1,N⁶-Etheno derivative of 7-de­aza-2,8-di­aza­adenosine

In the tricyclic nucleoside 7-(β-D-ribo­furan­osyl)-7H-imidazo­[1,2-c]­pyrazolo­[4,3-e][1,2,3]­triazine, C₁₁H₁₂N₆O₄, the con­formation of the N-gly­cosyl bond is intermediate between anti and high anti [χ = −103.5 (3)°]. The ribo­furan­ose moiety adopts a ₃T² sugar pucker (S-type sugar) and the conformation at the exocyclic C—C bond is ap (gauche–trans). Molecules of the title compound form a three-dimensional network via three medium–strong intermolecular hydrogen bonds (one O—H...N and two O—H...O bonds).

S1. Comment

Synthetic nucleoside analogues have proved to be of great value for the therapy of human diseases and are used as structural or functional probes in molecular biology (Simons, 2001; Service, 1998). The title compound 7-(β-D-ribofuranosyl)imidazo[1,2-c]-7H-pyrazolo [4,3-e][1,2,3]triazine (7-deaza-2,8-diaza-1,N⁶-ethenoadenosine), (I), contains structural elements of the tricycle nucleosides ε-adenosine, (II), and 2-aza-ε-adenosine, (III). Compounds (II) and (III) have been investigated extensively because of their strong fluorescence, which makes them useful fluorescent probes in biochemical studies (Barrio et al., 1972; Secrist et al., 1972), as well as because of their biological properties, such as cytotoxic activity (Tsou et al., 1974). Recently, our interest became focused on 2-azapurines and their nucleosides (Sugiyama et al., 2001; Seela et al., 2004). Compound (I) was synthesized from 8-aza-7-deazaadenosine via an etheno derivative, in which carbon-2 was replaced by nitrogen (Lin & Seela, 2004). In contrast to (II) and (III), compound (I) shows no significant fluorescence. We describe here the single-crystal X-ray structure determination of the title compound.

The preferred conformation at the N-glycosylic bond in natural purine ribonucleosides is usually in the anti range. The orientation of the nucleobase of (I) relative to the sugar moiety (syn/anti) was defined in analogy to purines (IUPAC-IUB Joint Commission on Biochemical Nomenclature, 1983) by the torsion angle χ (O4'—C1'—N9—C4) using the atom numbering shown in Fig. 1. The value of χ [−103.5 (3)°] is intermediate between anti and high anti. Compound (II) exhibits an anti conformation (χ=-153.8°; Jaskolski, 1982). The length of the C1'—N9 glycosyl bond is 1.459 (3) Å, identical to the standard glycosyl bond length of about 1.46 Å for purine nucleosides.

In contrast to the heterocyclic base moiety of (II), which is not planar but has a `U' shape (Jaskolski, 1982), the tricyclic base moiety of (I) is nearly planar. The r.m.s. deviations of the base ring-forming atoms from their calculated least-squares planes are 0.01 Å, the maximum deviation being 0.018 (2) Å (for atom N3). Atom C1' of the sugar moiety deviates from the tricyclic plane by 0.058 (3) Å.

The sugar moiety of (I) exhibits a pseudo-rotation phase angle, P, of 183.4° and an amplitude, τ_m, of 42.4° (Rao et al., 1981), indicating that the sugar is in the south (S) conformation. The sugar has a C2'-endo and C3'-exo conformation, with the major puckering at C3' and the minor at C2' (₃T²). The electronegative hydroxy group at atom C2' is in a pseudo-equatorial orientation and that at C3' is in a pseudo-axial orientation. The base is in a pseudo-equatorial orientation. Usually, ribonucleosides show the N-conformation, while 2'-deoxyribonucleosides prefer the S-conformation. It can thus be concluded that introduction of the etheno bridge into the 7-deaza-2,8-diazaadenosine molecule significantly changes the electronic structure of its base fragment and influences even the sugar moiety by stereoelectronic effects. The C3'—C4'—C5'—O5' torsion angle is −172.0 (2)°, which corresponds to an ap (gauche-trans) conformation according to the IUPAC-IUB recommendation. This configuration may reflect the electrostatic repulsion between atoms N8 and O5'.

In solution, the sugar puckering of (I) is in the N \leftrightarrow S pseudo-rotational equilibrium with 64% S as calculated by PSEUROT (Van Wijk et al., 1999). Thus the solution and the solid-state structure are similar and both differ from the situation typical for ribonucleosides. The other pseudo-rotational parameters of (I) are P_N=-1.6, P_S=193.7, Ψ=32.0 and Ψ_S=35.0 (Altona & Sundaralingam, 1972).

The crystal structure of (I) is stabilized by three medium-strong hydrogen bonds, listed in Table 2 and shown in Fig. 2, which arrange the nucleoside molecules into a compact three-dimensional network, with the aromatic nucleobases stacked head to tail.

S2. Experimental

The title compound was prepared from 8-aza-7-deazaadenosine (Lin & Seela,2004), and crystals suitable for X-ray analysis were grown from a solution in ethanol and water (m.p. 483 K).

S3. Refinement

In the absence of suitable anomalous scatterers, Friedel equivalents could not be used to determine the absotute structure. Therefore, Friedel equivalents were merged before the final refinements. The known configuration of the parent molecule was used to define the enantiomer of the final model. All H atoms were initially found in a difference Fourier synthesis. In order to maximize the data/parameter ratio, H atoms bonded to C atoms were placed in idealized positions (C—H = 0.93–0.98 Å) and constrained to ride on their parent atoms, with U_iso(H) values of 1.2U_eq(C). Hydroxy H atoms, initially placed in the difference map positions, were later positioned geometrically and assumed to ride on their parent O atoms, under the constraint that the O—H distances be equal.

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 the molecule of (I), showing the atomic numbering scheme. Displacement ellipsoids of non-H atoms are drawn at the 50% probability level. H atoms are represented by spheres of arbitrary size.
	Fig. 2. The crystal packing of (I), viewed along the a axis, showing the intermolecular hydrogen-bonding network.

(I)

Crystal data

C11H12N6O4	Dx = 1.564 Mg m^−3
Mr = 292.27	Melting point: 483 K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 49 reflections
a = 6.8229 (5) Å	θ = 4.7–15.0°
b = 8.9565 (11) Å	µ = 0.12 mm^−1
c = 20.310 (6) Å	T = 293 K
V = 1241.2 (4) Å^3	Block, colourless
Z = 4	0.52 × 0.4 × 0.36 mm
F(000) = 608

Data collection

Bruker P4 diffractometer	Rint = 0.046
Radiation source: fine-focus sealed tube	θmax = 29.0°, θmin = 2.0°
Graphite monochromator	h = −9→1
2θ/ω scans	k = −1→12
2583 measured reflections	l = −1→27
1927 independent reflections	3 standard reflections every 97 reflections
1520 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.114	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ^2(Fo^2) + (0.054P)^2 + 0.3012P] where P = (Fo^2 + 2Fc^2)/3
1927 reflections	(Δ/σ)max < 0.001
202 parameters	Δρmax = 0.23 e Å^−3
5 restraints	Δρmin = −0.26 e Å^−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 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	0.7726 (4)	0.8750 (2)	0.47221 (9)	0.0292 (5)
N2	0.7705 (4)	0.8690 (2)	0.40446 (10)	0.0360 (5)
N3	0.7643 (4)	0.7395 (2)	0.37797 (9)	0.0337 (5)
C4	0.7651 (4)	0.6186 (3)	0.41808 (10)	0.0257 (5)
C5	0.7678 (4)	0.6137 (3)	0.48665 (10)	0.0269 (5)
C6	0.7696 (4)	0.7558 (3)	0.51666 (10)	0.0275 (5)
C7	0.7674 (5)	0.4596 (3)	0.50190 (12)	0.0343 (6)
H7	0.7692	0.4209	0.5444	0.041*
N8	0.7640 (4)	0.3776 (2)	0.44751 (10)	0.0357 (5)
N9	0.7634 (4)	0.4749 (2)	0.39632 (9)	0.0290 (5)
C10	0.7740 (5)	1.0057 (3)	0.50799 (14)	0.0376 (7)
H10	0.7757	1.1028	0.4918	0.045*
C11	0.7721 (5)	0.9619 (3)	0.57158 (13)	0.0377 (6)
H11	0.7727	1.0274	0.6071	0.045*
N12	0.7693 (4)	0.8069 (3)	0.57758 (10)	0.0352 (5)
C1'	0.7536 (4)	0.4283 (3)	0.32755 (10)	0.0280 (5)
H1'	0.7836	0.5146	0.2996	0.034*
O2'	1.0794 (3)	0.3610 (3)	0.29795 (11)	0.0437 (5)
H2'	1.1614 (15)	0.2965 (18)	0.3059 (19)	0.066*
C2'	0.8920 (4)	0.3027 (3)	0.30986 (13)	0.0317 (6)
H2'1	0.8975	0.2300	0.3459	0.038*
O3'	0.8116 (3)	0.3314 (2)	0.19583 (9)	0.0410 (5)
H3'	0.783 (6)	0.2860 (19)	0.1621 (4)	0.061*
C3'	0.7855 (4)	0.2349 (3)	0.25068 (12)	0.0332 (6)
H3'1	0.8289	0.1328	0.2414	0.040*
O4'	0.5603 (3)	0.3784 (2)	0.31275 (9)	0.0348 (4)
C4'	0.5729 (4)	0.2406 (3)	0.27494 (12)	0.0301 (5)
H4'	0.483 (5)	0.248 (4)	0.2419 (16)	0.036*
O5'	0.3058 (3)	0.1158 (3)	0.32956 (11)	0.0468 (5)
H5'	0.253 (6)	0.039 (3)	0.3165 (18)	0.070*
C5'	0.5115 (5)	0.1102 (4)	0.31735 (16)	0.0420 (7)
H5'1	0.5441	0.0174	0.2953	0.050*
H5'2	0.5819	0.1133	0.3588	0.050*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0370 (12)	0.0232 (9)	0.0274 (9)	0.0005 (11)	−0.0001 (9)	−0.0028 (8)
N2	0.0535 (15)	0.0273 (10)	0.0274 (9)	0.0032 (13)	−0.0025 (11)	0.0004 (8)
N3	0.0474 (13)	0.0285 (10)	0.0253 (8)	0.0017 (13)	−0.0017 (10)	0.0006 (8)
C4	0.0297 (12)	0.0247 (10)	0.0227 (9)	0.0000 (12)	0.0011 (10)	−0.0038 (9)
C5	0.0322 (13)	0.0267 (11)	0.0218 (9)	−0.0001 (13)	−0.0009 (10)	−0.0010 (9)
C6	0.0290 (13)	0.0291 (11)	0.0244 (9)	0.0004 (13)	−0.0003 (10)	−0.0007 (10)
C7	0.0486 (17)	0.0277 (12)	0.0266 (11)	0.0002 (14)	0.0013 (13)	0.0008 (9)
N8	0.0508 (14)	0.0254 (10)	0.0309 (9)	0.0001 (12)	−0.0010 (11)	0.0006 (9)
N9	0.0404 (13)	0.0221 (9)	0.0244 (8)	0.0018 (10)	−0.0027 (10)	−0.0035 (8)
C10	0.0452 (18)	0.0242 (11)	0.0435 (13)	0.0013 (13)	0.0007 (14)	−0.0081 (11)
C11	0.0431 (16)	0.0335 (13)	0.0363 (12)	−0.0016 (14)	0.0020 (13)	−0.0141 (11)
N12	0.0445 (14)	0.0353 (11)	0.0259 (9)	−0.0022 (12)	0.0003 (11)	−0.0085 (9)
C1'	0.0328 (13)	0.0276 (11)	0.0234 (9)	0.0021 (11)	−0.0043 (10)	−0.0060 (9)
O2'	0.0330 (10)	0.0442 (12)	0.0539 (12)	0.0011 (10)	0.0008 (10)	−0.0088 (11)
C2'	0.0325 (13)	0.0300 (13)	0.0327 (12)	0.0032 (11)	−0.0015 (11)	−0.0061 (11)
O3'	0.0547 (13)	0.0394 (10)	0.0288 (8)	0.0015 (11)	0.0030 (9)	−0.0053 (8)
C3'	0.0414 (15)	0.0274 (12)	0.0308 (11)	0.0048 (13)	−0.0026 (11)	−0.0094 (10)
O4'	0.0322 (9)	0.0337 (10)	0.0385 (10)	0.0044 (9)	−0.0031 (8)	−0.0139 (9)
C4'	0.0354 (13)	0.0264 (12)	0.0286 (11)	0.0040 (12)	−0.0049 (11)	−0.0080 (11)
O5'	0.0447 (12)	0.0357 (11)	0.0601 (13)	−0.0029 (11)	0.0035 (11)	0.0030 (11)
C5'	0.0446 (16)	0.0326 (14)	0.0488 (16)	0.0004 (14)	−0.0054 (14)	0.0029 (14)

Geometric parameters (Å, º)

N1—N2	1.377 (3)	C1'—O4'	1.425 (3)
N1—C10	1.378 (3)	C1'—C2'	1.512 (4)
N1—C6	1.398 (3)	C1'—H1'	0.9800
N2—N3	1.279 (3)	O2'—C2'	1.402 (4)
N3—C4	1.355 (3)	O2'—H2'	0.820 (16)
C4—N9	1.361 (3)	C2'—C3'	1.530 (4)
C4—C5	1.393 (3)	C2'—H2'1	0.9800
C5—C6	1.411 (3)	O3'—C3'	1.421 (3)
C5—C7	1.415 (3)	O3'—H3'	0.820 (14)
C6—N12	1.319 (3)	C3'—C4'	1.533 (4)
C7—N8	1.327 (3)	C3'—H3'1	0.9800
C7—H7	0.9300	O4'—C4'	1.456 (3)
N8—N9	1.356 (3)	C4'—C5'	1.510 (4)
N9—C1'	1.459 (3)	C4'—H4'	0.91 (3)
C10—C11	1.350 (4)	O5'—C5'	1.426 (4)
C10—H10	0.9300	O5'—H5'	0.82 (3)
C11—N12	1.394 (3)	C5'—H5'1	0.9700
C11—H11	0.9300	C5'—H5'2	0.9700
N2—N1—C10	124.1 (2)	O4'—C1'—H1'	108.6
N2—N1—C6	128.0 (2)	N9—C1'—H1'	108.6
C10—N1—C6	107.94 (19)	C2'—C1'—H1'	108.6
N3—N2—N1	117.1 (2)	C2'—O2'—H2'	109.0 (10)
N2—N3—C4	118.14 (18)	O2'—C2'—C1'	109.5 (2)
N3—C4—N9	124.09 (19)	O2'—C2'—C3'	116.4 (2)
N3—C4—C5	128.7 (2)	C1'—C2'—C3'	100.7 (2)
N9—C4—C5	107.2 (2)	O2'—C2'—H2'1	109.9
C4—C5—C6	113.8 (2)	C1'—C2'—H2'1	109.9
C4—C5—C7	104.4 (2)	C3'—C2'—H2'1	109.9
C6—C5—C7	141.8 (2)	C3'—O3'—H3'	108.9 (10)
N12—C6—N1	109.9 (2)	O3'—C3'—C2'	108.4 (2)
N12—C6—C5	135.9 (2)	O3'—C3'—C4'	110.5 (2)
N1—C6—C5	114.19 (18)	C2'—C3'—C4'	100.59 (19)
N8—C7—C5	111.0 (2)	O3'—C3'—H3'1	112.2
N8—C7—H7	124.5	C2'—C3'—H3'1	112.2
C5—C7—H7	124.5	C4'—C3'—H3'1	112.2
C7—N8—N9	106.4 (2)	C1'—O4'—C4'	108.82 (19)
N8—N9—C4	111.01 (18)	O4'—C4'—C5'	109.8 (2)
N8—N9—C1'	123.38 (19)	O4'—C4'—C3'	104.7 (2)
C4—N9—C1'	125.56 (19)	C5'—C4'—C3'	114.8 (2)
C11—C10—N1	105.0 (2)	O4'—C4'—H4'	107 (2)
C11—C10—H10	127.5	C5'—C4'—H4'	107 (2)
N1—C10—H10	127.5	C3'—C4'—H4'	114 (2)
C10—C11—N12	111.9 (2)	C5'—O5'—H5'	110 (3)
C10—C11—H11	124.0	O5'—C5'—C4'	110.2 (3)
N12—C11—H11	124.0	O5'—C5'—H5'1	109.6
C6—N12—C11	105.3 (2)	C4'—C5'—H5'1	109.6
O4'—C1'—N9	109.5 (2)	O5'—C5'—H5'2	109.6
O4'—C1'—C2'	107.1 (2)	C4'—C5'—H5'2	109.6
N9—C1'—C2'	114.3 (2)	H5'1—C5'—H5'2	108.1
C10—N1—N2—N3	−178.2 (3)	C6—N1—C10—C11	0.1 (3)
C6—N1—N2—N3	0.4 (5)	N1—C10—C11—N12	−0.1 (4)
N1—N2—N3—C4	−1.6 (4)	N1—C6—N12—C11	0.0 (4)
N2—N3—C4—N9	−178.4 (3)	C5—C6—N12—C11	180.0 (3)
N2—N3—C4—C5	1.5 (4)	C10—C11—N12—C6	0.1 (4)
N3—C4—C5—C6	0.1 (4)	N8—N9—C1'—O4'	73.7 (3)
N9—C4—C5—C6	−180.0 (2)	C4—N9—C1'—O4'	−103.5 (3)
N3—C4—C5—C7	−180.0 (3)	N8—N9—C1'—C2'	−46.5 (4)
N9—C4—C5—C7	−0.1 (3)	C4—N9—C1'—C2'	136.4 (3)
N2—N1—C6—N12	−178.8 (3)	O4'—C1'—C2'—O2'	156.5 (2)
C10—N1—C6—N12	−0.1 (3)	N9—C1'—C2'—O2'	−81.9 (3)
N2—N1—C6—C5	1.2 (4)	O4'—C1'—C2'—C3'	33.4 (2)
C10—N1—C6—C5	180.0 (3)	N9—C1'—C2'—C3'	154.9 (2)
C4—C5—C6—N12	178.7 (3)	O2'—C2'—C3'—O3'	−43.5 (3)
C7—C5—C6—N12	−1.1 (7)	C1'—C2'—C3'—O3'	74.7 (3)
C4—C5—C6—N1	−1.3 (4)	O2'—C2'—C3'—C4'	−159.5 (2)
C7—C5—C6—N1	178.9 (4)	C1'—C2'—C3'—C4'	−41.3 (2)
C4—C5—C7—N8	−0.2 (4)	N9—C1'—O4'—C4'	−135.5 (2)
C6—C5—C7—N8	179.6 (4)	C2'—C1'—O4'—C4'	−11.1 (3)
C5—C7—N8—N9	0.4 (3)	C1'—O4'—C4'—C5'	107.7 (2)
C7—N8—N9—C4	−0.4 (3)	C1'—O4'—C4'—C3'	−16.1 (2)
C7—N8—N9—C1'	−177.9 (3)	O3'—C3'—C4'—O4'	−78.3 (2)
N3—C4—N9—N8	−179.8 (3)	C2'—C3'—C4'—O4'	36.0 (2)
C5—C4—N9—N8	0.3 (3)	O3'—C3'—C4'—C5'	161.2 (2)
N3—C4—N9—C1'	−2.3 (5)	C2'—C3'—C4'—C5'	−84.4 (3)
C5—C4—N9—C1'	177.8 (3)	O4'—C4'—C5'—O5'	70.4 (3)
N2—N1—C10—C11	178.9 (3)	C3'—C4'—C5'—O5'	−172.0 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O5′—H5′···O3′^i	0.82 (3)	1.93 (3)	2.720 (3)	162 (4)
O3′—H3′···N12^ii	0.82 (1)	1.94 (1)	2.758 (3)	174 (2)
O2′—H2′···O5′^iii	0.82 (2)	1.96 (2)	2.761 (3)	167 (1)

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