1902
V. V. Filiche6 et al. / Tetrahedron Letters 43 (2002) 1901–1903
Scheme 1. Reagents and conditions: (a) NEt3, DMF, 50 h, 105–110°C; (b) 1 M MeONa in MeOH, 30 min, rt; (c) compound 5,
NaN[Si(CH3)3]2, DMF, 20 h, 100°C; (d) 80% aq. HOAc.
References
The interaction of compound 3 with 5%-O-benzoyl-2,3%-
anhydrothymidine (2) in the presence of triethylamine,
analogous to the above mentioned interaction with an
excess of nucleoside 2, gave a complex mixture of
products.
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1421–1448.
3. Zubarev, V. Yu.; Filichev, V. V.; Trifonov, R. E.;
Ostrovskii, V. A. Mendeleev Commun. 1999, 116–117.
4. Zubarev, V. Yu.; Trifonov, R. E.; Filichev, V. V.;
Ostrovskii, V. A.; Abell, A. D.; Edmonds, M. K. J.
Chem. Soc., Perkin Trans. 2 2001, 417–421.
5. Ostrovskii, V. A.; Studentsov, E. P.; Poplavskii, V. S.;
Ivanova, N. V.; Gurskaya, G. V.; Zavodnik, V. E.; Jasko,
M. V.; Semizarov, D. G.; Krayevsky, A. A. Nucleosides
Nucleotides 1995, 31, 1289–1300.
In place of 2, we used 1-(2-deoxy-3-O-methanesulfonyl-
5-O-trityl-b- -threo-pentofuranosyl)thymine (5) as the
D
starting nucleoside.8,9 The more reactive thymidine 5
permitted the reaction to proceed under milder condi-
tions to afford a mixture of products among which
compound 6 possessing two different protecting groups
was present. The step-by-step deprotection of the mix-
ture at different pH (TLC control) gave the intermedi-
ate 7, isolated by silica gel column chromatography
followed by treatment under basic conditions to afford
the target bisnucleoside 8.10 The structures of the N-2
isomeric tetrazole-containing thymidine derivatives 3, 4
and 8 were confirmed by the characteristic signals of
the endocyclic carbon in their respective 13C NMR
6. Separation of the reaction mixture was carried out by
silica gel column chromatography [Kieselgel 100 (0.063–
0.100), Fluka] using a gradient of CHCl3 in CCl4 (0–
100%, v/v), then a gradient of MeOH in CHCl3 (0–3.5%,
v/v)]. TLC was performed on aluminium silica gel F254
sheets (Merck, Germany), products were visualised by
UV light followed by developing with a 0.5% solution of
CuCl2 in MeOH, elution system CHCl3–MeOH (9:1, v/v).
NMR spectra were recorded on a Bruker DPX–300
spectrometer (with TMS as an internal standard) at 300.1
(1H) and 75.5 MHz (13C). Compound 3, colourless crys-
tals, yield 25%, mp 90–92°C (decomp.). Rf 0.35. 1H NMR
(DMSO-d6) l: 1.64 (3H, s, CH3), 2.90 (2H, m, H-2%), 3.09
(4H, m, 2 tetrazole C-5–CH2CH2O), 3.79 (4H, m, 2
tetrazole C-5–CH2CH2O), 4.59 (3H, m, H-5%+H-4%), 5.94
(1H, m, H-3%), 6.46 (1H, t, J 6.3 Hz, H-1%), 7.55 (3H, m,
C6H4), 7.68 (1H, s, H-6), 7.96 (2H, m, C6H5), 11.40 (1H,
s, NH), 15.82 (1H, br.s, tetrazole NH). 13C NMR
(DMSO-d6) l: 165.5 (2,5-tetrazole C-5), 164.2 (PhCO),
163.7 (C-4), 153.9 (NH-tetrazole C-5), 150.5 (C-2), 136.1
(C-6), 133.7, 129.4, 129.2, 128.9 (C6H5), 110.3 (C-5), 84.3
(C-1%), 80.3 (C-4%), 67.7, 67.2 (CH2CH2OCH2CH2), 63.8
(C-3%), 62.4 (C-5%), 35.8 (C-2%), 25.8 (2,5-tetrazole C-5–
CH2CH2O), 23.9 (NH-tetrazole C-5–CH2CH2O), 11.9
(CH3). Anal. calcd for C23H26N10O6: C, 51.30; H, 4.87;
N, 26.01. Found: C, 51.44; H, 4.95; N, 26.07.
1
spectra.3–5 The H and 13C NMR spectra of 1,5-bis[2-
(3%-deoxythymidine-3%-yl)tetrazol-5-yl]-3-oxapentane (8)
were simpler than those of compounds 3 and 4 imply-
ing a symmetric structure for ether 8.
Thus, as a part of an investigation of the reactivity of
polynuclear tetrazoles with different electrophiles, we
have synthesised new mono- and bis-3%-substituted
thymidine derivatives containing 1,5-bis(tetrazol-5-yl)-
3-oxapentane (1) as a linker. These compounds are of
interest both as inhibitors of DNA chain elongation
and as antisense agents. We also found that the interac-
tion of 1-(2-deoxy-3-O-methanesulfonyl-5-O-trityl-b-D-
threo-pentofuranosyl)thymine (5) with NH-tetrazole 3
in the presence of a base gave only the corresponding
N-2 isomer 6.
We believe that this work will be useful in the synthesis
of the nucleoside systems containing azole polycyclic
moieties in the future.
7. Compound 4 was purified by anion-exchange chromatog-
raphy on cellulose DE-32 (Reanal, HCO3−-form) column
[elution with a gradient of NH4HCO3 in H2O (0–0.3 M)].
This work was supported by the Russian Foundation
for Basic Research (grant no 01-03-32531).