First Analog of Pyrimidine Nucleosides with Two D-Ribofuranose Residues

Article abstract of DOI:10.1134/S1070428020010285

The reaction of 1,3-bis(pent-4-yn-1-yl)-6-methyluracil with 2,3,5-tri-O-acetyl-β-D-ribofuranosyl azide gave 1,3-bis{3-[1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-1,2,3-triazol-4-yl]propyl}-6-methyluracil which was deprotected by treatment with a solution of sodium methoxide in methanol to obtain 1,3-bis{3-[1-(β-D-ribofuranosyl)-1H-1,2,3-triazol-4-yl]propyl]-6-methyluracil as a first analog of pyrimidine nucleosides containing two D-ribofuranose fragments.

Full text of DOI:10.1134/S1070428020010285

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 1, pp. 181–184. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 1, pp. 148–152.
SHORT
COMMUNICATIONS
First Analog of Pyrimidine Nucleosides
with Two D-Ribofuranose Residues
a
a
a
a
a,
R. R. Sharipova , L. F. Saifina , M. G. Belenok , V. E. Semenov , and V. E. Kataev *
a
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center,
Russian Academy of Sciences, Kazan, 420088 Russia
*
e-mail: kataev@iopc.ru
Received June 25, 2019; revised November 21, 2019; accepted November 22, 2019
Abstract—The reaction of 1,3-bis(pent-4-yn-1-yl)-6-methyluracil with 2,3,5-tri-O-acetyl-β-D-ribofuranosyl
azide gave 1,3-bis{3-[1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-1,2,3-triazol-4-yl]propyl}-6-methyluracil
which was deprotected by treatment with a solution of sodium methoxide in methanol to obtain 1,3-bis{3-[1-(β-
D-ribofuranosyl)-1H-1,2,3-triazol-4-yl]propyl]-6-methyluracil as a first analog of pyrimidine nucleosides con-
taining two D-ribofuranose fragments.
Keywords: nucleosides, nucleoside analogs, uracil, [3+2]-cycloaddition, click chemistry, 1,2,3-triazoles.
DOI: 10.1134/S1070428020010285
During the past decade, extensive studies have been
performed in the field of synthesis of so-called pyrimi-
dine nucleoside analogs [1–6] in which the D-ribose or
deoxy-D-ribose residue (hereinafter, D-ribofuranose is
meant) is replaced by a five-membered carbocycle [1]
or heterocycle [2], one or more heterorings are fused to
the nucleobase [3], or the latter is replaced by a nitro-
gen heterocycle such as 1,2,4-triazole [4]. Most of the
synthesized compounds were found to exhibit diverse
biological activities [1–3, 5, 6].
sodium methoxide in methanol to remove acetyl pro-
tecting groups. We thus obtained the first pyrimidine
nucleoside analog 7 containing two D-ribofuranose
fragments (Scheme 1). Compound 2 was synthesized
by alkylation of 6-methyluracil (1) with 5-bromopent-
1-yne in the presence of sodium hydride, and azide 5
was prepared according to the known procedure [10] in
three steps starting from D-ribose. The anomeric proton
1
of 5 resonated in the H NMR spectrum as a doublet at
δ 5.35 ppm with a vicinal coupling constant of 2 Hz,
which indicated that azide 5 was pure β-anomer [10].
Correspondingly, compounds 6 and 7 were also pure
β-anomers. Study of biological activity of nucleoside
analog 7 is now in progress.
By the Huisgen–Meldal–Sharpless reaction of
1
,3-bis(5-azidopentyl)-6-methyluracil with terminal
alkynes we previously synthesized 6-methyluracil
derivatives with 1,2,3-triazole terminal groups in the
alkyl chains attached to nitrogen atoms of the pyrimi-
dine ring [7]. These compounds can be regarded as
nucleoside analogs; after modification of the 1,2,3-tri-
azole moiety, they showed a high antimicrobial activity
6-Methyl-1,3-di(pent-4-yn-1-yl)pyrimidine-
2,4(1H,3H)-dione (2). Sodium hydride, 2.20 g
(0.092 mol), was added to a solution of 5 g (0.04 mol)
of 6-methyluracil (1) in 200 mL of anhydrous DMF,
and the mixture was stirred at 70°C for 8 h. The
mixture was cooled to room temperature, 33.10 g
(0.32 mol) of 5-bromopent-1-yne was added, and the
mixture was stirred at 120°C for 24 h. The solvent was
evaporated, the residue was treated with 150 mL of
chloroform, the precipitate was filtered off, and the
filtrate was concentrated to a volume of 20 mL and
passed through a column charged with silica gel
(60 mesh). The column was eluted in succession with
[8] and the ability to undergo aggregation in supramo-
lecular systems [9]. Herein, we utilized the opposite
approach to the synthesis of nucleoside analogs, ac-
cording to which a pyrimidine derivative with terminal
alkynyl substituents, namely 1,3-di(pent-4-yn-1-yl)-6-
methyluracil (2), reacted with an azide partner,
2
,3,5-tri-O-acetyl-β-D-ribofuranosyl azide (5). The
Meldal–Sharpless reaction of 2 and 5 afforded bis-
,2,3-triazole derivative 6 which was treated with
1
1
81

182
SHARIPOVA et al.
Scheme 1.
5
O
Me
O
1
1
16
NaH
HC
CH
HN
1
3
+
Br
N
N
CH
9
7
12
14
O
N
H
Me
O
1
2
O
OH
OH
AcO
AcO
(
(
1) MeOH, H
N3
2) Ac O/AcOH
Me SiN , SnCl
3 3 4
2
O
OAc
O
HO
OH
AcO OAc
AcO OAc
3
4
5
1
3
Me
5
Me
O
O
1
3
N
N
N
N
7
10
O
O
CuSO , NaAsc
MeONa
MeOH
9
4
12
16
4
t-BuOH/H O
2
1
2
+ 5
N
N
N
N
N
1
5
17
OAc
HO
OH
AcO
N
N
5'
N
N
5''
N
N
N
O
O
O
O
1'
1
''
3
'
3
''
AcO OAc
HO OH
AcO OAc
HO OH
6
7
light petroleum ether and petroleum ether–ethyl acetate
in a mixture of 40 mL of tert-butyl alcohol and 40 mL
of water was added dropwise, and the mixture was
stirred at 50°C for 5 days, concentrated under reduced
pressure, diluted with water, and extracted with methy-
lene chloride. The extract was washed with water and
(
1.5 : 1 by volume). Yield 6.49 g (63%), mp 61°C.
1
H NMR spectrum (600 MHz, CDCl ), δ, ppm: 1.84–
3
4
1
2
2
(
7
.87 m (4H, 8-H, 13-H), 1.93 t (1H, 11-H, J = 2.8 Hz),
4
.00 t (1H, 16-H, J = 2.7 Hz), 2.21–2.23 m (2H, 9-H),
.24 s (6-CH ), 2.25–2.27 m (2H, 14-H), 3.90–3.93 t
dried over MgSO , and the solvent was distilled off
3
4
3
3
2H, 7-H, J = 7.7 Hz), 3.98–4.00 t (2H, 12-H, J =
.0 Hz), 5.55 s (1H, 5-H). C NMR spectrum (CDCl ),
under reduced pressure. Yield 2.0 g (87%), off-white
1
3
1
3
amorphous powder. H NMR spectrum (400 MHz,
8
13
δ , ppm: 15.85 (C ), 16.29 (C ), 20.51 (6-CH ), 40.46
(
8
1
2
C
3
CDCl ), δ, ppm: 2.05–2.16 m (22H, OAc, 8-H, 11-H),
3
7
12
10
15
11
C ), 44.14 (C ), 68.51 (C ), 69.51 (C ), 82.58 (C ),
2
4
.23 s (3H, 13-H), 2.75–2.88 m (4H, 9-H, 12-H), 3.86–
.04 m (4H, 7-H, 10-H), 4.18–4.26 m and 4.37–4.42 m
1
6
5
6
2
3.39 (C ), 101.73 (C ), 151.14 (C ), 152.00 (C ),
62.12 (C ). Mass spectrum, m/z: 259.1 [M + H] ,
81.1 [M + Na] , 297.2 [M + K] . Found, %: C 69.68;
4
+
(
5
2H each, 5′-H, 5″-H), 4.44–4.49 m (2H, 4′-H, 4″-H),
.54 s (1H, 5-H), 5.56–5.64 m (2H, 2′-H, 2″-H), 5.78–
5.83 m (2H, 3′-H, 3″-H), 6.12 d (2H, 1′-H, 1″-H, J =
+
+
H 7.10; N 10.93. C H N O . Calculated, %: C 69.74;
1
5
18
2
2
H 7.02; N 10.84. M 258.14.
13
3
.7 Hz), 7.62 s (1H, 15-H), 7.68 s (1H, 17-H). C NMR
1
3
spectrum (CDCl ), δ , ppm: 19.79 (C ); 20.51 (2C),
6
-Methyl-1,3-bis{3-[1-(2,3,5-tri-O-acetyl-β-D-
3
C
2
0.58 (2C), 20.81 (2C) (CH CO); 22.83, 23.19, 26.79,
ribofuranosyl)-1H-1,2,3-triazol-4-yl]propyl}pyrimi-
dine-2,4(1H,3H)-dione (6). Azide 5, 1.6 g (5.4 mmol),
was dissolved in a mixture of 15 mL of tert-butyl
alcohol and 5 mL of water, 1.34 g (5.4 mmol) of
CuSO ·5H O in 5 mL of water was added, and 1.07 g
3
12
7
5′
5″
27.97, 40.68, 44.65 (C –C ); 63.16 (C ), 63.18 (C ),
70.95 (C ), 71.02 (C ), 74.38 (C ), 74.41 (C ), 80.86
(C ), 80.93 (C ), 89.94 (C ), 90.06 (C ), 101.77 (C ),
120.46 (C ), 120.55 (C ), 147.08 (C ), 148.01 (C ),
4
′
4″
3′
3″
2
′
2″
1′
1″
5
1
5
17
14
16
4
2
6
2
4
(5.4 mmol) of sodium ascorbate in 5 mL of water was
151.49 (C ), 152.24 (C ), 162.31 (C ); 169.34, 169.38,
then added. A solution of 0.7 g (2,7 mmol) of uracil 2
169.53, 169.54, 170.44, 170.55 (CH CO). Mass
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 1 2020

FIRST ANALOG OF PYRIMIDINE NUCLEOSIDES
183
+
+
of 10–6 g/L and introduced through a Rheodyne 7725
injector (USA), sample volume 20 μL]; the data were
acquired using TrapControl 7.0 software (Bruker
Daltonik, Germany) and processed by DataAnalysis
spectrum, m/z: 861.4 [M + H] , 883.4 [M + Na] , 899.4
[
+
M + K] . Found, %: C 51.65; H 5.70; N 13.10.
C H N O . Calculated, %: C 51.62; H 5.62;
N 13.02. M 860.82.
-Methyl-1,3-bis{3-[1-(β-D-ribofuranosyl)-1H-
,2,3-triazol-4-yl]propyl}pyrimidine-2,4(1H,3H)-
dione (7). A freshly prepared 0.1 M solution of sodium
methoxide in methanol was added dropwise with
stirring to a solution of 1.6 g (2 mmol) of compound 6
in 10 mL of anhydrous methanol until pH 8. The mix-
ture was stirred at room temperature for 2 days, while
intermittently adding new portions of methanolic
sodium methoxide when pH reached 7. The progress of
the reaction was monitored by TLC. The mixture was
then neutralized with Amberlyst 15, and the solvent
3
7
48
8
16
4
.0 SP4 (Bruker Daltonik, Germany). The progress of
6
reactions and the purity of compounds were monitored
by thin-layer chromatography on Sorbfil plates (Imid
Ltd., Krasnodar, Russia); spots were visualized by
treatment with a 5% solution of sulfuric acid, followed
by heating to 120°C. 6-Methyluracil (1) and D-ribose
were commercial products (Acros Organics, Belgium).
1
ACKNOWLEDGMENTS
The authors thank the Spectral and Analytical Joint
Center (Kazan Scientific Center, Russian Academy of
Sciences) for technical support of the present study.
was distilled off under reduced pressure. Yield 0.98 g
87%), white amorphous powder. H NMR spectrum
1
(
(
1
400 MHz, CD OD), δ, ppm: 1.97–2.08 m (4H, 8-H,
3
FUNDING
1-H), 2.26 s (3H, 6-CH ), 2.75 t (2H, 9-H, J =
3
7
5
.4 Hz), 2.80 t (2H, 12-H, J = 7.3 Hz), 3.69 d.d (2H,
′-H, 5″-H, J = 12.2, 3.3 Hz), 3.81 d.d (2H, 5′-H, 5″-H,
This study was performed under financial support by the
Russian Science Foundation (project no. 19-13-00003).
J = 12.2, 3.2 Hz), 3.92 t (2H, 7-H, J = 7.0 Hz), 3.97 t
2H, 10-H, J = 7.1 Hz), 4.09–4.15 m (2H, 4′-H, 4″-H),
(
CONFLICT OF INTEREST
The authors declare the absence of conflict of interest.
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4
3
1
1
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13
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3
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1
3
(
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5′
5″
4′
4″
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