Synthesis and antiviral evaluation of 2'-deoxy-2'-C-trifiuoromethyl beta-D-ribonucleoside analogues bearing the five naturally occurring nucleic acid bases.

Article abstract of DOI:10.1039/b303093h

2'-Deoxy-2'-C-trifluoromethyl-beta-D-ribonucleoside derivatives bearing the five naturally occurring acid bases have been synthesized. All these derivatives were prepared by glycosylation reactions of purine and pyrimidine bases with a suitable peracylated 2-deoxy-2-C-trifluoromethyl sugar precursor to afford anomeric mixtures of protected nucleosides. After separation and deprotection, the resulting beta-nucleoside analogues were tested for their activity against HIV, HBV and several RNA viruses. However, none of these compounds showed significant antiviral activity nor cytotoxicity.

Full text of DOI:10.1039/b303093h

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Synthesis and antiviral evaluation of 2Ј-deoxy-2Ј-C-trifluoromethyl
ꢀ-D-ribonucleoside analogues bearing the five naturally occurring
nucleic acid bases†
Frédéric Jeannot,a Gilles Gosselina,b and Christophe Mathé*a
a Laboratoire de Chimie Organique Biomoléculaire de Synthèse,
UMR 5625 CNRS-Université Montpellier II, case courrier 008, Place Eugène Bataillon,
34095 Montpellier Cedex 5, France. E-mail: cmathe@univ-montp2.fr;
Fax: ϩ(33) 4 67 04 20 29
b Laboratoire Coopératif Idenix-CNRS-Université Montpellier II, case courrier 008,
Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
Received 21st March 2003, Accepted 1st May 2003
First published as an Advance Article on the web 13th May 2003
2Ј-Deoxy-2Ј-C-trifluoromethyl-β--ribonucleoside derivatives bearing the five naturally occurring acid bases have
been synthesized. All these derivatives were prepared by glycosylation reactions of purine and pyrimidine bases
with a suitable peracylated 2-deoxy-2-C-trifluoromethyl sugar precursor to afford anomeric mixtures of protected
nucleosides. After separation and deprotection, the resulting β-nucleoside analogues were tested for their activity
against HIV, HBV and several RNA viruses. However, none of these compounds showed significant antiviral activity
nor cytotoxicity.
Introduction
Results and discussion
Nucleoside analogues represent one of the main class of thera-
peutic agents in antiviral chemotherapy, and to date, numerous
nucleoside derivatives have been approved for the treatment of
various viral diseases including Herpes viruses, Human
Immunodeficiency Virus (HIV) and Hepatitis B virus (HBV)
infections.1 The mechanism of action of those compounds is
based upon the intracellular phosphorylation to their 5Ј-tri-
phosphate form which can interact with virus-specific poly-
merases, acting as inhibitors or chain terminators of viral
nucleic acid synthesis. In order to discover new nucleoside
derivatives endowed with potential antiviral activity, modifi-
cations of the base and/or the sugar moiety of natural nucleo-
sides can be attempted. As a part of our ongoing research
program on trifluoromethyl nucleoside analogues,2 we have
The synthesis of the title nucleoside analogues involved the
preparation of an appropriate trifluoromethyl sugar precursor,
namely,
1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-
methyl--ribofuranose (6) (Scheme 1). Several method-
ologies have been described in the literature for introducing
trifluoromethyl groups into organic compounds.5 However,
the utilization of (trifluoromethyl)trimethylsilane (Me3SiCF3)
(Ruppert’s reagent) as a nucleophilic trifluoromethylating
reagent is rapidly becoming the method of choice.6,7 Such
methodology requires the previous preparation of a suitable
2-keto sugar intermediate, then reaction with Me3SiCF3. A
similar strategy has been already reported in the literature.8 For
our purpose, we chose as starting material methyl 3,5-di-O-
(4-chlorobenzyl)-α-ribofuranoside (1) which was obtained
from commercially available -ribose following a procedure
already described.9 Oxidation of the secondary alcohol of 1
was achieved using the Dess–Martin periodinane reagent10 in
anhydrous dichloromethane. The protected 2-keto sugar deriv-
ative was not isolated but converted via two steps into methyl
3,5-di-O-(4-chlorobenzyl)-2-C-trifluoromethyl-α--ribofurano-
side (2), in 67% overall yield from 1, following reaction with
Me3SiCF3 in the presence of tetrabutylammonium fluoride
(TBAF) as a catalyst in tetrahydrofuran (THF) then desilyl-
ation of the trimethylsilylated ether intermediate with TBAF in
synthesized
2Ј-deoxy-2Ј-C-trifluoromethyl-β--ribonucleo-
side derivatives bearing the five naturally occurring nucleic
acid bases (11, 12 and 17–19) (Chart 1), all of them being
hitherto unknown except for 18 which has been succinctly
reported.3,4
1
methanol. H, 19F and 13C NMR spectra showed that the tri-
fluoromethyl group added stereoselectively to the less hindered
β-face giving only the ribo epimer. Our results are in accordance
with those previously described in the literature.4,8 The deriv-
atisation of tertiary alcohols as their methyl oxalyl esters has
been shown to be a convenient method for deoxygenation reac-
tions.11 In contrast to the deoxygenation of alcohols using Bar-
ton–McCombie type methodology,12 the use of methyl oxalyl
esters provided good alternative for removal of hindered sec-
ondary alcohols or tertiary alcohols. However, all attempts to
prepare a methyl oxalyl ester [by varying the number of equiv-
alents of methyl oxalyl chloride, the concentration, the temper-
ature] from 2 failed. To overcome this problem, 4-chlorobenzyl
protecting groups were removed using catalytic hydrogenation.
Chart 1 2Ј-Deoxy-2Ј-C-trifluoromethyl-β--ribonucleoside
analogues.
† This work has been presented in preliminary form at the Fifteenth
International Round Table on Nucleosides, Nucleotides and Nucleic
Acids, Sept. 10–14, 2002, Leuven, Belgium.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 9 6 – 2 1 0 2
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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obtained in 88% yield after silica gel column chromatography.
Later, peracylated 2-deoxy-2-C-trifluoromethyl sugar 6 was
used for the condensation reactions with the heterocyclic bases
and provided in each case an anomeric mixture of protected
nucleosides (Schemes 2 and 3) due to the lack of 2-O-acyl type
participating group. After the condensation reactions, the mix-
tures of protected nucleosides were separated by silica gel col-
umn chromatography to afford the corresponding β-anomers.
The syntheses of the 2Ј-deoxy-2Ј-C-trifluoromethyl-β--
ribonucleoside purine derivatives 11 and 12 are depicted in
Scheme
1
Reagents and conditions: (a) ref. 9 (b) Dess–Martin
periodinane, CH2Cl2; (c) i) CF3SiMe3, TBAFc, THF; ii) TBAF,
THF, MeOH; (d) i) H2, Pd/C (5%), AcONa, MeOH; ii) BzCl, pyridine;
(e) i) MeCO2COCl, pyridine, CH2Cl2; ii) (Me3Si)3SiH, AIBN, toluene;
(f ) AcOH, Ac2O, H2SO4.
Scheme 2 Reagents and conditions: (a) adenine, SnCl4, CH3CN, rt;
(b) silylated 2-amino-6-chloropurine, TMSOTf, toluene, reflux;
(c) MeONa, MeOH, rt; (d) HS(CH2)2OH, MeONa, MeOH, reflux.
The resulting methyl 2-C-trifluoromethyl-α--ribofuranoside
was not isolated but treated, after work-up, with an excess of
benzoyl chloride in anhydrous pyridine to afford exclusively
methyl 3,5-di-O-benzoyl-2-C-trifluoromethyl-α-ribofuranoside
(3) in 80% yield after silica gel column chromatography. The
latter was treated with methyl oxalyl chloride and pyridine in
anhydrous dichloromethane to give the corresponding 2-O-
methyl oxalyl ester derivative, which was subsequently deoxy-
genated with tris(trimethylsilyl)silane hydride in the presence of
α,αЈ-azoisobutyronitrile (AIBN) to afford after purification on
silica gel column chromatography a mixture of methyl 3,5-di-O-
benzoyl-2-deoxy-2-C-trifluoromethyl-α--arabinofuranoside
(4) and methyl 3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-methyl-
α--ribofuranoside (5) [ratio 4 : 5 = 13 : 87 as determined by 1H
NMR]. Therefore, we were able to separate after tedious silica
gel column chromatography, compound 5 from the epimeric
mixture. Pure methyl 3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-
methyl-α--ribofuranoside (5) was obtained in 41% yield as
isolated product from 3 and fully characterized. Structural
1
assignments of compounds 4 and 5 were based upon their H
NMR spectra. In particular, the 1-H proton of 4 appeared as a
doublet with a coupling constant (J1,2 = 1.6 Hz) as expected for
a methyl 2-deoxy-2-C-trifluoromethyl-α--arabinofuranoside
structure while the 1-H proton of the ribo epimer 5 exhibited a
doublet with a larger coupling constant (J1,2 = 4.6 Hz). The
formation of the 2-deoxy-2-C-trifluoromethyl-ribo epimer (5)
as the major compound was probably favoured due to the steric
hindrance of the α-face of the sugar ring in precursor 3. Finally,
compound 5 was converted into 1-O-acetyl-3,5-di-O-benzoyl-
2-deoxy-2-C-trifluoromethyl--ribofuranose (6) which was
Scheme 3 Reagents and conditions: (a) silylated uracil or thymine,
TMSOTf, CH3CN, 50 ЊC; (b) MeONa, MeOH, rt; (d) i) 1-
methylpyrrolidine, CH3CN, (CF3CO)2O, 0 ЊC; ii) 4-nitrophenol, 0 ЊC;
iii) conc. aq. NH3, dioxane, 55 ЊC; iv) NH3–MeOH, rt
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 9 6 – 2 1 0 2
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Scheme 2. A glycosylation reaction with adenine and 6 using
stannic [tin()] chloride (SnCl4) as a catalyst13 in anhydrous
acetonitrile afforded protected nucleosides 7 and 8 as an ano-
triphosphate forms, would all account for their antiviral inactiv-
ity. Further research would be needed to support these hypo-
theses, but since no significant antiviral activity emerged
from the present data, it does not seem worthwhile to pursue
additional studies on 2Ј-deoxy-2Ј-C-trifluoromethyl-β--
ribonucleoside analogues.
1
meric mixture (ratio β : α = 77 : 23 determined by H NMR).
Separation by silica gel column chromatography gave pure
compound 7 in 41% which upon treatment with sodium
methanolate in methanol provided the desired nucleoside 11 in
74% yield after purification. In order to prepare the guanosine
analogue (12), a condensation reaction of 2-amino-6-chloro-
purine with 6 was carried out under Vorbrüggen conditions14
using trimethylsilyl trifluoromethane sulfonate (TMSOTf ) as a
catalyst in refluxing toluene to afford nucleosides 9 and 10.
After separation, compound 9 was fully characterized. In par-
ticular, the UV spectrum showed a λmax value in accordance
to previously reported data for N 9-2-amino-6-chloropurine
nucleoside derivatives.15,16 Finally, 9 was treated with 2-mer-
captoethanol and sodium methanolate in refluxing methanol to
provide the target nucleoside 12 in 83%.
Experimental
Evaporation of solvents was carried out on a rotary evaporator
under reduced pressure. Melting points were determined in
open capillary tubes on a Gallenkamp MFB-595–010 M appar-
atus and are uncorrected. UV spectra were recorded on an
1
Uvikon 931 (Kontron) spectrophotometer. H NMR spectra
were recorded at 400 MHz, 13C NMR spectra at 100 MHz and
19F NMR at 235 MHz in (CD3)2SO at ambient temperature
with a Brüker DRX 400. Chemical shifts (δ) are quoted in parts
per million (ppm) referenced to the residual solvent peak,
(CD3)CD2HSO being set at δH 2.49 and δC 39.5 relative to
tetramethylsilane (TMS). 19F chemical shifts are reported using
trichlorofluoromethane as external reference. Deuterium
exchange and COSY experiments were performed in order to
confirm proton assignments. Coupling constants, J, are
reported in Hertz. 2D 1H–13C heteronuclear COSY were
recorded for the attribution of 13C signals. FAB mass spectra
were recorded in the positive-ion or negative-ion mode on a
JEOL SX 102. The matrix was a mixture (50 : 50, v/v) of gly-
cerol and thioglycerol (G–T) or 3-nitrobenzyl alcohol (NBA).
Specific rotations were measured on a Perkin-Elmer Model 241
spectropolarimeter (path length 1 cm), and are given in units of
10Ϫ1 deg cm2 gϪ1. Elemental analyses were carried out by the
Service de Microanalyses du CNRS, Division de Vernaison
(France). Thin layer chromatography was performed on pre-
coated aluminium sheets of Silica Gel 60 F254 (Merck, Art.
5554), visualization of products being accomplished by UV
absorbency followed by charring with 5% ethanolic sulfuric
acid and heating. Column chromatography was carried out on
Silica Gel 60 (Merck, Art. 9385). All moisture-sensitive reac-
tions were carried out under rigorous anhydrous conditions
under an argon atmosphere using oven-dried glassware. Sol-
vents were dried and distilled prior to use and solids were dried
over P2O5 under reduced pressure.
The syntheses of the 2Ј-deoxy-2Ј-C-trifluoromethyl β--ribo-
nucleoside pyrimidine derivatives 17, 18 and 19 are depicted
in Scheme 3. Briefly, glycosylation reactions with uracil or
thymine and sugar 6, under Vorbrüggen conditions, using
TMSOTf as a catalyst in anhydrous acetonitrile at 50 ЊC
afforded an anomeric mixture of compounds 13 and 14, and of
compounds 15 and 16. After separation, compounds 13 and 15
were obtained in 31% and 32.6%, respectively. The 2Ј-deoxy-2Ј-
C-trifluoromethyl β--ribonucleoside analogues of uracil (17)
and thymine (18) were obtained from 13 and 15 following
treatment with sodium methanolate in methanol in 85% and
90% yield after purification via silica gel column chromato-
graphy, respectively. On the other hand, compound 13 was con-
verted into the corresponding cytosine derivative 19 by using a
nitrophenylation–amonolysis17 procedure in 53% overall yield.
The yields obtained during the glycosylation reactions with 6
and the heterocyclic bases were moderate, but provided in
almost all cases the corresponding β-anomer as the major com-
pound. Indeed, it has been reported that reactions at C-1 of
carbohydrates via cationic intermediates are difficult to achieve
with a trifluromethyl group in position 2 owing to the high
electron withdrawing effect of such a group.18 The preferential
formation of the β-anomers could be attributed to a steric
hindrance of the α-face on the sugar due to the presence of the
trifluoromethyl group whose the size is closer to that of an
isopropyl group.19 The stereochemical assignments of the
Methyl 3,5-di-O-(4-chlorobenzyl)-ꢁ-D-ribofuranoside 1
1
nucleosides at the protected or final stage were made using H
Compound (1) was obtained as a colourless oil from com-
mercially available -ribose following a procedure initially
developed by Martin et al.9 The physico-chemicals properties
were similar to those previously described δH(200 MHz; CDCl3;
Me4Si) 3.4 (2 H, m, 5-H and 5Ј-H), 3.5 (3 H, s, OCH3), 3.75
(1 H, dd, J 7 and J 3.2, 3-H), 4.15 (2 H, m, 2-H and 4-H),
4.57 (4 H, m, 2 × CH2Ar), 4.92 (1 H, d, J 4.6, 1-H), 7.1–7.3
(8 H, m, 2 × C6H4Cl); m/z (FAB > 0; NBA) 435 (M ϩ Na)ϩ; m/z
(FAB < 0; NBA) 411 (M Ϫ H)Ϫ.
NMR spectra. The anomers with higher field resonance for
H-4Ј protons were assigned as the β-anomers while the ones
with lower chemical shifts were attributed to the α-anomers on
account of the deshielding effect of the heterocyclic base.
Biological evaluation
The target nucleosides 11, 12 and 17–19 were tested for their
effects on the replication of HIV, HBV and several RNA
viruses (including yellow fever virus and bovine viral diarrhoea
virus) in cell culture experiments. However, none of these
compounds demonstrated significant antiviral activity nor
cytoxicity at the highest concentration tested (usually 100 µM).
Methyl 3,5-di-O-(4-chlorobenzyl)-2-C-trifluoromethyl-
ꢁ-D-ribofuranoside 2
Dess–Martin periodinane (58.7 g, 138 mmol) was added to
solution of compound 1 (38 g, 92.2 mmol) in anhydrous
dichloromethane (424 cm3) at 0ЊC. The mixture was stirred for
48 hours at room temperature, then diethyl ether (820 cm3) was
added. The resulting precipitate was filtered. A solution of
saturated aqueous sodium hydrogen carbonate (containing
94.9 g of sodium thiosulfate pentahydrate) (870 cm3) was added
to the filtrate and the mixture was stirred for 10 minutes until
the two phases became clear. The organic phase was separated,
washed with brine (1000 cm3), dried over sodium sulfate and
evaporated under reduced pressure. The resulting ketone was
not purified but directly coevaporated several times with
anhydrous toluene. To a solution of the resultant ketone in
Conclusion
The syntheses of 2Ј-deoxy-2Ј-C-trifluoromethyl-β--ribonucle-
osides bearing the five naturally occurring acid bases were
undertaken with the hope of discovering new nucleoside deriv-
atives endowed with antiviral effects. However, none of the tar-
get compounds exhibited significant antiviral activity. Several
factors could be responsible for the inactivity of these nucleo-
side derivatives. Their inability to enter cells or to serve as sub-
strates for intracellular enzymes catalysing phosphorylation, as
well as a lack of inhibition of viral polymerases by their
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 9 6 – 2 1 0 2
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anhydrous tetrahydrofuran (23 cm3) were added trifluoromethyl
trimethylsilane (69.5 ml, 139 mmol) and tetrabutyl ammonium
fluoride trihydrate (0.185 g). After 1 hour, the mixture was
washed with a solution of saturated ammonium chloride
(500 cm3) and extracted with diethyl ether (3 × 500 cm3). The
combined extracts were dried over sodium sulfate and evapor-
ated under reduced pressure. The crude material was dissolved
in methanol (93 cm3) and a 1 mol dmϪ3 solution of tetrabutyl
ammonium fluoride (93 cm3, 93 mmol) in tetrahydrofuran was
added. After 2 hours at room temperature, the mixture was
evaporated. The residue was subjected to silica gel column
chromatography using ethyl acetate–petroleum ether (1 : 9) as
eluent to give methyl 3,5-di-O-(4-chlorobenzyl)-2-C-trifluoro-
methyl-α--ribofuranoside 2 (30 g, 67%) as a colourless oil
(Found: C, 52.79; H, 4.46; Cl, 15.07; F, 11.74. C21H21Cl2F3O5
requires C, 52.41; H, 4.40; Cl, 14.73; F, 11.84%); [α]2D0
ϩ293 (c 1.00 in DMSO); δH(400 MHz; CDCl3; Me4Si)
3.43 (3 H, s, OCH3), 3.44 (1 H, dd, J 10.9 and J 5, 5Ј-H),
3.52 (1 H, dd, J 10.9 and 3.4, 5-H), 3.63 (1 H, s, 2-OH),
3.78 (1 H, d, J 7.1, 3-H), 3.99 (1 H, m, 4-H), 4.31 (1 H, d,
J 11.7, CH–Ar), 4.36 (1 H, d, J 12.2, CH–Ar), 4.42 (1 H, d, J
12.2, CH–Ar), 4.67 (1 H, d, J 11.7, CH–Ar), 4.92 (1 H, s, 1-H),
7.18 (8 H, m, 2 × C6H4Cl); δC(100 MHz; CDCl3; Me4Si) 54.6
(CH3), 67.4 (5-C), 71.3 (CH2), 71.6 (CH2), 74.9 (3-C), 78.2 (q,
bined organic layers were dried over sodium sulfate, evaporated
to dryness and coevaporated with anhydrous toluene. This
crude material was then dissolved in anhydrous toluene
(372 cm3) and α,αЈ-azobisisobutyronitrile (3.4 g, 20.7 mmol)
and tris(trimethylsilyl)silane hydride (25.5 cm3, 82.6 mmol)
were added. The resulting solution was heated under reflux for
12 hours. After cooling to room temperature, the solvent was
removed under reduced pressure. Chromatography of the resi-
due on a silica gel column using diethyl ether–petroleum ether
(1 : 9) as eluent provided a mixture of the title compounds
methyl
3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-α--
arabinofuranoside 4 and methyl 3,5-di-O-benzoyl-2-deoxy-2-C-
trifluoromethyl-α--ribofuranoside 5 (ratio 4 : 5: 13 : 87 deter-
mined by 1H NMR) as a colourless oil. Further chromato-
graphy gave fractions with pure compound 5 (7.2 g, 41%)
(Found: C, 59.41; H, 4.76. C21H19F3O6 requires C, 59.44; H,
4.51%); [α]2D0 ϩ117 (c 0.99 in DMSO); δH(400 MHz; CDCl3;
Me4Si) 3.02 (1 H, m, 2-H), 3.41 (3 H, s, OCH3), 4.47 (1 H, m,
4-H), 4.55–4.70 (2 H, m, 5-H and 5Ј-H), 5.23 (1 H, d, J 4.6,
1-H), 5.64 (1H, dd, J 7.4 and J 2.8, 3-H), 7.4–8.0 (10 H, m,
2 × C6H5CO); δC(100 MHz; CDCl3; Me4Si) 50.6 (q, 2JC–F 28.6,
2-C), 56.0 (CH3), 64.3 (5-C), 71.8 (3-C), 83.2 (4-C), 102.9 (1-C),
124.0 (q, 1JC–F = 277.9, CF3), 128.9–134.0 (Car), 166.4 (2 × CO);
3
δF(235 MHz; CDCl3; CCl3F) Ϫ61.2 (d, JF–H = 8.9 Hz, CF3);
2JC–F 28.6, 2-C), 79.0 (4-C), 100.3 (1-C), 123.5 (q, JC–F 282.6,
m/z (FAB > 0; GT) 849 (2M ϩ H)ϩ, 425 (M ϩ H)ϩ, 393
(M Ϫ MeOH)ϩ, 105 (PhCO)ϩ. Additional fractions with an
inseparable mixture of compounds 4 and 5 were obtained
δH(400 MHz; CDCl3; Me4Si) 3.10 (1 H, m, 2-H[arabino] ϩ
2-H[ribo]), 3.41 (3 H, s, OCH3[ribo]), 3.43 (3 H, s, OCH3-
[arabino]), 4.47–4.83 (3 H, m, 4-H[ribo] ϩ 5-H[ribo], 5Ј-H-
[ribo], 4-H[arabino] ϩ 5-H[arabino], 5Ј-H[arabino]), 5.30 (1 H,
d, J 1.6, 1-H[arabino]), 5.23 (1 H, d, J 4.6, 1-H[ribo]), 5.80 (1H,
m, 3-H[ribo] ϩ 3-H[arabino]), 7.4–8.0 (10 H, m, 2 × C6H5CO);
1
CF3), 127.5–135,2 (2 × C6H4); δF(235 MHz; CDCl3; CCl3F)
Ϫ79.9 (s, CF3); m/z (FAB < 0; GT) 479 (M Ϫ H)Ϫ, 355
(M Ϫ ClBn)Ϫ.
Methyl 3,5-di-O-benzoyl-2-C-trifluoromethyl-ꢁ-D-ribofuranoside
3
A solution of compound 2 (30 g, 62.5 mmol) in methanol
(550 cm3) was hydrogenated in the presence of Pd/C (5%) (30 g)
and sodium acetate (5.1 g, 62.5 mmol). After 24 h of stirring,
the suspension was filtered through a sintered funnel covered
with Celite and the filtrate was evaporated under reduced pres-
sure. To a solution of this crude material in pyridine (625 cm3)
was added benzoyl chloride (110 cm3, 948 mmol). The reaction
mixture was stirred for 12 hours, then diluted with chloroform
(500 cm3) and finally poured into a solution of saturated
sodium hydrogen carbonate (3 × 500 cm3). The organic phase
was separated, washed with water (3 × 500 cm3), dried over
sodium sulfate, evaporated to dryness and coevaporated several
times with toluene. The residue was purified on silica gel
column chromatography using ethyl acetate–petroleum ether
(1 : 9) as eluent to give methyl 3,5-di-O-benzoyl-2-C-trifluoro-
methyl-α--ribofuranoside 3 (22 g, 80%) as a colourless oil
(Found: C, 57.38; H, 4.51. C21H19F3O7 requires C, 57.28; H,
4.35%); [α]2D0 ϩ175 (c 1.00 in DMSO); δH(400 MHz; CDCl3;
Me4Si) 2.96 (1 H, br s, 2-OH), 3.54 (3 H, s, OCH3), 4.45 (2 H, m,
5Ј-H and 4-H), 4.62 (1 H, m, 5-H), 5.08 (1 H, s, 1-H), 5.60 (1 H,
d, J 7.1, 3-H), 7.3–8.0 (10 H, m, 2 × C6H5CO); δC(100 MHz;
CDCl3; Me4Si) 56.6 (CH3), 63.1 (5-C), 70.2 (3-C), 78.6 (4-C),
79.4 (q, 2JC–F 29.8, 2-C), 101.4 (1-C), 124.3 (q, 1JC–F 283, CF3),
127.3–134.0 (Car), 165.2 (CO), 166.4 (CO); δF(235 MHz;
CDCl3; CCl3F) Ϫ80.0 (s, CF3); m/z (FAB > 0; GT) 441
(M ϩ H)ϩ, 409 (M Ϫ MeOH)ϩ, 105 (C6H5CO)ϩ; m/z (FAB < 0;
GT) 879 (2M Ϫ H)Ϫ, 439 (M Ϫ H)Ϫ, 121 (C6H5CO2)Ϫ.
3
RMN 19F δF(235 MHz; CDCl3; CCl3F) Ϫ 69.4 (d, JF–H 10.8,
CF3, [arabino]), Ϫ61,2 (d, 3JF–H = 8,9 Hz, CF3, [ribo]).
1-O-Acetyl-3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-D-
ribofuranose 6
Acetic anhydride (12 cm3) was added to a solution of com-
pound 5 (7.2 g, 17 mmol) in acetic acid (50.9 cm3) at 0 ЊC.
Sulfuric acid (1.3 cm3) was then added dropwise. The reaction
mixture was stirred at room temperature for 1 hour then diluted
with a mixture of ice–water. The aqueous phase was extracted
with chloroform (3 × 200 cm3). The combined extracts were
washed with a solution of saturated sodium hydrogen carb-
onate (3 × 400 cm3), water (3 × 400 cm3) and dried over sodium
sulfate. The solvent was removed under reduced pressure
to afford 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-
methyl--ribofuranose 6 as a colourless oil (6.8 g, 88%). An
analytical sample of 6 was obtained after crystallisation from
petroleum ether providing the β-anomer; mp 129 ЊC; [α]2D0 Ϫ16
(c 1.05 in DMSO); δH(400 MHz; CDCl3; Me4Si) 1.92 (3 H, s,
CH3CO), 3.43 (1 H, m, 2-H), 4.43 (1 H, dd, J 12.0 and J 4.4,
5Ј-H), 4.60 (2 H, m, 5-H and 4-H), 5.83 (1 H, m, 3-H), 6.57
(1 H, d, J 2.6, 1-H), 7.3–8.00 (10 H, m, 2 × C6H5CO); δC(100
MHz; CDCl3; Me4Si) 19.8 (CH3), 50.2 (q, 2JC–F 27.4, 2-C), 62.6
1
(5-C), 70.7 (3-C), 81.4 (4-C), 95.5 (1-C), 123.2 (q, JC–F 279.4,
CF3), 127.3–132.8 (Car), 164.5 (CO), 164.9 (CO), 168.1 (CO);
3
δF(235 MHz; CDCl3; CCl3F) Ϫ64.8 (d, JF–H 8.7, CF3); m/z
Methyl 3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-
ꢁ-D-arabinofuranoside 4 and methyl 3,5-di-O-benzoyl-2-deoxy-
2-C-trifluoromethyl-ꢁ-D-ribofuranoside 5
(FAB > 0; NBA; HRMS) Found 453.1161 (M ϩ H)ϩ, requires
453.1149.
9-(3,5-Di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-ꢀ-D-ribo-
furanosyl)adenine 7 and 9-(3,5-di-O-benzoyl-2-deoxy-2-C-tri-
fluoromethyl-ꢁ-D-ribofuranosyl)-adenine 8
Stannic chloride (0.4 cm3, 3.41 mmol) was added cautiously to a
stirred suspension of adenine (0.25 g, 1.85 mmol) and 1-O-
acetyl-3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl--ribo-
furanose 6 (0.7 g, 1.54 mmol) in dry acetonitrile (14 cm3) at
To a solution of compound 3 (18.2 g, 41.4 mmol) in anhydrous
dichloromethane (136 cm3) and pyridine (10 cm3, 125 mmol)
was added methyl oxalyl chloride (7.6 cm3, 82.6 mmol). The
reaction mixture was stirred for 3 hours under argon at room
temperature, then washed with a solution of saturated sodium
hydrogen carbonate (3 × 500 cm3). The aqueous phase was
extracted with dichloromethane (3 × 500 cm3) and the com-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 9 6 – 2 1 0 2
2099

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room temperature. After 72 h, pyridine (6 cm3) was added to the
resultant solution. The white precipitate was filtered and
washed with chloroform (3 × 50 cm3). The combined filtrates
were washed with a solution of saturated sodium hydrogen car-
bonate (3 × 100 cm3), water (3 × 100 cm3), dried over sodium
sulfate and evaporated. Silica gel column chromatography of
the residue using a stepwise gradient of methanol (1–2%) in
dichloromethane afforded a mixture of the title compound
9-(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-β--ribo-
furanosyl)adenine 7 and 9-(3,5-di-O-benzoyl-2-deoxy-2-C-tri-
fluoromethyl-α--ribofuranosyl)adenine 8 as a white foam
278.6, CF3), 129.3–135.0 (Car), 142.0 (8-C), 151.0 (4-C), 153.4
(6-C), 160.8 (2-C), 165.3 (CO), 166.2 (CO); δF(235 MHz;
DMSO-d6; CCl3F) Ϫ62.5 (d, 3JF–H 9.3, CF3); m/z (FAB > 0; GT)
1123 (2M ϩ H)ϩ, 562 (M ϩ H)ϩ, 393 (S)ϩ, 170 (BH2)ϩ, 105
(PhCO)ϩ; m/z (FABϪ; GT) 1121 (2M Ϫ H)Ϫ, 560 (M Ϫ H)Ϫ, 168
(B)Ϫ, 121 (PhCO2)Ϫ. Compound 10: δH(400 MHz; DMSO-d6;
Me4Si) 4.59 (3 H, m, 2Ј-H, 5Ј-H and 5Љ-H), 5.47 (1 H, t, J 5.8,
4Ј-H), 5.97 (1 H, d, J 6.4, 3Ј-H), 6.76 (1 H, d, J 7.0, 1Ј-H), 7.00
(2 H, br s, NH2), 7.5–8.0 (10 H, m, 2 × C6H5CO), 8.46 (1 H, s,
8-H); δC(100 MHz; DMSO-d6; Me4Si) 48.8 (q, 2JC–F 27.7, 2Ј-C),
64.5 (5Ј-C), 73.6 (3Ј-C), 82.7 (1Ј-C), 85.0 (4Ј-C), 123.6 (5-C),
124.6 (q, 1JC–F 278.0, CF3), 129.7–134.8 (Car), 142.2 (8-C), 150.4
(4-C), 154.5 (6-C), 160.8 (2-C), 165.7 (CO), 166.4 (CO); δF(235
MHz; DMSO-d6; CCl3F) Ϫ59.8 (d, 3JF–H 9.3, CF3).
1
(ratio 7 : 8: 77 : 23 determined by H NMR). Further chrom-
atography gave fractions with pure compound 7 (0.32 g, 39%)
mp 186 ЊC (from petroleum ether) (Found: C, 57.03; H, 3.85; N,
13.10; F, 10.91. C25H20F3N5O5 requires C, 56.93; H, 3.82; N,
13.28; F, 10.81%); [α]2D0 Ϫ27 (c 1.00 in DMSO); λmax(ethanol)/
nm 230 (ε/dm3 molϪ1 cmϪ1 29 000), 260 (16 000), λmin 247
(14600); δH(400 MHz; DMSO-d6; Me4Si) 4.63 (1 H, dd, J 10.6
and J 4.3, 5Љ-H), 4.66–4.77 (2 H, m, 4Ј-H and 5Ј-H), 5.02 (1 H,
m, 2Ј-H), 6.24 (1 H, dd, J 6.6 and J 3, 3Ј-H), 6.78 (1 H, d, J 8.0,
1Ј-H), 7.45 (2 H, br s, NH2), 7.5–8.1 (10 H, m, 2 × C6H5CO),
8.08 (1 H, s, 2-H), 8.48 (1 H, s, 8-H); δC(100 MHz; DMSO-d6;
9-(2-Deoxy-2-C-trifluoromethyl-ꢀ-D-ribofuranosyl)adenine 11
To a solution of 9-(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-
methyl-β--ribofuranosyl)adenine 10 (0.28 g, 0.53 mmol) in dry
methanol (5.3 cm3) was added sodium methylate (0.086 g,
1.59 mmol). The reaction mixture was stirred at room temper-
ature for 3 hours and neutralized with a 1 M chlorhydric acid
solution, then evaporated to dryness. The residue was subjected
to silica gel column chromatography using methanol–dichoro-
methane (1 : 9) as eluent to give 9-(2-deoxy-2-C-trifluoro-
methyl-β--ribofuranosyl)adenine 11 (0.125 g, 74%) which was
lyophylizated from water (Found: C, 38.38; H, 3.99; N, 20.14.
C11H12F3N5O3ؒ1.3 H2O requires C, 38.56; H, 4.29; N, 20.44%);
[α]2D0 Ϫ89 (c 1.00 in DMSO); λmax(ethanol)/nm 260 (ε/dm3 molϪ1
cmϪ1 14 500); δH(400 MHz; DMSO-d6; Me4Si) 3.74 (1 H, m,
5Ј-H), 3.63 (1 H, m, 5Љ-H), 4.09 (1 H, br s, 4Ј-H), 4.20 (1 H, m,
2Ј-H), 4.69 (1 H, m, 3Ј-H), 5.40 (1H, t, J 5.3, 5Ј-OH), 6.10 (1 H,
d, J 5.5, 3Ј-OH), 6.57 (1 H, d, J 8.8, 1Ј-H), 6.22 (2 H, br s, NH2),
8.23 (1 H, s, 2-H), 8.51 (1 H, s, 8-H); δC(100 MHz; DMSO-d6;
2
Me4Si) 47.5 (q, JC–F 26.9, 2Ј-C), 64.0 (5Ј-C), 72.7 (3Ј-C),
1
82.0 (4Ј-C), 83.4 (1Ј-C), 120.2 (5-C), 125.4 (q, JC–F 278.8,
CF3), 129.4–134.9 (Car), 140.9 (8-C), 150.4 (4-C), 153.7 (2-C),
157.1 (6-C), 165.4 (CO), 166.2 (CO); δF(235 MHz; DMSO-d6;
CCl3F) Ϫ62.3 (d, 3JF–H 9.3, CF3); m/z (FAB > 0; GT) 1055 (2M
ϩ H)ϩ, 620 (M ϩ G ϩ H)ϩ, 528 (M ϩ H)ϩ, 393 (S)ϩ, 136
(BH2)ϩ, 105 (PhCO)ϩ; m/z (FAB < 0; GT) 526 (M Ϫ H)Ϫ, 134
(B)Ϫ, 121 (PhCO2)Ϫ. Additional fractions of compound 8 con-
taminated with a trace amount of compound 7 were obtained.
Compound 8 δH(400 MHz; DMSO-d6; Me4Si) 4.62–4.92 (3 H,
m, 2Ј-H, 5Ј-H and 5Љ-H), 5.51 (1 H, m, 4Ј-H), 6.05 (1 H, m,
3Ј-H), 6.98 (1 H, d, J 7.0, 1Ј-H), 7.51–8.80 (14 H, m, 2 ×
C6H5CO, NH2, 2-H and 8-H); δF(235 MHz; CDCl3; CCl3F)
Ϫ59.7 (d, 3JF–H 9.4, CF3).
2
Me4Si) 50.4 (q, JC–F 25.4, 2Ј-C), 62.2 (5Ј-C), 71.3 (3Ј-C), 83.1
1
(1Ј-C), 88.8 (4Ј-C), 119.9 (5-C), 125.9 (q, JC–F 278.4, CF3),
140.4 (8-C), 149.9 (4-C), 153.6 (2-C), 157.0 (6-C); δF(235 MHz;
DMSO-d6; CCl3F) Ϫ61.4 (d, 3JF–H 9.3 Hz, CF3); m/z (FAB > 0;
GT) 639 (2M ϩ H)ϩ, 412 (M ϩ G ϩ H)ϩ, 320 (M ϩ H)ϩ,
185 (S)ϩ, 136 (BH2)ϩ; m/z (FAB < 0; GT) 637 (2M Ϫ H)Ϫ, 318
(M Ϫ H)Ϫ, 134 (B)Ϫ.
2-Amino-6-chloro-9-(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-
methyl-ꢀ-D-ribofuranosyl)purine 9 and 2-amino-6-chloro-9-(3,5-
di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-ꢁ-D-ribofuranosyl)-
purine 10
9-(2-Deoxy-2-C-trifluoromethyl-ꢀ-D-ribofuranosyl)guanine 12
Bis(trimethylsilyl)acetamide (10.5 cm3, 42.8 mmol) was added
to a stirred suspension of 2-amino-6-chloro-purine (1.8 g, 10.6
mmol) in dry toluene (20 cm3). The resulting suspension was
heated under reflux for 2 hours, then 1-O-acetyl-3,5-di-O-
benzoyl-2-deoxy-2-C-trifluoromethyl--ribofuranose 6 (4.4 g,
9.73 mmol), previously dissolved in dry toluene (20 cm3), and
trimethylsilyl triflate (2.25 cm3, 11.64 mmol) were added. The
reaction mixture was refluxed for 30 minutes then cooled to
room temperature. Ethyl acetate (50 cm3) was added and the
organic layer was washed with a solution of saturated sodium
hydrogen carbonate (3 × 50 cm3), dried and evaporated under
reduced pressure. Silica gel column chromatography of the
residue using petroleum ether–diethyl ether (3 : 7) as eluent
afforded successively the title compounds 2-amino-6-chloro-9-
(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-β--ribofuran-
osyl)purine 9 (0.3 g, 5.5%) and 2-amino-6-chloro-9-(3,5-di-O-
benzoyl-2-deoxy-2-C-trifluoromethyl-α--ribofuranosyl)purine
10 (0.3 g, 5.5%) as white foams. Compound 9: mp 105 ЊC (from
diethyl ether–petroleum ether) (Found: C, 53.42; H, 3.57; N,
11.84; Cl, 6.11; F, 10.30. C25H19F3N5O5ؒ0.15 Et2O requires C,
53.66; H, 3.61; N, 12.22; Cl, 6.19; F, 9.95%); [α]2D0 Ϫ5 (c 1.02 in
DMSO); λmax(ethanol)/nm 236 (ε/dm3 molϪ1 cmϪ1 24 800), 310
(6 600), λmin 267 (2 200); δH(400 MHz; DMSO-d6; Me4Si) 4.67 (3
H, m, 4Ј-H, 5Ј-H and 5Љ-H), 4.87 (1 H, m, 2Ј-H), 6.18 (1 H, dd,
J 6.9 and J 3.1, 3Ј-H), 6.66 (1 H, d, J 7.8, 1Ј-H), 7.11 (2 H, br s,
NH2), 7.5–8.0 (10 H, m, 2 × C6H5CO), 8.49 (1 H, s, 8-H); δC(100
To
a solution of 2-amino-6-chloro-9-(3,5-di-O-benzoyl-2-
deoxy-2-C-trifluoromethyl-β--ribofuranosyl)purine 10 (0.15 g,
0.26 mmol) in dry methanol (21.6 cm3) were added 2-mer-
captoethanol (0.075 cm3, 1.06 mmol) and sodium methylate
(0.057 g, 1.05 mmol). The reaction mixture was heated under
reflux for 12 hours then neutralized with a 1 M chlorhydric acid
solution and evaporated. The residue was subjected to silica gel
column chromatography using a stepwise gradient of methanol
(0–15%) in chloroform to afford the title compound 9-(2-deoxy-
2-C-trifluoromethyl-β--ribofuranosyl)guanine 12 (0.075 g,
83%) after filtration on Millex HV-4 (0.45 µm, Millipore) mp
217 ЊC (from methanol–chloroform) (Found: C, 39.32; H, 4.11;
N, 18.35; F, 15.07. C11H12F3N5O4ؒ1.2 H2O requires C, 39.21;
H, 4.53; N, 18.74; F, 15.25%); [α]2D0 Ϫ61 (c 1.01 in DMSO);
λmax(ethanol)/nm 253 (ε/dm3 molϪ1 cmϪ1 11 000); δH(400 MHz;
DMSO-d6; Me4Si) 3.57–3.69 (2 H, m, 5Ј-H and 5Љ-H), 4.03
(2 H, m, 4Ј-H and 2Ј-H), 4.61 (1 H, m, 3Ј-H), 5.18 (1 H, t,
J 5.2, 5Ј-OH), 6.04 (1 H, d, J 5.2, 3Ј-OH), 6.33 (1 H, d, J 8.9,
1Ј-H), 6.60 (2 H, br s, NH2), 8.08 (1 H, s, 8-H), 10.76 (1H, br s,
2
N–H ); δC(100 MHz; DMSO-d6; Me4Si) 50.4 (q, JC–F 25.6,
2Ј-C), 62.0 (5Ј-C), 71.2 (3Ј-C), 81.7 (1Ј-C), 88.4 (4Ј-C), 117.3
(5-C), 125.9 (q, 1JC–F 279, CF3), 136.2 (8-C), 152.0 (4-C), 154.7
(2-C), 157.4 (6-C); δF(235 MHz; DMSO-d6; CCl3F) Ϫ61.3
(d, 3JF–H 9.2 Hz, CF3); m/z (FAB > 0; GT) 671 (2M ϩ H)ϩ, 428
(M ϩ G ϩ H)ϩ, 336 (M ϩ H)ϩ, 185 (S)ϩ, 152 (BH2)ϩ; m/z (FAB
< 0; GT) 669 (2M Ϫ H)Ϫ, 426 (M ϩ G Ϫ H)Ϫ, 334 (M Ϫ H)Ϫ,
150 (B)Ϫ.
2
MHz; DMSO-d6; Me4Si) 47.6 (q, JC–F 7.2, 2Ј-C), 64.1 (5Ј-C),
72.6 (3Ј-C), 81.9 (4Ј-C), 82.8 (1Ј-C), 124.3 (5-C), 125.4 (q, 1JC–F
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 9 6 – 2 1 0 2
2100

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1-(3,5-Di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-ꢀ-D-ribo-
furanosyl)uracil 13 and 1-(3,5-di-O-benzoyl-2-deoxy-
2-C-trifluoromethyl-ꢁ-D-ribofuranosyl)uracil 14
(1 H, dd, J 7.6 and J 4.1, 3Ј-H), 6.50 (1 H, d, J 7.8, 1Ј-H), 7.5–
8.0 (11 H, m, 2 × C6H5CO and 6-H), 11.58 (1 H, br s, N–H );
δC(100 MHz; DMSO-d6; Me4Si) 12.8 (CH3), 47.7 (q, 2JC–F 29.9,
2Ј-C), 64.2 (5Ј-C), 71.8 (3Ј-C), 81.1 (4Ј-C), 84.1 (1Ј-C), 111.6 (5-
A mixture of uracil (1 g, 8.92 mmol), hexamethyldisilazane
(44.6 cm3) and a catalytic amount of ammonium sulfate was
refluxed for 14 hours. The resultant clear solution was concen-
trated to dryness under reduced pressure. TMSOTf (0.55 cm3,
2.84 mmol) was added to a solution of sugar 6 (1 g, 2.21 mmol)
and silylated base in dry acetonitrile (20 cm3). The reaction
mixture was stirred for 4 days at 50 ЊC, diluted with dichloro-
methane (50 cm3), washed with a solution of saturated sodium
hydrogen carbonate (3 × 100 cm3), water (3 × 100 cm3), dried
over sodium sulfate and evaporated to dryness. Chromato-
graphy of the residue on a silica gel column using petroleum
ether–diethyl ether (3 : 7) as eluent afforded successively the title
compounds 1-(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-
β--ribofuranosyl)uracil 13 (0.35 g, 31%) and 1-(3,5-di-O-ben-
zoyl-2-deoxy-2-C-trifluoromethyl-α--ribofuranosyl)uracil 14
(0.15 g, 14%) as white foams. Compound 13 mp 220–221 ЊC
(from diethyl ether) (Found: C, 57.03; H, 3.74; N, 5.54; F, 11.38.
C24H19F3N2O7 requires C, 57.15; H, 3.80; N, 5.55; F, 11.30%);
[α]2D0 Ϫ8 (c 0.99 in DMSO); λmax(ethanol)/nm 260 (ε dm3 molϪ1
cmϪ1 10 900), 230 (29 200), λmin 248 (11 200); δH(400 MHz;
DMSO-d6; Me4Si) 4.28 (1 H, m, 2Ј-H), 4.60 (3 H, m, 4Ј-H, 5Ј-H
and 5Љ-H), 5.75 (1 H, d, J 8.1, 5-H), 5.97 (1 H, dd, J 7.5 and
J 3.5, 3Ј-H), 6.46 (1 H, d, J 7.6, 1Ј-H), 7.5–8.00 (11 H, m, 2 ×
C6H5CO and 6-H), 11.60 (1 H, br s, N–H ); δC(100 MHz;
1
C), 125.5 (q, JC–F 278.6, CF3), 129.3–134.9 (Car), 136.8 (6-C),
151.0 (2-C), 166.3 (CO), 164.2 (4-C), 165.4 (CO); δF(235 MHz;
DMSO-d6; CCl3F) Ϫ62.5 (d, 3JF–H 9.5 Hz, CF3); m/z (FAB > 0;
GT) 1037 (2M ϩ H)ϩ, 611 (M ϩ G ϩ H)ϩ, 519 (M ϩ H)ϩ; m/z
(FAB < 0; NBA) 1035 (2M Ϫ H)Ϫ, 517 (M Ϫ H)Ϫ, 121
(PhCO2)Ϫ. Compound 16 δH(400 MHz; DMSO-d6; Me4Si) 1.73
(3 H, s, CH3), 4.44 (3 H, m, 2Ј-H, 5Ј-H and 5Љ-H), 5.37 (1 H, t,
J 6.4, 4Ј-H), 5.90 (1 H, d, J 5.7, 3Ј-H), 6.74 (1 H, d, J 7.2, 1Ј-H),
7.5–8.1 (11 H, m, 2 × C6H5CO and 6-H), 11.47 (1H, br s, N–H );
δC(100 MHz; DMSO-d6; Me4Si) 13.0 (CH3), 48.3 (q, 2JC–F 26.8,
2Ј-C), 64.3 (5Ј-C), 73.5 (3Ј-C), 83.8 (1Ј-C), 84.3 (4Ј-C), 110.0
1
(5-C), 125.0 (q, JC–F 278.0, CF3), 129.3–134.8 (Car), 137.3
(6-C), 151.1 (2-C), 164.6 (4-C), 165.3 (CO), 166.3 (CO); δF(235
MHz; DMSO-d6; CCl3F) Ϫ59.3 (d, 3JF–H 9.5 Hz, CF3).
1-(2-Deoxy-2-C-trifluoromethyl-ꢀ-D-ribofuranosyl)uracil 17
To a solution of 1-(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-
methyl-β--ribofuranosyl)uracil 13 (0.28 g, 0.55 mmol) in
dry methanol (5.5 cm3) was added sodium methylate (0.12 g,
2.22 mmol). The reaction mixture was stirred at room temper-
ature for 20 minutes and neutralized with a 1 M chlorhydric
acid solution, then evaporated to dryness. The residue was
subjected to silica gel column chromatography, using 10%
methanol in chloroform as eluent, to give 9-(2-deoxy-2-C-tri-
fluoromethyl-β--ribofuranosyl)uracil 17 (0.14 g, 85%) (Found:
C, 40.66; H, 3.73; N, 9.30; F, 19.36. C10H11F3N2O5 requires C,
40.55; H, 3.74; N, 9.46; F, 19.24%); [α]2D0 Ϫ37 (c 1.03 in DMSO);
λmax(ethanol)/nm 260 (ε/dm3 molϪ1 cmϪ1 10 300); δH(400 MHz;
DMSO-d6; Me4Si) 3.33 (1 H, m, 2Ј-H), 3.56 (2 H, m, 5Ј-H and
5Љ-H), 3.89 (1 H, br s, 4Ј-H), 4.42 (1 H, br s, 3Ј-H), 5.2 (1 H, br s,
5Ј-OH), 5.72 (1 H, d, J 8.1, 5-H), 5.92 (1 H, d, J 4.9, 3Ј-OH),
6.38 (1 H, d, J 8.7, 1Ј-H), 7.83 (1 H, d, 6-H), 11.40 (1 H, br s,
N–H ); δC(100 MHz; DMSO-d6; Me4Si) 50.5 (q, 2JC–F 25, 2Ј-C),
61.9 (5Ј-C), 71.0 (3Ј-C), 83.0 (1Ј-C), 88.0 (4Ј-C), 103.7 (5-C),
128.5 (q, 1JC–F 278.3, CF3), 140.9 (6-C), 151.1 (2-C), 163.7 (4-C);
2
DMSO-d6; Me4Si) 47.7 (q, JC–F 28.6, 2Ј-C), 64.2 (5Ј-C), 71.9
(3Ј-C), 81.2 (4Ј-C), 84.9 (1Ј-C), 103.8 (5-C), 125.5 (q, 1JC–F 279,
CF3), 129.3–134.9 (Car), 141.9 (6-C), 150.9 (2-C), 163.6 (4-C),
165.4 (CO), 166.2 (CO); δF(235 MHz; DMSO-d6; CCl3F) Ϫ62.6
(d, 3JF–H 9.6, CF3); m/z (FAB > 0; GT) 1009 (2M ϩ H)ϩ, 597 (M
ϩ G ϩ H)ϩ, 505 (M ϩ H)ϩ, 393 (S)ϩ, 113 (BH2)ϩ, 105 (PhCO)ϩ;
m/z (FAB < 0; GT) 503 (M Ϫ H)Ϫ, 111 (B)Ϫ. Compound 14
δH(400 MHz; DMSO-d6; Me4Si) 4.45 (3 H, m, 2Ј-H, 5Ј-H and
5Љ-H), 5.28 (1 H, t, J 6.3, 4Ј-H), 5.64 (1 H, d, J 8.2, 5-H), 5.91
(1 H, dd, J 6.0, 3Ј-H), 6.73 (1 H, d, J 7.2, 1Ј-H), 7.5–8.1 (11 H,
m, 2 × C6H5CO and 6-H), 11.50 (1 H, br s, N–H ); δC(100 MHz;
2
DMSO-d6; Me4Si) 48.3 (q, JC–F 27.6, 2Ј-C), 64.3 (5Ј-C), 73.5
(3Ј-C), 84.0 (1Ј-C), 84.3 (4Ј-C), 102.3 (5-C), 125.0 (q, 1JC–F 278,
CF3), 129.5–134.9 (Car), 142.0 (6-C), 151.0 (2-C), 163.8 (4-C),
165.4 (CO), 166.3 (CO); δF(235 MHz; DMSO-d6; CCl3F) Ϫ59.5
(d, 3JF–H 9.5, CF3).
δF(235 MHz; DMSO-d6; CCl3F) Ϫ61.4 (d, JF–H 9.3, CF3);
3
m/z (FAB > 0; GT) 593 (2M ϩ H)ϩ, 389 (M ϩ G ϩ H)ϩ, 297
(M ϩ H)ϩ, 185 (S)ϩ, 113 (BH2)ϩ; m/z (FAB < 0; GT) 591
(2M Ϫ H)Ϫ, 387 (M ϩ G ϩ H)Ϫ, 295 (M Ϫ H)Ϫ, 111 (B)Ϫ.
1-(3,5-Di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-ꢀ-D-ribo-
furanosyl)thymine 15 and 1-(3,5-di-O-benzoyl-2-deoxy-
2-C-trifluoromethyl-ꢁ-D-ribofuranosyl)-thymine 16
1-(2-Deoxy-2-C-trifluoromethyl-ꢀ-D-ribofuranosyl)thymine 18
To a solution of 1-(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoro-
methyl-β--ribofuranosyl)thymine 15 (0.4 g, 0.77 mmol) in dry
methanol (7.7 cm3) was added sodium methylate (0.166 g,
3.08 mmol). The reaction mixture was stirred at room temper-
ature for 15 minutes and neutralized with a 1 M chlorhydric
acid solution, then evaporated to dryness. The residue was
subjected to silica gel column chromatography using methanol–
dichoromethane (1 : 9) as eluent to give 1-(2-deoxy-2-C-tri-
fluoromethyl-β--ribofuranosyl)thymine 18 (0.215 g, 90%)
which was lyophilizated from water (Found: C, 41.72; H, 4.16;
N, 8.72. C11H13F3N2O5ؒ0.3 H2O requires C, 41.86; H, 4.34; N,
8.88%); [α]2D0 Ϫ41 (c = 1.02 in DMSO); λmax(ethanol)/nm 267
(ε/dm3 molϪ1 cmϪ1 9 300); δH(400 MHz; DMSO-d6; Me4Si) 1.76
(3 H, s, CH3), 3.35 (1 H, m, 2Ј-H), 3.56 (2 H, m, 5Ј-H and 5Љ-H),
3.87 (1 H, br s, 4Ј-H), 4.42 (1 H, dd, J 5.8 and J 2, 3Ј-H), 5.22
(1 H, br s, 5Ј-OH), 5.91 (1 H, br s, 3Ј-OH), 6.37 (1 H, d, J 8.8,
1Ј-H), 7.66 (1 H, d, J 0.7, 6-H), 11.41 (1 H, br s, N–H ); δC(100
A mixture of thymine (1.11 g, 8.8 mmol), hexamethyldisilazane
(44.2 cm3) and a catalytic amount of ammonium sulfate was
refluxed for 14 hours. The resultant clear solution was concen-
trated to dryness under reduced pressure. TMSOTf (0.55 cm3,
2.84 mmol) was added to a solution of sugar 6 (1 g, 2.21 mmol)
and silylated base in dry acetonitrile (22 cm3). The reaction
mixture was stirred for 4 days at 50 ЊC, diluted with dichloro-
methane (50 cm3), washed with a solution of saturated sodium
hydrogen carbonate (3 × 100 cm3), water (3 × 100 cm3), dried
over sodium sulfate and evaporated to dryness. Chromato-
graphy of the residue on a silica gel column using petroleum
ether–diethyl ether (3 : 7) as eluent afforded successively the title
compounds 1-(3,5-di-O-benzoyl-2-deoxy-2-C-trifluoromethyl-
β--ribofuranosyl)thymine 15 (0.37 g, 32.6%) and 1-(3,5-di-O-
benzoyl-2-deoxy-2-C-trifluoromethyl-α--ribofuranosyl)-
thymine 16 (0.13 g, 11.4%) as white foams. Compound 15
mp 210 ЊC (from diethyl ether) (Found: C, 58.01; H, 4.05; N,
5.41; F, 11.03. C25H21F3N2O7 requires C, 57.92; H, 4.08; N, 5.40;
F, 10.99%); [α]2D0 Ϫ14 (c 1.00 in DMSO); λmax(ethanol)/nm 267
(ε/dm3 molϪ1 cmϪ1 11 900), 229 (29 970), λmin 250 (11 200);
δH(400 MHz; DMSO-d6; Me4Si) 1.73 (3 H, d, J 0.7, CH3), 4.23
(1 H, m, 2Ј-H), 4.59–4.68 (3 H, m, 4Ј-H, 5Ј-H and 5Љ-H), 6.00
2
MHz; DMSO-d6; Me4Si) 13.1 (CH3), 50.2 (q, JC–F = 25 Hz,
2Ј-C), 61.9 (5Ј-C), 71.0 (3Ј-C), 82.8 (1Ј-C), 87.8 (4Ј-C), 111.2 (5-
1
C), 125.8 (q, JC–F = 278.2 Hz, CF3), 136.3 (6-C), 151.2 (2-C),
3
164.6 (4-C); δF(235 MHz; DMSO-d6; CCl3F) Ϫ61.3 (d, JF–H
9.4, CF3); m/z (FAB > 0; GT) 621 (2M ϩ H)ϩ, 403 (M ϩ G ϩ
H)ϩ, 311 (M ϩ H)ϩ, 185 (S)ϩ, 127 (BH2)ϩ; m/z (FAB < 0; NBA)
619 (2M Ϫ H)Ϫ, 401 (M ϩ G Ϫ H)Ϫ, 309 (M Ϫ H)Ϫ, 125 (B)Ϫ.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 9 6 – 2 1 0 2
2101

View Article Online
1-(2-Deoxy-2-C-trifluoromethyl-ꢀ-D-ribofuranosyl)cytosine 19
Acknowledgements
A solution of compound 13 (0.5 g, 0.99 mmol) and 1-methyl-
pyrrolidine (1 cm3, 9.61 mmol) in anhydrous acetonitrile
(4.9 cm3) was cooled down to 0 ЊC. Trifluoroacetic anhydride
(0.35 cm3, 2.47 mmol) was then added. After 45 minutes at 0 ЊC,
4-nitrophenol (0.415 g, 3 mmol) was added to the solution.
After stirring for 3 hours at 0 ЊC, the solution was then poured
into a solution of saturated sodium hydrogen carbonate
(20 cm3), and the resultant mixture was extracted with di-
chloromethane (3 × 20 cm3). The combined organic layers were
dried over sodium sulfate and evaporated under reduced pres-
sure. The residue was dissolved in dioxane (5 cm3) and concen-
trated aqueous ammonia (1 cm3, d 0.89) was added. The reac-
tion mixture was stirred at 55 ЊC for 12 hours. The resulting
yellow solution was concentrated under reduced pressure and
directly treated with methanolic ammonia (previously saturated
at Ϫ10 ЊC and tightly stoppered) (25 cm3) for 12 hours at room
temperature. After evaporation to dryness under reduced pres-
sure, the residue was subjected to silica gel column chromato-
graphy using methanol–dichloromethane (1 : 9) as eluent to
afford the title compound 1-(2-deoxy-2-C-trifluoromethyl-β--
ribofuranosyl)cytosine 19 (0.155 g, 53%). An analytical sample
of compound 19 was obtained as its chlorohydrate salt mp
220 ЊC (from ethanol) (Found: C, 36.63; H, 3.93; N, 12.65.
C10H13ClF3N3O4ؒ0.1EtOH requires C, 36.43; H, 4.08; N,
12.50%); [α]2D0 ϩ3 (c 1.00 in DMSO); λmax(ethanol)/nm 270
(ε dm3 molϪ1 cmϪ1 8 500); δH(400 MHz; DMSO-d6; Me4Si) 3.43
(1 H, m, 2Ј-H), 3.61 (2 H, m, 5Ј-H and 5Љ-H), 3.96 (1 H, m,
4Ј-H), 4.47 (1 H, m, 3Ј-H), 5.07 (1 H, br s, OH), 5.99 (1 H, br s,
OH), 6.23 (1 H, d, J 7.8, 5-H), 6.32 (1 H, d, J 7.3, 1Ј-H), 8.22
(1 H, d, 6-H), 8.80 (1 H, br s, NH2), 9.93 (1 H, br s, NH2);
We gratefully acknowledge Professor P. La Colla (Università
degli Studi di Cagliari, Italy) for the biological results. F. J. is
particularly grateful to the Ministère de lЈEducation Nationale,
de la Recherche et de la Technologie, France, for a doctoral
fellowship.
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2
δC(100 MHz; DMSO-d6; Me4Si) 51.3 (q, JC–F 25, 2Ј-C), 61.3
(5Ј-C), 70.3 (3Ј-C), 84.3 (1Ј-C), 88.3 (4Ј-C), 95.9 (5-C), 125.7
1
(q, JC–F 279, CF3), 144.7 (6-C), 147.7 (2-C), 160.2 (4-C);
δF(235 MHz; DMSO-d6; CCl3F) Ϫ61,4 (d, 3JF–H 9.5, CF3); m/z
(FAB > 0; GT) 185 (S)ϩ, 112 (BH2)ϩ; m/z (FAB < 0; GT) 330
(M Ϫ H)Ϫ.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 9 6 – 2 1 0 2
2102