Polymethylene derivatives of nucleic bases with ω-functional groups: V. Pyrimidine- and purine-containing γ-butyrophenones

Article abstract of DOI:10.1007/s11171-005-0075-8

New polymethylene derivatives of nucleic bases containing a keto function in the ω-position were synthesized by alkylation of nucleic bases with 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane and the subsequent deblocking of the keto group; their physicochemical properties were studied.

Full text of DOI:10.1007/s11171-005-0075-8

Russian Journal of Bioorganic Chemistry, Vol. 31, No. 6, 2005, pp. 549–555. Translated from Bioorganicheskaya Khimiya, Vol. 31, No. 6, 2005, pp. 609–615.
Original Russian Text Copyright © 2005 by Kritzyn, Komissarov.
Polymethylene Derivatives
of Nucleic Bases with w-Functional Groups:
V.1 Pyrimidine- and Purine-Containing g-Butyrophenones
, 2
A. M. Kritzyn* and V. V. Komissarov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, ul. Vavilova 32, Moscow, 119991 Russia
Received April 22, 2004; in final form, May 21, 2005
Abstract—New polymethylene derivatives of nucleic bases containing a keto function in the ω-position were
synthesized by alkylation of nucleic bases with 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane and the subsequent
deblocking of the keto group; their physicochemical properties were studied.
Key words: alkylation, butyrophenones, nucleosides, polymethylene analogues
21
INTRODUCTION
logues bearing various functional groups in ω-position
of polymethylene chain.
Some practically important antiviral agents have
been found among acyclic nucleoside analogues,
including polymethylene derivatives of nucleic bases.
3
RESULTS AND DISCUSSION
A number of comprehensive reviews [2–5] are devoted
to the preparation and properties of such widely used in
medicine drugs as acyclovir, valacyclovir, gancyclovir,
bucyclovir, pencyclovir, femcyclovir, and others. Acy-
clic nucleoside analogues are also interesting for study-
ing action mechanisms of enzymes, whereas their
structure–function relationships serve a rational basis
for the design of medicines of new generations [6–8].
HBG specifically inhibits HSV-1 and HSV-2 viral
thymidine kinases and does not affect the cellular thy-
midine kinase [9, 10]. The molecule of this acyclic
nucleoside analogue contains a polymethylene chain of
four carbon atoms, which is terminated with the func-
tional hydroxyl group.
A series of highly active neuroleptics of the buty-
rophenone family (haloperidol, trifluperidol, droperi-
dol, etc.) are known [11]. They belong to antipsychotic
agents heavily blocking the dopamine receptors and, as
a rule, lacking a hypnotic sedative activity because of a
stimulating component. A modified piperidine hetero-
cycle with a p-fluorobutyrophenone residue at its N
atom serves as an analogue of nucleic base in these
structures.
It appeared therefore interesting to synthesize and
study physicochemical properties of pyrimidine and
pyrine-containing γ-butyrophenones within the frames
of our systematic studies of acyclic nucleoside ana-
Alkylation of heterocyclic bases with γ-chlorobuty-
rophenone (I) is an evident method for the preparation
of pyrimidine γ-butyrophenones. The starting alkylat-
ing agent was obtained using the reported procedures
[12] (Scheme 1). The treatment of γ-butyrolactone with
thionyl chloride converted it into γ-chlorobutyryl chlo-
ride. This was used to acylate benzene under the
Friedel–Crafts conditions. An attempt to alkylate thym-
ine with butyrophenone (I) in the presence of DBU
according to the procedure we developed earlier [13]
resulted in cyclopropylphenylketone (II) in 55% yield
rather than in the expected N1-mono- and N1,N3-bis-
derivatives; the products of nucleic base alkylation
were not found in the reaction mixture. A comparable
yield (78%) of (II) was obtained under the classical
conditions of synthesis of cyclopropane derivatives by
the treatment of γ-chloroketones with aqueous alkali
[12]. We supposed that, in this case, nitrogen-contain-
ing organic bases (e.g., DBU) exert a similar effect and
the reaction course is not affected by nucleic base. This
hypothesis was confirmed by the fact that the heating of
equimolar amounts of (I) and DBU in DMF at 80–
100°ë for 20 h led to ~60% yield of cyclopropylphe-
none (II). We found in this manner that the oxo group
of alkylating agent should be protected. The dioxolane
group proved to be convenient for this aim. It was easily
introduced by the reflux of γ-chlorobutyrophenone (I)
in toluene with excess ethylene glycol in the presence
of triethyl orthoformate and a catalytic amount of p-tol-
uenesulfonic acid. The reaction resulted in 84% yield of
(III) (Scheme 2), which was used for the alkylation of
nucleic bases.
1
For communication IV, see [1].
Corresponding author; fax: +7 (095) 135-1405; e-mail:
amk@eimb.ru
Abbreviations: DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; HBG,
9-(4-hydroxybutyl)guanine.
2
3
1068-1620/05/3106-0549 © 2005 Pleiades Publishing, Inc.

550
KRITZYN, KOMISSAROV
SOCl2, ZnCl2
O
Cl
boiling
O
O
Cl
O
O
AlCl3, C6H6
0°C
1) thymine, DBU, DMF, 80°C or
2) NaOH, H2O, boiling
Cl
1) Yield 55%
2) Yield 78%
(I)
(II)
Scheme 1.
O
B
A) DBU, DMF, 80°C or
B) NaH, DMF, 80°C
(I) + BH
(VI‡)–(VIh)
HO(CH2)2OH, HC(OEt)3,
TosOH, C6H5CH3, boiling
for ‡–f C) AcOH, H2O, boiling
for g, h D) Et3N, EtOH, H2O, boiling; then C)
O
O
O
Cl
B
O
A) DBU, DMF, 80°C or
B) NaH, DMF, 80°C
+ BH
(III)
(IV‡)–(IVh)
For compounds (IV) B =
+
‡: uracil-1-yl; b: thym-1-yl;
c: cytos-1-yl; d: aden-9-yl;
e: aden-3-yl; f: hypoxant-9-yl;
g: N2-(methylpropionyl)guan-9-yl;
h: N2-(methylpropionyl)guan-3-yl.
For compounds (V) B =
O
O
B
O
O
‡: uracil-1,3-diyl; b: thymine-1,3-diyl
For compounds (VI) B =
(V‡), (Vb)
‡–f: as for compounds (IV);
g: guan-9-yl; h: guan-3-yl
Scheme 2.
Thymine and uracil interacted with chlorophenone
(III) under the standard conditions we described in [13]
using DBU as a base (method A). N1-Alkylated (IVa)
and (IVb) and N1,N3-bisalkylated (Va) and (Vb) deriv-
atives of uracil and thymine were obtained by this
method. Cytosine was alkylated by method B: the
nucleic base was preliminarily converted into sodium
salt by the reaction with sodium hydride in DMF and
then coupled with (III) to give 31% of the target (IVc)
[13].
The resulting pyrimidine derivatives were isolated
and purified by column chromatography on silica gel.
Their structures were confirmed by elemental analysis,
mass, UV, and NMR spectra (see Tables 1, 2, and the
Experimental section).
Reagent (III) was also used for alkylation of hypox-
antine, N2-(2-methylpropionyl)guanine, and adenine.
The reaction with hypoxantine by method Ä in DMF
resulted in ~50% yield of N9-derivative (IVÂ), which
was isolated by column chromatography on silica gel.
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POLYMETHYLENE DERIVATIVES OF NUCLEIC BASES…V.
551
1
Table 1. H NMR spectra of the synthesized compounds (VIa)–(VIh)
Compounds (VI), δ, ppm
Protons
a
b*
c
d
e
f
g
h
1 H, H1 or H3
1 H, H2 or H5
1 H, H6 or H8
11.17, s
11.12, s
–
–
–
–
12.26, s 10.52, s 10.67, s
5.50, d**
5.63, d*** 8.10, s
7.76, s
8.35, s
7.90, s
4.41, t
7.85, s
8.18, s
–
–
–
7.63, d** 7.49, s 7.15, d*** 8.15, s
7.69, s
6.36, s
4.03, t
7.89, s
6.03, s
4.25, t
2 H, 2-NH2 or 4-NH2 or 6-NH2
2 H, J 7.16, H1'
–
–
6.91 s
7.14, s
4.23, t
3.74, t
1.94, m
3.07, t
7.93, d
7.51, m
7.61, t
3.71, t 3.70, t
1.94, m 1.91, m
3.07, t 3.02, t
7.94, d 7.93, d
7.51, m 7.52, m
7.62, t 7.63, t
4.48, t
2 H, H2'
2.18, m 2.26, m 2.17, m 2.10, m 2.14, m
3.06, t 3.10, t 3.07, t 3.04, t 3.00, t
7.91, d 7.90, d 7.92, d 7.90, d 7.90, d
7.50, m 7.51, m 7.50, m 7.50, m 7.50, m
2 H, J 6.88, H3'
2 H, J 7.48, H6' and H10'
2 H, H7' and H9'
1 H, J 7.16, H8'
7.62, t
7.62, t
7.60, t
7.61, t
7.62, t
Notes: * For (VIb), the resonances of 5-CH group are: 1.73, 3 H, s.
3
** J 7.8.
*** J 7.16.
Table 2. 13C NMR spectra of the synthesized compounds (VIa)–(VIh)
Compounds (VI), δ, ppm
Carbon atoms
a
b*
c
d
e
f
g
e
C2
151.0
163.7
101.0
145.5
–
150.9
164.2
108.5
141.2
–
155.8
165.9
93.2
152.3
149.6
118.8
155.9
140.8
42.4
143.4
149.7
120.4
155.0
152.4
48.93
23.4
147.7
148.8
114.5
153.0
139.5
48.5
153.5
151.2
116.7
156.8
137.4
42.2
154.5
C4
152.6
108.1
159.9
143.1
45.6
C5
C6
145.9
–
C8
C1'
47.0
46.7
48.0
C2'
23.0
23.0
23.5
24.1
24.1
24.0
25.1
C3'
34.7
34.7
34.9
34.9
34.9
34.5
34.9
34.7
C4'
199.0
136.6
128.6
127.8
133.0
199.0
136.6
128.6
127.8
133.0
199.2
136.6
128.7
127.8
133.1
198.9
136.5
128.6
127.8
133.1
198.9
136.1
128.6
127.8
133.1
200.1
135.7
128.7
127.8
133.5
198.9
136.6
128.6
127.8
133.1
198.9
136.6
128.6
127.7
133.0
C5'
C6' and C10'
C7' and C9'
C8'
* The 5-CH group of (VIb) resonates at 11.8 ppm.
3
The alkylation of N2-(2-methylpropionyl)guanine
yielded a mixture of N9- (IVg) and N7-acylated (IVh)
guanine derivatives smoothly separated by column
chromatography on silica gel.
was also isolated from the reaction mixture [1, 14]; it
was purified by ion-exchange chromatography on a sul-
fated cation-exchanger Dowex 50 × 8 (H+ form). The
1,3-dioxolane group was quantitatively removed during
the purification process. The yield of homogeneous N3-
isomer (IVe) was 6%.
The structures of the resulting purine bases were
confirmed by elemental analyses, mass, UV, and NMR
spectra (see Tables 1, 2 and the Experimental section).
The N9-derivative (IVd), isolated in a rather low
yield (29%), was the product of the reaction of adenine
sodium salt with (III) by the method B. No product of
N3-alkylation was in this reaction (cf. [1]). However,
the yield of N9-isomer considerably increased (up to
56%) when adenine was alkylated by method A. A
The protective dioxolane group was quantitatively
removed from the nucleic base derivatives by reflux
small amount of very contaminated N3-isomer (IVe) with 50% acetic acid for 30 min (method C). This
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 31 No. 6 2005

552
KRITZYN, KOMISSAROV
method enabled the preparation of compounds (VIa)– pling constants, in Hz; tetramethylsilane was an inter-
(VIf). The target guanine derivatives (VIg) and (VIh) nal standard. TLC was carried out on precoated Kiesel-
were obtained by the preliminary deblocking the 2- gel 60 F254 plates (Merck, Germany) using chloroform–
amino group in (IVg) and (IVh) by a prolonged reflux
in a water–alcohol mixture in the presence of triethyl-
amine (method D).
The solvents were evaporated in a vacuum, and the
mixture of intermediates was hydrolyzed under acidic
conditions described above for the removal of the 1,3-
dioxolane fragment. Derivatives (VIg) and (VIh) were
obtained in good yields.
The UV spectra of the compounds synthesized
exhibit the absorption band at 245 nm (ε 13000 M–1
cm–1) resulting from the electron transfer from carbonyl
group to phenyl radical, which, for most compounds, is
overlapped with the absorption band of the nucleic base
chromophore. This makes the UV spectra low informa-
tive.
ethanol elution systems at the following ratios: (A) 1 :
0, (B) 19 : 1, (C) 18 : 2, (D) 17 : 3, and (E) 17.5 : 2.5.
For column chromatography, silica gel L 40/100 (Che-
mapol, Czech Republic) was used.
4-Chloro-1-phenylbutan-1-one (I). Anhydrous
aluminum chloride (28 g, 0.21 mmol) was portionwise
added for 25 min to a stirred solution of 4-chlorobu-
tanoyl chloride [12] (28.2 g, 0.2 mmol) in dry benzene
(40 ml) cooled to 0°ë. The resulting solution was
stirred for 1 h at 0°ë and for 1 h at 20°ë and then poured
on ice (200 g). The organic layer was separated; the
aqueous layer was extracted with benzene (2 × 30 ml);
and the combined extracts were dried with anhydrous
sodium sulfate and evaporated. The residue was dis-
tilled in a vacuum to give 31.3 g (85.9%) of (I); bp 145–
.
147°ë/8 mmHg; MS, m/z: 182.6 [M]+ , calc. for
The structures of the compounds synthesized were
convincingly confirmed by 1H and 13C NMR spectros-
copy (Tables 1, 2). Three groups of signals are present
in the NMR spectra: the resonances from the corre-
sponding atoms of nucleic base, those of atoms of poly-
methylene chain, and the signals of terminal functional
group. The structures of isomeric pairs (VId) and (VIe)
and (VIg) and (VIh) were assigned on the basis of the
presence of characteristic “alkylation effects” in the 13C
NMR spectra [1, 14]. An upfield shift of the C2 reso-
nance (~8.9 ppm) and a downfield shift of C8
(~11.6 ppm) are observed for the N9-isomer (VIe) in
1
C10H11ClO: 182.6; H NMR (CDCl3): 2.08 (2 H, m,
CH2CH2Cl), 3.01 (2 H, t, J 7.0, COCH2), 3.54 (2 H, t, J
6.2, CH2Cl), 7.33 (2 H, m, m-H of Ph), 7.43 (1 H, t, J
7.5, p-H of Ph), and 7.84 (2 H, d, J 8.1, Ó-H of Ph); 13C
NMR (CDCl3): 26.78 (CH2CH2Cl), 35.21 (COCH2),
44.61 (CH2Cl), 127.89 (2 C), 128.54 (2 C), 133.04, and
136.69 (ë6H5), and 198.69 (CO).
2-(3-Chloropropyl)-2-phenyl-1,3-dioxolane (III).
4-Chloro-1-phenylbutan-1-one (30 g, 0.164 mol) (I),
ethylene glycol (21 ml, 0.378 mol), p-toluenesulfonic
acid monohydrate (3 g, 0.015 mol), and triethyl ortho-
comparison with the N3-isomer (VId). Unlike the N9- formate (68.4 ml, 0.411 mol) were added to dry toluene
isomer (VIg), the C5 resonance in the N7-isomer (VIh)
is shifted upfield (~8.6 ppm) and the C8 resonance,
downfield (~5.7 ppm) (Table 2).
(250 ml). The solution was refluxed with a Dean–Stark
trap for 8 h, and evaporated in a vacuum of a water jet
pump. Cold dichloromethane (50 ml) was added to the
residue, the precipitated p-toluenesulfonic acid was fil-
tered off, dichloromethane was evaporated, and the res-
idue was distilled in a vacuum to give 31.3 g (84%) of
the product; bp 126–127°C/1 mm Hg; MS, m/z: 226.7
[M]+, calc. for C12H15ClO2: 226.7; 1H NMR (DMSO-d6):
1.74 (2 H, m, CH2CH2Cl), 1.96 (2 H, t, J 7.5,
CH2CH2CH2Cl), 3.59 (2 H, t, J 6.9, CH2Cl), 3.68 and
3.97 (2 H × 2, 2 m, OCH2CH2O), 7.28–7.42 (5 H, m,
EXPERIMENTAL
Guanine, adenine, uracil, thymine, cytosine, and
hypoxantine were from Sigma (United States); 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), from Aldrich
(United States); sodium hydride (80% suspension in
mineral oil) and aluminum chloride, from Fluka (Swit-
zerland); p-toluenesulfonic acid, from Pierce (United
States); triethyl orthoformate and ethylene glycol, from
Acros Organics (Belgium), and Dowex 50 × 8, from
Serva (Germany).
Ph); 13C NMR (DMSO-d6): 26.86 (CH2CH2Cl), 37.14
(CH2CH2CH2Cl), 45.21 (CH2Cl), 64.19 (2C,
OCH2CH2O), 109.29 (OCO), 125.29 (2 C), 127.78 and
128.10 (2 C), and 142.24 (Ph).
Solvents were purified and dried by standard proce-
dures [12]. UV-spectra were registered on a Cary 50
spectrophotometer (Varian, Australia) at pH 1, 7 and
14; λmax are given in nm and ε, in M–1 cm–1. Mass spec-
tra were registered on a MS-30 mass spectrometer
(Kratos, Japan) at electron impact ionization. NMR
spectra were registered on a Bruker AMXIII-400 (Ger-
many) with a working frequency of 400.13 MHz for 1H
and 100.6 MHz for 13C NMR nuclei. The spectra were
obtained at 300 K in DMSO-d6 or CDCl3 (Acros Organ-
Alkylation of nucleic bases with 2-(3-chloropro-
pyl)-2-phenyl-1,3-dioxolane (III) using DBU as a
base (method A). Alkylating agent (III) (3.4 g,
15 mmol) and DBU (2.3 g, 15 mmol) were added to a
suspension of nucleic base or its protected derivative
(10 mmol) in dry DMF (25 ml), and the mixture was
heated at 80–100°ë for 20 h (TLC monitoring). The
reaction mixture was cooled and evaporated in a vac-
uum to dryness. The residue was suspended in minimal
volume of chloroform and chromatographed on a silica
ics, Belgium). Chemical shifts are given in ppm; cou- gel column (5 × 28 cm, 200 g), eluted with a gradient of
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POLYMETHYLENE DERIVATIVES OF NUCLEIC BASES…V.
553
ethanol in chloroform (0 to 20%). The target fractions 3.66 and 3.96 (2 H × 2, 2 m, OCH2CH2O), 7.29–7.38 (5
H, m, Ph), 7.46 (1 H, s, H6), and 11.10 (1 H, s, H1); 13C
NMR (DMSO-d6): 11.80 (5-CH3), 23.09 (C2'), 36.73
(C3'), 47.20 (C1'), 64.20 (2 C, OCH2CH2O), 108.42
(C5), 109.29 (C4'), [125.30 (2 C), 127.80, 128.10 (2 C),
and 142.30] (Ph), 141.39 (C6), 150.80 (C2), and 164.23
(C4).
were evaporated, and the residue was recrystallized
from ethanol or an ethyl acetate–octane mixture.
Alkylation of adenine and cytosine sodium salts
with
2-(3-chloropropyl)-2-phenyl-1,3-dioxolane
(III) (method B). Sodium hydride (80% suspension in
mineral oil, 0.33 g, 11 mmol) was added to a stirred
suspension of nucleic base (10 mmol) in dry DMF
(25 ml), the mixture was stirred for 30 min at 20°ë, and
(III) (2.7 g, 12 mmol) was added. The reaction mixture
was heated at 80–100°ë for 20 h (TLC monitoring).
DMF was removed in a vacuum, and the residue was
shaken with water (20 ml) and chloroform (50 ml). The
organic layer was separated, and the water layer was
extracted with chloroform (5 × 30 ml). The combined
extracts were dried with anhydrous sodium sulfate,
evaporated, and the residue was chromatographed on a
silica gel column as described in method Ä. The target
fractions were evaporated and the residue was recrys-
tallized from alcohol or an ethyl acetate–octane mix-
ture.
1,3-Bis[3-(2-Phenyl-1,3-dioxolan-2-yl)propyl]thy-
mine (Vb) was obtained by method A in 22% yield; Rf
0.87 (A); oil; UV: 273 (7600) at pH 1, 273 (7600) at pH
7, and 273 (7600) at pH 14; MS, m/z: 506.6 [M]+, 507.6
1
[M + H]+; calc. for C29H34N2O6: 506.6; H NMR
(DMSO-d6): 1.52 and 1.61 (2 H × 2, 2 m, H2' and H2''),
1.77 (3 H, s, 5-CH3), 1.83 (4 H, m, H3' and H3''), 3.66
(2 H, t, J 6.88, Hl'), 3.66 and 3.95 (4 H × 2, 2 m,
OCH2CH2O), 3.77 (2 H, t, J 6.88, Hl''), 7.37 (10 H, m,
Ph), and 7.50 (1 H, s, H6); 13C NMR (DMSO-d6): 12.49
(5-CH3), 21.70 (C2'), 22.96 (C2''), 36.68 (C3'), 37.37
(C3''), 40.40 (C1'), 48.36 (C1''), 64.18 (4 C,
OCH2CH2O), 107.6 (C5), 109.29 (C4'), 109.35 (C4''),
[125.29 (4 C), 127.70, 127.78, 128.03 (2 C), 128.07 (2
C), 142.29, 142.40] (Ph), 139.92 (C6), 150.69 (C2),
and 162.99 (C4).
1-[3-(2-Phenyl-1,3-dioxolan-2-yl)propyl]uracil
(IVa) was obtained by method Ä; yield 41%; Rf 0.78
(B); mp 186–187°ë (EtOAc–octane); MS, m/z: 302.3
[M]+, 303.3 [M + H]+, calc. for C16H18N2O4: 302.3; 1H
NMR (DMSO-d6): 1.59 (2 H, m, H2'), 1.82 (2 H, t, J
7.5, H3'), 3.61 (2 H, t, J 7.16, Hl'), 3.68 and 3.97 (2 H
× 2, 2 m, OCH2CH2O), 5.50 (1 H, d, J 7.8, H5), 7.29–
7.39 (5 H, m, Ph), 7.58 (1 H, d, J 7.8, H6), and 11.14 (1
H, s, H1); 13C NMR (DMSO-d6): 22.87 (C2'), 36.52
(C3'), 47.34 (C1'), 64.10 (2 C, OCH2CH2O), 106.65
(C5), 109.18 (C4'), [125.13 (2 C), 127.62, 127.91 (2 C),
142.19] (Ph), 145.41 (C6), 150.71 (C2), and 163.45
(C4).
1-[3-(2-Phenyl-1,3-dioxolan-2-yl)propyl]cytosine
(IVc) was obtained by method B in 31% yield; Rf 0.19
(C); mp 230–231°C (ethanol); MS, m/z: 301.3 [M]+,
302.3 [M + H]+; calc. for C16H19N3O3: 301.3; 1H NMR
(DMSO-d6): 1.57 (2 H, m, H2'), 1.80 (2 H, t, J 7.5, H3'),
3.60 (2 H, t, J 7.16, Hl'), 3.67 and 3.97 (2 H × 2, 2 m,
OCH2CH2O), 5.61 (1 H, d, J 7.16, H5), 6.83 (2 H, br. s,
4-NH2), 7.27–7.38 (5 H, m, Ph), 7.48 (1 H, d, J 7.16,
H6). 13C NMR (DMSO-d6): 23.34 (C2'), 36.92 (C3'),
48.54 (C1'), 64.21 (2 C, OCH2CH2O); 93.05 (C5),
109.41 (C4'), [125.30 (2 C), 127.73, 128.06 (2 C), and
142.42] (Ph), 145.91 (C6), 155.72 (C2), and 165.82
(C4).
9-[3-(2-Phenyl-1,3-dioxolan-2-yl)propyl]adenine
(IVd) was obtained by method A in 56% yield; Rf 0.65
(E); mp 151–152°C (EtOAc–octane); MS, m/z: 325.4
[M]+, 326.4 [M + H]+; calc. for C17H19N5O2: 325.4; 1H
NMR (DMSO-d6): 1.82 (4 H, m, H2' and H3'), 3.64 and
3.93 (2 H × 2, 2 m, OCH2CH2O), 4.13 (2 H, t, J 7.16,
1,3-Bis[3-(2-phenyl-1,3-dioxolan-2-yl)propyl]ura-
cil (Va) was obtained by method A in 13% yield; Rf 0.9
(B); oil; UV: 266 (8300) at pH 1, 266 (8300) at pH 7,
and 266 (8300) at pH 14; MS, m/z: 492.6 [M]+, 493.6
1
[M + H]+; calc. for C28H32N2O6: 492.6; H NMR
(CDCl3): 1.73 (4 H, m, H2' and H2''), 1.92 (4 H, m, H3'
and H3''), 3.71 (2 H, t, J 7.48, Hl'), 3.75 and 3.99 (4 H
× 2, 2 m, OCH2CH2O), 3.92 (2 H, t, J 7.48, Hl''), 5.63
(1 H, d, J 7.8, H5), 7.04 (1 H, d, J 7.8, H6), and 7.23–
7.44 (10 H, m, Ph); 13C NMR (CDCl3): 22.00 (C2'), Hl'), 7.19 (2 H, br. s, 6-NH2), 7.25–7.33 (5 H, m, Ph),
8.08 (1 H, s, H2), and 8.28 (1 H, s, H8); 13C NMR
(DMSO-d6): 24.14 (C2'), 36.87 (C3'), 42.78 (C1'),
64.12 (2 C, OCH2CH2O), 109.29 (C4'), 118.74 (C5),
125.21 (2 C), 127.70, 127.99 (2 C), and 142.17 (Ph),
140.73 (C8), 149.45 (C4), 152.31 (C2), and 155.89
(C6).
23.32 (C2''), 36.95 (C3'), 37.86 (C3''), 41.26 (C1'),
49.57 (C1''), 64.62 (2 C) and 64.67 (2 C) (OCH2CH2O),
101.52 (C5), 110.01 (C4'), 110.2 (C4''), [125.69 (2 C),
125.78 (2 C), 127.82 (2 C), 128.13 (2 C), 128.35 (2 C),
and 142.23 (2 C)] (Ph), 142.79 (C6), 151.38 (C2), and
163.13 (C4).
1-[3-(2-Phenyl-1,3-dioxolan-2-yl)propyl]thymine
By method B, the yield was 29%. Physicochemical
(IVb) was obtained by method A in 54% yield; Rf 0.47
characteristics were identical to those reported for the
(A); mp 167–168°ë (EtOAc–octane); MS, m/z: 316.3 substance obtained by method A.
[M]+, 317.3 [M + H]+; calc. for C16H18N2O4: 316.3; 1H
9-[3-(Phenyl-1,3-dioxolan-2-yl)propyl]hypoxan-
tine (IVf) was obtained by method A in 29% yield; Rf
0.27 (B); mp 212–213°C (EtOAc–octane); MS, m/z:
NMR (DMSO-d6): 1.57 (2 H, m, H2'), 1.73 (3 H, s, 5-
CH3), 1.81 (2 H, t, J 7.5, H3'), 3.58 (2 H, t, J 7.16, Hl'),
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 31 No. 6 2005

554
KRITZYN, KOMISSAROV
326.3 [M]+, 327.3 [M + H]+; calc. for C17H18N4O3: 258.3 [M]+, 269.3 [M + H]+; calc. for C14H14N2O3:
1
258.3.
326.3; H NMR (DMSO-d6): 1.74–1.85 (4 H, m, H2'
and H3'), 3.64 and 3.94 (2 H × 2, 2 m, OCH2CH2O),
4.30 (2 H, t, J 6.84, Hl'), 7.25–7.35 (5 H, m, Ph), 7.95
(1 H, s, H2), 8.18 (1 H, s, H8), and 12.26 (1 H, s, H1);
13C NMR (DMSO-d6): 24.33 (C2'), 36.78 (C3'), 46.24
(C1'), 64.18 (2 C, OCH2CH2O), 109.21 (C4'), 114.77
(C5), [125.24 (2 C), 127.78, 128.07 (2 C), 142.22] (Ph),
140.22 (C8),145.40 (C2), 148.29 (C4), and 154.24
(C6).
1-(4-Oxo-4-phenylbutyl)thymine (VIb) was
obtained by method C in 97% yield; Rf 0.47 (A); mp
182–183°ë (ethanol); UV: 249 (12 500), 272 (8700)
(shoulder) at pH 1, 249 (12 500), 272 (8700) at pH 7,
and 249 (12 200), 272 (7200) (shoulder) at pH 14; MS,
m/z: 272.3 [M]+, 273.3 [M + H]+; calc. for C15H16N2O3:
272.3.
1-(4-Oxo-4-phenylbutyl)cytosine
(VIc)
was
N2-(2-Methylpropionyl)-9-[3-(2-phenyl-1,3-diox-
olan-2-yl)propyl]guanine (IVg) was obtained by
method A in 15% yield; Rf 0.52 (B); mp 171–172°C
obtained by method C in 99% yield; Rf 0.19 (C); mp
232°ë (dec., ethanol); UV: 247 (11 200), 283 (11300)
at pH 1, 245 (13700), 274 (8000)(shoulder) at pH 7, and
245 (13700), 274 (8000) (shoulder) at pH 14; MS, m/z:
257.3 [M]+, 258.3 [M] + H]+, calc. for C14H15N3O2:
257.3.
(EtOAc–octane); MS, m/z: 411.5 [M]+, 412.5 [M + H]+;
1
calc. for C21H25N5O4: 411.5; H NMR (DMSO-d6):
1.10 (6 H, d, J 6.84, COCH(CH3)2), 1.79 (4 H, m, H2'
and H3'), 2.78 (1 H, m, COCH(CH3)2), 3.64 and 3.94 (2
H × 2, 2 m, OCH2CH2O), 4.03 (2 H, t, J 6.38, Hl'),
7.26–7.33 (5 H, m, Ph), 7.93 (1 H, s, H8), and 11.94 (2
H, br. s, H1 and 2-NH); 13C NMR (DMSO-d6): 18.84 (2
C, COCH(CH3)2), 24.23 (C2'), 34.66 (COCH(CH3)2),
36.79 (C3'), 43.04 (C1'), 64.20 (2 C, OCH2CH2O),
109.17 (C4'), 120.10 (C5), [125.26 (2 C), 127.81,
128.10 (2 C), 142.15] (Ph), 139.75 (C8), 147.79 (C4),
148.52 (C2), 154.88 (C6), and 180.13 (COCH(CH3)2).
9-(4-Oxo-4-phenylbutyl)adenine
(VId)
was
obtained by method C in 96% yield; Rf 0.65 (E); mp
220–221°ë (ethanol); UV, 253 (18600) at pH 1, 253
(18600) at pH 7; and 253 (18600) at pH 14; MS, m/z:
281.3 [M]+, 282.3 [M + H]+, calc. for C15H15N5O:
281.3.
3-(4-Oxo-4-phenylbutyl)adenine
(VIe)
was
obtained during purification of (IVe) on a Dowex 50 ×
8 (H+) column. The fraction containing (IVe) obtained
by method A was dissolved in ethanol (30 ml) and
loaded on a Dowex column. The column was succes-
sively washed with ethanol, water, and 5% ammonia.
The target (VIe) was eluted with EtOH, the solvent was
evaporated in a vacuum, and the residue was crystal-
lized from a 5 : 1 EtOAc–octane mixture to give 6% of
(VIe); Rf 0.45 (E); mp 210°C (dec); UV, plateau 249
(13300)–278 (14300) at pH 1, plateau 249 (12100)–
275 (11700) at pH 7, and plateau 249 (11700)–275
N2-(2-Methylpropionyl)-7-[3-(2-phenyl-1,3-diox-
olan-2-yl)propyl]guanine (IVh) was obtained by
method A in 10% yield; Rf 0.46 (B); mp 215–216°ë
(EtOAc–octane); MS, m/z: 411.5 [M]+, 412.5 [M + H]+;
1
calc. for C21H25N5O4: 411.5; H NMR (DMSO-d6):
1.11 (6 H, d, J 6.84, COCH(CH3)2), 1.73–1.83 (4 H, m,
H2' and H3'), 2.74 (1 H, m, COCH(CH3)2), 3.64 and
3.94 (2 H × 2, 2 m, OCH2CH2O), 4.25 (2 H, t, J 6.84,
Hl'), 7.25–7.33 (5 H, m, Ph), 8.11 (1 H, s, H8), and (10900) at pH 14; MS, m/z: 281.3 [M]+, 282.3 [M +
11.75 (2 H, br. s, H1 and 2-NH); 13C NMR (DMSO-d6): H]+, calc. for C15H15N5O: 281.3.
18.85 (2 C, COCH(CH3)2); 25.17 (C2'), 34.69 (C3'),
36.47 (COCH(CH3)2), 46.16 (C1'), 64.19 (2 C,
OCH2CH2O), 109.22 (C4'), 111.17 (C5), [125.25 (2 C),
127.76, 128.07 (2 C), 142.24] (Ph), 144.24 (C8),
147.00 (C4), 152.46 (C2), 157.26 (C6), and 179.91
(COCH(CH3)2).
9-(4-Oxo-4-phenylbutyl)hypoxantine (VIf) was
obtained by method C in 98% yield; Rf 0.17 (B); mp
225°C (ethanol); UV, 248 (14 000) at pH 1, 248
(16600) at pH 7, and 248 (13 000) at pH 14; MS, m/z:
282.3 [M]+, 283.3 [M + H]+, calc. for C15H14N4O2:
282.3.
The removal of the 1,3-dioxolane protective
group and the synthesis of derivatives (VIa)–(VIh)
(method C). Glacial acetic acid (15 ml) and water
(15 ml) were added to derivatives (IVa)–(IVf)
(3 mmol), and the reaction mixture was refluxed for
30 min. The solvents were removed in a vacuum, the
residue was stirred with a saturated sodium bicarbonate
solution (30 ml), and the resulting precipitate was fil-
tered and washed with water (~10 ml) and cold ethanol
(5 ml).
The removal of isobutyroyl group in the guanine
derivatives (method D). Triethylamine (0.23 ml,
1.6 mmol) was added to a solution of protected guanine
derivatives (IVg) or (IVh) (0.33 g, 0.8 mmol) in ethanol
(9 ml) and water (1.5 ml). The resulting solution was
refluxed (TLC monitoring), and the solvents were
removed in a vacuum. The crude products were used
without further purification.
9-(4-Oxo-4-phenylbutyl)guanine
obtained in 73% yield from (IVg) successively using
was methods D and C; Rf 0.25 (D); mp 255–256°C (etha-
obtained by method C in 98% yield; Rf 0.78 (B); mp
(VIg)
was
1-(4-Oxo-4-phenylbutyl)uracil
(VIa)
nol); UV: 250 (18 900) and 279 (7500) (shoulder) at pH
165–166°ë (ethanol); UV: 251 (14 000) at pH 1, 249 1, 249 (19 500) and 272 (8800) (shoulder) at pH 7, 248
(13100) at pH 7, and 249 (12 800) at pH 14; MS, m/z: (19 500) and 271 (10 500) (shoulder) at pH 14; MS,
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 31 No. 6 2005

POLYMETHYLENE DERIVATIVES OF NUCLEIC BASES…V.
555
m/z: 297.3 [M]+, 298.3 [M + H]+, calc. for C15H15N5O2:
297.3.
4. De Clercq, E., Rev. Med. Virol., 1995, vol. 5, pp. 149–
157.
5. Perry, C.M. and Faulds, D., Drugs, 1996, vol. 52,
7-(4-Oxo-4-phenylbutyl)guanine (VIh) was
obtained in 46% yield from (IVh) successively using
methods D and C followed by chromatography on a sil-
ica gel column; Rf 0.36 (D); UV: 248 (24 400) and 279
(8200) (shoulder) at pH 1, 245 (15 800) and 285 (7200)
at pH 7, and 243 (16 900) and 283 (7100) at pH 14; MS,
m/z: 297.3 [M]+, 298.3 [M + H]+, calc. for C15H15N5O:
297.3.
pp. 754–772.
6. Kritsyn, A.M. and Florent’ev, V.L., Bioorg. Khim., 1977,
vol. 3, pp. 149–171.
7. Phadtare, S. and Zemlicka, J., J. Am. Chem. Soc., 1989,
vol. 111, pp. 5925–5931.
8. Ashton, W.T., Meurer, L.C., Tolman, R.L., Karkas, J.D.,
Liou, R., Perry, H.C., Czelusniak, S.M., and Klein, R.J.,
Nucleosides Nucleotides, 1989, vol. 8, pp. 1157–1158.
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osides Nucleotides, 1987, vol. 6, pp. 775–783.
10. Birnbaum, K.B., Stolarski, R., and Shugar, D., Nucleo-
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ACKNOWLEDGMENTS
We are grateful to A.R. Khomutov for the fruitful
discussion of results.
The work was supported by the Russian Foundation
for Basic Research, project no. 03-04-49224.
11. Mashkovskii, M.D., Lekarstvennye sredstva (Medi-
cines), Moscow: Novaya Volna, 2000, vol. 1, pp. 75–80.
12. Tietze, L.F. and Eicher, T., Reaktionen und Synthesen im
organische-chemischen Praktikum und Forschungslab-
oratorium, New York: Georg Thieme Verlag Stutgart,
1991. Translated under the title Preparativnaya organ-
icheskaya khimiya, Moscow: Mir, 1999.
13. Makinskii, A.A., Kritsyn, A.M., Ul’yanova, E.A.,
Zakharova, O.D., and Nevinskii, G.A., Bioorg. Khim.,
2000, vol. 26, pp. 735–742.
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