New "sp 2 -bonded" carbanucleosides

Article abstract of DOI:10.1134/S1070428009020171

By reaction of 2,3-dichloro-, 2,3,5-trichloro-, 2,5-dichloro-3- phenylsulfonyl-, 2-chloro-3-phenylsulfonyl-4,4-ethylenedioxycyclopent-2-en-1- ones with uracyl 3- and 2-uracyl derivatives were obtained of the corresponding chlorocyclopentenone.

Full text of DOI:10.1134/S1070428009020171

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 2, pp. 256−258. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © N.A. Ivanova, A.G. Mustafin, F.G. Usmanova, S.P. Ivanov, M.S. Miftakhov, 2009, published in Zhurnal Organicheskoi
Khimii, 2009, Vol. 45, No. 2, pp. 267−269.
New “sp2-Bonded” Carbanucleosides
N. A. Ivanova, A. G. Mustafin, F. G. Usmanova, S. P. Ivanov, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054 Russia
e-mail: bioreg@anrb.ru
Received March 17, 2008
Abstract—By reaction of 2,3-dichloro-, 2,3,5-trichloro-, 2,5-dichloro-3-phenylsulfonyl-, 2-chloro-3-phenylsulfonyl-
4,4-ethylenedioxycyclopent-2-en-1-ones with uracyl 3- and 2-uracyl derivatives were obtained of the corresponding
chlorocyclopentenone.
DOI: 10.1134/S1070428009020171
The steady growth and the pandemic character of
HIV/AIDS-disease, the fast adaptability of the pathogens
to the applied drugs stimulate the search for new
pharmaceuticals for the treatment of these and probable
concurrent infections. Nowadays the most important in
the treatment of viral infections remain the drugs based
on nucleosides that regretfully are not free of dis-
advantages. The main among the latter are metabolic
instability and cytotoxicity. In this respect carbanucleo-
sides are preferable where an oxygen in the furanose
part of the molecule is replaced by a methylene fragment.
This modification supplied them, in contrast to the parent
nucleosides, with a higher metabolic stability with respect
to phosphorylases and hydrolases which quickly cleave
the glycoside bond in the nucleosides. Among them can
be cited the permitted anti-HIV drugs: Carbovir [1],
Abacavir [2], Entecavir [3] [for the treatment of HSV-
infections (virus of a simple herpes)] (see scheme).
We first studied the uracyl reaction with the basic
trichlorocyclopentenone I. Inasmuch as the uracyl was
a weak nucleophile, we used as a base sodium hydride to
attain more complete proceeding of the reaction. The
experiment showed that the AdNE reaction proceeded
quickly and with a complete conversion of the initial
chlorocyclopentenone. However we met some difficulties
in further workup of the reaction mixture and in isolation
of the products. Because of the poor solubility of the
uracyl in the most organic solvents we added DMSO as
a cosolvent to create a homogeneous medium. This fact
complicated the isolation and purification of target product
V. It turned out that the chromatographic mobility (Rf) of
DMSO, uracyl, and the reaction product were nearly
identical, and therefore the purification of the reaction
product by column chromatography on silica gel was very
difficult. Besides the reaction product possessed low
solubility comparable with uracyl, therefore at the
chromatographic separation the reaction mixture was
applied to the column as a dispersion, and this also nega-
tively affected the separation quality.
The cyclopentenone blocks I–IV we have formerly
synthesized [4, 5] seem suitable objects for the AdNΕ
reaction with nucleic bases and a way to new types of
polyheterofunctionalized carbanucleosides.
Scheme.
O
N
OH
N
HN
N
N
N
N
N
N
NH
NH2
N
N
N
NH2
NH2
HO
HO
HO
HO
Abacavir
Carbovir
256
Entecavir

NEW “sp2-BONDED” CARBANUCLEOSIDES
257
The structure and composition of compounds obtained
Another mode of reaction turned out the be more
convenient, namely, the boiling of the initial substrate with
1.5 equiv of uracyl in aqueous alkali for 5 h. The crystalline
substance that precipitated in the course of the reaction
was isolated by recrystallization from aqueous methanol.
As a result of this reaction modification target compound
V was obtained in 67% yield. Dichlorocyclopentenone
II proved to be less active: the comparable yield of
compound VI was attained in 18 h.
1
were established from IR, H and 13C NMR spectra,
and also from the elemental analysis. The singlet signals
of amide group protons in the 1H NMR spectra of adducts
obtained V–VIII appearing in a very weak field (8–11
ppm) indicate the N1-substitution in the uracyl ring.
Thus as a result of the reactions of chlorocyclopente-
nones III and IV with uracyl we obtained the correspond-
ing 3- and 2-uracyl cyclopentenone derivatives. The most
active were in this reaction 2,5-dichloro-3-phenylsulfonyl-
and 2,3,5-trichloro-4,4-ethylenedioxycyclopent-2-en-1-
ones (III) and (I), evidently because of the activating
effect of the Cl atom at C5'.
O
O
Cl
X
Cl
X
O
5'
à or b
O
O
HN
The developed method of the reaction of chlorocyclo-
pentenones with uracyl is an efficient way of building up
structures of new vinyl (sp2-bonded) carbanucleosides,
and the combining in their structure of pharmacophore
fragments, uracyl and chlorocyclopentenone, gives a hope
to find in them an interesting biological activity.
N
6
Cl
O
O
5
O
V, VI
I, II
a: 1.5 equiv of uracyl, NaH, DMSO–THF, 20°C; b: 1.5 equiv
of uracyl, NaOH, THF–H2O, 80°C; X = Cl (I, V), H (II, VI).
In attampt to optimize the synthesis and design of the
product we studied the uracyl reaction with phenyl-
sulfonyl-substituted chlorocyclopentenones III and IV.
It was expected that highly active cyclopentenone blocks
III and IV containing Cl and PhSO2 would easier react
with the weak N-nucleophiles like uracyl and its deriv-
atives. The presence in the cyclopentenones of two
reaction sites suggested that the reaction might proceed
along two directions (AdNE-replacement of a vinyl Cl
atom or SO2Ph group and SN2-substitution of sp3-Cl
adjacent to the carbonyl) and might yield respectively
three types of products. We isolated from the reaction
only the products of replacement of the vinyl Cl atom
and the SO2Ph group in the ratio 3:1. Interestingly, in
contrast to the above described reactions of these com-
pounds with C-nucleophiles, in this case we observed
a prevailing formation of the products of substitution of
vinyl Cl atom: vinylsulfones VII and VIII.
EXPERIMENTAL
IR spectra were recorded on spectrophotometers UR-
20 and Specord M-80 (from films or mulls in mineral oil).
1H and 13C NMR spectra were recorded on a spec-
trometer BrukerAM-300 (at operating frequencies 300.13
and 75.47 MHz respectively); internal reference TMS,
solvent DMSO-d6. The reaction progress was monitored
and the purity of compounds obtained was checked by
TLC and HPLC. TLC was performed on Sorbfil PTSKh-
AF-A plates, spots visualized by alkaline solution of
KMnO4 [6]. The chromatographic analysis was carried
out on a system Staier (Akvilon, Russia) with the use of
a column 250×4.6 mm with a stationary phase Luna C
18 (Phenomenex, USA) with particle size 5 μm. Eluent
water–acetonitrile, gradient elution, flow rate 1 ml/min.
Detection was performed at λ 215 nm.
Reactions of chlorocyclopentenones I–IV with
uracyl. a. To a suspension of 0.62 mmol of NaH in 2 ml
of THF was added 1 ml of DMSO and 0.62 mmol of
uracyl, and the mixture was stirred for 30 min at room
temperature, then to the reaction mixture was added
dropwise a solution of 0.41 mmol of an appropriate
chlorocyclopentenone in 5 ml of THF. The reaction
mixture was stirred for 30 min, excess NaH was quench-
ed with water at cooling (0–5°C), 10 ml of chloroform
was added and 10% HCl to pH 7, the mixture was stirred
for 20 min, reaction products were extracted into CHCl3.
The organic extracts were washed with a saturated NaCl
O
O
O
X
Cl
X
HN
O
N
à or b
V, VI +
O
O
PhO2S
PhO2S
O
O
III, IV
VII, VIII
a: 1.5 equiv of uracyl, NaH, DMSO–THF, 20°C; b: 1.5 equiv
of uracyl, NaOH, THF–H2O, 80°C; X = Cl (III, VII), H (IV,
VIII).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009

IVANOVA et al.
258
solution, dried with MgSO4, and concentrated in
a vacuum. The reaction products were isolated by column
chromato-graphy on SiO2.
chromatography on SiO2 of the reaction mixture (eluent
chloroform–methanol, 9:1). Yield 65% (b). Colorless
crystals, mp 280–282°C, Rf 0.34 (chloroform–methanol,
7:3). IR spectrum, ν, cm–1: 3527 (C–N), 3117 (C–N),
1747 (C=O), 1735 (C=O), 1715 (C=O), 1697(Carom), 1650
b. To a solution of 1.23 mmol of NaOH in 4 ml of
water was added 1.23 mmol of uracyl, the mixture was
stirred for 40 min at room temperature, and then thereto
was slowly added dropwise a solution of 0.82 mmol of
chlorocyclopentenone in 4 ml of THF. The reaction
mixture was boiled at stirring till complete consumption
of the initial compound (5–6 h). On completion of the reac-
tion into the reaction mixture 10% water solution of HCl
was added till pH 7, the mixture was stirred for 30 min
and evaporated in a vacuum to dryness. The reaction
products either were isolated by column chromatography
on SiO2 or the precipitated reaction product was filtered
off and recrystallized from a mixture MeOH–H2O, 20:1.
1
(Carom), 1624 (C=C), 1385 (SO2), 1160 (SO2). H NMR
spectrum, δ, ppm: 3.95–4.33 m (4H, 2CH2O), 4.24 s (2H,
H5'), 5.78 d (1H, H5, J 7.9 Hz), 7.25 d (1H, H6, J 7.9
Hz), 7.58–7.70 m (5H, Harom), 7.85 br.s (1H, NH). 13C
NMR spectrum, δ, ppm: 63.71 (C5'), 65.54 and 65.79
(2CH2O), 105.75 (C5), 106.99 (C4'), 125.47 (CO), 127.64
(cm), 128.54 (Cï), 127.35 (C5), 129.00 (C6), 137.14 (Cθ),
141.40 (C2'), 147.94 (C3'), 162.41 (C4), 180.84 (C1').
Found, %: C 48.13; H 3.16; Cl 8.14; N 6.40; S 7.42.
C17H13ClN2O7S. Calculated, %: C 48.06; H 3.08; Cl 8.35;
N 6.59; S 7.55.
1-(3-Phenylsulfonyl-4,4-ethylenedioxycyclopent-
2-en-1-one-2-yl)-1,3-dihydropyrimidine-2,4-dione
(VIII) was obtained from sulfone IV, complete
conversion within 18 h, isolated by column chromato-
graphy on SiO2 of the reaction mixture (eluent chloro-
form–methanol, 9:1). Yield 44% (a), 63% (b), Colorless
crystals, mp 228–230°C, Rf 0.31 (chloroform–methanol,
7:3). IR spectrum, ν, cm–1: 3190 (NH), 3099 (C–N), 1759
(C=O), 1726 (C=O), 1703 (C=O), 1620 (Carom), 1360
(SO2), 1150 (SO2), 1043 (C–O–C). 1H NMR spectrum, δ,
ppm: 2.84 s (2H, H5'), 4.05–4.50 m (4H, 2CH2O), 5.82 d
(1H, H5, J 7.9 Hz), 7.23 d (1H, H6, J 7.9 Hz), 7.61–
7.93 m (5H, Harom), 9.25 br.s (1H, NH). 13C NMR
spectrum, δ, ppm: 46.44 (C52 ), 65.20 and 65.42 (2CH2O),
101.14 (C5), 106.46 (C42 ), 126.91 (CO), 128.21 (Cm),
133.67 (Cï), 137.84 (Cθ), 148.15 (C22), 142.10 (C32),
142.15 (C6), 147.36 (C2), 162.41 (C4), 187.20 (C12 ).
Found, %: C 52.41; H 3.77; N 7.35; S 8.03. C17H14N2O7S.
Calculated, %: C 52.30; H 3.61; N 7.18; S 8.21.
1-(2,5-Dichloro-4,4-ethylenedioxycyclopent-2-
en-1-one-3-yl)-1,3-dihydropyrimidine-2,4-dione (V)
was obtained from chloroenone I, complete conversion
within 8 h. Yield 30% (a), 67% (b). Colorless crystals,
mp 254°C (MeOH–H2O, 20:1), Rf 0.40 (chloroform–
methanol, 9:1, double elution). IR spectrum, ν, cm–1: 3530
(C–N), 3110, 3095, 3055 (C–N), 1747 (C=O), 1718
(C=O), 1640 (C=O), 1590 (C=C). 1H NMR spectrum, δ,
ppm: 3.94–4.22 m (4H, 2CH2O), 5.45 s (1H, H52 ), 5.76 d
(1H, H5, J 8.0 Hz), 7.52 s (1H, H6, J 8.0 Hz), 11.74 br.s
(1H, NH). 13C NMR spectrum, δ, ppm: 60.78 (C52), 64.90
and 65.22 (2CH2O), 101.65 (C5), 106.17 (C42), 132.47
(C22), 139.24 (C6), 149.50 (C32), 145.36 (C2), 185.55 (C12).
Found, %:C41.59;H2.39;Cl22.38;N8.89. C11H8Cl2N2O5.
Calculated, %: C 41.40; H 2.53; Cl 22.22; N 8.78.
1-(2-Chloro-4,4-ethylenedioxycyclopent-2-en-1-
one-3-yl)-1,3-dihydropyrimidine-2,4-dione (VI) was
obtained from chloroenone II, complete conversion within
18 h. Yield 62% (b). Colorless crystals, mp 240–242°C
(MeOH–H2O, 20:1), Rf 0.39 (chloroform–methanol, 5:1).
IR spectrum, ν, cm–1: 3527 (C–N), 3117 (C–N), 1747
(C=O), 1735 (C=O), 1715 (C=O), 1650 (C=C), 1624
(C=C). 1H NMR spectrum, δ, ppm: 3.01 s (2H, H52 ), 3.91–
4.15 m (4H, 2CH2O), 5.81 d.d (1H, H6, J1 8.0, J2 2.0 Hz),
7.63 s (1H, H5, J1 8.0 Hz), 11.78 br.s (1H, NH). 13C NMR
spectrum, δ, ppm: 46.25 (C52 ), 65.84 (2CH2O), 102.77
(C5), 108.37 (C42 ), 135.25 (C22 ), 141.85 (C6), 147.15
(C32 ), 153.18 (C2), 162.93 (C4), 192.74 (C12 ). Found, %:
C 46.58; H 3.35; Cl 12.68; N 9.99. C11H9ClN2O5.
Calculated, %: C 46.41; H 3.19; Cl 12.45; N 9.84.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009