7-Vinyl-8-aza-7-de­aza-2′-deoxy­adenosine monohydrate

In the title compound, 4-amino-1-(2-deoxy-β-D-eythro-pento­furan­osyl)-3-vinyl-1H-pyrazolo­[3,4-d]­pyrimidine monohydrate, C₁₂H₁₅N₅O₃·H₂O, the conformation of the gly­cosyl bond is anti. The furan­ose moiety is in an S conformation with an unsymmetrical twist, and the conformation at the exocyclic C—C(OH) bond is +sc (gauche, gauche). The vinyl side chain is bent out of the heterocyclic ring plane by 147.5 (5)°. The three-dimensional packing is stabilized by O—H...O, O—H...N and N—H...O hydrogen bonds.

S1. Comment

The 7-substituted 8-aza-7-deazapurine 2'-deoxyribonucleosides (3-substituted pyrazolo[3,4-d]pyrimidine 2'-deoxyribonucleosides) are studied as analogues of natural DNA constituents. Compound (II) (Seela & Steker, 1985; Seela et al., 1999a; Seela & Kaiser, 1988) has attracted attention as it is in ideal shape mimic of 2'-deoxyadenosine. Purine numbering is used throughout the manuscript. The 7-substited derivatives of compound (II) have a stabilizing effect on oligonucleotide duplexes (Seela et al., 1999b; Seela & Zulauf, 1999). Thus, the 7-position of an 8-aza-7-deazapurine 2'-deoxyribonucleoside is an attractive site for modification as it is the 5-position of a pyrimidine nucleoside (Gourlain et al., 2001). Cheng et al. (1976) reported that 5-vinyl-2'-deoxyuridine, (III), has the capacity for viral and tumour inhibition. A single-crystal X-ray analysis of (III) was reported in 1978 (Hamor et al., 1978). This manuscript reports on the single-crystal X-ray structure of 4-amino-1-(2-deoxy-β-D-eythro- pentofuranosyl)-3-vinyl-1H-pyrazolo[3,4-d]pyrimidine monohydrate, (I), containing a vinyl side chain in the 7-position.

Canonical purine 2'-deoxyribonucleosides tend to adopt an anti conformation. The orientation of the base relative to the sugar moiety (syn/anti) of purine nucleosides is defined by the torsion angle χ (O4'—C1'—N9—C4) (IUPAC–IUB Joint Commission on Biochemical Nomenclature, 1983). In the crystal structure of (I) (Fig. 1), the conformation of the glycosylic bond is between anti and high-anti [χ = −106.9 (5)°]. A similar conformation was observed for the parent 8-aza-7-deazapurine 2'-deoxyribonucleoside (II), with χ = −106.3 (2)° (Seela et al., 1999a). Halogen substituents at the 7-position drive the conformation to high-anti, with χ = −74.1 (4) (7-bromo) and −73.2 (4)° (7-iodo) (Seela et al., 2000). This phenomenon might be caused by stereoelectronic effects of the base. As the vinyl group has an electron withdrawing influence on the heterocyclic base, the pK_a value of protonation is decreased from 4.0 in (II) to 3.54 in (I). The glycosylic bond length in (I) (N9—C1' = 1.460 (4) Å] is slightly longer than that in (II) [1.442 (2) Å].

The pseudorotation phase, P, and the puckering amplitude, τ, angles (Rao et al., 1981) show that the sugar ring of (I) adopts an S conformation, with an unsymmetrical twist of the C4'-endo—C3'-exo bond (between ³E and ₃T⁴), having a P value of 205.6 (4)° and τ of 30.2 (2)°. In (II), the sugar ring conformation is ₃T², [P = 182.2 (2)° and τ = 41.2 (2)°]. The conformation about the C4'—C5' bond of (I) is +sc (gauche, gauche), with dihedral angle γ 42.1 (4)°, whereas in (II), the C4'—C5' bond adopts an -ap (trans) conformation with γ equal to −178.73 (16)°.

The base moiety of (I) is nearly planar, but the vinyl side chain deviates from the plane. The r.m.s. deviation of ring atoms N9, N8, C7, C5, C6, N1, C2, N3 and C4 from the least-squares plane through these atoms is 0.012 Å, with a maximum deviation of −0.024 (4) Å (atom C6). Atom C1' is displaced from this plane by −0.014 (6) Å. The torsion angle of the vinyl group to the C5/C7/C71/C72 heterocycle is 147.5 (5)°. In (III), the vinyl group is inclined by 12° to the pyrimidine ring (Hamor et al., 1978). Such a deviation was also observed in the propynyl group in 8-aza-7-deaza-7-propynyladenosine (Lin et al., 2004). The conformation of the conjugated diene system (N8—C7—C71=C72) is s-Z. This conformation occurs because of the steric repulsion between the vinyl chain and the 6-amine group.

In the three-dimensional network, the bases are stacked (3.3 Å apart; Fig. 2). Each nucleoside is connected to one water molecule, which is coordinated by hydrogen bonds. The water molecule acts as an acceptor, [O10], of a hydrogen bond from atom O3' and as a donor of two H atoms in bonds to atoms N3 and O5' (Table 2). Hence three nucleosides are connected by one water molecule. There is an intramolecular hydrogen bond between the O5'/H5' group and atom N8, which we have not observed in related nucleosides. Other intermolecular and intramolecular hydrogen bonds are summarized in Table 2.

S2. Experimental

Compound (I) was synthesized by a known procedure (Seela & Zulauf, 1998) and was crystallized as the monohydrate from aqueous methanol. For the diffraction experiment, a single-crystal was fixed at the top of a Lindemann capillary with epoxy resin.

S3. Refinement

In the absence of suitable anomalous scattering, Friedel equivalents could not be used to determine the absotute structure. Therefore, Friedel pairs were merged before the final refinements. The known configuration of the parent molecule was used to define the enantiomer of the final nucleoside. All H atoms were initially found in a difference Fourier synthesis. H atoms bonded to C and N atoms were placed in idealized positions (C—H = 0.93–0.98 Å and N—H = 0.86 Å) and constrained to ride on their parent atoms with U_iso(H) values of 1.2U_eq(C) and 1.5U_eq(N). Treatment of water H atoms?

Computing details

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: SHELXTL (Sheldrick, 1997); program(s) used to solve structure: SHELXTL; program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 1999).

Figures

	Fig. 1. A perspective view of (I). Displacement ellipsoids of non-H atoms are drawn at the 50% probability level and H atoms are shown as spheres of arbitrary size.
	Fig. 2. The crystal packing of (I), viewed down the a axis, showing the hydrogen bonds as dotted lines.

(I)

Crystal data

C12H15N5O3·H2O	F(000) = 624
Mr = 295.31	Dx = 1.430 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 28 reflections
a = 6.6513 (8) Å	θ = 4.9–12.5°
b = 9.603 (5) Å	µ = 0.11 mm^−1
c = 21.481 (3) Å	T = 293 K
V = 1372.1 (7) Å^3	Block, colourless
Z = 4	0.42 × 0.28 × 0.20 mm

Data collection

Bruker P4 diffractometer	Rint = 0.040
Radiation source: fine-focus sealed tube	θmax = 29.0°, θmin = 2.3°
Graphite monochromator	h = −1→9
2θ/ω scans	k = −1→13
2800 measured reflections	l = −29→1
2100 independent reflections	3 standard reflections every 97 reflections
1180 reflections with I > 2σ(I)	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)] = 0.058	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.113	w = 1/[σ^2(Fo^2) + (0.0349P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.02	(Δ/σ)max < 0.001
2100 reflections	Δρmax = 0.22 e Å^−3
205 parameters	Δρmin = −0.21 e Å^−3
5 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0074 (11)

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
N1	0.7445 (6)	0.5975 (3)	0.54376 (12)	0.0360 (7)
C2	0.7462 (7)	0.5638 (4)	0.48368 (14)	0.0372 (9)
H2	0.7467	0.4687	0.4755	0.045*
N3	0.7474 (6)	0.6450 (3)	0.43335 (11)	0.0329 (7)
C4	0.7511 (7)	0.7810 (3)	0.44955 (14)	0.0309 (8)
C5	0.7518 (7)	0.8351 (3)	0.50977 (13)	0.0283 (8)
N6	0.7363 (5)	0.7665 (3)	0.61930 (10)	0.0383 (8)
H6A	0.7328	0.7013	0.6467	0.057*
H6B	0.7352	0.8523	0.6308	0.057*
C6	0.7433 (7)	0.7341 (4)	0.55823 (14)	0.0309 (8)
C7	0.7561 (7)	0.9829 (3)	0.50242 (12)	0.0306 (8)
C71	0.7639 (7)	1.0921 (4)	0.54974 (14)	0.0367 (9)
H71	0.7004	1.0757	0.5876	0.044*
C72	0.8549 (7)	1.2113 (4)	0.54196 (19)	0.0523 (13)
H72A	0.9197	1.2306	0.5046	0.063*
H72B	0.8549	1.2769	0.5738	0.063*
N8	0.7576 (5)	1.0140 (3)	0.44211 (10)	0.0321 (7)
N9	0.7518 (6)	0.8909 (3)	0.40996 (10)	0.0327 (7)
C1'	0.7540 (7)	0.8897 (4)	0.34202 (13)	0.0343 (9)
H1'	0.7249	0.7951	0.3274	0.041*
C2'	0.6036 (6)	0.9899 (4)	0.31293 (16)	0.0415 (10)
H2'1	0.4883	0.9398	0.2967	0.050*
H2'2	0.5575	1.0573	0.3434	0.050*
C3'	0.7170 (6)	1.0614 (4)	0.26076 (13)	0.0341 (10)
H3'1	0.6723	1.1579	0.2555	0.041*
O3'	0.7050 (5)	0.9861 (3)	0.20340 (11)	0.0461 (8)
H3'	0.586 (2)	0.977 (5)	0.194 (2)	0.069*
O4'	0.9466 (4)	0.9300 (3)	0.32001 (11)	0.0378 (7)
C4'	0.9360 (7)	1.0549 (4)	0.28232 (17)	0.0367 (10)
H4'	1.0219	1.0421	0.2457	0.044*
O5'	0.8724 (6)	1.2346 (3)	0.36217 (12)	0.0588 (10)
H5'	0.844 (8)	1.181 (4)	0.3912 (15)	0.088*
C5'	1.0097 (7)	1.1807 (4)	0.31795 (19)	0.0545 (13)
H5'1	1.1331	1.1559	0.3393	0.065*
H5'2	1.0420	1.2537	0.2884	0.065*
O10	0.3108 (5)	0.9789 (3)	0.17403 (11)	0.0519 (9)
H10A	0.305 (7)	1.040 (3)	0.1415 (11)	0.078*
H10B	0.262 (8)	0.898 (2)	0.1583 (14)	0.078*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.038 (2)	0.0340 (17)	0.0360 (14)	−0.002 (2)	0.0022 (19)	0.0077 (13)
C2	0.043 (2)	0.0257 (17)	0.0423 (18)	0.001 (3)	0.002 (3)	−0.0004 (16)
N3	0.0355 (18)	0.0308 (15)	0.0323 (13)	−0.003 (2)	0.0000 (19)	−0.0002 (12)
C4	0.031 (2)	0.0325 (18)	0.0295 (15)	−0.003 (3)	−0.005 (2)	0.0037 (14)
C5	0.027 (2)	0.0308 (16)	0.0269 (15)	0.001 (2)	0.003 (2)	−0.0004 (14)
N6	0.055 (2)	0.0372 (15)	0.0222 (12)	−0.001 (2)	0.0005 (17)	0.0064 (12)
C6	0.024 (2)	0.0363 (19)	0.0323 (17)	0.002 (2)	−0.002 (2)	0.0059 (15)
C7	0.030 (2)	0.0340 (18)	0.0280 (15)	−0.001 (3)	−0.005 (2)	0.0009 (14)
C71	0.048 (3)	0.035 (2)	0.0276 (15)	−0.001 (3)	0.002 (2)	0.0009 (15)
C72	0.071 (4)	0.041 (2)	0.045 (2)	−0.003 (3)	0.008 (2)	−0.008 (2)
N8	0.0401 (18)	0.0293 (15)	0.0268 (13)	−0.001 (2)	0.0001 (19)	0.0009 (12)
N9	0.048 (2)	0.0266 (15)	0.0236 (12)	−0.002 (2)	−0.0020 (19)	0.0032 (11)
C1'	0.042 (2)	0.0365 (18)	0.0245 (14)	−0.001 (3)	−0.001 (2)	−0.0023 (14)
C2'	0.037 (2)	0.056 (2)	0.032 (2)	0.004 (2)	−0.0028 (19)	0.006 (2)
C3'	0.046 (3)	0.0311 (18)	0.0253 (15)	0.003 (2)	−0.0019 (18)	0.0030 (15)
O3'	0.056 (2)	0.0555 (16)	0.0270 (12)	0.002 (2)	−0.0017 (14)	−0.0029 (12)
O4'	0.0384 (17)	0.0426 (15)	0.0324 (13)	0.0081 (14)	0.0032 (13)	0.0077 (13)
C4'	0.043 (3)	0.037 (2)	0.0297 (18)	0.000 (2)	0.0044 (19)	0.0057 (18)
O5'	0.100 (3)	0.0368 (16)	0.0397 (15)	−0.001 (2)	0.0022 (19)	0.0011 (13)
C5'	0.063 (3)	0.047 (2)	0.053 (2)	−0.009 (3)	0.002 (3)	−0.001 (2)
O10	0.065 (2)	0.0538 (17)	0.0372 (13)	−0.0075 (18)	−0.0046 (16)	0.0010 (13)

Geometric parameters (Å, º)

N1—C2	1.331 (4)	C1'—O4'	1.419 (5)
N1—C6	1.348 (4)	C1'—C2'	1.523 (5)
C2—N3	1.333 (4)	C1'—H1'	0.9800
C2—H2	0.9300	C2'—C3'	1.515 (5)
N3—C4	1.352 (4)	C2'—H2'1	0.9700
C4—N9	1.355 (4)	C2'—H2'2	0.9700
C4—C5	1.394 (4)	C3'—O3'	1.431 (4)
C5—C6	1.424 (4)	C3'—C4'	1.530 (6)
C5—C7	1.429 (5)	C3'—H3'1	0.9800
N6—C6	1.349 (4)	O3'—H3'	0.823 (10)
N6—H6A	0.8600	O4'—C4'	1.449 (4)
N6—H6B	0.8600	C4'—C5'	1.512 (5)
C7—N8	1.330 (3)	C4'—H4'	0.9800
C7—C71	1.461 (4)	O5'—C5'	1.416 (5)
C71—C72	1.306 (5)	O5'—H5'	0.83 (4)
C71—H71	0.9300	C5'—H5'1	0.9700
C72—H72A	0.9300	C5'—H5'2	0.9700
C72—H72B	0.9300	O10—H10A	0.910 (15)
N8—N9	1.370 (3)	O10—H10B	0.910 (15)
N9—C1'	1.460 (4)
C2—N1—C6	117.4 (3)	N9—C1'—C2'	113.5 (3)
N1—C2—N3	130.1 (3)	O4'—C1'—H1'	109.0
N1—C2—H2	114.9	N9—C1'—H1'	109.0
N3—C2—H2	114.9	C2'—C1'—H1'	109.0
C2—N3—C4	110.9 (3)	C3'—C2'—C1'	105.2 (3)
N3—C4—N9	126.2 (3)	C3'—C2'—H2'1	110.7
N3—C4—C5	126.8 (3)	C1'—C2'—H2'1	110.7
N9—C4—C5	107.0 (3)	C3'—C2'—H2'2	110.7
C4—C5—C6	115.1 (3)	C1'—C2'—H2'2	110.7
C4—C5—C7	105.5 (3)	H2'1—C2'—H2'2	108.8
C6—C5—C7	139.3 (3)	O3'—C3'—C2'	112.4 (3)
C6—N6—H6A	120.0	O3'—C3'—C4'	107.1 (3)
C6—N6—H6B	120.0	C2'—C3'—C4'	103.4 (3)
H6A—N6—H6B	120.0	O3'—C3'—H3'1	111.2
N1—C6—N6	116.7 (3)	C2'—C3'—H3'1	111.2
N1—C6—C5	119.6 (3)	C4'—C3'—H3'1	111.2
N6—C6—C5	123.7 (3)	C3'—O3'—H3'	108 (3)
N8—C7—C5	109.3 (3)	C1'—O4'—C4'	111.6 (3)
N8—C7—C71	121.1 (3)	O4'—C4'—C5'	111.3 (3)
C5—C7—C71	129.6 (3)	O4'—C4'—C3'	104.4 (3)
C72—C71—C7	123.8 (4)	C5'—C4'—C3'	115.5 (4)
C72—C71—H71	118.1	O4'—C4'—H4'	108.5
C7—C71—H71	118.1	C5'—C4'—H4'	108.5
C71—C72—H72A	120.0	C3'—C4'—H4'	108.5
C71—C72—H72B	120.0	C5'—O5'—H5'	115 (4)
H72A—C72—H72B	120.0	O5'—C5'—C4'	115.0 (4)
C7—N8—N9	107.3 (3)	O5'—C5'—H5'1	108.5
C4—N9—N8	110.8 (2)	C4'—C5'—H5'1	108.5
C4—N9—C1'	128.4 (3)	O5'—C5'—H5'2	108.5
N8—N9—C1'	120.7 (3)	C4'—C5'—H5'2	108.5
O4'—C1'—N9	109.9 (3)	H5'1—C5'—H5'2	107.5
O4'—C1'—C2'	106.5 (3)	H10A—O10—H10B	105 (3)
C6—N1—C2—N3	0.1 (8)	C5—C4—N9—N8	1.4 (5)
N1—C2—N3—C4	1.3 (7)	N3—C4—N9—C1'	−1.7 (8)
C2—N3—C4—N9	−179.5 (5)	C5—C4—N9—C1'	179.2 (4)
C2—N3—C4—C5	−0.5 (7)	C7—N8—N9—C4	−1.3 (5)
N3—C4—C5—C6	−1.5 (7)	C7—N8—N9—C1'	−179.3 (4)
N9—C4—C5—C6	177.7 (4)	C4—N9—C1'—O4'	−106.9 (5)
N3—C4—C5—C7	180.0 (5)	N8—N9—C1'—O4'	70.7 (5)
N9—C4—C5—C7	−0.9 (5)	C4—N9—C1'—C2'	134.0 (5)
C2—N1—C6—N6	178.3 (4)	N8—N9—C1'—C2'	−48.3 (6)
C2—N1—C6—C5	−2.4 (7)	O4'—C1'—C2'—C3'	15.0 (4)
C4—C5—C6—N1	3.0 (6)	N9—C1'—C2'—C3'	136.0 (4)
C7—C5—C6—N1	−179.2 (6)	C1'—C2'—C3'—O3'	88.1 (4)
C4—C5—C6—N6	−177.8 (5)	C1'—C2'—C3'—C4'	−27.0 (4)
C7—C5—C6—N6	0.0 (9)	N9—C1'—O4'—C4'	−119.2 (3)
C4—C5—C7—N8	0.1 (6)	C2'—C1'—O4'—C4'	4.1 (4)
C6—C5—C7—N8	−177.9 (5)	C1'—O4'—C4'—C5'	104.0 (4)
C4—C5—C7—C71	−178.2 (5)	C1'—O4'—C4'—C3'	−21.2 (4)
C6—C5—C7—C71	3.9 (11)	O3'—C3'—C4'—O4'	−89.6 (3)
N8—C7—C71—C72	−30.6 (7)	C2'—C3'—C4'—O4'	29.3 (4)
C5—C7—C71—C72	147.5 (5)	O3'—C3'—C4'—C5'	147.9 (3)
C5—C7—N8—N9	0.8 (5)	C2'—C3'—C4'—C5'	−93.2 (4)
C71—C7—N8—N9	179.2 (4)	O4'—C4'—C5'—O5'	−76.7 (4)
N3—C4—N9—N8	−179.5 (5)	C3'—C4'—C5'—O5'	42.1 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H6A···O4′^i	0.86	2.39	2.995 (4)	128
N6—H6B···O3′^ii	0.86	2.24	3.010 (4)	150
O3′—H3′···O10	0.82 (2)	1.88 (2)	2.698 (5)	173 (5)
O5′—H5′···N8	0.83 (4)	2.02 (4)	2.832 (4)	164 (4)
O10—H10A···N3^iii	0.91 (3)	1.93 (3)	2.831 (4)	169 (4)
O10—H10B···O5′^iv	0.91 (3)	1.86 (3)	2.755 (4)	169 (4)

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