2′-De-oxy-5-propynyluridine: A nucleoside with two conformations in the asymmetric unit

Article abstract of DOI:10.1107/S0108270109044850

The title compound, 1-(2-de-oxy-Β-d-erythro-pentofuranos-yl)-5-(prop- 1-yn-yl)pyrimidin-2,4(1H,3H)-dione, C₁₂H₁₄N ₂O₅, shows two conformations in the crystalline state: conformer 1 adopts a C2′-endo (close to ² E; S-type) sugar pucker and an anti nucleobase orientation [χ = -134.04 (19)°], while conformer 2 shows an S sugar pucker (twisted C2′-endo-C3′-exo), which is accompanied by a different anti base orientation [χ = -162.79 (17)°]. Both mol-ecules show a +sc (gauche, gauche) conformation at the exocyclic C4′ - C5′ bond and a coplanar orientation of the propynyl group with respect to the pyrimidine ring. The extended structure is a three-dimensional hydrogen-bond network involving intermolecular N - H...O and O - H...O hydrogen bonds. Only O atoms function as H-atom acceptor sites.

Full text of DOI:10.1107/S0108270109044850

organic compounds
Acta Crystallographica Section C
Crystal Structure
tolerated by DNA polymerases when corresponding triphos-
phates are used (Roychowdhury et al., 2004).
Communications
ISSN 0108-2701
20-Deoxy-5-propynyluridine: a
nucleoside with two conformations
in the asymmetric unit
Simone Budow,a Henning Eickmeier,b Hans Reuterb and
Frank Seelaa,c
*
aLaboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotech-
nology, Heisenbergstrasse 11, 48149 Munster, Germany, bAnorganische Chemie II,
¨
Institut fur Chemie, Universitat Osnabruck, Barbarastrasse 7, 49069 Osnabruck,
¨
¨
¨
¨
Germany, and cLaboratorium fur Organische und Bioorganische Chemie, Institut fur
¨
¨
Chemie, Universitat Osnabruck, Barbarastrasse 7, 49069 Osnabruck, Germany
¨
¨
¨
Correspondence e-mail: frank.seela@uni-osnabrueck.de
Received 17 September 2009
Accepted 27 October 2009
Online 21 November 2009
The title compound, 1-(2-deoxy-ꢀ-d-erythro-pentofuranosyl)-
5-(prop-1-ynyl)pyrimidin-2,4(1H,3H)-dione, C12H14N2O5, shows
two conformations in the crystalline state: conformer 1 adopts
This background prompted us to perform a single-crystal
X-ray analysis of (I). Compound (I) was synthesized from
5-iodo-20-deoxyuridine, (IIb), and propyne gas, employing the
palladium-catalyzed Sonogashira cross-coupling reaction
(Hobbs, 1989; Froehler et al., 1992). Slow crystallization of
5-propynyl-20-deoxyuridine from methanol gave colourless
crystals which were submitted to single-crystal X-ray analysis.
The crystal structures of the closely related compounds
20-deoxyuridine, (IIa) (Rahman & Wilson, 1972), 20-deoxy-5-
ethynyluridine, (IIc) (Barr et al., 1978), 5-propynylarabinour-
idine, (III) (Cygler et al., 1984), and 20-deoxy-5-propynylcyti-
dine, (IV) (Seela et al., 2007), have been reported before and
are now compared with the crystal structure of (I).
2
a C20-endo (close to E; S-type) sugar pucker and an anti
nucleobase orientation [ꢁ = ꢀ134.04 (19)ꢁ], while conformer 2
shows an S sugar pucker (twisted C20-endo–C30-exo), which is
accompanied by a different anti base orientation [ꢁ =
ꢀ162.79 (17)ꢁ]. Both molecules show a +sc (gauche, gauche)
conformation at the exocyclic C40—C50 bond and a coplanar
orientation of the propynyl group with respect to the
pyrimidine ring. The extended structure is a three-dimensional
hydrogen-bond network involving intermolecular N—Hꢂ ꢂ ꢂO
and O—Hꢂ ꢂ ꢂO hydrogen bonds. Only O atoms function as
H-atom acceptor sites.
In the asymmetric unit of (I), two conformational states
exist, which differ mainly in their conformation around the
Comment
5-Propynylated pyrimidine nucleosides have been shown to
increase duplex stability (Barnes & Turner, 2001; Froehler et
al., 1992; He & Seela, 2002) and can strengthen triplex
formation (Gilbert & Feigon, 1999). This makes them useful
for the development of polymer therapeutics by antisense or
antigene technology with the aim of gene silencing (Mano-
haran, 2004; Praseuth et al., 1999; Crooke, 2004). The struc-
tural changes caused by the incorporation of 20-deoxy-5-
propynyluridine, (I), instead of dT in duplex DNA increase
base stacking and enhance the hydrophobic interactions
between the side chains (He & Seela, 2002). The electron-
withdrawing propynyl group at position 5 of pyrimidine
nucleosides enforces hydrogen bonding, which is reflected by a
decrease of the pKa value from 9.3 (20-deoxyuridine; Fox &
Shugar, 1952) to 8.7 for 20-deoxy-5-propynyluridine. As the
5-subsituent of a pyrimidine nucleoside lies in the major
groove of the DNA duplex (Ahmadian et al., 1998), it is
Figure 1
Overlay of molecules (I-1) and (I-2) [in the electronic version of the
paper, (I-1) contains red balls and (I-2) contains black balls].
Acta Cryst. (2009). C65, o645–o648
doi:10.1107/S0108270109044850
# 2009 International Union of Crystallography o645

organic compounds
N-glycosylic bond and the exocyclic C40—C50 bond, as
demonstrated by Fig. 1. They are defined as conformers 1 and
2, denoted (I-1) and (I-2), respectively. Similar observations
were made on the related crystals of (IIa) and (IV). The three-
dimensional structures of the molecules of (I-1) and (I-2), are
shown in Fig. 2, and selected geometric parameters are listed
in Table 1.
The heterocyclic ring systems of (I-1) and (I-2) are nearly
planar. The r.m.s. deviations of the ring atoms from their
˚
calculated least-squares planes are 0.0154 and 0.0164 A,
˚
respectively, with a maximum deviation of 0.0227 (14) A for
˚
atom C14 of (I-1) and 0.0269 (13) A for atom N21 of (I-2). In
both molecules, the exocyclic groups lie above and below the
heterocyclic plane of the pyrimidine ring system.
For pyrimidine nucleosides, the orientation of the nucleo-
base relative to the sugar moiety (syn/anti) is defined by the
torsion angle ꢁ (O40—C10—N1—C2; IUPAC–IUB Joint
Commission on Biochemical Nomenclature, 1983).
Commonly, an anti conformation at the N-glycosylic bond is
observed for pyrimidine nucleosides, and only in rare cases has
a syn conformation been reported (Saenger, 1984). Both
molecules of (I) adopt an anti conformation with respect to the
sugar ring. The glycosoylic bond torsion angles are ꢁ =
ꢀ134.04 (19)ꢁ for (I-1) and ꢁ = ꢀ162.79 (17)ꢁ for (I-2). For the
molecules of the parent unsubstituted 20-deoxyuridine (IIa),
and the closely related (IIc) and (III), anti conformations of
the glycosylic bonds were reported, with ꢁ within the range of
values found for the molecules of (I) [ꢁ = ꢀ153.65 and
ꢀ156.54ꢁ for (IIa), ꢀ 157.36ꢁ for (IIc) and ꢀ153.65ꢁ for (III)].
The propynyl groups of (I-1) and (I-2) are almost linear,
with a C15A—C15B—C15C angle of 177.3 (2)ꢁ for (I-1) and a
C25A—C25B—C25C angle of 178.5 (2)ꢁ for (I-2). In each
molecule, the propynyl group is in a coplanar orientation with
respect to the pyrimidine ring. The angles of inclination are
close to 0ꢁ [0.4 (7)ꢁ for (I-1) and 0.8 (5)ꢁ for (I-2)]. Other
nucleosides exhibit propynyl groups that are slightly inclined
with respect to the nucleobase moiety. For the propynyl
0
˚
The glycosylic N11—C11 bond of (I-1) [1.473 (3) A] is
shorter than the corresponding bond length observed for (I-2)
0
˚
[N21—C21 = 1.486 (2) A]. These values are similar to the
bond lengths found for the related molecules of (IIa) (1.45 and
˚
1.50 A), (IIc) [1.478 (3) A] and (III) (1.485 A), as well as for
˚
˚
˚
(IV) [1.475 (2) and 1.490 (2) A].
The 20-deoxyribofuranosyl moieties of (I-1) and (I-2) show
an S-type sugar conformation, which is consistent with the
preferred conformation of 20-deoxyribonucleosides. Molecule
(I-1) exhibits a pseudorotational phase angle P = 170.1 (2)ꢁ,
with the maximum amplitude ꢂm = 42.7 (1)ꢁ, which corre-
2
sponds to a C20-endo puckering (close to E), and molecule
(I-2) shows a twisted C20-endo-C30-exo (2T3) sugar confor-
mation with P = 172.9 (2)ꢁ and ꢂm = 36.2 (1)ꢁ (Rao et al., 1981).
The S-type sugar conformation of (I-1) and (I-2) observed in
the crystalline state is consistent with the predominant S
(71%) conformation of molecule (I) found in solution. This
value is very close to the value observed for (IIa) (70% S),
indicating that the propynyl group introduced at position 5 of
the pyrimidine moiety has almost no effect on the sugar
conformation of (I). The sugar conformation of compound (I)
in solution was determined from the vicinal 3J(H,H) coupling
1
constants of the H NMR spectra measured in a dimethyl
sulfoxide/D2O mixture, applying the program PSEUROT 6.3
(Van Wijk et al., 1999). An S conformation with a 20-endo
sugar pucker was also observed in the crystalline state for (IIa)
and (IIc).
The conformation about the exocyclic C40—C50 bond is
defined by the torsion angle ꢃ (O50—C50—C40—C30). For both
molecules of (I), ꢃ adopts a +synclinal (+sc, gauche, gauche)
conformation, with ꢃ = 62.6 (3)ꢁ for (I-1) and ꢃ = 50.1 (3)ꢁ for
(I-2). In the crystal structures of (IIa) and (III), the torsion
angle ꢃ is within the same range (40–71ꢁ; +sc, gauche, gauche),
whereas a ꢀantiperiplanar (ꢀap, gauche, trans) conformation
has been reported for the exocyclic group of (IIc).
Figure 2
Perspective views of (a) molecule (I-1) and (b) molecule (I-2), showing
the atom-numbering schemes. Displacement ellipsoids are drawn at the
50% probability level and H atoms are shown as small spheres of
arbitrary size.
ꢃ
o646 Budow et al. C12H14N2O5
Acta Cryst. (2009). C65, o645–o648

organic compounds
Data collection
Bruker APEXII CCD
diffractometer
Absorption correction: multi-scan
(SADABS; Bruker, 2008)
Tmin = 0.866, Tmax = 0.932
22751 measured reflections
3046 independent reflections
2749 reflections with I > I > 2ꢆ(I)
Rint = 0.032
Refinement
R[F2 > 2ꢆ(F2)] = 0.033
wR(F2) = 0.088
S = 1.04
3046 reflections
363 parameters
1 restraint
H atoms treated by a mixture of
independent and constrained
refinement
ꢀ3
˚
Áꢇmax = 0.22 e A
ꢀ3
˚
Áꢇmin = ꢀ0.23 e A
Table 1
Selected geometric parameters (A, ).
ꢁ
˚
N11—C110
C15—C15A
C15A—C15B
C15B—C15C
1.473 (3)
1.431 (3)
1.194 (3)
1.464 (3)
N21—C210
C25—C25A
C25A—C25B
C25B—C25C
1.486 (2)
1.433 (3)
1.197 (3)
1.462 (3)
Figure 3
The crystal packing of (I), showing the intermolecular hydrogen-bonding
network (projection parallel to the a axis).
C15B—C15A—C15
C15A—C15B—C15C
175.8 (2)
177.3 (2)
C25B—C25A—C25
C25A—C25B—C25C
178.8 (2)
178.5 (2)
C12—N11—C110—O140 ꢀ134.04 (19)
C22—N21—C210—O240 ꢀ162.79 (17)
C130—C140—C150—O150 62.6 (3)
C230—C240—C250—O250 50.1 (3)
groups of (III) and (IV-1), the angles of inclination are 3.7 and
3.5ꢁ, respectively, whereas for molecule (IV-2), the propynyl
group is inclined by 4.4ꢁ.
In the crystal structure of nucleoside (I), molecules (I-1)
and (I-2) are linked into an infinite three-dimensional network
by several intermolecular hydrogen bonds (Table 2 and Fig. 3).
Molecules of one conformation are linked to those of the
other conformation resulting in an alternating arrangement of
the conformers. Both molecules form identical hydrogen-
bonding patterns (N13—H13ꢂ ꢂ ꢂO22i, O130—H13Bꢂ ꢂ ꢂO24ii,
Table 2
Hydrogen-bond geometry (A, ).
ꢁ
˚
D—Hꢂ ꢂ ꢂA
D—H
Hꢂ ꢂ ꢂA
Dꢂ ꢂ ꢂA
D—Hꢂ ꢂ ꢂA
N13—H13ꢂ ꢂ ꢂO22i
0.91 (3)
0.86 (3)
0.94 (4)
0.90 (3)
0.79 (3)
0.80 (4)
1.94 (3)
1.98 (4)
2.06 (4)
1.91 (3)
2.01 (3)
2.04 (4)
2.851 (2)
2.727 (2)
2.921 (3)
2.801 (2)
2.760 (2)
2.824 (3)
174 (2)
144 (3)
152 (3)
171 (2)
158 (3)
166 (4)
O130—H13Bꢂ ꢂ ꢂO24ii
iii
O150—H15ꢂ ꢂ ꢂO130
N23—H23ꢂ ꢂ ꢂO12iv
O230—H23Bꢂ ꢂ ꢂO14v
iii
O150—H15ꢂ ꢂ ꢂO130 , N23—H23ꢂ ꢂ ꢂO12iv, O230—H23Bꢂ ꢂ ꢂ
vi
O250—H25ꢂ ꢂ ꢂO230
vi
O14v, O250—H25ꢂ ꢂ ꢂO230 ; see Table 2 for symmetry codes
1
2
Symmetry codes: (i) x þ 1; y þ 1; z; (ii) ꢀx þ 2; y þ ; ꢀz þ 2; (iii) x ꢀ 1; y; z; (iv) x ꢀ 1,
1
2
1
2
and geometry); only O atoms act as acceptors in hydrogen
bonding. Most probably as a result of ‘hydrophobic inter-
actions’, the lipophilic propynyl groups of molecules (I-1) and
(I-2) are arranged in proximal positions with respect to each
other while maintaining an opposite chain orientation of the
propynyl groups.
y ꢀ 1; z; (v) ꢀx; y ꢀ ; ꢀz þ 1; (vi) ꢀx; y þ ; ꢀz þ 1.
In the absence of suitable anomalous scattering, Friedel equiva-
lents could not be used to determine the absolute structure. Refine-
ment of the Flack (1983) parameter led to inconclusive values for this
parameter [0.3 (6)]. Therefore, Friedel equivalents (2617) 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. In order to maximize the data/parameter ratio, H atoms
bonded to C atoms were placed in geometrically idealized positions,
Experimental
Compound (I) was synthesized from 20-deoxy-5-iodouridine (IIb) and
propyne gas according to literature procedures (Hobbs, 1989;
Froehler et al., 1992) and was crystallized slowly from methanol as
colourless crystals (474 K). For the diffraction experiment, a single
crystal was mounted on a MiTeGen MicroMounts fibre in a thin
smear of oil.
˚
with C—H distances of 0.95–1.00 A and Uiso(H) = xUeq(C), where x =
1.5 for the methyl groups and 1.2 for the other H atoms. All H atoms
bonded to O and N atoms were located in a difference Fourier map
and allowed to refine freely. The refined O—H distances are in the
˚
range 0.79 (3)–0.94 (4) A and the N—H distances are 0.90 (3) and
˚
0.91 (3) A.
Crystal data
3
˚
Data collection: APEX2 (Bruker, 2008); cell refinement: SAINT
(Bruker, 2008); data reduction: SAINT; program(s) used to solve
structure: SHELXTL (Sheldrick, 2008); program(s) used to refine
structure: SHELXTL; molecular graphics: SHELXTL; software used
to prepare material for publication: SHELXTL and PLATON (Spek,
2009).
C12H14N2O5
Mr = 266.25
Monoclinic, P21
V = 1207.12 (16) A
Z = 4
Mo Kꢄ radiation
ꢅ = 0.12 mmꢀ1
T = 130 K
˚
a = 5.6201 (4) A
˚
b = 11.3645 (9) A
c = 19.0281 (16) A
ꢀ = 96.659 (4)ꢁ
˚
0.32 ꢄ 0.23 ꢄ 0.15 mm
ꢃ
Acta Cryst. (2009). C65, o645–o648
Budow et al. C12H14N2O5 o647

organic compounds
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Acta Cryst. (2009). C65, o645–o648