A locked derivative of 8-aza-7-deaza­adenosine

The title compound [systematic name: (1S,3S,4R,7S)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-hydroxy­methyl-2,5-dioxabicyclo­[2.2.1]heptan-7-ol], C₁₁H₁₃N₅O₄, belongs to a family of nucleosides with modifications in both the sugar and nucleobase moieties: these modifications are known to increase the thermodynamic stability of DNA and RNA duplexes. There are two symmetry-independent mol­ecules in the asymmetric unit that differ significantly in conformation, and both exhibit a high-anti conformation about the N-glycosidic bond, with χ torsion angles of −85.4 (3) and −87.4 (3)°. The sugar C atom attached to the nucleobase N atom is −0.201 (4) and 0.209 (4) Å from the 8-aza-7-deaza­adenine skeleton plane in the two mol­ecules. The mol­ecules are assembled into layers via hydrogen bonds and π–π stacking inter­actions between the modified nucleobases.

S1. Comment

Modifications influencing the properties of native nucleic acids can be introduced into the nucleobase, the sugar ring or the phosphodiester backbone. The introduction of the 2'-C,4'-C-oxomethylene linker into the nucleotide sugar moiety is known to `lock' chemically the pentofuranose ring in the 3'-endo conformation, which is ideal for recognition of RNA and predominates in the A-type helical duplexes (Koshkin et al., 1998; Obika et al., 1998; Kaur et al., 2007). Oligonucleotides incorporating these bicyclic analogues are termed `locked nucleic acids' (LNA) (Koshkin et al., 1998). LNAs show unprecedented thermodynamic stability when hybridized with complementary DNA or RNA strands, and this substantially increases the melting point temperature when compared to unmodified duplexes (Koshkin et al., 1998; Obika et al., 1997; Kierzek et al., 2006; Pasternak et al., 2007). Owing to their many unusual properties, LNAs are expected to have an impact in many areas of medicine and biotechnology (Petersen & Wengel, 2003; Kaur et al., 2007).

Increased stability of oligonucleotide duplexes can also be achieved by nucleobase modifications. For example, oligonucleotides containing 8-aza-7-deaza-2'-deoxyadenosine (the numbering scheme used is as for the purine skeleton) form duplexes with slightly increased stability compared with those containing unmodified adenine (Seela & Kaiser, 1988). This stability can be further enhanced when C7-modified 8-aza-7-deazaadenines are incorporated into oligonucleotide strands (Seela & Zulauf, 1999). 8-Aza-7-deazaadenine is considered to be one of the universal bases due to similar thermodynamic stability when interacting with all four natural nucleobases (Seela & Debelak, 2000; Seela & Debelak, 2001).

In this paper, we report the synthesis (Fig. 1) and crystal structure of the title compound, (VII), a locked derivative of 8-aza-7-deazaadenosine and a sugar- and nucleobase-modified nucleoside derivative. Compound (VII) was prepared using a silyl method (Vorbrüggen & Krolikiewicz, 1975) with 8-aza-7-deazaadenine and a precursor of the LNA derivative of ribose used for the condensation reaction. The reaction yielded two products, with the major product (60%) transformed into (VII) using standard procedures (Koshkin et al., 1998). Compound (VII) was identified as the major product: the minor product, presumably the N⁸ isomer, was not isolated.

Molecules of (VII), comprising a rigid sugar moiety locked in the 3'-endo conformation, can be considered as having two conformational degrees of freedom (O—H bonds not considered). The two torsions are: (i) the angle χ (O4'—C1'—N9—C4) at the N-glycosidic bond and (ii) the angle γ (C3'—C4'—C5'—O5') at the bond between the hydroxymethylene group and the pentofuranose ring [for nomenclature of torsion angles, see IUPAC–IUB Joint Commission on Biochemical Nomenclature (1983)]. There are two symmetry-independent molecules (A and B) in the asymmetric unit of (VII) (Fig. 2) and for both molecules the χ angle, which describes the orientation of the base relative to the sugar residue (syn/anti), has a value which lies in the high-anti conformation range [-85.4 (3) and -87.4 (3)° for molecules A and B, respectively], whereas in the adenine analogue, the nucleobase is in the anti orientation (χ = -163.8°; Morita et al., 2003). The high-anti conformation of (VII) along with the C3'-endo `locked' sugar moiety conformation leads to intramolecular C—H···N interactions and, in molecule A, a H3'···N8 contact of 2.35 Å is present; in molecule B N8 forms contacts with H2' and H3' (2.59 and 2.46 Å, respectively). From previous studies, conformations about the glycosidic bond in locked purine nucleosides can be either anti or high-anti: structural evidence of the guanine analogue of (VII) (Rosenbohm et al., 2004) has two molecules adopting the high-anti conformation (χ = -75.5 and -78.2°) and two cases with an anti conformation [χ = -174.5° and -177.8° (Z' = 4)]. Similarly, in 8-aza-7-deazadenine nucleosides, both anti and high-anti conformations are preferred, with a sugar residue showing a large diversity of puckering types (Sprang et al., 1978; Seela, Becher et al., 1999; Seela, Zulauf et al., 1999; Seela et al., 2000, 2005; Lin et al., 2005). In both molecules of (VII), the conformation around the C4'—C5' bond is gauche–gauche [+sc from torsion angles of γ; 56.2 (3)° and 49.0 (3)°].

The nucleobase is nearly planar (as expected), with an r.m.s. deviation of the ring atoms N1—N9 from the best plane of less than 0.015 Å. The sugar C1' atom is displaced from the heteroplane by -0.201 (4) and 0.209 (4) Å for molecules A and B, respectively, in opposite directions from the nucleobase plane. Consequently, the A and B molecules comprise two rigid fragments having similar torsion angle χ and angle γ but showing significant differences in their three-dimensional shape (Fig. 3). Thus, the reported crystal structure shows that configurational changes at the nucleobase N9 atom can be an additional factor influencing the stereochemistry.

In the crystal structure, molecules assemble into (001) layers via hydrogen bonds and π–π stacking interactions (Fig. 4). From eight N—H and O—H proton donors of molecules A and B, one N—H group is not involved in hydrogen bonding and six are involved as N—H···O and O—H···N hydrogen bonds (i.e. interactions between the locked sugar and modified nucleobase) (Table 1). The numerous and strong interactions, supported by head-to-head stacking interactions between slightly inclined [5.32 (3)°] 8-aza-7-deazaadenine moieties of the two symmetry-independent molecules, assemble (VII) into a one-dimensional polymeric structure extended along the b axis (Fig. 3a). This rod-type structure is generated by operation of a twofold screw axis parallel to b and by translation along b. In turn, the shortest hydrogen bond, viz. between O5'B—H and O2'B, links two B molecules belonging to adjacent rods and are related by unit translation along a. This interaction, supported additionally by π–π stacking interactions between nucleobases, leads to the formation of a two-dimensional assembly with 8-aza-7-deazaadenine π-stacks (inner) and sugar moieties (outer) (Fig. 4a,b). Thus, the crystal structure of (VII) is stabilized mainly by interactions between the modified nucleobase and the locked sugar residue, and π–π stacking interactions between the nucleobase units.

Related literature

For related literature, see: IUPAC–IUB Joint Commission on Biochemical Nomenclature (1983); Kaur et al. (2007); Kierzek et al. (2006); Koshkin et al. (1998); Lin et al. (2005); Morita et al. (2003); Obika et al. (1997, 1998); Pasternak et al. (2007); Petersen & Wengel (2003); Pfundheller & Lomholt (2002); Robins (1956); Rosenbohm et al. (2004); Seela & Debelak (2000, 2001); Seela & Kaiser (1988); Seela & Zulauf (1999); Seela, Becher et al. (1999); Seela, Zulauf et al. (1999); Seela et al. (2000, 2005); Sprang et al. (1978); Vorbrüggen & Krolikiewicz (1975).

S2. Experimental

8-Aza-7-deazaadenine was prepared according to literature procedures (Robins, 1956) and the pentafuranose precursor (Pfundheller & Lomholt, 2002). The chemical synthesis of (VII) was performed by a silyl method (Vorbrüggen & Krolikiewicz, 1975) where 8-aza-7-deazaadenine and the precursor of the LNA derivative of ribose were used for the condensation reaction. This condensation leads to two products and in addition to the N⁹-substituted nucleoside derivative (III) (major product), the N⁸-substituted nucleoside (minor product) was presumably also obtained. The major product of condensation (circa 60% of reaction mixture) was transformed into (VII) according to standard procedures (Koshkin et al., 1998). Details of the synthetic procedures yielding (VII) are shown in the scheme and in the supplementary CIF. Crystals suitable for X-ray analysis in the form of colourless very thin plates were obtained by recrystallization from methanol. ¹H NMR (Bruker AVANCEII spectrometer 400.13 MHz, CD₃OD, 298 K): δ 8.19 (1H, s, H2), 8.12 (1H, s, H7), 6.24 (1H, s, H1'), 5.10 (1H, s, H2'), 4.37 (1H, s, H3'), 4.11 and 3.89 (2H, 2xd, H6',H6''), 3.89 (2H, s, H5', H5''). ¹³C NMR (100.61 MHz, CD₃OD, 298 K): δ 159.86 (C6), 157.14 (C2), 155.19 (C4), 134.81 (C7), 101.82 (C5), 88.93 (C4'), 85.91 (C1'), 82.12 (C2'), 73.81 (C3'), 73.11 (C6'), 59.43 (C5').

S3. Refinement

The absolute configuration of (VII) was assigned from the known chirality of the starting material. In the absence of significant anomalous scattering, Friedel pairs were merged before the final refinement. All H atoms were located in electron-density difference maps. However, for the structure refinement, carbon-bound H atoms were placed in calculated positions, with C—H = 0.93–0.98 Å, and treated as riding on their parent atoms, with U_iso(H) = 1.2U_eq(C). Positional and isotropic displacement parameters of the H atoms of N—H and O—H groups were fully refined, except for the O5'A—H5AO bond where the O—H distance was restrained to 0.90 (3) Å.

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2007); cell refinement: CrysAlis CCD (Oxford Diffraction, 2007); data reduction: CrysAlis RED (Oxford Diffraction, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Stereochemical Workstation Operation Manual (Siemens, 1989) and Mercury (Macrae et al., 2006); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The synthesis of (VII). (i) Hexamethylenedisilazane (HMDS), (NH4)2SO4, 4 h, 403 K; (ii) trimethylsilyl trifluoromethanesulfonate (TMSOTf), CH3CN, 48 h, 353 K; (iii) LiOH.H2O,THF, H2O, 4 h, room temperature; (iv) BzOLi, DMF, 18 h, 353 K; (v) NH4OH, pyridine, 24 h, 328 K; (vi) HCO2NH4, Pd/C, MeOH, 2 h, 333 K. Bn, benzyl (PhCH2–); Ms, methylsulfonyl (MeSO2).
	Fig. 2. The molecular structure of (VII), showing the two symmetry-independent molecules, viz. A (top) and B (bottom), with displacement ellipsoids drawn at the 30% probability level.
	Fig. 3. Superposition of the two symmetry-independent molecules of (VII): (a) the superposition in which 2,5-dioxabicyclo[2.2.1]heptane moieties were fitted and (b) the superposition in which 8-aza-7-deazaadenine fragments were fitted. Molecule A is shown with dashed lines and molecule B is shown with full lines. O and N atoms are represented as spheres.
	Fig. 4. The crystal packing of (VII): (a) the (001) layer assembly via hydrogen bonds and nucleobase stacking interactions and (b) projection of the crystal packing along the 8-aza-7-deazaadenine π-stacks. Hydrogen bonds are shown with dashed lines. For clarity, only H atoms of O—H and N—H groups are shown.

(1S,3S,4R,7S)- 3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptan-7-ol

Crystal data

C11H13N5O4	F(000) = 1168
Mr = 279.26	Dx = 1.604 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 7680 reflections
a = 7.1097 (2) Å	θ = 2.3–28.0°
b = 14.7372 (5) Å	µ = 0.13 mm^−1
c = 22.0732 (7) Å	T = 293 K
V = 2312.77 (13) Å^3	Plate, colourless
Z = 8	0.4 × 0.2 × 0.01 mm

Data collection

Kuma KM-4-CCD κ-geometry diffractometer	1723 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.041
Graphite monochromator	θmax = 25.0°, θmin = 4.1°
ω scans	h = −8→8
18884 measured reflections	k = −17→17
2346 independent reflections	l = −26→26

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)] = 0.027	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.056	H atoms treated by a mixture of independent and constrained refinement
S = 0.97	w = 1/[σ^2(Fo^2) + (0.0309P)^2] where P = (Fo^2 + 2Fc^2)/3
2346 reflections	(Δ/σ)max = 0.001
392 parameters	Δρmax = 0.13 e Å^−3
1 restraint	Δρmin = −0.19 e Å^−3

Special details

Experimental. 8-Aza-7-deazaadenine (I) (0.135 g, 1.00 mmol) and NH4SO4 (6 mg) were suspended in hexamethyldisilane (1.5 ml). The reaction mixture was stirred at reflux for 4 h, then cooled to room temperature. The solvent was removed under reduced pressure, the residue was evaporated twice with small amount of anhydrous CH3CN and combined with pentafuranose derivative (II) (0.5 g, 1 mmol) and evaporated to oil. The components were dissolved in anhydrous CH3CN (2.6 ml) and cooled to 0°C. Trimethylsilyl trifluoromethanesulfonate (0.31 ml, 1.3 mmol) was added dropwise under stirring and the solution was stirred 48 h at 80°C. A saturated aqueous solution of NaHCO3 was added and extracted 3 times with CH2Cl2. The combined organic phases were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–6% MeOH in CH2Cl2, v/v) to give major product (III) (0,12 g, 0.21 mmol). Compound (III) was dissolved in a mixture of THF (0.44 ml) and water (0.62 ml). LiOH.H2O (0.054 g, 1.03 mmol) was added and the mixture was stirred at room temperature for 4 h. The solution was neutralized to pH 7.0 with CH3COOH. A saturated aqueous solution of NaHCO3 was added and extracted 3 times with CH2Cl2. The organic phase was dried with anhydrous Na2SO4 and concentrated under reduced pressure to give (IV). Solid lithium benzoate (0.08 g, 0.615 mmol) was added to a solution of compound (IV) in anhydrous DMF (1 ml) and the reaction mixture was stirred at 90°C overnight. The solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added and extracted 3 times with CH2Cl2. The organic phase was dried with anhydrous sodium sulfate and evaporated. Derivative (V) was dissolved in a mixture of pyridine (0.41 ml) and 28% aqueous ammonium hydroxide (0.79 ml) and kept at 55°C for 24 h. The reaction mixture was evaporated and then coevaporated twice with toluene, and purified by silica gel column chromatography. The column was eluted with a mixture of CH2Cl2 and gradually increasing methanol, up to 15% v/v. The fractions containing product were evaporated and afforded (VI). To a solution of compound (VI) in anhydrous methanol (1.5 ml) were added Pd/C (0.053 g) and ammonium formate (0.115 g, 1.83 mmol). The mixture was stirred at 60°C for 2 h. The hot solution was filtered through a Celite pad and washed repeatedly with hot MeOH. The filtrate was evaporated and crystallization from methanol gave compound (VII) as thin, colourless plates.

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
N1A	0.6020 (4)	0.81209 (15)	0.19490 (10)	0.0345 (6)
C2A	0.6158 (4)	0.7965 (2)	0.25483 (12)	0.0381 (8)
H2A	0.6006	0.7363	0.2665	0.046*
N3A	0.6482 (3)	0.85458 (15)	0.29978 (9)	0.0330 (6)
C4A	0.6712 (4)	0.93997 (17)	0.27803 (11)	0.0262 (6)
C5A	0.6651 (4)	0.96647 (18)	0.21787 (11)	0.0268 (6)
C6A	0.6234 (4)	0.89811 (19)	0.17519 (12)	0.0294 (7)
C7A	0.6965 (4)	1.06109 (19)	0.21931 (12)	0.0337 (7)
H7A	0.7008	1.0980	0.1852	0.040*
N8A	0.7187 (3)	1.09031 (15)	0.27509 (10)	0.0372 (6)
N9A	0.7030 (3)	1.01543 (14)	0.31198 (9)	0.0298 (5)
N10A	0.6049 (4)	0.9130 (2)	0.11601 (11)	0.0386 (7)
H1AN	0.558 (4)	0.869 (2)	0.0936 (13)	0.057 (11)*
H2AN	0.613 (4)	0.9665 (19)	0.1007 (12)	0.040 (9)*
O4'A	0.5084 (3)	1.04047 (11)	0.39803 (7)	0.0311 (4)
C1'A	0.6984 (4)	1.02401 (18)	0.37725 (11)	0.0311 (7)
H1'A	0.7462	0.9681	0.3957	0.037*
C2'A	0.8053 (4)	1.10502 (17)	0.40264 (11)	0.0313 (7)
H2'A	0.9261	1.1176	0.3830	0.038*
O2'A	0.8148 (3)	1.09121 (12)	0.46726 (8)	0.0412 (5)
C3'A	0.6585 (4)	1.17909 (17)	0.39588 (11)	0.0275 (7)
H3'A	0.6196	1.1872	0.3536	0.033*
O3'A	0.7017 (3)	1.26301 (13)	0.42427 (8)	0.0381 (5)
H3AO	0.768 (5)	1.293 (2)	0.3989 (14)	0.068 (12)*
C4'A	0.5146 (4)	1.12567 (17)	0.43227 (10)	0.0289 (7)
C5'A	0.3215 (4)	1.1634 (2)	0.44097 (11)	0.0385 (7)
H5'1	0.2470	1.1201	0.4637	0.046*
H5'2	0.3301	1.2186	0.4648	0.046*
O5'A	0.2280 (3)	1.18311 (13)	0.38564 (9)	0.0417 (5)
H5AO	0.303 (4)	1.2204 (17)	0.3613 (11)	0.050*
C6'A	0.6256 (4)	1.1056 (2)	0.48933 (11)	0.0396 (8)
H6'1	0.6209	1.1563	0.5173	0.048*
H6'2	0.5780	1.0518	0.5095	0.048*
N1B	0.8770 (4)	0.29378 (16)	0.21992 (10)	0.0415 (6)
C2B	0.9119 (4)	0.29161 (19)	0.27971 (13)	0.0371 (7)
H2B	0.9495	0.2356	0.2949	0.045*
N3B	0.9006 (3)	0.35821 (14)	0.32052 (9)	0.0303 (5)
C4B	0.8515 (4)	0.43783 (18)	0.29372 (11)	0.0248 (7)
C5B	0.8117 (4)	0.44987 (18)	0.23279 (10)	0.0273 (6)
C6B	0.8248 (4)	0.3734 (2)	0.19592 (12)	0.0355 (7)
C7B	0.7718 (4)	0.5434 (2)	0.22656 (12)	0.0361 (7)
H7B	0.7409	0.5714	0.1902	0.043*
N8B	0.7840 (3)	0.58555 (15)	0.27876 (10)	0.0358 (6)
N9B	0.8334 (3)	0.51994 (14)	0.32091 (8)	0.0276 (5)
N10B	0.7895 (5)	0.3771 (2)	0.13560 (11)	0.0617 (9)
H1BN	0.793 (5)	0.326 (2)	0.1145 (16)	0.074 (13)*
H2BN	0.726 (6)	0.427 (3)	0.1225 (18)	0.107 (17)*
O4'B	0.7384 (2)	0.52935 (11)	0.42491 (7)	0.0291 (5)
C1'B	0.8861 (4)	0.54658 (17)	0.38172 (10)	0.0270 (6)
H1'B	1.0004	0.5143	0.3939	0.032*
C2'B	0.9164 (4)	0.64873 (17)	0.38801 (11)	0.0292 (7)
H2'B	0.9808	0.6777	0.3539	0.035*
O2'B	1.0053 (3)	0.66159 (13)	0.44663 (7)	0.0357 (5)
C3'B	0.7164 (4)	0.68094 (16)	0.39905 (11)	0.0265 (6)
H3'B	0.6326	0.6652	0.3654	0.032*
O3'B	0.6982 (3)	0.77235 (12)	0.41610 (8)	0.0402 (5)
H3BO	0.674 (5)	0.802 (2)	0.3820 (14)	0.062 (11)*
C4'B	0.6928 (4)	0.61660 (16)	0.45259 (11)	0.0252 (6)
C5'B	0.5062 (4)	0.61003 (19)	0.48334 (11)	0.0331 (7)
H5'3	0.5053	0.5590	0.5111	0.040*
H5'4	0.4815	0.6649	0.5062	0.040*
O5'B	0.3654 (3)	0.59792 (16)	0.43772 (10)	0.0475 (6)
H5BO	0.272 (5)	0.619 (2)	0.4476 (16)	0.071 (14)*
C6'B	0.8599 (4)	0.64319 (18)	0.49144 (11)	0.0319 (7)
H6'3	0.8325	0.6967	0.5155	0.038*
H6'4	0.8965	0.5941	0.5182	0.038*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1A	0.0467 (15)	0.0259 (14)	0.0308 (14)	0.0022 (12)	−0.0062 (12)	0.0002 (11)
C2A	0.050 (2)	0.0244 (18)	0.0396 (18)	0.0027 (15)	−0.0026 (16)	0.0001 (14)
N3A	0.0448 (16)	0.0236 (14)	0.0306 (12)	0.0029 (12)	−0.0030 (11)	−0.0018 (11)
C4A	0.0264 (15)	0.0210 (16)	0.0313 (15)	0.0015 (13)	0.0004 (13)	0.0000 (14)
C5A	0.0285 (15)	0.0235 (17)	0.0285 (15)	−0.0002 (14)	0.0029 (12)	−0.0015 (13)
C6A	0.0259 (16)	0.0312 (17)	0.0312 (17)	0.0061 (13)	0.0024 (13)	−0.0002 (14)
C7A	0.0435 (18)	0.0302 (17)	0.0275 (16)	−0.0012 (15)	0.0069 (15)	0.0027 (13)
N8A	0.0504 (16)	0.0277 (14)	0.0335 (13)	−0.0084 (13)	0.0066 (12)	0.0029 (12)
N9A	0.0382 (14)	0.0227 (13)	0.0286 (12)	−0.0029 (12)	0.0003 (10)	−0.0001 (11)
N10A	0.0550 (17)	0.0312 (18)	0.0295 (16)	0.0028 (15)	−0.0042 (13)	0.0001 (14)
O4'A	0.0364 (11)	0.0296 (11)	0.0274 (9)	−0.0060 (9)	0.0019 (9)	−0.0046 (9)
C1'A	0.0365 (17)	0.0305 (16)	0.0263 (14)	0.0009 (15)	−0.0014 (13)	0.0012 (13)
C2'A	0.0331 (16)	0.0317 (16)	0.0291 (15)	−0.0018 (15)	−0.0039 (13)	0.0001 (13)
O2'A	0.0453 (13)	0.0462 (13)	0.0322 (11)	0.0014 (11)	−0.0134 (10)	0.0032 (9)
C3'A	0.0358 (17)	0.0223 (15)	0.0245 (14)	−0.0040 (13)	−0.0051 (13)	−0.0056 (12)
O3'A	0.0543 (15)	0.0298 (12)	0.0302 (11)	−0.0106 (11)	0.0030 (11)	−0.0054 (10)
C4'A	0.0374 (17)	0.0301 (17)	0.0192 (14)	−0.0038 (14)	−0.0012 (13)	−0.0047 (12)
C5'A	0.0456 (19)	0.0421 (18)	0.0277 (15)	−0.0032 (17)	0.0054 (14)	−0.0033 (14)
O5'A	0.0362 (13)	0.0505 (13)	0.0385 (12)	−0.0041 (10)	−0.0016 (10)	0.0051 (10)
C6'A	0.052 (2)	0.0408 (18)	0.0261 (15)	−0.0048 (17)	−0.0040 (15)	0.0054 (14)
N1B	0.0565 (17)	0.0351 (16)	0.0330 (14)	0.0027 (13)	−0.0016 (13)	−0.0064 (12)
C2B	0.0420 (18)	0.0283 (18)	0.0411 (18)	0.0019 (15)	−0.0016 (15)	−0.0012 (15)
N3B	0.0369 (14)	0.0246 (14)	0.0292 (12)	0.0009 (11)	−0.0018 (11)	0.0014 (12)
C4B	0.0225 (16)	0.0270 (17)	0.0249 (15)	0.0010 (12)	−0.0011 (12)	−0.0010 (13)
C5B	0.0286 (15)	0.0304 (18)	0.0229 (15)	0.0025 (13)	0.0005 (12)	−0.0009 (12)
C6B	0.0394 (19)	0.0418 (19)	0.0254 (16)	0.0006 (16)	0.0012 (13)	−0.0041 (14)
C7B	0.0443 (18)	0.0400 (19)	0.0242 (16)	0.0044 (15)	−0.0035 (13)	0.0038 (14)
N8B	0.0444 (15)	0.0320 (14)	0.0311 (13)	0.0110 (12)	−0.0031 (12)	0.0043 (12)
N9B	0.0361 (14)	0.0243 (13)	0.0225 (11)	0.0062 (11)	−0.0015 (10)	0.0002 (11)
N10B	0.100 (3)	0.056 (2)	0.0288 (16)	0.011 (2)	−0.0061 (16)	−0.0116 (15)
O4'B	0.0379 (12)	0.0214 (10)	0.0282 (10)	−0.0014 (9)	0.0062 (8)	−0.0025 (8)
C1'B	0.0277 (15)	0.0323 (17)	0.0210 (14)	0.0053 (13)	−0.0011 (12)	0.0005 (12)
C2'B	0.0330 (16)	0.0307 (17)	0.0238 (14)	−0.0031 (14)	0.0021 (13)	−0.0008 (13)
O2'B	0.0287 (10)	0.0496 (12)	0.0287 (10)	−0.0039 (10)	−0.0023 (9)	−0.0097 (9)
C3'B	0.0338 (17)	0.0216 (16)	0.0243 (14)	0.0015 (13)	0.0013 (13)	−0.0008 (12)
O3'B	0.0656 (15)	0.0226 (12)	0.0324 (12)	0.0070 (11)	0.0020 (11)	0.0012 (9)
C4'B	0.0287 (16)	0.0222 (16)	0.0246 (14)	0.0008 (13)	0.0035 (12)	−0.0029 (12)
C5'B	0.0365 (17)	0.0336 (17)	0.0291 (15)	−0.0007 (15)	0.0040 (14)	−0.0036 (13)
O5'B	0.0294 (13)	0.0679 (16)	0.0453 (13)	0.0063 (13)	−0.0002 (11)	−0.0187 (12)
C6'B	0.0346 (17)	0.0354 (18)	0.0258 (14)	0.0017 (14)	0.0006 (13)	−0.0008 (13)

Geometric parameters (Å, º)

N1A—C2A	1.346 (3)	N1B—C6B	1.340 (3)
N1A—C6A	1.349 (3)	N1B—C2B	1.343 (3)
C2A—N3A	1.331 (3)	C2B—N3B	1.335 (3)
C2A—H2A	0.9300	C2B—H2B	0.9300
N3A—C4A	1.357 (3)	N3B—C4B	1.360 (3)
C4A—N9A	1.360 (3)	C4B—N9B	1.357 (3)
C4A—C5A	1.385 (3)	C4B—C5B	1.386 (3)
C5A—C6A	1.411 (4)	C5B—C6B	1.393 (4)
C5A—C7A	1.413 (4)	C5B—C7B	1.414 (4)
C6A—N10A	1.331 (3)	C6B—N10B	1.356 (4)
C7A—N8A	1.314 (3)	C7B—N8B	1.312 (3)
C7A—H7A	0.9300	C7B—H7B	0.9300
N8A—N9A	1.376 (3)	N8B—N9B	1.387 (3)
N9A—C1'A	1.447 (3)	N9B—C1'B	1.448 (3)
N10A—H1AN	0.88 (3)	N10B—H1BN	0.88 (3)
N10A—H2AN	0.86 (3)	N10B—H2BN	0.91 (4)
O4'A—C1'A	1.447 (3)	O4'B—C1'B	1.440 (3)
O4'A—C4'A	1.466 (3)	O4'B—C4'B	1.460 (3)
C1'A—C2'A	1.522 (4)	C1'B—C2'B	1.527 (3)
C1'A—H1'A	0.9800	C1'B—H1'B	0.9800
C2'A—O2'A	1.442 (3)	C2'B—O2'B	1.452 (3)
C2'A—C3'A	1.517 (3)	C2'B—C3'B	1.519 (4)
C2'A—H2'A	0.9800	C2'B—H2'B	0.9800
O2'A—C6'A	1.446 (3)	O2'B—C6'B	1.457 (3)
C3'A—O3'A	1.420 (3)	C3'B—O3'B	1.405 (3)
C3'A—C4'A	1.520 (4)	C3'B—C4'B	1.524 (3)
C3'A—H3'A	0.9800	C3'B—H3'B	0.9800
O3'A—H3AO	0.86 (3)	O3'B—H3BO	0.89 (3)
C4'A—C5'A	1.494 (4)	C4'B—C5'B	1.493 (4)
C4'A—C6'A	1.515 (3)	C4'B—C6'B	1.517 (4)
C5'A—O5'A	1.421 (3)	C5'B—O5'B	1.431 (3)
C5'A—H5'1	0.9700	C5'B—H5'3	0.9700
C5'A—H5'2	0.9700	C5'B—H5'4	0.9700
O5'A—H5AO	0.93 (2)	O5'B—H5BO	0.77 (4)
C6'A—H6'1	0.9700	C6'B—H6'3	0.9700
C6'A—H6'2	0.9700	C6'B—H6'4	0.9700
C2A—N1A—C6A	118.0 (2)	C6B—N1B—C2B	117.4 (2)
N3A—C2A—N1A	129.5 (3)	N3B—C2B—N1B	129.4 (3)
N3A—C2A—H2A	115.3	N3B—C2B—H2B	115.3
N1A—C2A—H2A	115.3	N1B—C2B—H2B	115.3
C2A—N3A—C4A	110.7 (2)	C2B—N3B—C4B	110.9 (2)
N3A—C4A—N9A	125.7 (2)	N9B—C4B—N3B	127.0 (2)
N3A—C4A—C5A	126.7 (2)	N9B—C4B—C5B	107.2 (2)
N9A—C4A—C5A	107.6 (2)	N3B—C4B—C5B	125.8 (2)
C4A—C5A—C6A	116.5 (2)	C4B—C5B—C6B	116.7 (2)
C4A—C5A—C7A	104.6 (2)	C4B—C5B—C7B	105.1 (2)
C6A—C5A—C7A	138.9 (3)	C6B—C5B—C7B	138.2 (2)
N10A—C6A—N1A	117.4 (3)	N1B—C6B—N10B	118.3 (3)
N10A—C6A—C5A	124.0 (3)	N1B—C6B—C5B	119.7 (2)
N1A—C6A—C5A	118.6 (2)	N10B—C6B—C5B	121.9 (3)
N8A—C7A—C5A	111.3 (2)	N8B—C7B—C5B	111.3 (2)
N8A—C7A—H7A	124.3	N8B—C7B—H7B	124.4
C5A—C7A—H7A	124.3	C5B—C7B—H7B	124.4
C7A—N8A—N9A	106.4 (2)	C7B—N8B—N9B	106.0 (2)
C4A—N9A—N8A	110.07 (18)	C4B—N9B—N8B	110.43 (19)
C4A—N9A—C1'A	128.1 (2)	C4B—N9B—C1'B	128.9 (2)
N8A—N9A—C1'A	121.4 (2)	N8B—N9B—C1'B	119.9 (2)
C6A—N10A—H1AN	117.7 (19)	C6B—N10B—H1BN	119 (2)
C6A—N10A—H2AN	122.0 (18)	C6B—N10B—H2BN	116 (3)
H1AN—N10A—H2AN	119 (3)	H1BN—N10B—H2BN	122 (4)
C1'A—O4'A—C4'A	106.18 (19)	C1'B—O4'B—C4'B	106.48 (17)
N9A—C1'A—O4'A	110.6 (2)	O4'B—C1'B—N9B	112.2 (2)
N9A—C1'A—C2'A	115.1 (2)	O4'B—C1'B—C2'B	102.50 (19)
O4'A—C1'A—C2'A	102.6 (2)	N9B—C1'B—C2'B	112.8 (2)
N9A—C1'A—H1'A	109.4	O4'B—C1'B—H1'B	109.7
O4'A—C1'A—H1'A	109.4	N9B—C1'B—H1'B	109.7
C2'A—C1'A—H1'A	109.4	C2'B—C1'B—H1'B	109.7
O2'A—C2'A—C3'A	103.4 (2)	O2'B—C2'B—C3'B	102.93 (19)
O2'A—C2'A—C1'A	106.1 (2)	O2'B—C2'B—C1'B	105.73 (19)
C3'A—C2'A—C1'A	100.6 (2)	C3'B—C2'B—C1'B	101.0 (2)
O2'A—C2'A—H2'A	115.0	O2'B—C2'B—H2'B	115.2
C3'A—C2'A—H2'A	115.0	C3'B—C2'B—H2'B	115.2
C1'A—C2'A—H2'A	115.0	C1'B—C2'B—H2'B	115.2
C2'A—O2'A—C6'A	105.60 (19)	C2'B—O2'B—C6'B	105.77 (18)
O3'A—C3'A—C2'A	115.8 (2)	O3'B—C3'B—C2'B	115.4 (2)
O3'A—C3'A—C4'A	111.3 (2)	O3'B—C3'B—C4'B	112.2 (2)
C2'A—C3'A—C4'A	92.2 (2)	C2'B—C3'B—C4'B	91.89 (19)
O3'A—C3'A—H3'A	112.0	O3'B—C3'B—H3'B	111.9
C2'A—C3'A—H3'A	112.0	C2'B—C3'B—H3'B	111.9
C4'A—C3'A—H3'A	112.0	C4'B—C3'B—H3'B	111.9
C3'A—O3'A—H3AO	107 (2)	C3'B—O3'B—H3BO	105 (2)
O4'A—C4'A—C5'A	110.9 (2)	O4'B—C4'B—C5'B	109.3 (2)
O4'A—C4'A—C6'A	106.1 (2)	O4'B—C4'B—C6'B	106.9 (2)
C5'A—C4'A—C6'A	116.4 (2)	C5'B—C4'B—C6'B	117.1 (2)
O4'A—C4'A—C3'A	101.04 (19)	O4'B—C4'B—C3'B	101.47 (17)
C5'A—C4'A—C3'A	119.6 (2)	C5'B—C4'B—C3'B	119.4 (2)
C6'A—C4'A—C3'A	100.9 (2)	C6'B—C4'B—C3'B	101.0 (2)
O5'A—C5'A—C4'A	113.3 (2)	O5'B—C5'B—C4'B	108.0 (2)
O5'A—C5'A—H5'1	108.9	O5'B—C5'B—H5'3	110.1
C4'A—C5'A—H5'1	108.9	C4'B—C5'B—H5'3	110.1
O5'A—C5'A—H5'2	108.9	O5'B—C5'B—H5'4	110.1
C4'A—C5'A—H5'2	108.9	C4'B—C5'B—H5'4	110.1
H5'1—C5'A—H5'2	107.7	H5'3—C5'B—H5'4	108.4
C5'A—O5'A—H5AO	110.4 (17)	C5'B—O5'B—H5BO	111 (3)
O2'A—C6'A—C4'A	103.5 (2)	O2'B—C6'B—C4'B	102.72 (18)
O2'A—C6'A—H6'1	111.1	O2'B—C6'B—H6'3	111.2
C4'A—C6'A—H6'1	111.1	C4'B—C6'B—H6'3	111.2
O2'A—C6'A—H6'2	111.1	O2'B—C6'B—H6'4	111.2
C4'A—C6'A—H6'2	111.1	C4'B—C6'B—H6'4	111.2
H6'1—C6'A—H6'2	109.0	H6'3—C6'B—H6'4	109.1
C6A—N1A—C2A—N3A	0.2 (5)	C6B—N1B—C2B—N3B	0.8 (5)
N1A—C2A—N3A—C4A	−0.9 (5)	N1B—C2B—N3B—C4B	−2.2 (4)
C2A—N3A—C4A—N9A	178.8 (3)	C2B—N3B—C4B—N9B	−177.5 (3)
C2A—N3A—C4A—C5A	−0.6 (4)	C2B—N3B—C4B—C5B	2.0 (4)
N3A—C4A—C5A—C6A	2.7 (4)	N9B—C4B—C5B—C6B	179.1 (2)
N9A—C4A—C5A—C6A	−176.8 (2)	N3B—C4B—C5B—C6B	−0.5 (4)
N3A—C4A—C5A—C7A	179.9 (3)	N9B—C4B—C5B—C7B	0.6 (3)
N9A—C4A—C5A—C7A	0.4 (3)	N3B—C4B—C5B—C7B	−179.0 (3)
C2A—N1A—C6A—N10A	−178.4 (3)	C2B—N1B—C6B—N10B	179.8 (3)
C2A—N1A—C6A—C5A	2.1 (4)	C2B—N1B—C6B—C5B	1.0 (4)
C4A—C5A—C6A—N10A	177.2 (3)	C4B—C5B—C6B—N1B	−1.1 (4)
C7A—C5A—C6A—N10A	1.4 (5)	C7B—C5B—C6B—N1B	176.8 (3)
C4A—C5A—C6A—N1A	−3.3 (4)	C4B—C5B—C6B—N10B	−179.9 (3)
C7A—C5A—C6A—N1A	−179.2 (3)	C7B—C5B—C6B—N10B	−2.0 (6)
C4A—C5A—C7A—N8A	−0.3 (3)	C4B—C5B—C7B—N8B	−0.5 (3)
C6A—C5A—C7A—N8A	175.8 (3)	C6B—C5B—C7B—N8B	−178.5 (3)
C5A—C7A—N8A—N9A	0.1 (3)	C5B—C7B—N8B—N9B	0.2 (3)
N3A—C4A—N9A—N8A	−179.8 (3)	N3B—C4B—N9B—N8B	179.1 (2)
C5A—C4A—N9A—N8A	−0.3 (3)	C5B—C4B—N9B—N8B	−0.5 (3)
N3A—C4A—N9A—C1'A	−7.6 (5)	N3B—C4B—N9B—C1'B	9.7 (5)
C5A—C4A—N9A—C1'A	171.9 (2)	C5B—C4B—N9B—C1'B	−169.9 (2)
C7A—N8A—N9A—C4A	0.1 (3)	C7B—N8B—N9B—C4B	0.2 (3)
C7A—N8A—N9A—C1'A	−172.7 (2)	C7B—N8B—N9B—C1'B	170.7 (2)
C4A—N9A—C1'A—O4'A	−85.3 (3)	C4'B—O4'B—C1'B—N9B	−121.4 (2)
N8A—N9A—C1'A—O4'A	86.1 (3)	C4'B—O4'B—C1'B—C2'B	−0.1 (2)
C4A—N9A—C1'A—C2'A	159.0 (3)	C4B—N9B—C1'B—O4'B	−87.4 (3)
N8A—N9A—C1'A—C2'A	−29.5 (4)	N8B—N9B—C1'B—O4'B	104.0 (2)
C4'A—O4'A—C1'A—N9A	−123.0 (2)	C4B—N9B—C1'B—C2'B	157.4 (2)
C4'A—O4'A—C1'A—C2'A	0.2 (2)	N8B—N9B—C1'B—C2'B	−11.2 (3)
N9A—C1'A—C2'A—O2'A	−168.9 (2)	O4'B—C1'B—C2'B—O2'B	70.9 (2)
O4'A—C1'A—C2'A—O2'A	70.9 (2)	N9B—C1'B—C2'B—O2'B	−168.3 (2)
N9A—C1'A—C2'A—C3'A	83.7 (3)	O4'B—C1'B—C2'B—C3'B	−36.1 (2)
O4'A—C1'A—C2'A—C3'A	−36.4 (2)	N9B—C1'B—C2'B—C3'B	84.8 (2)
C3'A—C2'A—O2'A—C6'A	34.3 (2)	C3'B—C2'B—O2'B—C6'B	34.1 (2)
C1'A—C2'A—O2'A—C6'A	−71.1 (3)	C1'B—C2'B—O2'B—C6'B	−71.4 (2)
O2'A—C2'A—C3'A—O3'A	61.1 (3)	O2'B—C2'B—C3'B—O3'B	61.5 (3)
C1'A—C2'A—C3'A—O3'A	170.6 (2)	C1'B—C2'B—C3'B—O3'B	170.7 (2)
O2'A—C2'A—C3'A—C4'A	−53.9 (2)	O2'B—C2'B—C3'B—C4'B	−54.3 (2)
C1'A—C2'A—C3'A—C4'A	55.6 (2)	C1'B—C2'B—C3'B—C4'B	54.9 (2)
C1'A—O4'A—C4'A—C5'A	163.9 (2)	C1'B—O4'B—C4'B—C5'B	163.08 (19)
C1'A—O4'A—C4'A—C6'A	−68.9 (2)	C1'B—O4'B—C4'B—C6'B	−69.3 (2)
C1'A—O4'A—C4'A—C3'A	36.0 (2)	C1'B—O4'B—C4'B—C3'B	36.1 (2)
O3'A—C3'A—C4'A—O4'A	−174.56 (19)	O3'B—C3'B—C4'B—O4'B	−173.8 (2)
C2'A—C3'A—C4'A—O4'A	−55.8 (2)	C2'B—C3'B—C4'B—O4'B	−55.3 (2)
O3'A—C3'A—C4'A—C5'A	63.5 (3)	O3'B—C3'B—C4'B—C5'B	66.1 (3)
C2'A—C3'A—C4'A—C5'A	−177.7 (2)	C2'B—C3'B—C4'B—C5'B	−175.4 (2)
O3'A—C3'A—C4'A—C6'A	−65.6 (3)	O3'B—C3'B—C4'B—C6'B	−63.9 (3)
C2'A—C3'A—C4'A—C6'A	53.2 (2)	C2'B—C3'B—C4'B—C6'B	54.6 (2)
O4'A—C4'A—C5'A—O5'A	−60.4 (3)	O4'B—C4'B—C5'B—O5'B	−67.0 (3)
C6'A—C4'A—C5'A—O5'A	178.2 (2)	C6'B—C4'B—C5'B—O5'B	171.4 (2)
C3'A—C4'A—C5'A—O5'A	56.5 (3)	C3'B—C4'B—C5'B—O5'B	49.1 (3)
C2'A—O2'A—C6'A—C4'A	1.3 (3)	C2'B—O2'B—C6'B—C4'B	2.1 (3)
O4'A—C4'A—C6'A—O2'A	69.0 (2)	O4'B—C4'B—C6'B—O2'B	68.5 (2)
C5'A—C4'A—C6'A—O2'A	−167.1 (2)	C5'B—C4'B—C6'B—O2'B	−168.6 (2)
C3'A—C4'A—C6'A—O2'A	−36.0 (3)	C3'B—C4'B—C6'B—O2'B	−37.2 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N10A—H1AN···O3′A^i	0.88 (3)	2.45 (3)	3.229 (4)	148 (3)
N10A—H2AN···O5′B^ii	0.86 (3)	2.12 (3)	2.980 (4)	179 (3)
O3′A—H3AO···N3B^iii	0.86 (3)	2.19 (3)	3.035 (3)	169 (3)
O5′A—H5AO···N1A^ii	0.93 (2)	1.96 (2)	2.869 (3)	166 (3)
N10B—H2BN···O4′A^i	0.91 (4)	2.40 (4)	3.292 (4)	165 (4)
O3′B—H3BO···N3A	0.89 (3)	1.98 (3)	2.861 (3)	171 (3)
O5′B—H5BO···O2′B^iv	0.77 (4)	2.00 (4)	2.734 (3)	162 (4)

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