Azines and azoles: CXXVII. Glycosylation of 5,7-dihydro-4H-pyrano-[2,3-d:6, 5-d′]dipyrimidine-4,6(3H)-dione and its 5-phenyl-substituted analog

Article abstract of DOI:10.1134/S1070363207040159

Glycosylation of 5-phenylpyrano[2,3-d:6,5-d′]dipyrimidine-4,6-diones through the corresponding di-O-trimethylsilyl derivative with excess 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose gives a mixture of 3-mono-and 3,7-bis(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-5

Full text of DOI:10.1134/S1070363207040159

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 4, pp. 589 595.
Pleiades Publishing, Ltd., 2007.
Original Russian Text E.V. Fedorova, V.V. Kvasha, E.P. Studentsov, A.V. Moskvin, B.A. Ivin, 2007, published in Zhurnal Obshchei Khimii, 2007,
Vol. 77, No. 4, pp. 630 636.
Azines and Azoles: CXXVII.1 Glycosylation of 5,7-Dihydro-
4H-pyrano-[2,3-d :6,5-d ]dipyrimidine-4,6(3H)-dione
and Its 5-Phenyl-Substituted Analog
E. V. Fedorovaa, V. V. Kvashab, E. P. Studentsovb, A. V. Moskvina, and B. A. Ivina
a St. Petersburg State Chemical and Pharmaceutical Academy,
ul. Professora Popova 14, St. Petersburg, 197376 Russia
b St. Petersburg State Institute of Technology,
Moskovskii pr. 26, St. Petersburg, 190013 Russia
Received October 31, 2006
Abstract Glycosylation of 5-phenylpyrano[2,3-d: 6,5-d ]dipyrimidine-4,6-diones through the corresponding
di-O-trimethylsilyl derivative with excess 1,2,3,5-tetra-O-acetyl- -D-ribofuranose gives a mixture of 3-mono-
and 3,7-bis(2,3,5-tri-O-acetyl- -D-ribofuranosyl)-5-phenylpyrano[2,3-d: 6,5-d ]dipyrimidines; in the reaction
with equimolar amounts of the reactants, only the monoriboside is formed. Isomeric N,N -disubstituted pyra-
nodipyrimidines, as well as mixtures of their mono- and disubstituted derivatives can be separated by frac-
tional crystallization. The alkylation of pyrano[2,3-d: 6,5-d ]dipyrimidine-4,6-dione and its 5-phenyl-substi-
tuted derivative with 2-oxabutane-1,4-diyl diacetate provides an efficient procedure for the synthesis of
acyclic analogs of glycosides based on pyrano[2,3-d: 6,5-d ]dipyrimidines.
DOI: 10.1134/S1070363207040159
A large number of synthetic pyrimidine nucleo-
sides are known to exhibit versatile antiviral activity
[2]. Introduction of carbohydrate moieties into their
molecules is anticipated to enhance the biological
effect of these compounds and extend its spectrum
due to structural similarity (or dissimilarity) to natural
nucleosides. From this viewpoint, interesting are both
free glycosides and their substituted analogs, e.g.,
acetylated derivatives; the presence of acyl groups in
the latter could considerably change their lipophilic
hydrophilic balance, so that such compounds could
be readily removed from human body by the action of
enzymes.
in the presence of a catalytic amount of ammonium
sulfate to obtain the corresponding bis(trimethylsil-
oxy)pyranodipyrimidines IIa and IIb in 80 90% yield
(Scheme 1). Compounds IIa and IIb are crystalline
substances that readily undergo hydrolysis on expo-
sure to atmospheric moisture; they are readily soluble
in anhydrous benzene, diethyl ether, methylene chlo-
ride, and chloroform. The subsequent ribosylation of
4,6-bis(trimethylsiloxy)-5-phenyl-5H-pyrano[2,3-d :
6,5-d ]dipyrimidine (IIb) with 2 equiv of 1,2,3,5-tetra-
O-acetyl- -D-ribofuranose in the presence of excess
(1.2 equiv) of tin(IV) chloride in anhydrous methylene
chloride (18 C, 24 h) lead to the formation of a mix-
ture of two acetylated ribosides, 3-mono- and 3,7-bis-
(2,3,5-tri-O-acetyl- -D-ribofuranosyll)-5-phenyl-5H-
pyrano[2,3-d : 6,5-d ]dipyrimidine-4,6(3H,7H)-diones
IIIb and IVb in an overall yield of 45% (Scheme 1).
When the reaction was complete, the catalyst was
removed by adding dimethyl sulfoxide which binds
SnCl4 to form the strong SnCl4 2DMSO complex in-
soluble in methylene chloride.
One of the most efficient procedures for the syn-
thesis of nucleosides is the silyl method [3], especially
the Vorbruggen Niedballa modification [4] which
allows direct introduction of a peracylated carbohy-
drate moiety to the endocyclic nitrogen atom in nitro-
gen-containing heterocycles with high regioselectivity
and stereospecificity.
The silylation of pyrano[2,3-d:6,5-d ]dipyrimidine-
4,6-diones Ia and Ib was carried out by heating in
excess hexamethyldisilazane for 3 4 h at 130 140 C
The condensation of 4,6-bis(trimethylsiloxy)-5-
phenyl-5H-pyrano[2,3-d : 6,5-d ]dipyrimidine (IIb)
with an equimolar amount of 1,2,3,5-tetra-O-acetyl- -
D-ribofuranose, other conditions being equal, gave
only one monosubstituted acetylated riboside IIIb.
Obviously, the ribosylation of compound IIb is a
1
For communication CXXVI, see [1].
589

590
FEDOROVA et al.
Scheme 1.
R1
Me3SiO
R1
OH
N
OH
OSiMe3
(Me3Si)2NH
(NH4)2SO4
N
N
N
N
N
N
N
O
O
Ia, Ib
IIa, IIb
AcR2OAc
(1) CH2Cl2/SnCl4
(2) MeOH
R1
R1
O
N
R1
O
O
N
O
O
O
O
N
HN
AcR2
R2Ac
R2Ac
N
N
N
N
N
N
N
N
O
O
R2Ac
R2Ac
IIIb, VIIb, Xb
IVa, IVb, VIIIb, XIb
IIIa
H+
H+
H+
R1
O
R1
O
O
R1
O
O
O
R2
R2
R2Ac
N
N
N
HN
N
N
N
N
N
N
N
O
N
O
O
R2
R2
Vb, XIIb
VIa, VIb, IXb
Va
R = H (a), Ph (b);
CH2OAc
O
CH2OAc
OAc
CH2OAc
OAc
AcO
(IIIa, IIIb, IVa, IVb),
O
O
R2Ac =
(VIIb, VIIIb),
(Xb, XIb);
OAc
AcO
OAc
OAc
OAc
CH2OH
CH2OH
CH2OH
HO
(Va, Vb, VIa, VIb),
HO
O
O
R2 =
OH
(XIIb).
OH
(IXb),
OH
OH
OH
OH
stepwise process, and pure mono- and diribosyl deriv-
atives of 5-arylpyranodipyrimidines could be ob-
tained by varying the reactant ratio.
3-Mono- and 3,7-bis(triacetylribofuranosyl)-5-
phenylpyrano[2,3-d : 6,5-d ]dipyrimidine-4,6-diones
IIIb and IVb are readily deacetylated with conserva-
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AZINES AND AZOLES: CXXVII.
591
Table 1. UV and 1H NMR spectra of pyrano[2,3-d: 6,5-d ]dipyrimidine-based glycosides III XIV
UV spectrum,
Comp.
no.
(EtOH),
max, nm
1H NMR spectrum (DMSO-d6), , ppm
IIIb
275 sh
1.89 2.06 m (9H, 3COCH3), 4.15 4.28 m (3H, H2 ,3,4), 4.97 s (1H, C5H), 5.37 5.50 m (2H,
C5 H2), 5.91 5.95 m (1H, C1 H), 7.18 7.25 m (5H, Harom), 8.07 8.47 s (2H, C2,8H), 12.66 br.s
(1H, NH)
IVa
IVb
Vb
277 sh
275 sh
274 sh
2.05 m (18H, 6CH3), 3.45 s (2H, C5H2), 4.09 4.19 m (6H, H2 ,3,4), 5.89 5.91 m [2H, (C1 H)2],
8.25 s (2H, C2,8H)
1.88 2.09 m (18H, 6COCH3), 4.14 4.29 m (6H, H2 ,3,4), 4.99 s (1H, C5H), 5.37 5.53 m [4H,
(C5 H2)2], 5.92 5.98 m [2H, (C1 H)2], 7.20 7.26 m (5H, Harom), 8.49 8.55 d (2H, C2,8H)
3.57 4.03 m (5H, H2 ,3,4, C5 H2), 4.66 br.s (3H, 3OH), 4.94 br.s (1H, C5H), 5.80 5.84 d (1H,
C1 H), 7.23 7.26 m (5H, Harom), 8.07 8.81 s (2H, C2,8H), 12.67 br.s (1H, NH)
VIb
274 sh
275 sh
3.62 4.04 m (10H, H2 ,3,4, C5 H2), 4.60 br.s (6H, 6OH), 4.97 br.s (1H, C5H), 5.77 5.84 d [2H,
(C1 H)2), 7.20 7.28 m (5H, Harom), 8.83 s (2H, C2,8H)
VIIb
CDCl3: 1.14 s (3H, COCH3), 1.94 2.18 m (9H, 3COCH3), 4.12 s (3H, C5 H + C6 H2), 5.09 5.15 s
(3H, C3 ,4 H + C5H), 5.49 s (1H, C2 H), 5.99 s (1H, C1 H), 7.25 7.33 m (5H, Harom), 7.91 8.21 s
(2H, C2,8H), 12.60 br.s (1H, NH)
VIIIb
IXb
275 sh
274 sh
CDCl3: 1.92 2.13 m (24H, 8COCH3), 4.08 4.31 m [6H, (C5 H)2 + (C6 H2)2], 5.05 5.47 m [7H,
(C2 ,3 ,4 H)2 + C5H], 6.28 6.35 s (2H, C1 H), 7.26 7.33 m (5H, Harom), 7.92 8.21 s (2H, C2,8H)
3.27 3.72 m [12H, (C6H2)2 + (C2 ,3 ,4 ,5 H)2], 4.94 5.13 m (9H, C5H + 8OH), 5.42 5.51 m (2H,
C1 H), 7.18 7.25 s (5H, Harom), 8.09 8.46 s (2H, C2,8H)
XIIb
276 sh
277 sh
276 sh
CDCl3: 3.26 3.63 m (5H, C6 H2 + C5 ,4 ,3 H), 4.25 s (5H, C2 H + 4OH), 4.94 s (1H, C5H), 5.44
5.55 m (1H, C1 H), 7.24 7.25 m (5H, Harom), 8.08 8.49 s (2H, C2,8H), 12.72 br.s (1H, NH)
CDCl3: 2.07 2.08 m (6H, 2COCH3), 3.64 s (2H, C5H), 3.82 s [4H, (C3H2)2], 4.20 d [4H,
(C2 H2)2], 5.93 s [4H, (C1 H2)2], 8.08 s (2H, C2,8H), 11.70 br.s (1H, NH)
XIIIa
XIIIb
2.01 m (6H, 2COCH3), 3.73 s [4H, (C3H2)2], 4.10 4.14 d [4H, (C2 H2)2], 5.13 s (1H, C5H),
5.18 5.43 m [4H, (C1 H2)2], 7.10 7.36 m (5H, Harom), 8.12 d (2H, C2,8H)
XIVb
275 sh
3.73 m [6H, (O C3H2 N)2 + 2OH], 3.96 [4H, s, (O C2 H2)2], 4.98 s (1H, C5H), 5.23 5.30 m
[4H, (C1 H2)2], 7.25 s (5H, Harom), 8.51 d (2H, C2,8H)
tion of the glycoside C N bond by the action of 3%
HCl in methanol (18 20 C, 24 h); we thus isolated
3-mono-and 3,7-bis( -D-ribofuranosyl)-5-phenylpy-
rano[2,3-d:6,5-d ]dipyrimidine-4,6-diones Vb and
VIb (Scheme 1).
of protons on C2 and C8 in the pyrimidine rings.
Monoribosides IIIb and Vb displayed two signals at
8.0 and 8.8 ppm, while only one signal at 8.5 8.8
ppm was present in the spectra of diribosides IVb and
VIb. The chemical shifts of 5-H ( 4.9 ppm) and
protons in the 5-phenyl group ( 7.2 7.28 ppm) are
almost similar for all compounds IIIb VIb, as well
as for initial phenylpyranodipyrimidine Ib. The posi-
tion of the anomeric proton signal (C1 H, 5.94 ppm)
and the corresponding spin spin coupling constant
The purity of the products was checked by TLC,
and their structure was confirmed by elemental anal-
1
ysis and H NMR, UV, and IR spectroscopy (Tables
1
1 and 2). The main difference in the H NMR spectra
1
J1 ,2 (1 Hz) in the H NMR spectra of IIIb and IVb in
of monoribosides IIIb and Vb, on the one hand, and
diribosides IVb and VIb, on the other, is the presence
of a downfield signal at 12.66 ppm from the NH
proton of the former. Methyl proton signals of O-
acetyl ribosides IIIb and IVb are located in the region
1.88 2.09 ppm, while the spectra of the correspond-
ing deacetylated derivatives Vb and VIb contain no
such signals. In keeping with published data [5 7],
signals in the region 3.5 6.5 ppm were assigned to
protons in the carbohydrate moieties. Characteristic
differences were also observed in the chemical shifts
DMSO-d6 indicate its -configuration [8].
In the UV spectra of alcoholic solutions of com-
pounds IIIb VIb we observed one strong absorption
maximum in the region 270 280 nm, which arises
from
* transitions in the aromatic and pyrimidine
fragments and the presence of a ribosyl moiety as
auxochrome.
The IR spectra of crystalline samples of ribonu-
cleosides IIIb VIb dispersed in mineral oil contain
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592
FEDOROVA et al.
Table 2. Yields, melting or decomposition points, Rf values, and elemental analyses of pyrano[2,3-d: 6,5-d ]dipyrimidine-
based glycosides III XIV
Found, %
H
Calculated, %
H
Comp. Yield,
no.
mp,
C
Rf
Formula
%
C
N
C
N
IIIb
IVa
IVb
Vb
12 (25) 175 (decomp.)
0.46a
0.62b
0.96b
0.78c
0.91c
0.22d
0.64d
0.60e
0.83e
0.38d
0.33d
0.76e
55.94
49.97
54.12
55.98
53.26
55.20
53.81
52.07
54.69
41.21
43.14
53.12
4.91
4.93
4.87
4.74
5.02
4.84
5.17
5.26
4.85
4.56
4.87
5.02
9.95
7.52
6.86
12.53
9.57
8.71
5.11
8.44
11.65
12.11
10.28
15.25
C26H24N4O10
C31H34N4O17
C37H38N4O17
C20H18N4O7
C25H26N4O11
C29H28N4O12
C43H46N4O21
C27H30N4O13
C21H20N4O8
C19H22N4O9
C25H26N4O9
C21H22N4O7
56.52
50.68
54.81
56.34
53.76
55.77
54.09
52.43
55.26
43.18
47.77
56.00
4.35
4.63
4.69
4.22
4.66
4.49
4.82
4.85
4.38
4.23
4.14
4.89
10.15
7.63
6.91
13.14
10.04
8.97
5.87
9.06
12.28
12.45
10.65
14.22
15
31
97
91
52 (decomp.)
199 201
120 (decomp.)
112 (decomp.)
VIb
VIIb
VIIIb
IXb
XIIb
XIIIa
XIIIb
XIVb
6.3 121 (decomp.)
32
145 (decomp.)
67 70
205 (decomp.)
157 160
109 114
142 145
97
57
43
64
94
a
b
c
d
Methylene chloride methanol, 15:1. Methylene chloride methanol, 20:1. Methylene chloride methanol, 3:1. Chloroform
e
methanol, 15:1.
Chloroform methanol, 3:1.
absorption bands characteristic of structural fragments
of their molecules. Stretching vibrations of the OH
and NH bonds give rise to absorption in the region
60% of unchanged initial pyranodipyrimidine Ia
which, unlike its ribosylated derivatives, is insoluble
in methylene chloride methanol. Isomer mixture
IIIa/IVa can be readily deacetylated with 3% me-
thanolic HCl, but the resulting pyrano[2,3-d:6,5-d ]-
dipyrimidine-based diribosides Va and VIa cannot be
1
3100 3500 cm ; a broad band in the region 1630
1750 cm 1 belongs to stretching vibrations of the C=O
groups in the pyrimidine fragment (and acetoxy
groups in the spectra of acetylated derivatives IIIb
and IVb); and absorption bands in the region 1120
1
separated (Scheme 1). The H NMR spectrum of mix-
ture IIIa/IVa contained signals from 5-H and 2-H/8-H
at 3.60 and 8.23 ppm, respectively. The absence of
NH signal in the spectrum indicates that molecules
IIIa and IVa contain two carbohydrate fragments.
1
1170 cm may be assigned to stretching vibrations of
the ribosyl C1 O C4 fragment.
We also tried to synthesize pyranodipyrimidine-
based ribosides following another widely used proce-
dure, namely, alkylation of the corresponding O-silyl
derivatives with acylated glycosyl halides. According
to the TLC data, treatment of 4,6-bis(trimethylsiloxy)-
5-phenyl-5H-pyrano[2,3-d:6,5-d ]dipyrimidine (IIb)
with freshly prepared 2,3,5-tri-O-acetyl- -D-ribofura-
nosyl chloride in anhydrous methylene chloride re-
sulted in the formation of mono- and diribosides IIIb
and IVb; however, their yield was considerably lower
than in the reaction with tetra-O-acetylribofuranose,
and it did not exceed 5 7%.
Unlike ribosylation, 4,6-bis(trimethylsiloxy)-5-
phenyl-5H-pyrano[2,3-d : 6,5-d ]dipyrimidine (IIb)
reacted with 1,2,3,4,6-penta-O-acetyl- -D-galactopy-
ranose and 1,2,3,4,6-penta-O-acetyl- -D-glucopyra-
nose much more slowly (72 h), and the overall yield
of the corresponding galacto- and glucopyranosides
VIIb/VIIIb and Xb/XIb was about 40%. The lower
reactivity of pyranoses compared to furanoses was
also observed in the synthesis of N-glycosides from
other heterocycles [3, 4].
It should be noted that glycosylation of 4,6-bis(tri-
methylsiloxy)-5-phenyl-5H-pyrano[2,3-d : 6,5-d ]di-
pyrimidine (IIb) with galactose pentaacetate also af-
forded a mixture of 3-mono- and 3,7-bis(2,3,4,6-tetra-
O-acetyl- -D-galactopyranosyl)-5-phenyl-5H-pyrano-
[2,3-d : 6,5-d ]dipyrimidine-4,6(3H,7H)-diones VIIb
and VIIIb (Scheme 1), which was separated by frac-
tional crystallization from ethanol and diethyl ether.
The structure of VIIb and VIIIb was confirmed by
The condensation of 1,2,3,5-tetra-O-acetyl- -D-
ribofuranose with 4,6-bis(trimethylsiloxy)-5H-pyrano-
[2,3-d:6,5-d ]dipyrimidine (Ia) having no substituent
on C5 occurred much more difficultly. Even after
48 h, the yield of an inseparable mixture of 1,9- and
3,7-bis(2,3,5-tri-O-acetyl- -D-ribofuranosyl)-5H-
pyrano[2,3-d : 6,5-d ]dipyrimidine-4,6(3H,7H)-diones
IIIa and IVa did not exceed 15%. Desilylation of the
reaction mixture by treatment with methanol gave
1
the H NMR spectra, as well as by deacetylation to
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AZINES AND AZOLES: CXXVII.
593
3,7-bis( -D-galactopyranosyl)-5-phenyl-5H-pyrano-
[2,3-d:6,5-d ]dipyrimidine-4,6(3H,7H)-dione (IXb).
Analysis of the spectra of galactosides VIIb IXb,
performed as described above for ribosides IIIb VIb,
confirmed the structure of both aglycone and carbo-
hydrate fragments in their molecules.
gen-containing base remains the same as in the ribose
fragment), is promising from the viewpoint of search-
ing for new antiviral agents [8, 9]. As acyclic analog
of monosaccharides we selected 2-oxabutane-1,4-diyl
diacetate. The condensation of 4,6-bis(trimethylsil-
oxy)-5-phenyl-5H-pyrano[2,3-d : 6,5-d ]dipyrimidine
(IIb) with excess 2-oxabutane-1,4-diyl diacetate
(Scheme 2) gave 3,7-bis[(2-acetoxyethoxy)methyl]-5-
phenyl-5H-pyrano[2,3-d : 6,5-d ]-dipyrimidine-4,6-
(3H,7H)-dione (XIIIb) as the only product, and its
deacetylation afforded 3,7-bis[(2-hydroxyethoxy)me-
thyl]-5-phenyl-5H-pyrano[2,3-d:6,5-d ]dipyrimidine-
4,6(3H,7H)-dione (XIVb). Trimethylsilyl derivative
of pyrano[2,3-d:6,5-d ]dipyrimidine (compound IIa)
reacted with 2-oxabutane-1,4-diyl diacetate much
more difficultly, and the product was 3-[(2-acetoxy-
ethoxy)methyl]-5H-pyrano[2,3-d:6,5-d ]dipyrimidine-
4,6(3H,7H)-dione (XIIIa).
The reaction of 4,6-bis(trimethylsiloxy)-5-phenyl-
5H-pyrano[2,3-d:6,5-d ]dipyrimidine
(IIb)
with
glucose pentaacetate gave a mixture of two glucosides
Xb and XIb which we failed to separate. By deace-
tylation of that mixture we obtain 3-( -D-glucopyra-
nosyl)-5-phenyl-5H-pyrano[2,3-d:6,5-d ]dipyrimidine-
4,6(3H,7H)-dione (XIIb) (Scheme 1).
It is known that replacement of ribose moiety in
nucleosides by an acyclic fragment, the general mo-
lecular geometry being retained (i.e., the distance
from C1 to the C3 OH group with respect to the nitro-
AcO
OAc
HO
O
OH
O
O
O
N
O
N
R
O
R
O
N
O
N
O
N
H+
N
N
(1) AcOCH2CH2OCH2OAc
N
O
CH2Cl2/SnCl4
XIIIb
XIVb
(2) DMSO
IIa, IIb
or
OAc
R
O
O
N
O
N
HN
N
O
XIIIa
R = H (a), Ph (b).
Inlike initial 5-phenylpyranodipyrimidine Ib, the
1H NMR spectra of XIIIb and XIVb in DMSO-d6
lacked signal from the aglycone NH proton. Signals
from protons in the acetoxyethoxy fragment of XIIIb
were located at 3.74 and 4.13 ppm, while the cor-
responding signals of deacetylated derivative XIVb
NH proton signals were present at 11.70 ppm, and
signals from 2-H/8-H, at 8.08 ppm. The spectral
pattern from the pseudoribose fragment in XIIIa was
similar to that observed for N,N -disubstituted
5-phenyl analog XIIIb, but the relative intensity was
twice as low.
appeared at
3.48 ppm. More downfield signals
( 5.23 5.43 ppm) belong to the NCH2O group. Ace-
tyl protons in XIIIb gave rise to a signal at
2.01 ppm. In addition, the spectra of XIIIb and XIVb
contained signals from 5-H ( 4.98 5.13 ppm), 2-H/
8-H ( 8.12 8.51 ppm), and benzene ring ( 7.18
We can conclude that the Vorbruggen glycosyla-
tion of pyrano[2,3-d:6,5-d ]dipyrimidine-4,6-diones
in aprotic solvents is can efficient route to the cor-
responding mono- and diglycosides whose ratio
depends on the initial reactant ratio. The alkylation of
pyrano[2,3-d:6,5-d ]dipyrimidine 4,6-diones with
1
7.36 ppm). In the H NMR spectrum of XIIIa, the
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594
FEDOROVA et al.
2-oxabutane-1,4-diyl diacetate gives acyclic analogs
of 5-arylpyrano[2,3-d:6,5-d ]dipyrimidine-based
glycosides, in which the (2-hydroxyethoxy)methyl
group mimics ribose fragment.
ride was added dropwise, the mixture was kept for
30 min at 0 C, and the precipitate, SnCl4 2DMSO,
was filtered off and washed with 5 ml of methylene
chloride. The filtrate was diluted with 4 ml of me-
thanol, heated for 15 min at 60 C, and evaporated
under reduced pressure (20 25 mm) at 30 40 C. Di-
ethyl ether, 30 ml, was added to the residue, and the
mixture was cooled to 20 C and evaporated under
reduced pressure to obtain a mixture of ribosides IIIb
and IVb (43%). Crystallization from ethanol gave
3,7-bis(2,3,5-tri-O-acetyl- -D-ribofuranosyl)-5-phenyl-
5H-pyrano[2,3-d : 6,5-d ]dipyrimidine-4,6(3H,7H)-di-
one (IVb). The mother liquor was evaporated, and the
residue was recrystallized from diethyl ether to isolate
3-(2,3,5-tri-O-acetyl- -D-ribofuranosyl)-5-phenyl-
5H-pyrano[2,3-d : 6,5-d ]dipyrimidine-4,6(3H,7H)-
dione (IIIb).
EXPERIMENTAL
The electronic absorption spectra were recorded
from solutions in water or ethanol on an SF-2000
spectrophotometer (1-cm quartz cells, concentration
5
4
1
10 to 10 M). The H NMR spectra were measured
from solutions in DMSO-d6 and CDCl3 on Bruker
AM-200 (200 MHz) and Bruker AM-500 (500 MHz)
spectrometers. The purity of products was checked,
and the progress of reactions was monitored, by thin-
layer chromatography on Silufol UV-254 plates; spots
were visualized under UV light or by treatment with
iodine vapor. The melting (decomposition) points
were determined in capillaries and were not corrected
(Tables 1, 2). The solvents and reagents used were
purified and dehydrated by standard procedures.
1,2,3,4,6-Penta-O-acetyl- -D-galactopyranose,
Compound IIIb was synthesized in a similar way
using equimolar amounts of silyl ether IIb and 1,2,3,5-
tetraO-acetyl- -D-ribofuranose. Yield 25%.
3,7- and 1,9-Bis(2,3,5-tri-O-acetyl- -D-ribo-
furanosyl)-5H-pyrano[2,3-d :6,5-d ]dipyrimidines
IVa and IIIa (a mixture of isomers) were obtained as
described above for compounds IIIb and IVb. Un-
changed pyranodipyrimidine Ia was filtered off, the
filtrate was evaporated under reduced pressure (20
25 mm), and the residue was reprecipitated from etha-
nol diethyl ether (5:1) and evacuated until a solid
foam-like material was obtained. We thus isolated an
amorphous hygroscopic mixture of compounds IIIa
and IVa which we failed to separate by fractional
crystallization.
1,2,3,4,6-penta-O-acetyl- -D-glucopyranose,
and
2-oxabutane-1,4-diyl diacetate were prepared accord-
ing to the procedures described in [10, 11].
4,6-Bis(trimethylsiloxy)-5H-pyrano[2,3-d:6,5-d ]-
dipyrimidine (IIa) and 4,6-bis(trimethylsiloxy)-5-
phenyl-5H-pyrano[2,3-d:6,5-d ]dipyrimidine (IIb)
(general procedure). A mixture of 0.005 mol of pyra-
nodipyrimidine Ia or Ib, 10 ml of hexamethyldisila-
zane, and 0.15 g of ammonium sulfate was heated
with stirring under reflux until it became homo-
geneous. Excess hexamethyldisilazane was distilled
off under reduced pressure (20 25 mm) (for more
complete removal of hexamethyldisilazane, benzene
was added), and the residue was kept under reduced
pressure until complete crystallization of compounds
IIa and IIb. The products are readily hydrolyzable on
exposure to atmospheric moisture.
3-( -D-Ribofuranosyl)-5-phenyl-5H-pyrano[2,3-
d:6,5-d ]dipyrimidine-4,6(3H,7H)-dione (Vb) and
3,7-bis( -D-ribofuranosyl)-5-phenyl-5H-pyrano-
[2,3-d:6,5-d ]dipyrimidine-4,6(3H,7H)-dione (VIb)
(general procedure). Acetylated riboside IIIb or IVb,
0.001 mol, was dissolved in 10 ml of methanol, 10 ml
of a 3% solution of hydrogen chloride in methanol
was added, and the mixture was stirred for 30 min and
was left to stand for 12 h. The solvent was distilled
off under reduced pressure (20 25 mm), the residue
was washed with diethyl ether, evacuated, and dis-
solved in 20 ml of methanol, the solution was evap-
orated by half, 30 ml of diethyl ether was added to
the residue, and the mixture was kept at 20 C. The
supernatant was removed by decanting, and the re-
sidue was dried under reduced pressure. We thus ob-
tained colorless crystals of 3,7-bis-( -D-ribofuranosyl)-
5-phenyl-5H-pyrano[2,3-d : 6,5-d ]dipyrimidine-4,6-
(3H,7H)-dione (VIb) or yellow crystals of 3-( -D-
ribofuranosyl)-5-phenyl-5H-pyrano[2,3-d : 6,5-d ]di-
pyrimidine-4,6(3H,7H)-dione (Vb).
3-(2,3,5-Tri-O-acetyl- -D-ribofuranosyl)-5-
phenyl-5H-pyrano[2,3-d :6,5-d ]dipyrimidine-4,6-
(3H,7H)-dione (IIIb) and 3,7-bis(2,3,5-tri-O-acetyl-
-D-ribofuranosyl)-5-phenyl-5H-pyrano[2,3-d:6,5-
d ]dipyrimidine-4,6(3H,7H)-dione (IVb). Silyl ether
IIb, 0.003 mol, was dissolved in 7 ml of anhydrous
methylene chloride under stirring with thorough pro-
tection from atmospheric moisture, and 0.006 mol of
anhydrous
1,2,3,5-tetra-O-acetyl- -D-ribofuranose
was added to the solution. A solution of tin(IV) chlo-
ride in 3 ml of methylene chloride was then added
dropwise under stirring and cooling, and the mixture
was stirred for 3 h at 18 20 C and was left to stand
for 12 h. The mixture was cooled to 0 C, a solution of
0.5 ml DMSO in 2 ml of anhydrous methylene chlo-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 4 2007

AZINES AND AZOLES: CXXVII.
595
3-(2,3,4,6-Tetra-O-acetyl- -D-galactopyranosyl)-
5-phenyl-5H-pyrano[2,3-d : 6,5-d ]dipyrimidine-
4,6(3H,7H)-dione (VIIb) and 3,7-bis(2,3,4,6-tetra-
O-acetyl- -D-galactopyranosyl)-5-phenyl-5H-py-
rano[2,3-d :6,5-d ]dipyrimidine-4,6(3H,7H)-dione
(VIIIb) were synthesized as described above for com-
pounds IIIb and IVb from 0.007 mol of silyl ether
IIb and 0.014 mol of anhydrous 1,2,3,4,6-penta-O-
acetyl- -D-galactopyranose. Crystallization from
ethanol gave compound VIIb. The mother liquor was
evaporated, and the residue was recrystallized from
hexane to isolate digalactoside VIIIb.
3-[(2-Acetoxyethoxy)methyl]-5H-pyrano[2,3-d:
6,5-d ]dipyrimidine-4,6(3H,7H)-dione (XIIIa) was
synthesized as described above for compound XIIa
using 3 equiv of 2-oxabutane-1,4-diyl diacetate.
3,7-(or 1,9)-Bis[(2-hydroxyethoxy)methyl]-5-
phenyl-5H-pyrano[2,3-d : 6,5-d ]dipyrimidine-
4,6(3H,7H)dione (XIVb) was synthesized as de-
scribed above for compounds Vb and VIb.
REFERENCES
1. Danilkina, N.A., Mikhailov, L.E., and Selivanov, S.I.,
3,7-Bis( -D-galactopyranosyl)-5-phenyl-5H-
pyrano[2,3-d:6,5-d ]dipyrimidine-4,6(3H,7H)-dione
(IXb) was synthesized as described above for com-
pounds Vb and VIb.
Zh. Obshch. Khim., 2006, vol. 42, no.6, p. 807.
2. Shneider, M.A. and Chizhov, N.P., Antibiot. Khimio-
ter., 1983, vol. 33, no. 2, p. 386.
3. Lukevics, E.Ya. and Zabolotskaya, A.E., Silil’nyi
metod sinteza nukleozidov (Silyl Method for the
Synthesis of Nucleosides), Riga: Zinatne, 1985.
3-( -D-Glucopyranosyl)-5-phenyl-5H-pyrano-
[2,3-d : 6,5-d ]dipyrimidine-4,6(3H,7H)-dione
(XIIb). The condensation of silyl ether IIb with
4. Vorbruggen, H. and Ruh-Pohlenz, C., Handbook of
Nucleoside Synthesis, New York: Wiley, 2002.
1,2,3,4,6-penta-O-acetyl- -D-glucopyranose
was
carried out as described above in the synthesis of
VIIb and VIIIb. As a result, a yellow amorphous
mixture of glucosides Xb and XIb was obtained,
which was difficult to separate. The mixture is readily
soluble in methylene chloride and methanol and in-
soluble in hexane. Its deacylation gave colorless
monoglucoside XIIb which crystallized from the
solution.
5. Schweizer, M.P., Witkowski, J.T., and Robins, R.K.,
J. Am. Chem. Soc., 1971, vol. 93, no. 1, p. 277.
6. Schweizer, M.P., Banta, E.B., Witkowski, J.T., and
Robins, R.K., J. Am. Chem. Soc., 1973, vol. 95,
no. 11, p. 3770.
7. Davies, D.B. and Danyluk, S.S., Can. J. Chem., 1970,
vol. 48, no. 19, p. 3112.
8. Moskvin, A.V., Ksenofontova, G.V., Studentsov, E.P.,
and Ivin, B.A., Russ. J. Gen. Chem., 1994, vol. 64,
no. 3, p. 440.
3,7-(or 1,9)-Bis[(2-acetoxyethoxy)methyl]-5-
phenyl-5H-pyrano[2,3-d :6,5-d ]dipyrimidine-4,6-
(3H,7H)dione (XIIIb) was synthesized as described
above for compounds IIIb and IVb from 0.009 mol
of silyl ether IIb and 0.03 mol of 2-oxabutane-1,4-
diyl diacetate in anhydrous methylene chloride. The
crude product was crystallized from methanol (the
mixture was heated for 15 min and volatile com-
ponents were removed under reduced pressure).
Hexane was added to the residue, the mixture was
cooled to 20 C, the solvent was removed by decant-
ing, and the residue was evacuated at a residual
pressure of 20 25 mm. Compound XIIIb was isolated
as light yellow crystals.
9. Moskvin, A.V., Ksenofontova, G.V., Studentsov, E.P.,
and Ivin, B.A., Russ. J. Gen. Chem., 1994, vol. 64,
no. 3, p. 447.
10. Zhdanov, Yu.A., Dorofeenko, G.N., Korol’chen-
ko, G.N., and Bogdanova, G.V., Praktikum po khimii
uglevodov (Practical Course of Carbohydrate Chem-
istry), Zhdanov, Yu.A., Ed., Moscow: Vysshaya
Shkola, 1973.
11. Robins, M.J. and Hatfield, P.W., Can. J. Chem., 1982,
vol. 60, no. 5, p. 547.
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