7-Iodo-8-aza-7-deaza-2′-deoxyadenosine and 7-bromo-8-aza-7-deaza-2′-deoxyadenosine

Article abstract of DOI:10.1107/S0108270100000780

The isomorphous structures of the title molecules, 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-3-iodo-1H-pyrazolo-[3,4-d] pyrimidine, (I), C₁₀H₁₂IN₅O₃, and 4-amino-3-bromo-1-(2-deoxy-β-D-erythro-pentofuranosy

Full text of DOI:10.1107/S0108270100000780

organic compounds
Acta Crystallographica Section C
Crystal Structure
compounds can now be prepared in a one-pot reaction with
increased yield compared with the two-step procedure (Seela
Communications
&
Zulauf, 1998). Compounds (I) and (II) crystallize isomor-
phously.
The ribonucleoside 8-aza-7-deazaadenosine (8-azatuber-
ISSN 0108-2701
0
0
0
cidin) exhibits a C1 -exo±C2 -endo conformation (Sprang et
0
7
-Iodo-8-aza-7-deaza-2 -deoxy-
al., 1978), and for the unsubstituted 8-aza-7-deaza-2 -deoxy-4-
2
0
adenosine a T
adenosine and 7-bromo-8-aza-
0
(S-type sugar) sugar-ring conformation was
3
0
determined (Seela, Zulauf et al., 1999). In contrast to this, an
unusual C1 -endo ( E) sugar-ring conformation is observed
7
-deaza-2 -deoxyadenosine
0
1
0
for (I) and (II). This can be seen from the torsion angle ꢂ
3
a
a
b
Frank Seela, * Matthias Zulauf, Hans Reuter and Guido
0
0
0
0
ꢀ
ꢀ
(
(
C2 ÐC3 ÐC4 ÐO4 ) of � 2.8 (4) for (I) and � 3.8 (4) for
b
Kastner
II), implying an almost planar arrangement of these four
0
atoms, with a deviation of C1 from the least-squares planes of
0
a
Laboratorium f uÈ r Organische und Bioorganische Chemie, Institut f uÈ r Chemie,
Ê
.488 (5) A for (I) and 0.496 (5) A for (II). The puckering
Ê
Universit aÈ t Osnabr uÈ ck, Barbarastrasse 7, D-49069 Osnabr uÈ ck, Germany, and
b
amplitude ꢃm and the pseudorotation phase angle P (Rao et
Anorganische Chemie II, Institut f uÈ r Chemie, Universit aÈ t Osnabr uÈ ck, Barbarastrasse
ꢀ ꢀ
al., 1981) for (I) are ꢃ = 34.8 (3) and P = 309.4 (4) , while for
m
7
, D-49069 Osnabr uÈ ck, Germany
ꢀ
ꢀ
Correspondence e-mail: fraseela@rz.uni-osnabrueck.de
(II) ꢃ = 35.0 (3) and P = 310.9 (4) .
m
The orientation of the base relative to the sugar (syn/anti) is
1
Received 18 October 1999
Accepted 17 January 2000
0
0
de®ned by the torsion angle ꢁ (O4 ÐC1 ÐN9ÐC4)
IUPAC±IUB Joint Commission on Biochemical Nomen-
clature, 1983); the preferred conformation around the
(
The isomorphous structures of the title molecules, 4-amino-1-
(
0
N-glycosidic bond of a natural 2 -deoxynucleoside is usually in
the anti range. It was shown that Coulomb repulsion between
2-deoxy-ꢀ-d-erythro-pentofuranosyl)-3-iodo-1H-pyrazolo-
3,4-d]pyrimidine, (I), C H IN O , and 4-amino-3-bromo-
[
1
0
12
5
3
0
the non-bonding electron pairs of O4 and N8 of 8-aza-
tubercidin (Sprang et al., 1978), formycin (Prusiner et al., 1973)
1
d]pyrimidine, (II), C H BrN O , have been determined. The
-(2-deoxy-ꢀ-d-erythro-pentofuranosyl)-1H-pyrazolo[3,4-
1
0
12
5
3
0
sugar puckering of both compounds is C1 -endo ( E). The
0
0
1
and 7-halogeno-8-aza-7-deaza-2 -deoxypurines (Seela, Becher
et al., 1999) forces the N-glycosidic conformation into the
high-anti (� sc) range (Klyne & Prelog, 1960). Compounds (I)
1
N-glycosidic bond torsion angle ꢁ is in the high-anti range
ꢀ
ꢀ
[
structure is stabilized by hydrogen bonds.
� 73.2 (4) for (I) and � 74.1 (4) for (II)] and the crystal
1
ꢀ
and (II) also adopt a high-anti conformation [ꢁ = � 73.2 (4)
ꢀ
for (I) and � 74.1 (4) for (II)].
The halogeno substituents possess a stereoelectronic effect
Seela, Becher et al., 1999; Rosemeyer et al., 1997); as a result,
the torsion angle ꢁ is signi®cantly lower compared with that
for 8-aza-7-deaza-2 -deoxyadenosine [ꢁ = � 106.3 (2) ; Seela,
Zulauf et al., 1999] and the high-anti conformation is
strengthened. Compared with (I) and (II), the 7-iodo-7-deaza-
Comment
(
0
Oligonucleotides containing 7-iodo-8-aza-7-deaza-2 -deoxy-
0
1
adenosine, (I), or 7-bromo-8-aza-7-deaza-2 -deoxyadenosine,
1
0
ꢀ
(
II) (Seela & Zulauf, 1998), show enhanced stability of
duplexes with antiparallel (aps) chain orientation (Seela et al.,
997; Seela & Zulauf, 1999). Purine skeleton numbering is
1
used throughout the following discussion. The X-ray struc-
tures of the related 7-bromo- and 7-iodo-8-aza-7-deazagua-
0
nine 2 -deoxynucleosides show that the steric and
stereoelectronic effects of the nucleobase are responsible for
the high-anti conformation of the base and also for the sugar-
ring conformation (Seela, Becher et al., 1999). In the light of
this, it was of interest to evaluate the crystal structures of the
0
Figure 1
7-halogeno-8-aza-7-deaza-2 -deoxyadenosines, (I) and (II),
and compare them with that of the unsubstituted 8-aza-7-de-
A perspective view of (I) showing the atomic numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as spheres of small arbitrary size.
0
aza-2 -deoxyadenosine (Seela, Zulauf et al., 1999). Both
Acta Cryst. (2000). C56, 489±491
# 2000 International Union of Crystallography ꢁ Printed in Great Britain ± all rights reserved 489

organic compounds
0
0
2
-deoxyadenosine adopts a C3 -exo (
0
E) sugar conformation
1
Experimental
3
with an almost perfect anti orientation of the base [ꢁ =
Compound (I) was prepared from 1-[2-deoxy-3,5-di-O-(p-toluoyl)-ꢀ-
d-erythro-pentofuranosyl]-3-iodo-4-methoxy-1H-pyrazolo[3,4-d]-
pyrimidine (Seela & Zulauf, 1998; 500 mg, 0.8 mmol) by treatment
ꢀ
�
147.1 (8) ; Seela et al., 1996]. The high-anti conformation of
I) and (II) may be stabilized through van der Waals inter-
(
actions resulting from the contact between N8 and C2 or one
0
with saturated NH /MeOH (150 ml, 3:1 v/v) for 5 h at 363 K in an
3
Ê
of its H atoms [NÐC = 2.761 (5) A and NÐH = 2.45 A for (I);
Ê
autoclave. The solvent was evaporated and the residue puri®ed by
¯ash chromatography on silica gel (column 10 Â 3 cm, methanol±
Ê
Ê
NÐC = 2.777 (5) A and NÐH = 2.47 A for (II)]. Similar
interactions were also observed for 8-azaadenosine (Singh &
Hodgson, 1974) and 8-azatubercidin (Sprang et al., 1978).
Another intramolecular attraction was determined between
the 7-halogeno substituent and one of the amino H atoms of
i
dichloromethane 1:9). Crystallization from PrOH yielded
1
colourless needles (yield 138 mg, 46%) which showed identical H
1
and C NMR data to those of a veri®ed sample (Seela & Zulauf,
3
1
3
998). Compound (II) was prepared from 3-bromo-1-[2-deoxy-
,5-di-O-(p-toluoyl)-ꢀ-d-erythro-pentofuranosyl]-4-methoxy-1H-
(
of the amino group. Therefore, two signals for the amino
I) and (II). This hydrogen bond leads to a hindered rotation
pyrazolo[3,4-d]pyrimidine (Seela
0
&
.86 mmol) by treatment with saturated NH
Zulauf, 1998; 500 mg,
/MeOH (150 ml, 3:1
3
1
protons can be observed in the H NMR spectra at ambient
v/v) for 5 h at 363 K in an autoclave. The solvent was evaporated
and the residue puri®ed by ¯ash chromatography on silica gel
(column 10 Â 3 cm, methanol±dichloromethane 1:9). Crystal-
temperature. The proton signals become indistinguishable at a
coalescence temperature of 340 K.
i
lization from PrOH yielded colourless needles (yield 148 mg,
1 13
2%) which showed identical H and C NMR data to those of a
5
veri®ed sample (Seela & Zulauf, 1998).
Compound (I)
Crystal data
�
3
C
10
H12IN
O
5 3
D
x
= 2.029 Mg m
r
M = 377.15
Mo Kꢅradiation
Monoclinic, P21
Ê
a = 9.259 (3) A
Cell parameters from 40
re¯ections
Ê
b = 7.2787 (10) A
ꢀ
ꢆ= 5.08±17.82
Ê
� 1
c = 9.767 (3) A
ꢀ
V = 617.4 (3) A
Z = 2
ꢇ= 2.607 mm
T = 293 (2) K
ꢀ
Ê
= 110.29 (2)
3
Needle, colourless
0.55 Â 0.15 Â 0.15 mm
Data collection
Siemens P4 diffractometer
R
int = 0.020
ꢀ
2ꢆ/!scans
ꢆmax = 27
Absorption correction: scan
(SHELXTL; Sheldrick, 1997a)
Tmin = 0.445, Tmax = 0.704
3057 measured re¯ections
1455 independent re¯ections (plus
1239 Friedel-related re¯ections)
h = � 11 ! 11
Figure 2
k = � 9 ! 9
A perspective view of (II) showing the atomic numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as spheres of small arbitrary size.
l = � 12 ! 12
3 standard re¯ections
every 97 re¯ections
intensity decay: none
2
668 re¯ections with I > 2ꢈ(I)
0
The exocyclic angle N8ÐN9ÐC1 is smaller than C4ÐN9Ð
0
ꢀ
Re®nement
C1 , by 6.3 (4) for (I) and by 5.6 (4) for (II), as observed for
other nucleosides adopting the high-anti conformation
2
Re®nement on F
2
R[F > 2ꢈ(F )] = 0.026
wR(F ) = 0.069
S = 1.036
2694 re¯ections
174 parameters
Only H-atom U's re®ned
(Á/ꢈ)max = 0.001
2
Ê
� 3
Áꢉmax = 0.63 e A
2
Ê
� 3
(Sprang et al., 1978; Prusiner et al., 1973). The conformation
0
about the C4 ÐC5 bond of (I) and (II) is in the trans (+ap)
Áꢉmin = � 0.65 e A
0
Extinction correction: SHELXL97
(Sheldrick, 1997b)
ꢀ
ꢀ
range [ꢄ= 175.4 (3) for (I), 175.2 (3) for (II)]. The halogeno
substituents of (I) and (II) lead to a lengthening of the
glycosidic bond, while the other bond lengths and torsion
angles of (I) and (II) are similar to those of 8-aza-7-deaza-2 -
deoxyadenosine (Seela, Zulauf et al., 1999).
Extinction coef®cient: 0.0102 (11)
Absolute structure: Flack (1983)
Flack parameter = � 0.01 (2)
2
2
2
o
w = 1/[ꢈ(F ) + (0.0411P)
0
+ 0.4360P]
where P = (F
2
o
2
c
+ 2F
)/3
Table 1
Selected geometric parameters (A, ) for (I).
Intermolecular hydrogen bonds formed by (I) and (II)
generate a three-dimensional network and provide additional
crystal stabilization (Tables 2 and 4).
The 8-aza-7-deazaadenine base of (I) and (II) is planar. The
deviations of the ring C and N atoms from the least-squares
Ê
ꢀ
0
N9ÐC1
1.480 (4)
127.5 (3)
0
0
0
C4ÐN9ÐC1
N8ÐN9ÐC1
121.2 (3)
Ê
plane are in the range of � 0.031 (5)±0.043 (3) A for (I) and
Ê
0.037 (5)±0.045 (3) A for (II). The bulky iodo substituent of
0
0
0
0
0
0
0
0
�
C4ÐN9ÐC1 ÐO4
C2 ÐC3 ÐC4 ÐO4
C3 ÐC4 ÐC5 ÐO5
� 73.2 (4)
� 2.8 (4)
175.4 (3)
101.6 (4)
21.3 (4)
C2 ÐC1 ÐO4 ÐC4
C3 ÐC4 ÐO4 ÐC1
32.8 (3)
� 18.8 (3)
175.4 (3)
114.1 (3)
54.4 (4)
0
0
0
0
0
0
0
0
0 0 0
Ê
(
I) lies � 0.091 (6) A and the bromo substituent of (II)
Ê
0 0 0
C3 ÐC4 ÐC5 ÐO5
�
0.084 (6) A out of the heterocyclic plane. For comparison,
the iodo atom of 7-iodo-7-deaza-2 -deoxyadenosine is located
0
0
0 0 0
O3 ÐC3 ÐC4 ÐC5
N8ÐN9ÐC1 ÐO4
0
0
0
0
0
0
0
0
0
C1 ÐC2 ÐC3 ÐC4
O4 ÐC4 ÐC5 ÐO5
Ê
0.135 (14) A out of the plane (Seela et al., 1996).
�
4
90 Frank Seela et al. ꢁ
10 5 3 5 3
C H12IN O and C10H12BrN O

organic compounds
Table 2
Hydrogen-bonding geometry (A, ) for (I).
Table 4
Hydrogen-bonding geometry (A, ) for (II).
Ê
ꢀ
Ê
ꢀ
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
N6ÐH61Á Á ÁO50
i
0.86
0.86
0.82
0.82
2.17
2.91
2.18
2.18
2.907 (4)
3.610 (3)
2.837 (4)
2.940 (4)
143.2
139.7
136.7
154.5
N6ÐH61Á Á ÁO5
0
i
0.86
0.85
0.82
0.82
2.12
2.84
2.21
2.08
2.870 (4)
3.510 (3)
2.828 (4)
2.890 (4)
145.9
136.4
131.9
171.9
N6ÐH62Á Á ÁI7
N6ÐH62Á Á ÁBr7
0
0
0
ii
0
0
ii
O3 ÐH3 1Á Á ÁN1
O3 ÐH3 1Á Á ÁN1
0 0
0
iii
iii
O5 ÐH5 Á Á ÁN3
O5 ÐH5 Á Á ÁN3
1
1
2
1
2
1
Symmetry codes: (i) � x;2 ‡ y;1 � z; (ii) 1 ‡ x;y;1 ‡ z; (iii) 1 � x;y � ;1 � z.
Symmetry codes: (i) � x; ‡ y;1 � z; (ii) 1 ‡ x;y;1 ‡ z; (iii) 1 � x;y � 2;1 � z.
All H atoms were found in difference Fourier syntheses but were
constructed in geometrically reasonable positions, with the exception
of the amino H atoms. These were ®rst re®ned with a common NÐH
distance and then ®xed on the amino N atoms using a riding model.
For all H atoms a common isotropic displacement parameter was
re®ned. The absolute con®gurations were con®dently proven by the
diffraction experiment.
Compound (II)
Crystal data
�
3
C
10
H12BrN
5
O
3
D
x
= 1.827 Mg m
M
r
= 330.16
Monoclinic, P21
Mo Kꢅradiation
Cell parameters from 35
re¯ections
Ê
a = 9.0930 (9) A
For both compounds, data collection: XSCANS (Siemens, 1996);
cell re®nement: XSCANS; data reduction: SHELXTL (Sheldrick,
1997a); program(s) used to solve structure: SHELXS97 (Sheldrick,
1997b); program(s) used to re®ne structure: SHELXL97 (Sheldrick,
1997b); molecular graphics: SHELXTL; software used to prepare
material for publication: SHELXTL.
Ê
ꢀ
� 1
b = 7.2595 (10) A
ꢆ= 4.74±16.32
ꢇ= 3.438 mm
T = 293 (2) K
Ê
c = 9.6369 (19) A
ꢀ
V = 600.16 (16) A
Z = 2
ꢀ
Ê
= 109.362 (11)
3
Needle, colourless
0.50 Â 0.12 Â 0.12 mm
Data collection
Siemens P4 diffractometer
ꢆ/!scans
Absorption correction: scan
SHELXTL; Sheldrick, 1997a)
min = 0.497, Tmax = 0.662
R
int = 0.035
ꢀ
2
ꢆmax = 27
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: LN1089). Services for accessing these data are
described at the back of the journal.
h = � 11 ! 11
(
T
k = � 9 ! 9
l = � 12 ! 12
2
1
959 measured re¯ections
411 independent re¯ections (plus
3 standard re¯ections
every 97 re¯ections
intensity decay: none
1193 Friedel-related re¯ections)
References
2
381 re¯ections with I > 2ꢈ(I)
Flack, H. D. (1983). Acta Cryst. A39, 876±881.
IUPAC±IUB Joint Commission on Biochemical Nomenclature (1983). Eur. J.
Biochem. 131, 9±15.
Klyne, W. & Prelog, V. (1960). Experientia, 16, 521±523.
Prusiner, P., Brennan, T. & Sundaralingam, M. (1973). Biochemistry, 12, 1196±
Re®nement
2
Re®nement on F
2
(Á/ꢈ)max = 0.001
2
Ê
� 3
Áꢉmax = 0.51 e A
R[F > 2ꢈ(F )] = 0.035
wR(F ) = 0.093
S = 1.052
2
Ê
� 3
Áꢉmin = � 0.54 e A
1202.
Extinction correction: SHELXL97
(Sheldrick, 1997b)
Rao, S. T., Westhof, E. & Sundaralingam, M. (1981). Acta Cryst. A37, 421±425.
Rosemeyer, H., Zulauf, M., Ramzaeva, N., Becher, G., Feiling, E., M uÈ hlegger,
K., M uÈ nster, I., Lohmann A. & Seela, F. (1997). Nucleosides Nucleotides, 16,
821±828.
Seela, F., Becher, G., Rosemeyer, H., Reuter, H., Kastner, G. & Mikhailopulo,
I. A. (1999). Helv. Chim. Acta, 82, 105±124.
Seela, F., Ramzaeva, N. & Zulauf, M. (1997). Nucleosides Nucleotides, 16, 963±
2
1
604 re¯ections
74 parameters
Extinction coef®cient: 0.0071 (17)
Absolute structure: Flack (1983)
Flack parameter = � 0.014 (11)
Only H-atom U's re®ned
2
2
2
w = 1/[ꢈ(F
0.2516P]
where P = (F
o
) + (0.0529P)
+
2
2
c
o
+ 2F
)/3
966.
Seela, F. & Zulauf, M. (1998). J. Chem. Soc. Perkin Trans. 1, pp. 3233±3239.
Seela, F. & Zulauf, M. (1999). J. Chem. Soc. Perkin Trans. 1, pp. 479±488.
Seela, F., Zulauf, M., Kastner, G. & Reuter, H. (1999). Acta Cryst. C55, 1947±
Table 3
Selected geometric parameters (A, ) for (II).
Ê
ꢀ
1950.
0
Seela, F., Zulauf, M., Rosemeyer, H. & Reuter, H. (1996). J. Chem. Soc. Perkin
Trans. 2, pp. 2373±2376.
Sheldrick, G. M. (1997a). SHELXTL. Release 5.1. Bruker AXS Inc., Madison,
Wisconsin, USA.
Sheldrick, G. M. (1997b). SHELXL97 and SHELXS97. University of
G oÈ ttingen, Germany.
Siemens (1996). XSCANS. Version 2.2. Siemens Analytical X-ray Instruments
Inc., Madison, Wisconsin, USA.
N9ÐC1
1.473 (4)
127.1 (3)
0
0
0
C4ÐN9ÐC1
N8ÐN9ÐC1
121.5 (3)
0
0
0
0
0
0
0
0
C4ÐN9ÐC1 ÐO4
C2 ÐC3 ÐC4 ÐO4
C3 ÐC4 ÐC5 ÐO5
� 74.1 (4)
� 3.8 (4)
175.2 (3)
101.9 (4)
22.5 (4)
C2 ÐC1 ÐO4 ÐC4
C3 ÐC4 ÐO4 ÐC1
32.5 (3)
� 18.3 (3)
175.2 (3)
113.1 (3)
54.9 (4)
0
0
0
0
0
0
0
0
0 0 0
0 0 0
C3 ÐC4 ÐC5 ÐO5
0
0
0 0 0
O3 ÐC3 ÐC4 ÐC5
Singh, P. & Hodgson, D. J. (1974). J. Am. Chem. Soc. 96, 5276±5278.
Sprang, S., Scheller, R., Rohrer, D. & Sundaralingam, M. (1978). J. Am. Chem.
Soc. 100, 2867±2872.
N8ÐN9ÐC1 ÐO4
0
0
0
0
0
0
0
0
C1 ÐC2 ÐC3 ÐC4
O4 ÐC4 ÐC5 ÐO5
Acta Cryst. (2000). C56, 489±491
Frank Seela et al. ꢁ
C
10
H12IN O
5 3
5
and C10H12BrN O
3
491