055 (8)
C2	0.0301 (10)	0.0357 (10)	0.0258 (11)	−0.0001 (8)	0.0020 (8)	0.0003 (8)
C2'	0.0394 (11)	0.0278 (9)	0.048 (2)	−0.0004 (8)	0.0177 (10)	−0.0007 (9)
C3'	0.0348 (10)	0.0316 (9)	0.0343 (13)	0.0036 (8)	0.0084 (9)	−0.0007 (8)
C4	0.0289 (10)	0.0384 (10)	0.0395 (13)	−0.0002 (9)	0.0074 (10)	0.0035 (8)
C4'	0.0380 (10)	0.0343 (10)	0.0322 (13)	−0.0047 (8)	0.0075 (10)	0.0008 (9)
C5	0.0285 (10)	0.0417 (11)	0.0387 (14)	−0.0044 (9)	0.0044 (9)	0.0020 (9)
C5'	0.080 (2)	0.0436 (14)	0.065 (2)	−0.0130 (13)	0.035 (2)	0.0027 (13)
C6	0.0291 (10)	0.0382 (10)	0.0345 (12)	−0.0034 (9)	−0.0002 (10)	−0.0035 (8)
C7	0.0406 (13)	0.076 (2)	0.061 (2)	−0.0246 (12)	0.0093 (12)	−0.0009 (14)

Geometric parameters (Å, º)

S4'—O4"	1.513 (2)	N1—C1'	1.465 (3)
S4'—C4'	1.819 (3)	N3—C2	1.368 (3)
S4'—C1'	1.870 (2)	N3—C4	1.388 (3)
O2—C2	1.218 (3)	C1'—C2'	1.525 (3)
O3'—C3'	1.420 (3)	C2'—C3'	1.510 (3)
O4—C4	1.236 (3)	C3'—C4'	1.530 (3)
O5'—C5'	1.399 (4)	C4—C5	1.439 (3)
O5'B—C5'	1.287 (7)	C4'—C5'	1.512 (3)
N1—C2	1.376 (3)	C5—C6	1.343 (4)
N1—C6	1.384 (3)	C5—C7	1.499 (3)
O4"—S4'—C4'	105.35 (12)	O3'—C3'—C4'	112.6 (2)
O4"—S4'—C1'	103.61 (10)	C2'—C3'—C4'	105.9 (2)
C4'—S4'—C1'	91.79 (10)	O4—C4—N3	118.6 (2)
C2—N1—C6	121.7 (2)	O4—C4—C5	125.6 (2)
C2—N1—C1'	118.2 (2)	N3—C4—C5	115.7 (2)
C6—N1—C1'	120.0 (2)	C5'—C4'—C3'	115.1 (2)
C2—N3—C4	126.3 (2)	C5'—C4'—S4'	109.9 (2)
N1—C1'—C2'	114.5 (2)	C3'—C4'—S4'	105.80 (14)
N1—C1'—S4'	112.34 (13)	C6—C5—C4	118.4 (2)
C2'—C1'—S4'	107.98 (15)	C6—C5—C7	123.0 (2)
O2—C2—N3	123.0 (2)	C4—C5—C7	118.6 (2)
O2—C2—N1	122.0 (2)	O5'B—C5'—O5'	112.6 (5)
N3—C2—N1	115.0 (2)	O5'B—C5'—C4'	118.3 (3)
C3'—C2'—C1'	107.4 (2)	O5'—C5'—C4'	112.3 (3)
O3'—C3'—C2'	108.9 (2)	C5—C6—N1	122.6 (2)
C2—N1—C1'—C2'	71.5 (2)	O3'—C3'—C4'—C5'	73.6 (3)
C6—N1—C1'—C2'	−105.3 (2)	C2'—C3'—C4'—C5'	−167.6 (2)
C2—N1—C1'—S4'	−52.1 (2)	O3'—C3'—C4'—S4'	−164.89 (14)
C6—N1—C1'—S4'	131.1 (2)	C2'—C3'—C4'—S4'	−46.0 (2)
O4"—S4'—C1'—N1	−126.9 (2)	O4"—S4'—C4'—C5'	46.4 (2)
C4'—S4'—C1'—N1	126.8 (2)	C1'—S4'—C4'—C5'	151.0 (2)
O4"—S4'—C1'—C2'	105.9 (2)	O4"—S4'—C4'—C3'	−78.4 (2)
C4'—S4'—C1'—C2'	−0.3 (2)	C1'—S4'—C4'—C3'	26.2 (2)
C4—N3—C2—O2	−174.8 (2)	O4—C4—C5—C6	−178.8 (2)
C4—N3—C2—N1	4.4 (3)	N3—C4—C5—C6	0.7 (3)
C6—N1—C2—O2	177.8 (2)	O4—C4—C5—C7	2.3 (3)
C1'—N1—C2—O2	1.1 (3)	N3—C4—C5—C7	−178.2 (2)
C6—N1—C2—N3	−1.4 (3)	C3'—C4'—C5'—O5'B	32.6 (6)
C1'—N1—C2—N3	−178.1 (2)	S4'—C4'—C5'—O5'B	−86.7 (5)
N1—C1'—C2'—C3'	−152.1 (2)	C3'—C4'—C5'—O5'	166.5 (3)
S4'—C1'—C2'—C3'	−26.2 (2)	S4'—C4'—C5'—O5'	47.2 (4)
C1'—C2'—C3'—O3'	167.8 (2)	C4—C5—C6—N1	1.9 (3)
C1'—C2'—C3'—C4'	46.5 (2)	C7—C5—C6—N1	−179.2 (2)
C2—N3—C4—O4	175.4 (2)	C2—N1—C6—C5	−1.7 (3)
C2—N3—C4—C5	−4.1 (3)	C1'—N1—C6—C5	175.0 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O4"^i	0.96	1.81	2.747 (3)	164
O3′—HO3′···O4^ii	0.91	1.90	2.769 (3)	157
O5′—HO5′···O2^iii	1.00	1.99	2.963 (4)	163
O5′B—–···O2^iv	–	–	2.907 (6)	–
O5′B—–···O5′^iii	–	–	2.373 (7)	–

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