Ethyl 3-(2′-deoxyuridin-5-yl)-3-hydroxy-2-iodopropanoate, a ­nucleoside analogue

In the title compound, C₁₄H₁₉IN₂O₈, an almost planar heterocyclic base is oriented anti with respect to the puckered sugar moiety. The sugar pucker is C2′-endo/C3′-exo, the N-glycosidic torsion angle is 166.4 (4)° and the conformation of O5′ is +sc. The mol­ecules are linked by hydrogen bonds of the types N—H...O and O—H...O.

S1. Comment

The title compound, (I), is an example of the 5-vinyl-2'-deoxyuridine derivatives, which have been found to inhibit replication of the herpes simplex virus type I (De Clercq et al., 1979). Studies of the structure-activity relationships of these 5-substituted derivatives indicated that the activity is associated with analogues in which the 5-substituent is conjugated with the pyrimidine ring (Griengl et al., 1985). The structural analysis of the compound (I) is a continuation of our earlier work involving systematic conformational studies on modified nucleosides with the aim of understanding structure-function relationships. \scheme

The absolute configuration of the structure has been determined, as indicated by the Flack parameter of -0.04 (3) (Flack, 1983) (Friedel number = ?). The 5-substituent is an aliphatic chain with a terminal carboxyl ethoxy group and it is twisted away from the N1—C6 ring [C4—C5—C7—C8 torsion angle = -61.6 (7)°], allowing the bulky I atom to lie out of the plane of the ring. The chain skeleton has an extended conformation. The terminal ethoxy group has a gauche conformation with respect to the skeleton [C9—O10—C10—C11 = 76.7 (9)°]. The C—I bond distance of 2.137 (6) Å compares closely with the value of 2.139 Å found for CH₃I (Bowen et al., 1958).

The heterocyclic base moiety is almost planar, the r.m.s. deviation of the atoms from their least-squares mean plane being 0.027 (5) Å and the maximum deviation being 0.044 (5) Å for C2. The bond lengths and angles for the nucleoside analogue are normal (Allen et al., 1987) with no significant deviation, indicating that the substitution at C5 has no effect on the molecular geometry. The C4=O4 [1.245 (6) Å] bond is 0.042 (6) Å longer than the C2=O2 [1.203 (7) Å] and C9=O9 [1.204 (7) Å] bonds; this elongation is attributed to the formation of a hydrogen bond between O4 and O3'; O2 and O9 do not form any hydrogen bonds in the structure of (I). Similar effects have been reported for the 1:1 complex of thiourea and parabanic acid (TUPA; Weber et al., 1987).

The glycosyl torsion angle τ (C2—N1—C1'-O4'), showing the relative orientation of the base with respect to the sugar ring, has a value of 166.4 (4)°, which lies at the extreme end of the range -160 to -175° for torsion angles τ observed in active anti-HIV nucleosides (Van Roey et al., 1989). This glycosyl angle τ places the C1'-O4' bond close to the plane of the conjugated system of the base, bringing O4' into close contact with hydrogen H6 on C6 of the base [H6···O4' = 2.352 (7) Å], resulting in steric hindrance between the base and sugar ring. The structural effects include lengthening of the C1'-N1 bond, which has a value 1.482 (7) Å in (I). Saenger (1984) has correlated the C1'-N1 bond length with the angle τ, and for τ near -167°, the expected N1—C1' bond length is 1.48 Å.

The C1'-O4' [1.411 (6) Å] bond is shorter than C4'-O4' [1.440 (7) Å], due to the anomeric effect (Kirby, 1983), which is a common feature of nucleosides. The pseudo rotation phase angle P [168.3 (6)°] and the maximum torsion angle ν_max [38.2 (7)°] are calculated from intraring torsion angles to describe the puckering of the five-membered ring of the sugar moiety; these values indicate an unsymmetrical twist of the sugar ring with C2'-endo/C3'-exo (²T₃; Saenger,1984) and are similar to those of active anti-HIV compounds, which have P values in the range 165–220° with C2'-endo/C3'-exo (Van Roey et al., 1989). The active conformer of 3'-azido-3'-deoxythymidine (known as AZT) has P = 175° with C2'-endo/C3'-exo (Dyer et al., 1988). The C3'-exo conformation places C5' in an axial position. The torsion angle Γ (uc?) [C3'-C4'-C5'-O5'= 74.9 (7)°] describing the orientation of the 5'-hydroxyl group relative to the sugar ring shows that C5'-O5' is in a gauche-gauche orientation (+sc) (Van Roey et al., 1989).

Each molecule in the crystal structure of (I) has four H atoms available for hydrogen-bond formation. These are bonded to three hydroxyl O atoms, O3', O5' and O7, and to the pyrimidine nitrogen N3. The hydroxyl groups act as both hydrogen-bond donors and acceptors. The hydroxyl groups and the ring N atom N3 form O—H···O and N—H···O hydrogen bonds with molecules related by translational symmetry along the a and b axes (Table 2), resulting in a two-dimensional network in the ab plane.

S2. Experimental

Compound (I) was synthesized by the reaction of (E)-5-(2-ethoxy carbonyl vinyl)-2'-deoxyuridine with I₂ and potassium iodate, as illustrated in the Scheme, according to the method of Kumar et al. (1989). Crystals of (I) were obtained from methanol by slow evaporation at room temperature.

S3. Refinement

The structure was solved by direct methods and successive Fourier syntheses. All H atoms attached to C or N were located geometrically and refined as part of a riding model, with U_iso(H) = 0.078 (6) Ų. All H atoms attached to hydroxyl-O atoms were located in circular difference Fourier syntheses and thereafter refined freely with U_iso(H) = 0.078 (6) Ų. The atom-numbering scheme used in Fig. 1 is consistent with the rules of the IUPAC-IUB Joint Commission on Biochemical Nomenclature (IUPAC-IUB, 1983).

Computing details

Data collection: CAD-4 Software (Enraf-Nonius, 1988); cell refinement: CAD-4 Software; data reduction: CAD-4 Software; program(s) used to solve structure: SHELXS86 (Sheldrick, 1990); 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. An ORTEPII (Johnson, 1976) plot of the molecule of (I) drawn at the 30% probability level.

Ethyl 3-(2'-deoxyuridin-5-yl)-3-hydroxy-2-iodopropanoate

Crystal data

C14H19IN2O8	F(000) = 468
Mr = 470.21	Dx = 1.763 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71069 Å
a = 6.748 (3) Å	Cell parameters from 25 reflections
b = 10.466 (4) Å	θ = 10.3–14.4°
c = 12.555 (4) Å	µ = 1.85 mm^−1
β = 92.36 (3)°	T = 293 K
V = 885.9 (6) Å^3	Block, colourless
Z = 2	0.35 × 0.25 × 0.20 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	1545 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.046
Graphite monochromator	θmax = 25°, θmin = 2.5°
ω–2θ scans	h = −8→8
Absorption correction: empirical (using intensity measurements) via ψ scan (North et al., 1968)	k = 0→12
Tmin = 0.607, Tmax = 0.690	l = 0→14
3290 measured reflections	3 standard reflections every 100 reflections
1649 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)] = 0.036	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.137	Calculated w = 1/[σ^2(Fo^2) + (0.0399P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.93	(Δ/σ)max = 0.002
1585 reflections	Δρmax = 0.34 e Å^−3
231 parameters	Δρmin = −0.31 e Å^−3
2 restraints	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.04 (3)

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 ALL reflections except for 64 with very negative F² or flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The observed criterion of F² > σ(F²) is used only for calculating _R_factor_obs 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
I	0.51789 (7)	0.26018 (12)	0.01926 (3)	0.0832 (2)
C7	0.4084 (6)	0.2547 (6)	0.2528 (3)	0.0343 (10)
H17	0.3148	0.3235	0.2339	0.078*
C8	0.4137 (9)	0.1655 (7)	0.1570 (5)	0.0497 (15)
H8	0.4965	0.0908	0.1743	0.078*
C9	0.1980 (10)	0.1229 (7)	0.1259 (5)	0.056 (2)
O9	0.0584 (7)	0.1941 (6)	0.1303 (5)	0.075 (2)
O10	0.1990 (9)	0.0011 (6)	0.1003 (5)	0.086 (2)
C10	−0.0022 (14)	−0.0469 (11)	0.0599 (10)	0.091 (3)
H110	−0.1066	−0.0138	0.1030	0.078*
H210	−0.0069	−0.1395	0.0609	0.078*
O7	0.3284 (5)	0.1857 (4)	0.3382 (3)	0.0417 (9)
H7	0.402 (6)	0.126 (5)	0.355 (4)	0.078 (6)*
C5	0.6034 (8)	0.3167 (5)	0.2837 (4)	0.0352 (12)
C4	0.7684 (8)	0.2403 (5)	0.3159 (4)	0.0376 (11)
C6	0.6265 (9)	0.4433 (6)	0.2849 (4)	0.0371 (12)
H6	0.5173	0.4946	0.2674	0.078*
N1	0.8052 (6)	0.5013 (4)	0.3110 (3)	0.0318 (9)
O4	0.7598 (7)	0.1216 (4)	0.3218 (4)	0.0605 (13)
C1'	0.8355 (8)	0.6415 (5)	0.3127 (4)	0.0344 (12)
H1'	0.9521	0.6638	0.2726	0.078*
C4'	0.6169 (9)	0.8133 (6)	0.3213 (5)	0.0427 (14)
H4'	0.6152	0.8855	0.2716	0.078*
O4'	0.6644 (6)	0.6983 (4)	0.2648 (3)	0.0427 (10)
C5'	0.4137 (9)	0.7976 (6)	0.3648 (6)	0.057 (2)
H15'	0.3230	0.7637	0.3099	0.078*
H25'	0.4196	0.7379	0.4239	0.078*
O5'	0.3449 (6)	0.9175 (5)	0.3996 (6)	0.077 (2)
H5'	0.236 (6)	0.933 (4)	0.371 (5)	0.078 (6)*
C3'	0.7830 (8)	0.8316 (6)	0.4036 (5)	0.042 (2)
H13'	0.7328	0.8673	0.4694	0.078*
C2'	0.8541 (10)	0.6965 (5)	0.4209 (5)	0.043 (2)
H12'	0.9906	0.6946	0.4483	0.078*
H22'	0.7714	0.6512	0.4698	0.078*
O2	1.1324 (5)	0.4784 (4)	0.3499 (4)	0.0477 (10)
N3	0.9445 (6)	0.3015 (4)	0.3385 (4)	0.0356 (10)
H3	1.0449	0.2551	0.3577	0.078*
C2	0.9729 (7)	0.4295 (6)	0.3331 (4)	0.0370 (12)
C11	−0.0237 (16)	0.0033 (12)	−0.0535 (10)	0.096 (4)
H111	−0.1490	−0.0234	−0.0850	0.078*
H211	0.0817	−0.0298	−0.0945	0.078*
H311	−0.0175	0.0950	−0.0527	0.078*
O3'	0.9423 (6)	0.9034 (5)	0.3691 (5)	0.0630 (14)
H3'	0.902 (2)	0.956 (6)	0.325 (5)	0.078 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
I	0.0614 (3)	0.1360 (6)	0.0528 (3)	0.0082 (4)	0.0080 (2)	0.0103 (5)
C7	0.027 (2)	0.028 (2)	0.048 (2)	0.002 (3)	−0.004 (2)	0.001 (3)
C8	0.039 (3)	0.059 (4)	0.050 (3)	0.003 (3)	−0.005 (2)	−0.005 (3)
C9	0.066 (4)	0.058 (4)	0.044 (3)	−0.018 (4)	−0.009 (3)	−0.020 (3)
O9	0.041 (2)	0.076 (3)	0.104 (4)	0.014 (3)	−0.022 (2)	−0.040 (3)
O10	0.092 (4)	0.069 (4)	0.098 (4)	−0.026 (4)	0.018 (3)	−0.026 (4)
C10	0.075 (6)	0.106 (8)	0.091 (7)	−0.040 (6)	−0.008 (5)	−0.030 (7)
O7	0.028 (2)	0.038 (2)	0.060 (2)	−0.001 (2)	0.008 (2)	0.008 (2)
C5	0.025 (3)	0.030 (3)	0.050 (3)	0.016 (2)	0.001 (2)	0.008 (2)
C4	0.038 (3)	0.021 (2)	0.054 (3)	−0.011 (3)	0.003 (2)	−0.006 (3)
C6	0.033 (3)	0.040 (3)	0.039 (3)	0.009 (2)	0.006 (2)	0.000 (3)
N1	0.023 (2)	0.028 (2)	0.044 (3)	−0.001 (2)	−0.002 (2)	0.002 (2)
O4	0.034 (2)	0.033 (2)	0.113 (4)	0.004 (2)	−0.016 (2)	0.016 (3)
C1'	0.031 (3)	0.031 (3)	0.040 (3)	0.003 (2)	−0.003 (2)	0.003 (2)
C4'	0.032 (3)	0.041 (3)	0.055 (4)	0.002 (2)	−0.002 (3)	0.004 (3)
O4'	0.049 (2)	0.027 (2)	0.050 (2)	0.011 (2)	−0.020 (2)	−0.004 (2)
C5'	0.037 (3)	0.032 (3)	0.102 (5)	0.004 (3)	−0.005 (3)	−0.012 (3)
O5'	0.028 (2)	0.055 (3)	0.147 (5)	0.012 (2)	0.002 (3)	−0.030 (3)
C3'	0.025 (3)	0.051 (4)	0.050 (3)	0.014 (3)	−0.008 (2)	−0.012 (3)
C2'	0.045 (4)	0.030 (3)	0.051 (4)	0.000 (3)	−0.019 (3)	−0.014 (3)
O2	0.026 (2)	0.038 (2)	0.080 (3)	0.001 (2)	−0.002 (2)	−0.007 (2)
N3	0.023 (2)	0.018 (2)	0.065 (3)	0.007 (2)	−0.005 (2)	0.009 (2)
C2	0.024 (3)	0.045 (3)	0.042 (3)	0.006 (3)	0.004 (2)	0.009 (2)
C11	0.088 (7)	0.105 (8)	0.095 (7)	−0.049 (7)	0.012 (6)	−0.023 (7)
O3'	0.023 (2)	0.046 (3)	0.119 (5)	0.003 (2)	−0.007 (2)	−0.006 (3)

Geometric parameters (Å, º)

I—C8	2.137 (6)	C1'—C2'	1.476 (8)
C7—O7	1.419 (6)	C1'—H1'	0.98
C7—C5	1.504 (7)	C4'—O4'	1.440 (7)
C7—C8	1.524 (8)	C4'—C3'	1.505 (8)
C7—H17	0.98	C4'—C5'	1.506 (9)
C8—C9	1.557 (8)	C4'—H4'	0.98
C8—H8	0.98	C5'—O5'	1.414 (8)
C9—O9	1.204 (7)	C5'—H15'	0.97
C9—O10	1.315 (9)	C5'—H25'	0.97
O10—C10	1.516 (10)	O5'—H5'	0.82
C10—C11	1.519 (13)	C3'—O3'	1.395 (8)
C10—H110	0.97	C3'—C2'	1.506 (8)
C10—H210	0.97	C3'—H13'	0.98
O7—H7	0.82	C2'—H12'	0.97
C5—C6	1.334 (8)	C2'—H22'	0.97
C5—C4	1.416 (7)	O2—C2	1.203 (7)
C4—O4	1.245 (6)	N3—C2	1.355 (7)
C4—N3	1.370 (7)	N3—H3	0.86
C6—N1	1.378 (7)	C11—H111	0.96
C6—H6	0.93	C11—H211	0.96
N1—C2	1.377 (7)	C11—H311	0.96
N1—C1'	1.482 (7)	O3'—H3'	0.82
C1'—O4'	1.411 (6)
O7—C7—C5	112.4 (4)	N1—C1'—H1'	110
O7—C7—C8	107.8 (5)	O4'—C4'—C3'	105.7 (5)
C5—C7—C8	114.8 (4)	O4'—C4'—C5'	108.2 (5)
O7—C7—H17	107	C3'—C4'—C5'	115.3 (6)
C5—C7—H17	107	O4'—C4'—H4'	109
C8—C7—H17	107	C3'—C4'—H4'	109
C7—C8—C9	108.8 (5)	C5'—C4'—H4'	109
C7—C8—I	111.9 (4)	C1'—O4'—C4'	109.7 (4)
C9—C8—I	105.3 (4)	O5'—C5'—C4'	109.3 (5)
C7—C8—H8	110	O5'—C5'—H15'	110
C9—C8—H8	110	C4'—C5'—H15'	110
I—C8—H8	110	O5'—C5'—H25'	110
O9—C9—O10	128.6 (7)	C4'—C5'—H25'	110
O9—C9—C8	122.4 (6)	H15'—C5'—H25'	108
O10—C9—C8	108.9 (6)	C5'—O5'—H5'	110
C9—O10—C10	112.9 (7)	O3'—C3'—C4'	114.6 (6)
O10—C10—C11	104.4 (9)	O3'—C3'—C2'	107.8 (5)
O10—C10—H110	111	C4'—C3'—C2'	101.7 (5)
C11—C10—H110	111	O3'—C3'—H13'	111
O10—C10—H210	111	C4'—C3'—H13'	111
C11—C10—H210	111	C2'—C3'—H13'	111
H110—C10—H210	109	C1'—C2'—C3'	102.6 (6)
C7—O7—H7	109	C1'—C2'—H12'	111
C6—C5—C4	117.9 (5)	C3'—C2'—H12'	111
C6—C5—C7	122.1 (5)	C1'—C2'—H22'	111
C4—C5—C7	120.0 (5)	C3'—C2'—H22'	111
O4—C4—N3	119.8 (5)	H12'—C2'—H22'	109
O4—C4—C5	122.8 (5)	C2—N3—C4	125.1 (4)
N3—C4—C5	117.4 (4)	C2—N3—H3	117
C5—C6—N1	122.7 (5)	C4—N3—H3	117
C5—C6—H6	119	O2—C2—N3	122.6 (5)
N1—C6—H6	119	O2—C2—N1	121.7 (6)
C2—N1—C6	120.8 (5)	N3—C2—N1	115.6 (5)
C2—N1—C1'	115.2 (4)	C10—C11—H111	109
C6—N1—C1'	123.9 (4)	C10—C11—H211	109
O4'—C1'—C2'	105.4 (5)	H111—C11—H211	109
O4'—C1'—N1	107.5 (4)	C10—C11—H311	109
C2'—C1'—N1	113.9 (5)	H111—C11—H311	109
O4'—C1'—H1'	110	H211—C11—H311	109
C2'—C1'—H1'	110	C3'—O3'—H3'	109
O7—C7—C8—C9	61.1 (6)	C2—N1—C1'—C2'	−77.2 (6)
C5—C7—C8—C9	−172.8 (5)	C6—N1—C1'—C2'	105.7 (6)
O7—C7—C8—I	177.1 (3)	C2'—C1'—O4'—C4'	19.4 (6)
C5—C7—C8—I	−56.8 (6)	N1—C1'—O4'—C4'	141.3 (4)
C7—C8—C9—O9	37.7 (9)	C3'—C4'—O4'—C1'	4.9 (6)
I—C8—C9—O9	−82.5 (7)	C5'—C4'—O4'—C1'	−119.1 (6)
C7—C8—C9—O10	−139.7 (6)	O4'—C4'—C5'—O5'	−167.1 (5)
I—C8—C9—O10	100.2 (6)	C3'—C4'—C5'—O5'	74.9 (7)
O9—C9—O10—C10	7.6 (12)	O4'—C4'—C3'—O3'	89.7 (6)
C8—C9—O10—C10	−175.3 (7)	C5'—C4'—C3'—O3'	−150.9 (5)
C9—O10—C10—C11	76.7 (9)	O4'—C4'—C3'—C2'	−26.3 (7)
O7—C7—C5—C6	−116.0 (6)	C5'—C4'—C3'—C2'	93.1 (7)
C8—C7—C5—C6	120.3 (7)	O4'—C1'—C2'—C3'	−35.6 (6)
O7—C7—C5—C4	62.1 (7)	N1—C1'—C2'—C3'	−153.2 (5)
C8—C7—C5—C4	−61.6 (7)	O3'—C3'—C2'—C1'	−83.5 (5)
C6—C5—C4—O4	176.9 (6)	C4'—C3'—C2'—C1'	37.4 (7)
C7—C5—C4—O4	−1.2 (9)	O4—C4—N3—C2	178.8 (6)
C6—C5—C4—N3	−4.7 (8)	C5—C4—N3—C2	0.4 (8)
C7—C5—C4—N3	177.1 (5)	C4—N3—C2—O2	−177.1 (5)
C4—C5—C6—N1	3.2 (9)	C4—N3—C2—N1	5.3 (8)
C7—C5—C6—N1	−178.7 (5)	C6—N1—C2—O2	175.5 (5)
C5—C6—N1—C2	2.8 (8)	C1'—N1—C2—O2	−1.7 (7)
C5—C6—N1—C1'	179.8 (5)	C6—N1—C2—N3	−6.8 (7)
C2—N1—C1'—O4'	166.4 (4)	C1'—N1—C2—N3	175.9 (5)
C6—N1—C1'—O4'	−10.8 (7)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C6—H6···O4′	0.93	2.35	2.694 (8)	101
O5′—H5′···O3′^i	0.82	2.01	2.732 (6)	147
O7—H7···O5′^ii	0.82	2.29	2.912 (7)	133
O3′—H3′···O4^iii	0.82	1.98	2.650 (7)	138
N3—H3···O7^iv	0.86	2.07	2.860 (6)	152

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