7-Deaza-2′-deoxy­inosine: a nucleoside showing ambiguous base-pairing properties against the four canonical DNA constituents

The title compound [systematic name: 7-(2-de­oxy-β-D-erythro-pentofuranos­yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one], C₁₁H₁₃N₃O₄, represents an acid-stable derivative of 2′-deoxy­inosine. It exhibits an anti glycosylic bond conformation, with a χ torsion angle of 113.30 (15)°. The furan­ose moiety adopts an S-type sugar pucker ⁴T₃, with P = 221.8 (1)° and τ_m = 40.4 (1)°. The conformation at the exocyclic C4′—C5′ bond of the furan­ose ring is ap (trans), with γ = 167.14 (10)°. The extended structure forms a three-dimensional hydrogen-bond network involving O—H...O, N—H...O and C—H...O hydrogen bonds. The title compound forms an uncommon hydrogen bond between a CH group of the pyrrole system and the ring O atom of the sugar moiety of a neighbouring mol­ecule.

S1. Comment

The naturally occurring ribonucleoside inosine, (IIIa), is known to form wobble base pairs at the ambiguous positions of the anticodon of tRNAs (Crick, 1966; Topal & Fresco, 1976). The corresponding 2'-deoxyinosine, (IIIb), is the classical universal nucleoside which shows ambiguous base pairing with the four natural constituents of DNA (Topal & Fresco, 1976). Recently, the base pairing properties of 7-deaza-2'-deoxyinosine, (I), were investigated and found to be similar to those of 2'-deoxyinosine (purine numbering is used throughout this discussion). Compared to the latter, it forms an extraordinarily stable N-glycosylic bond (Seela & Mittelbach, 1999; Seela & Kaiser, 1986). Also, substituted derivatives of 7-deaza-2'-deoxyinosine have been reported with halogen substituents or alkynyl residues at the 7-position of the nucleobase (Seela & Ming, 2008). 7-Deaza-2'-deoxyinosine derivatives with a terminal triple bond in the side chain were functionalized by the Huisgen–Meldal–Sharpless azide–alkine `click' reaction (Seela & Ming, 2008). As nothing is known about the conformational properties of compound (I), a single-crystal X-ray analysis was performed. The conformation and molecular dimensions of (I) are compared with the similar structures (II)–(IV).

The three-dimensional structure of (I) is shown in Fig. 1, and selected geometric parameters are listed in Table 1. The orientation of the nucleobase relative to the sugar moiety is anti with a torsion angle χ = 113.30 (15)° (χ = O4'—C1'—N9—C4; IUPAC–IUB Joint Commission on Biochemical Nomenclature, 1983). For the related 7-deazaadenosine [2'-deoxytubercidin, (II)], this conformation falls into the range between anti and high-anti, with χ = -104.4 (2)° (Zabel et al., 1987). Inosine (IIIa) crystallizes in at least two distinct crystal forms, inosine (Bugg et al., 1968) and inosine dihydrate (Thewalt et al., 1970). The dihydrate crystal of (IIIa) has two conformationally different molecules in the asymmetric unit (Thewalt et al., 1970). Molecule A of inosine dihydrate adopts an anti conformation with χ = -133.18 (1)°, while molecule B shows a syn conformation [χ = -58.40 (1)°; Thewalt et al., 1970]. Similarly, 7-deaza-2'-deoxyxanthosine, (IV), shows the syn conformation [χ = 61.9 (4)°; Seela et al., 2002]. In contrast, in the absence of water, the conformation of inosine is anti with χ = -174.26 (5)° (Munns & Tollin, 1970). The length of the N9—C1' glycosylic bond of (I) is 1.4509 (15) Å, which is within the range of the corresponding bonds in compounds (II) [1.449 (2) Å; Zabel et al., 1987] and (IIIa) [1.477 (4) Å for inosine; 1.462 Å for molecule A and 1.452 Å for molecule B of inosine dihydrate; Munns & Tollin, 1970; Thewalt et al., 1970].

According to common rules, the displacement of the sugar ring atoms is endo when lying on the same side of the sugar plane as atom C5', or exo when lying on the opposite side. The most frequently observed sugar ring conformations of purine nucleosides are C2'-endo and C3'-endo, also called S (south) and N (north) (Arnott & Hukins, 1972). The pseudorotation phase angle P and the maximum puckering amplitude τ_m (Rao et al., 1981) show that the sugar ring of (I) adopts an S conformation with an unsymmetrical twist of C3'-exo–C4'-endo (⁴T₃), with P = 221.8 (1)° and τ_m = 40.4 (1)°. This pucker is consistent with that observed in solution (69% S; Ramzaeva et al., 1999). In the case of (II), the sugar ring conformation is ²T₁ (S) with P = 186.6 (2)° (Zabel et al., 1987). The sugar moiety of compound (IV) also adopts an S (²T₃) conformation, with P = 155.4 (3)° and τ_m = 35.9 (2)° (Seela et al., 2002), while compound (IIIa) displays the N conformation in the anhydrous crystal (P = 7.8° and τ_m = 41.8°, C2'-exo–C3'-endo; Munns & Tollin, 1970) and the S conformation (C2'-endo) for both independent molecules of inosine dihydrate (Thewalt et al., 1970).

The torsion angle γ (O5'—C5'—C4'—C3') characterizes the orientation of the exocyclic 5'-hydroxyl group relative to the 2'-deoxyribose ring. In the crystal structures of compounds (I) and (II), γ is 167.14 (10) and 179.6 (2)°, respectively. These values show that both C4'—C5' bonds are in an antiperiplanar (+ap, gauche, trans) orientation, while the exocyclic 5'-hydroxyl group of compound (IV) falls into the +sc conformation with a torsion angle γ = 51.9 (4)°. However, for anhydrous inosine (IIIa), the conformation of the torsion angle around the C4'—C5' bond is γ = -168.9 (4)° (gauche, trans; Munns & Tollin, 1970), while both independent molecules in the crystal structure of inosine dihydrate adopt a trans, gauche conformation, with γ = -55.34 (1) and -73.38 (1)° for molecules A and B, respectively (Thewalt et al., 1970).

The 7-deazapurine ring of (I) is nearly planar. The deviations of the ring atoms from the least-squares plane (N1/C2/N3/C4/C5–C8/N9) are in the range of -0.0132 (14) (C5) to 0.0190 (12) Å (C6), with an r.m.s. deviation of 0.0093 Å. The C1' substituent and atom O6 lie 0.049 (2) and 0.066 (2) Å, respectively, above this plane.

The structure of nucleoside (I) is stabilized by several intermolecular hydrogen bonds, leading to the formation of an infinite three-dimensional hydrogen-bond network (Table 2 and Fig. 2). Within one layer, the nucleobases are arranged head-to-tail and are stacked. Compound (I) has six principle hydrogen donor sites, N1—H, C2—H, C7—H, C8—H, O3'—H and O5'—H, but five acceptor sites, N3, O6, O3', O4', O5'. However, only five of the donors and four of the acceptors are involved in the interactions. Hydrogen bonds are formed between adjacent sugar–sugar, base–base and sugar–base moieties. The C8—H group does not take part in hydrogen bonding, which is different to the crystal structure of inosine (Munns & Tollin, 1970). Instead, compound (I) forms a hydrogen bond between C7—H7A of the pyrrole system and ring atom O4' of the sugar moiety of a neighbouring molecule.

S2. Experimental

Compound (I) was prepared as described by Seela & Mittelbach (1999). Slow crystallization from aqueous solution afforded colourless crystals [m.p. 508–509 K (decomposed)].

S3. Refinement

In the absence of suitable anomalous scattering, Friedel equivalents could not be used to determine the absotute structure. Refinement of the Flack parameter (Flack, 1983) led to inconclusive values (Flack & Bernardinelli, 2000) for this parameter [0.7 (6)]. Therefore, Friedel equivalents (1499) were merged before the final refinement. The known configuration of the parent molecule was used to define the enantiomer employed in the refined model. All H atoms were found in a difference Fourier synthesis. Subsequently, the H atoms were placed in geometrically idealized positions, with C—H = 0.93–0.98 Å and N—H = 0.86 Å (AFIX 43 in SHELXTL; Sheldrick, 2008), and constrained to ride on their parent atoms, with U_iso(H) = 1.2U_eq(parent atom). The hydroxy groups were refined as rigid groups allowed to rotate but not tip (AFIX 147 in SHELXTL), with O—H = 0.82 Å and U_iso(H) = 1.5U_eq(O).

Computing details

Data collection: APEX2 (Bruker, 2006); cell refinement: APEX2 (Bruker, 2006); data reduction: APEX2 (Bruker, 2006); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and PLATON (Spek, 2003).

Figures

	Fig. 1. A perspective view of compound (I), with the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as spheres of arbitrary size.
	Fig. 2. The intermolecular hydrogen-bonding network in the crystal structure of (I), viewed parallel to the b axis. Hydrogen bonds are indicated by dashed lines. Uninvolved H atoms have been omitted.

7-(2-deoxy-β-D-erythro-pentofuranosyl)-3,7-dihydro-4H- pyrrolo[2,3-d]pyrimidin-4-one

Crystal data

C11H13N3O4	F(000) = 528
Mr = 251.24	Dx = 1.468 Mg m^−3
Monoclinic, C2	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: C 2y	Cell parameters from 9626 reflections
a = 19.9633 (6) Å	θ = 2.4–33.8°
b = 5.2733 (2) Å	µ = 0.11 mm^−1
c = 11.2390 (4) Å	T = 296 K
β = 106.109 (2)°	Needle, colourless
V = 1136.70 (7) Å^3	0.3 × 0.2 × 0.2 mm
Z = 4

Data collection

Bruker APEXII CCD area-detector diffractometer	1793 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.026
Graphite monochromator	θmax = 30.0°, θmin = 1.9°
ϕ and ω scans	h = −28→28
62751 measured reflections	k = −7→7
1829 independent reflections	l = −15→15

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)] = 0.032	H-atom parameters constrained
wR(F^2) = 0.094	w = 1/[σ^2(Fo^2) + (0.0672P)^2 + 0.1712P] where P = (Fo^2 + 2Fc^2)/3
S = 1.10	(Δ/σ)max < 0.001
1829 reflections	Δρmax = 0.27 e Å^−3
165 parameters	Δρmin = −0.23 e Å^−3
1 restraint	Absolute structure: syn
Primary atom site location: structure-invariant direct methods

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	0.30750 (6)	0.4109 (3)	0.14551 (10)	0.0376 (3)
H1	0.2952	0.4825	0.0740	0.045*
C2	0.36826 (8)	0.4893 (4)	0.22670 (13)	0.0405 (4)
H2	0.3941	0.6127	0.1999	0.049*
N3	0.39265 (6)	0.4035 (3)	0.33911 (11)	0.0363 (3)
C4	0.35081 (6)	0.2250 (3)	0.36847 (10)	0.0269 (2)
C5	0.28785 (6)	0.1303 (3)	0.29246 (11)	0.0279 (2)
C6	0.26429 (7)	0.2252 (3)	0.16966 (11)	0.0297 (3)
O6	0.21131 (5)	0.1604 (3)	0.08650 (9)	0.0392 (3)
C7	0.26341 (7)	−0.0559 (4)	0.36227 (12)	0.0358 (3)
H7	0.2228	−0.1511	0.3359	0.043*
C8	0.31129 (8)	−0.0669 (4)	0.47521 (13)	0.0367 (3)
H8	0.3085	−0.1728	0.5398	0.044*
N9	0.36496 (6)	0.1035 (3)	0.47955 (9)	0.0292 (2)
C1'	0.42648 (7)	0.1432 (3)	0.58264 (11)	0.0273 (2)
H1'	0.4586	0.2579	0.5572	0.033*
C2'	0.46472 (8)	−0.1036 (3)	0.63357 (12)	0.0337 (3)
H2'A	0.4463	−0.2457	0.5796	0.040*
H2'B	0.5143	−0.0890	0.6424	0.040*
C3'	0.45063 (7)	−0.1357 (3)	0.75975 (11)	0.0270 (2)
H3'B	0.4070	−0.2285	0.7513	0.032*
O3'	0.50633 (6)	−0.2565 (3)	0.84568 (10)	0.0388 (3)
H3'A	0.4911	−0.3452	0.8922	0.058*
C4'	0.44318 (6)	0.1393 (3)	0.79527 (10)	0.0240 (2)
H4'	0.4895	0.2168	0.8229	0.029*
O4'	0.40467 (5)	0.2566 (2)	0.68147 (8)	0.0313 (2)
C5'	0.40603 (7)	0.1761 (3)	0.89358 (12)	0.0297 (3)
H5'B	0.3568	0.1408	0.8590	0.036*
H5'C	0.4243	0.0576	0.9608	0.036*
O5'	0.41470 (5)	0.4292 (2)	0.94066 (10)	0.0366 (2)
H5'A	0.3765	0.4979	0.9272	0.055*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0331 (5)	0.0526 (8)	0.0233 (4)	−0.0086 (6)	0.0018 (4)	0.0087 (5)
C2	0.0344 (6)	0.0522 (10)	0.0304 (6)	−0.0153 (7)	0.0017 (5)	0.0115 (7)
N3	0.0308 (5)	0.0457 (8)	0.0280 (5)	−0.0123 (6)	0.0010 (4)	0.0084 (5)
C4	0.0254 (5)	0.0326 (6)	0.0208 (4)	−0.0039 (5)	0.0036 (4)	0.0020 (5)
C5	0.0252 (5)	0.0345 (6)	0.0226 (5)	−0.0058 (5)	0.0043 (4)	−0.0009 (5)
C6	0.0260 (5)	0.0403 (7)	0.0217 (5)	−0.0027 (5)	0.0048 (4)	−0.0017 (5)
O6	0.0305 (4)	0.0579 (8)	0.0250 (4)	−0.0093 (5)	0.0005 (3)	−0.0042 (5)
C7	0.0354 (6)	0.0409 (8)	0.0303 (6)	−0.0136 (6)	0.0076 (5)	0.0002 (6)
C8	0.0404 (7)	0.0407 (8)	0.0284 (6)	−0.0129 (7)	0.0085 (5)	0.0047 (6)
N9	0.0303 (5)	0.0341 (6)	0.0213 (4)	−0.0064 (4)	0.0041 (4)	0.0039 (4)
C1'	0.0286 (5)	0.0308 (6)	0.0205 (4)	0.0010 (5)	0.0036 (4)	0.0025 (5)
C2'	0.0409 (6)	0.0349 (7)	0.0249 (5)	0.0101 (6)	0.0084 (5)	0.0004 (5)
C3'	0.0313 (6)	0.0238 (5)	0.0251 (5)	0.0036 (5)	0.0064 (4)	0.0020 (4)
O3'	0.0442 (5)	0.0365 (6)	0.0336 (5)	0.0146 (5)	0.0073 (4)	0.0115 (5)
C4'	0.0252 (5)	0.0241 (5)	0.0208 (5)	0.0028 (4)	0.0034 (4)	0.0013 (4)
O4'	0.0387 (5)	0.0309 (5)	0.0215 (4)	0.0111 (4)	0.0038 (3)	0.0020 (4)
C5'	0.0323 (5)	0.0318 (7)	0.0258 (5)	0.0005 (5)	0.0093 (4)	−0.0007 (5)
O5'	0.0356 (5)	0.0375 (6)	0.0369 (5)	0.0036 (5)	0.0102 (4)	−0.0096 (5)

Geometric parameters (Å, º)

N1—C2	1.3640 (17)	C1'—C2'	1.537 (2)
N1—C6	1.381 (2)	C1'—H1'	0.9800
N1—H1	0.8600	C2'—C3'	1.5297 (18)
C2—N3	1.3025 (18)	C2'—H2'A	0.9700
C2—H2	0.9300	C2'—H2'B	0.9700
N3—C4	1.3586 (18)	C3'—O3'	1.4067 (15)
C4—N9	1.3613 (16)	C3'—C4'	1.5224 (18)
C4—C5	1.4011 (16)	C3'—H3'B	0.9800
C5—C6	1.4200 (17)	O3'—H3'A	0.8200
C5—C7	1.425 (2)	C4'—O4'	1.4364 (14)
C6—O6	1.2489 (15)	C4'—C5'	1.5044 (17)
C7—C8	1.3620 (18)	C4'—H4'	0.9800
C7—H7	0.9300	C5'—O5'	1.4287 (19)
C8—N9	1.3887 (18)	C5'—H5'B	0.9700
C8—H8	0.9300	C5'—H5'C	0.9700
N9—C1'	1.4509 (15)	O5'—H5'A	0.8200
C1'—O4'	1.4314 (15)
C2—N1—C6	124.85 (12)	N9—C1'—H1'	109.5
C2—N1—H1	117.6	C2'—C1'—H1'	109.5
C6—N1—H1	117.6	C3'—C2'—C1'	103.82 (11)
N3—C2—N1	124.56 (14)	C3'—C2'—H2'A	111.0
N3—C2—H2	117.7	C1'—C2'—H2'A	111.0
N1—C2—H2	117.7	C3'—C2'—H2'B	111.0
C2—N3—C4	112.75 (11)	C1'—C2'—H2'B	111.0
N3—C4—N9	124.31 (11)	H2'A—C2'—H2'B	109.0
N3—C4—C5	127.37 (11)	O3'—C3'—C4'	111.56 (11)
N9—C4—C5	108.31 (12)	O3'—C3'—C2'	111.90 (11)
C4—C5—C6	117.79 (12)	C4'—C3'—C2'	101.19 (10)
C4—C5—C7	107.23 (11)	O3'—C3'—H3'B	110.6
C6—C5—C7	134.94 (12)	C4'—C3'—H3'B	110.6
O6—C6—N1	119.48 (12)	C2'—C3'—H3'B	110.6
O6—C6—C5	127.91 (14)	C3'—O3'—H3'A	109.5
N1—C6—C5	112.61 (11)	O4'—C4'—C5'	110.33 (10)
C8—C7—C5	106.47 (12)	O4'—C4'—C3'	104.10 (10)
C8—C7—H7	126.8	C5'—C4'—C3'	114.80 (11)
C5—C7—H7	126.8	O4'—C4'—H4'	109.1
C7—C8—N9	109.89 (13)	C5'—C4'—H4'	109.1
C7—C8—H8	125.1	C3'—C4'—H4'	109.1
N9—C8—H8	125.1	C1'—O4'—C4'	107.96 (10)
C4—N9—C8	108.09 (11)	O5'—C5'—C4'	111.02 (12)
C4—N9—C1'	125.35 (11)	O5'—C5'—H5'B	109.4
C8—N9—C1'	126.54 (12)	C4'—C5'—H5'B	109.4
O4'—C1'—N9	107.92 (10)	O5'—C5'—H5'C	109.4
O4'—C1'—C2'	106.93 (10)	C4'—C5'—H5'C	109.4
N9—C1'—C2'	113.45 (13)	H5'B—C5'—H5'C	108.0
O4'—C1'—H1'	109.5	C5'—O5'—H5'A	109.5
C6—N1—C2—N3	−1.8 (3)	C7—C8—N9—C4	0.33 (19)
N1—C2—N3—C4	−0.1 (3)	C7—C8—N9—C1'	−178.35 (15)
C2—N3—C4—N9	179.16 (16)	C4—N9—C1'—O4'	113.30 (15)
C2—N3—C4—C5	0.4 (2)	C8—N9—C1'—O4'	−68.2 (2)
N3—C4—C5—C6	1.1 (2)	C4—N9—C1'—C2'	−128.42 (15)
N9—C4—C5—C6	−177.81 (13)	C8—N9—C1'—C2'	50.05 (19)
N3—C4—C5—C7	179.10 (16)	O4'—C1'—C2'—C3'	9.40 (14)
N9—C4—C5—C7	0.22 (17)	N9—C1'—C2'—C3'	−109.45 (12)
C2—N1—C6—O6	−176.92 (17)	C1'—C2'—C3'—O3'	−148.28 (12)
C2—N1—C6—C5	3.1 (2)	C1'—C2'—C3'—C4'	−29.37 (13)
C4—C5—C6—O6	177.42 (15)	O3'—C3'—C4'—O4'	159.06 (10)
C7—C5—C6—O6	0.1 (3)	C2'—C3'—C4'—O4'	39.91 (13)
C4—C5—C6—N1	−2.6 (2)	O3'—C3'—C4'—C5'	−80.23 (14)
C7—C5—C6—N1	−179.98 (18)	C2'—C3'—C4'—C5'	160.62 (10)
C4—C5—C7—C8	−0.01 (19)	N9—C1'—O4'—C4'	138.63 (11)
C6—C5—C7—C8	177.51 (17)	C2'—C1'—O4'—C4'	16.24 (14)
C5—C7—C8—N9	−0.2 (2)	C5'—C4'—O4'—C1'	−159.35 (11)
N3—C4—N9—C8	−179.26 (15)	C3'—C4'—O4'—C1'	−35.70 (13)
C5—C4—N9—C8	−0.33 (17)	O4'—C4'—C5'—O5'	−75.63 (13)
N3—C4—N9—C1'	−0.6 (2)	C3'—C4'—C5'—O5'	167.14 (10)
C5—C4—N9—C1'	178.37 (13)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O6^i	0.86	2.01	2.8511 (17)	168
O3′—H3′A···O5′^ii	0.82	2.12	2.8835 (18)	155
O5′—H5′A···O6^iii	0.82	1.92	2.7353 (15)	174
C2—H2···O3′^iv	0.93	2.29	3.1395 (19)	151
C7—H7···O4′^v	0.93	2.54	3.4005 (17)	153

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