Stereospecific synthesis of unnatural β-L-enantiomers of 2-chloroadenine pentofuranonucleoside derivatives

Article abstract of DOI:10.1039/a904380b

2′,3′-Dideoxy- (1), 2′,3′-unsaturated- (2), 2′,3′-dideoxy-3′-fluoro- (3), 3′-azido-2′,3′-dideoxy- (4) and 2′-deoxy- (5) β-L-ribofuranonucleosides of 2-chloroadenine have been synthesised and their antiviral properties examined. All these derivatives were stereospecifically prepared by glycosylation of 2,6-dichloropurine with a suitable peracylated L-xylo-furanose (6). Treatment of the resulting protected β-L-nucleoside with methanolic ammonia followed by appropriate chemical modifications gave the 2-chloro-9-(2-deoxy-β-L-threo-pentofuranosyl)adenine 11. Its 5′-O-benzoyl derivative 12 was then converted to nucleosides 1 and 2 via radical deoxygenation reaction or base-promoted β-elimination of the corresponding mesyl ester. Additionally, compounds 3-5 were obtained from 12 either by reaction with (diethylamino)sulfur trifluoride or via Mitsunobu reactions using diphenylphosphoryl azide or benzoic acid as incoming nucleophiles. The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant antiviral activity nor cytotoxicity.

Full text of DOI:10.1039/a904380b

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Stereospecific synthesis of unnatural ꢀ-L-enantiomers of
2-chloroadenine pentofuranonucleoside derivatives
Arnaud Marchand, Thierry Lioux, Christophe Mathé,* Jean-Louis Imbach and Gilles Gosselin
Laboratoire de Chimie Organique Biomoléculaire de Synthèse, U.M.R. CNRS 5625,
Université Montpellier II, Sciences et Techniques du Languedoc, 34095 Montpellier Cedex 5,
France
Received (in Cambridge) 2nd June 1999, Accepted 30th June 1999
2Ј,3Ј-Dideoxy- (1), 2Ј,3Ј-unsaturated- (2), 2Ј,3Ј-dideoxy-3Ј-fluoro- (3), 3Ј-azido-2Ј,3Ј-dideoxy- (4) and 2Ј-deoxy- (5)
β--ribofuranonucleosides of 2-chloroadenine have been synthesised and their antiviral properties examined. All
these derivatives were stereospecifically prepared by glycosylation of 2,6-dichloropurine with a suitable peracylated
-xylo-furanose (6). Treatment of the resulting protected β--nucleoside with methanolic ammonia followed
by appropriate chemical modifications gave the 2-chloro-9-(2-deoxy-β--threo-pentofuranosyl)adenine 11. Its
5Ј-O-benzoyl derivative 12 was then converted to nucleosides 1 and 2 via radical deoxygenation reaction or base-
promoted β-elimination of the corresponding mesyl ester. Additionally, compounds 3–5 were obtained from 12
either by reaction with (diethylamino)sulfur trifluoride or via Mitsunobu reactions using diphenylphosphoryl azide
or benzoic acid as incoming nucleophiles. The prepared compounds were tested for their activity against HIV and
HBV viruses, but they did not show significant antiviral activity nor cytotoxicity.
it was of interest to synthesise in a stereospecific manner and
Introduction
to evaluate the corresponding 2Ј,3Ј-dideoxy- (1), 2Ј,3Ј-di-
dehydro-2Ј,3Ј-dideoxy- (2), 3Ј-fluoro-2Ј,3Ј-dideoxy- (3) and
3Ј-azido-2Ј,3Ј-dideoxy- (4) β--ribofuranonucleosides of 2-
chloroadenine, all of them hitherto unknown except for 1.12
Furthermore, we have also undertaken the synthesis and the
antiviral evaluation of the 2Ј-deoxy derivative 5, the enantiomer
of 2-chloro-2Ј-deoxyadenosine,13 a potent antitumoural agent
(Chart 1).
Since the discovery of the human immunodeficiency virus
(HIV) as the causative agent1,2 of the acquired immuno-
deficiency syndrome (AIDS), there has been a considerable
effort in the search of new compounds which could inhibit the
replication of HIV. Among them, nucleoside analogues have
gained a decisive place. To date, six nucleoside reverse tran-
scriptase inhibitors, namely, 3Ј-azido-3Ј-deoxythymidine
(AZT), 2Ј,3Ј-dideoxyinosine (ddI), 2Ј,3Ј-dideoxycytidine (ddC),
2Ј,3Ј-didehydro-3Ј-deoxythymidine (d4T), 2Ј,3Ј-dideoxy-3Ј-
thia-β--cytidine (3TC) and (1S,4R)-4-(2-amino-6-cyclo-
propyl-9H-purin-9-yl)cyclopent-2-enemethanol
(Abacavir)
have been approved by the Food and Drug Administration
(FDA) for the treatment of HIV infection. All these nucleoside
derivatives share the same features, i.e., they are converted to
their 5Ј-triphosphate by cellular kinases, which then exerts its
biological effect as a virus-specific reverse transcriptase inhibi-
tor or a chain terminator because it lacks a hydroxy group at
the C-3Ј position.3 However, inherent drug resistance4 and
toxicity5 of the currently used anti-HIV drugs have prompted
the development of new agents possessing potent and broad
antiviral activities. In recent years, several -enantiomer nucleo-
side analogues, the mirror images of the natural -nucleosides,
have emerged as powerful antiviral agents,6 and in this regard it
is noteworthy that 3TC7,8 was also recently approved by the
FDA for use in hepatitis B virus (HBV) therapy. Their potent
antiviral effect lies in the fact that -nucleosides are phos-
phorylated by cellular kinases to their triphosphate form, which
interacts selectively with viral polymerases while having
minimal interactions with cellular polymerases. For our part,
we have shown recently that various purine β--2Ј,3Ј-dideoxy-
nucleoside analogues, namely β--2Ј,3Ј-dideoxyadenosine
(β--ddA) and β--2Ј,3Ј-didehydro-2Ј,3Ј-dideoxyadenosine
(β--d4A)9 as well as β--2Ј,3Ј-dideoxy-3Ј-fluoroadenosine
(3Ј-fluoro-β--ddA) and β--3Ј-azido-2Ј,3Ј-dideoxyadenosine10
(3Ј-azido-β--ddA) (X = H) were potent and selective anti-HIV
and -HBV agents (Chart 1). On the basis of these findings and
owing to the fact that 2-chloro substitution on the adenine agly-
cone (X = Cl) might be expected to increase biological activity,11
Chart 1
Results and discussion
A number of synthetic strategies have been described in the
J. Chem. Soc., Perkin Trans. 1, 1999, 2249–2254
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literature for the preparation of various dideoxynucleosides
and analogues from nucleosides.14–16 For our purpose, we
decided for the synthesis of the target molecules 1–5 to con-
dense a suitable protected -xylo-furanose with the com-
mercially available 2,6-dichloropurine. In accord with Baker’s
rule,17 and owing to 2-O-acyl participation during the conden-
sation, we selected as starting sugar 1,2-di-O-acetyl-3,5-di-O-
benzoyl--xylo-furanose 6 (Scheme 1). This sugar was prepared
hydroxy groups in the 3Ј and 5Ј positions was achieved by treat-
ment of 8 with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane
(TIPSCl).21 The resulting protected nucleoside 9 was treated
with O-phenyl chloro(thio)formate [PhOC(᎐S)Cl] and 4-(di-
᎐
methylamino)pyridine (DMAP) in acetonitrile to give the cor-
responding 2Ј-O-[phenoxy(thiocarbonyl)] intermediate, which
was subsequently deoxygenated with tris(trimethylsilyl)silane22
in dry toluene in the presence of α,αЈ-azoisobutyronitrile
(AIBN) to afford the 2Ј-deoxy-β--threo derivative 10 in 93%
overall yield. Desilylation of compound 10 was readily effected
by treatment with tetrabutylammonium fluoride (TBAF) on
silica gel23,24 in tetrahydrofuran (THF) at room temperature for
30 min, and the unprotected 2Ј-deoxynucleoside 11 was thereby
obtained as a crystalline solid in 76% yield after silica gel
column chromatography.
In order to prepare the target compounds 1–5, the 2Ј-deoxy-
β--threo-pentofuranonucleoside 11 was selectively converted
into the 5Ј-O-benzoyl key derivative 12 (Scheme 2). The latter
Scheme 2 Reagents and conditions: (a) BzCl, pyridine–DMF, 0 ЊC,
20 min; (b) (i) DMAP, PhO(C᎐S)Cl, CH3CN, rt, 68 h; (ii) (Me3Si)3SiH,
᎐
AIBN, 1,4-dioxane, reflux, 2 h; (c) (i) MsCl, pyridine, rt, 18 h; (ii)
TBAF, THF, rt, 1 h; (d) MeOH–NH3, rt, 18 h.
was then subject to a deoxygenation reaction to yield the
protected 2Ј,3Ј-dideoxynucleoside intermediate. Removal of the
benzoyl group with methanolic ammonia afforded the desired
dideoxynucleoside derivative 1.12 Introduction of a double
bound between the 2Ј- and 3Ј-position from 12 was achieved via
a base-promoted β-elimination. The first step involved the
preparation of the corresponding 3Ј-O-mesyl ester by treatment
with mesyl chloride in pyridine, which upon reaction with
TBAF in THF25 gave the derivative 13. Deprotection of 13
with methanolic ammonia provided the 2Ј,3Ј-didehydro-2Ј,3Ј-
dideoxynucleoside 2 obtained as a crystalline solid in 67% yield
after silica gel column chromatography. Additionally, the syn-
theses of 2Ј,3Ј-dideoxy-3Ј-fluoro- (3), 3Ј-azido-2Ј,3Ј-dideoxy- (4)
and 2Ј-deoxy- (5) β--ribofuranonucleoside derivatives were
accomplished from the key 5Ј-O-benzoyl compound 12 via
nucleophilic substitutions with inversion of configuration at the
3Ј-position (Scheme 3). Several methodologies for the synthesis
Scheme 1 Reagents and conditions: (a) 2,6-dichloropurine, SnCl4,
CH3CN, rt, 2 h; (b) MeOH–NH3, rt, 20 h; (c) TIPSCl, DMAP, pyridine,
rt, 72 h; (d) (i) DMAP, PhO(C᎐S)Cl, CH3CN, rt, 1 h; (ii) (Me3Si)3SiH,
᎐
AIBN, toluene, reflux, 3 h; (e) TBAF on silica gel, THF, rt, 30 min.
from commercial -xylose following a synthetic pathway previ-
ously described.18 The glycosylation reaction was carried out
using stannic [tin()] chloride as a catalyst19 and afforded 9-
(2-O-acetyl-3,5-di-O-benzoyl-β--xylo-furanosyl)-2,6-dichloro-
purine 7 in 86% yield after silica gel column chromatography.
The structure of 7 was fully established from 1H, 13C NMR and
UV spectra.20 Treatment of compound 7 with methanolic
ammonia removed the sugar protecting groups with con-
comitant amination of the 6-position to give 2-chloro-9-(β--
xylo-furanosyl)adenine 8. Simultaneous protection of the
2250
J. Chem. Soc., Perkin Trans. 1, 1999, 2249–2254

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Conclusions
From the present work, it appears that β--nucleoside anal-
ogues of 2-chloroadenine do not induce inhibition of HIV and
HBV replication, in contrast to their unchlorinated counter-
parts.9,10 Several factors could be responsible for the inactivity
of these nucleoside derivatives. Their inability to enter cells or
to serve as substrates for intracellular enzymes catalysing
triphosphorylation, as well as a lack of inhibition of viral
polymerases by their triphosphate forms, would all account
for their inactivity against HIV and HBV. Further research
would be needed to support these hypotheses, but since no
significant antiviral activity emerged from the present data, it
does not seem worthwhile to pursue additional studies of the
β--nucleoside analogues of 2-chloroadenine.
Experimental
Evaporation of solvents was carried out on a rotary evaporator
under reduced pressure. Mps were determined in open capillary
tubes on a Gallenkamp MFB-595-010 M apparatus and are
uncorrected. UV spectra were recorded on an Uvikon 931
(Kontron) spectrophotometer. 1H NMR spectra were recorded
at 400 MHz and 13C NMR spectra at 100 MHz in (CD3)2SO at
ambient temperature with a Bruker DRX 400. Chemical shifts
are given in δ-values, (CD3)(CD2H)SO being set at δH 2.49 and
δC 39.5 as a reference. Deuterium exchange and COSY experi-
ments were performed in order to confirm proton assignments.
Scheme 3 Reagents and conditions: (a) DAST, CH2Cl2, 0 ЊC, 15 min;
(b) DEAD, DPPA, PPh3, THF, 0 ЊC, 20 min; (c) DEAD, benzoic acid,
PPh3, THF, 0 ЊC, 15 min; (d) MeOH–NH3, rt, 18 h.
1
Coupling constants, J, are reported in Hz. 2D H–13C hetero-
nuclear COSY spectra 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
3-nitrobenzyl alcohol (NBA) or a mixture (50:50, v/v) of
glycerol and 1-thioglycerol (G–T). Only the nominal mass of
ions corresponding to the mass of the lightest chlorine isotope
is given. However, the chlorine-isotope peak intensity patterns
were ascertained; they agreed with the formula of the ions.
Specific rotations were measured on a Perkin-Elmer Model 241
spectropolarimeter (path length 1 cm), and [α]D-values 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 precoated aluminium sheets of Silica Gel 60 F254 (Merck,
Art. 5554), visualisation of products being accomplished by
UV absorbance followed by charring with 10% ethanolic sul-
furic acid and heating. Column chromatography was carried
out on Silica Gel 60 (Merck, Art. 9385).
of nucleosides fluorinated in the carbohydrate moiety have been
extensively described in the literature.26 For our purpose, we
selected as fluorinating agent (diethylamino)sulfur trifluoride
(DAST). This reagent has been widely used for the preparation
of various 3Јα-fluorodideoxynucleosides under mild conditions
and with satisfactory yields.27,28 Thus, reaction of DAST with
12 in dry dichloromethane at 0 ЊC, followed by methanolic
ammonia treatment afforded, after silica gel column chromato-
graphy, the 2Ј,3Ј-dideoxy-3Ј-fluoro-β--ribofuranonucleoside 3
as a crystalline solid in 38% overall yield. Introduction of the
azido group and inversion of the hydroxy group at C-3Ј were
achieved via Mitsunobu reactions29 using as incoming nucleo-
philes diphenylphosphoryl azide (DPPA) or benzoic acid,
respectively. Hence, reaction of 12 with diethyl azodicarb-
oxylate (DEAD), DPPA and triphenylphosphine in dry THF at
0 ЊC, followed by debenzoylation with methanolic ammonia
provided, after purification on silica gel column, the 3Ј-azido-
2Ј,3Ј-dideoxy-β--ribofuranonucleoside 4 as the sole product in
68% yield from 12. On the other hand, treatment of 12 with
DEAD, benzoic acid and triphenylphosphine in dry THF at
0 ЊC gave an inseparable mixture of compounds 13 and 14.
Therefore, deprotection with methanolic ammonia and separ-
ation of the product mixture by silica gel column chrom-
atography afforded the 2Ј,3Ј-unsaturated nucleoside 2 and the
desired 2Ј-deoxy-β--ribofuranonucleoside 5 in 17 and 47%
yield, respectively. Formation of the 2Ј,3Ј-unsaturated nucleo-
side as a side-product is probably due to a β-elimination of the
transperiplanar H-2Ј α proton from the 3Ј-O-[oxyphosphonium
salt] intermediate, resulting from the OH-3Ј activation step.30
9-(2-O-Acetyl-3,5-di-O-benzoyl-ꢀ-L-xylo-furanosyl)-2,6-
dichloropurine 7
Stannic chloride (3.45 cm3, 29.4 mmol) was added cautiously
under argon to a stirred solution of 2,6-dichloropurine (4.62 g,
24.5 mmol) and 1,2-di-O-acetyl-3,5-di-O-benzoyl--xylo-furan-
ose 6 (9.00 g, 20.4 mmol) in dry acetonitrile (450 cm3) at room
temperature. After 2 h, the resulting solution was concentrated
under reduced pressure to a small volume (approximately 50
cm3) and sodium hydrogen carbonate (20 g) and water (20 cm3)
were added carefully. When the vigorous evolution of carbon
dioxide had ceased, the mixture was filtered through a sintered
funnel covered with Celite. The Celite was then triturated and
washed several times with boiling chloroform (1000 cm3). The
combined filtrates were concentrated to approximately 150 cm3,
washed with water, dried over sodium sulfate and evaporated.
Column chromatography of the residue on silica gel using a
stepwise gradient of ethyl acetate (0–12%) in dichloromethane
afforded the title compound 7 as a white foam (10.03 g, 86%),
which was crystallised from 95% ethanol, mp 91 ЊC (Found: C,
54.85; H, 3.58; N, 9.59. C26H20Cl2N4O7 requires C, 54.65; H,
3.53; N, 9.80%); [α]D20 Ϫ44.0 (c 1.02 in Me2SO); λmax (95%
EtOH)/nm 274 (ε 5600), 231 (15 500); δH[(CD3)2SO] 2.13 (3H, s,
Biological evaluation
The unprotected nucleosides 1–5, 8 and 11 were tested for their
in vitro inhibitory effects on the replication of HIV-1 in CEM-
SS and MT-4 cell systems. None of these compounds showed
marked antiviral effects or detectable alteration of host-cell
morphology at the highest concentration tested (generally 10Ϫ1
mmol dmϪ3). When evaluated in anti-HBV assays in HepG2
cells, none of the tested compounds showed any antiviral effect
(up to a concentration of 0.1 × 10Ϫ1 mmol dmϪ3) nor cyto-
toxicity (up to a concentration of 2 × 10Ϫ1 mmol dmϪ3).
J. Chem. Soc., Perkin Trans. 1, 1999, 2249–2254
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CH3CO), 4.69 (2H, m, 5Ј-H and 5Љ-H), 4.95 (1H, m, 4Ј-H), 5.88
(1H, dd, J3Ј,2Ј 2.1, J3Ј,4Ј 6.8, 3Ј-H), 6.10 (1H, m, 2Ј-H), 6.40 (1H,
d, J1Ј,2Ј 3.3, 1Ј-H), 7.5–7.9 (10H, m, PhCO), 8.96 (1H, s, 8-H);
δC[(CD3)2SO] 21.4 (CH3CO), 62.9 (5Ј-C), 76.2 (3Ј-C), 79.0 (2Ј-
C), 79.3 (4Ј-C), 88.3 (1Ј-C), 129.4–134.7 (PhCO and 5-C), 147.4
(8-C), 150.9 (6-C), 152.2 (4-C), 153.7 (2-C), 165.4 (CO), 166.2
(CO), 170.2 (CO); m/z (FAB > 0, GT) 571 (M ϩ H)ϩ, 383 (S)ϩ,
189 (BH2)ϩ; m/z (FAB < 0, GT) 569 (M Ϫ H)Ϫ, 187 (B)Ϫ.
solution was heated under reflux for 3 h. After cooling to room
temperature, the solvent was removed under reduced pressure.
Chromatography of the residue on a silica gel column using as
eluent a stepwise gradient of methanol (0–3%) in dichloro-
methane afforded the title compound 10 (2.71 g, 93%) which was
crystallised from acetonitrile, mp 158 ЊC (Found: C, 49.69, H,
7.27, N, 13.45. C22H38ClN5O4Si2 requires C, 50.02; H, 7.25; N,
13.26%); [α]D20 ϩ65.0 (c 1.12 in Me2SO); λmax (95% EtOH)/
nm 264 (ε 14 000); δH[(CD3)2SO] 0.90–1.16 (28H, m, CH3 and
CH TIPS), 2.47 (1H, m, 2Ј-H), 2.93 (1H, septuplet, J2Љ,3Ј
5.0, J2Љ,1Ј 8.3, J2Љ,2Ј 14.5, 2Љ-H), 3.82–3.91 (2H, m, 5Ј-H and
5Љ-H), 4.06 (1H, m, 4Ј-H), 4.61 (1H, br s, 3Ј-H), 6.27 (1H, d,
1Ј-H), 7.83 (2H, br s, NH2), 8.24 (1H, s, 8-H); δC[(CD3)2SO]
12.7–13.6 (CH TIPS), 17.8–18.2 (CH3 TIPS), 41.1 (2Ј-C), 59.4
(5Ј-C), 70.7 (3Ј-C), 83.2 (1Ј-C), 84.1 (4Ј-C), 118.4 (5-C), 140.2
(8-C), 151.1 (4-C), 154.0 (2-C), 157.6 (6-C); m/z (FAB > 0,
NBA) 528 (M ϩ H)ϩ, 170 (BH2)ϩ; m/z (FAB < 0, NBA) 526
(M Ϫ H)Ϫ, 168 (B)Ϫ.
2-Chloro-9-(ꢀ-L-xylo-furanosyl)adenine 8
A solution of 7 (10.03 g, 17.5 mmol) in methanolic ammonia
(previously saturated at Ϫ10 ЊC and tightly stoppered) (450
cm3) was stirred for 20 h at room temperature, then evaporated
to dryness. The crude material obtained was dissolved in water
(100 cm3) and the resulting solution was washed with dichloro-
methane (2 × 100 cm3). The aqueous layer was evaporated
under reduced pressure and the residue was subjected to silica
gel column chromatography, with a stepwise gradient of
methanol (0–10%) in dichloromethane to afford the title com-
pound 8 (3.52 g, 67%), which was crystallised from acetonitrile,
mp 178 ЊC (Found: C, 39.25; H, 4.25; N, 22.33. C10H12-
ClN5O4ؒ2/5H2O requires C, 38.88; H, 4.18; N, 22.67%); [α]D20
ϩ66.0 (c 1.06 in Me2SO); λmax (95% EtOH)/nm 264 (ε 15 400);
δH[(CD3)2SO] 3.46 (1H, m, 5Ј-H), 3.54 (1H, m, 5Љ-H), 3.84 (1H,
br s, 3Ј-H), 3.97 (1H, br s, 4Ј-H), 4.08 (1H, br s, 2Ј-H), 4.56 (1H,
t, J 5.6, 5Ј-OH), 5.36 (1H, br s, 3Ј-OH), 5.59 (1H, d, J1Ј,2Ј 1.3,
1Ј-H), 5.71 (1H, br s, 2Ј-OH), 7.63 (2H, br s, NH2), 8.04 (1H, s,
8-H); δC[(CD3)2SO] 58.3 (5Ј-C), 73.7 (3Ј-C), 79.5 (2Ј-C), 82.7
(4Ј-C), 88.0 (1Ј-C), 116.5 (5-C), 138.8 (8-C), 148.9 (4-C), 151.8
(2-C), 155.6 (6-C); m/z (FAB > 0, GT) 302 (M ϩ H)ϩ, 170
(BH2)ϩ; m/z (FAB < 0, GT) 300 (M Ϫ H)Ϫ, 168 (B)Ϫ.
2-Chloro-9-(2-deoxy-ꢀ-L-threo-pentofuranosyl)adenine 11
To a stirred solution of 10 (2.70 g, 5.11 mmol) in anhydrous
THF (100 cm3) was added 1.1 mmol FϪ gϪ1 TBAF on silica gel
(9.30 g, 10.2 mmol). The resulting suspension was stirred for 30
min at room temperature, then filtered. The resin was washed
several times with methanol and the combined filtrates were
evaporated to dryness. The residue was subjected to silica gel
column chromatography, with a stepwise gradient of methanol
(0–10%) in dichloromethane to afford the title compound 11
(1.10 g, 76%), which was crystallised from acetonitrile, mp
194 ЊC; [α]D20 ϩ81.0 (c 1.01 in Me2SO); λmax (95% EtOH)/nm
264 (ε 14 500); δH[(CD3)2SO] 2.24 (1H, dd, J2Ј,1Ј 8.4, J2Ј,2Ј 14.3,
2Ј-H), 2.73 (1H, septuplet, J2Љ,1Ј 1.9, J2Љ,3Ј 5.4, 2Ј-H), 3.58 (1H,
m, 5Ј-H), 3.72 (1H, m, 5Љ-H), 3.91 (1H, m, 4Ј-H), 4.33 (1H, m,
3Ј-H), 4.66 (1H, t, J 5.6, 5Ј-OH), 5.44 (1H, d, J 4.5, 3Ј-OH),
6.18 (1H, dd, 1Ј-H), 7.78 (2H, br s, NH2), 8.34 (1H, s, 8-H);
δC[(CD3)2SO] 41.6 (2Ј-C), 60.7 (5Ј-C), 69.8 (3Ј-C), 83.2 (1Ј-C),
86.3 (4Ј-C), 118.6 (5-C), 141.0 (8-C), 150.8 (4-C), 153.7 (2-C),
157.6 (6-C); m/z (FAB > 0, GT) 286 (M ϩ H)ϩ, 170 (BH2)ϩ; m/z
(FAB < 0, GT) 284 (M Ϫ H)Ϫ, 168 (B)Ϫ.
2-Chloro-9-[3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-ꢀ-
L-xylo-furanosyl]adenine 9
1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane (2.30 cm3, 7.30
mmol) was added to a solution of 8 (2.01 g, 6.63 mmol) and
DMAP (0.40 g, 3.32 mmol) in dry pyridine (21 cm3). The result-
ing suspension was stirred at room temperature for 72 h then
evaporated under reduced pressure. Chromatography of the
residue on a silica gel column using as eluent a stepwise gradi-
ent of methanol (0–3%) in dichloromethane led to the title
compound 9 (3.03 g, 84%) which was crystallised from aceto-
nitrile, mp 219 ЊC (Found: C, 48.37; H, 7.30; N, 12.74. C22H38-
ClN5O5Si2 requires C, 48.55; H, 7.04; N, 12.87%); [α]D20
ϩ49.5 (c 1.06 in Me2SO); λmax (95% EtOH)/nm 264 (ε 15 000);
δH[(CD3)2SO] 0.88–1.12 (28H, m, CH3 and CH TIPS), 3.89–
3.98 (2H, m, 5Ј-H and 5Љ-H), 4.25 (1H, d, J3Ј,2Ј 2.7, 3Ј-H), 4.31
(1H, m, 4Ј-H), 4.47 (1H, d, J2Ј,1Ј 3.5, 2Ј-H), 5.86 (1H, br s, 1Ј-H),
6.23 (1H, d, J 3.6, 2Ј-OH), 7.84 (2H, br s, NH2), 8.08 (1H, s,
8-H); δC[(CD3)2SO] 12.6–13.6 (CH TIPS), 17.7–18.2 (CH3
TIPS), 58.9 (5Ј-C), 76.2 (3Ј-C), 81.3 (2Ј-C), 83.0 (4Ј-C), 90.7
(1Ј-C), 118.5 (5-C), 139.8 (8-C), 150.8 (4-C), 154.0 (2-C), 157.6
(6-C); m/z (FAB > 0, NBA) 544 (M ϩ H)ϩ, 170 (BH2)ϩ; m/z
(FAB < 0, NBA) 1085 (2M Ϫ H)Ϫ, 542 (M Ϫ H)Ϫ, 168 (B)Ϫ.
9-(5-O-Benzoyl-2-deoxy-ꢀ-L-threo-pentofuranosyl)-2-chloro-
adenine 12
Benzoyl chloride (0.47 cm3, 4.08 mmol) in dry pyridine (6.5
cm3) was added to a stirred solution of 11 (0.775 g, 2.72 mmol)
in a pyridine–DMF mixture (4:1; 37 cm3) at 0 ЊC under argon.
After 20 min, water was added (5 cm3) and the solvents were
removed under reduced pressure. Chloroform (100 cm3) was
added and the organic phase was washed successively with sat-
urated aqueous sodium hydrogen carbonate (2 × 100 cm3) and
water (100 cm3), dried over sodium sulfate and evaporated to
dryness. Column chromatography of the residue on silica gel
with as eluent a stepwise gradient of methanol (0–5%) in
dichloromethane afforded the title compound 12 (0.93 g, 88%),
which was crystallised from ethanol, mp 179–181 ЊC (Found:
C, 52.09; H, 4.29; N, 17.65. C17H16ClN5O4 requires C, 52.38; H,
4.14; N, 17.97%); [α]D20 ϩ1 (c 0.97 in Me2SO); λmax (95%
EtOH)/nm 265 (ε 16 800); λmin 245 (ε 10 100); δH[(CD3)2SO] 2.28
(1H, m, 2Ј-H), 2.81 (1H, septuplet, J2Љ,3Ј 5.6, J2Љ,1Ј 8.6, J2Љ,2Ј 14.2,
2Љ-H), 4.29 (1H, m, 4Ј-H), 4.43–4.51 (2H, m, 3Ј-H and 5Ј-H),
4.61 (1H, dd, J5Љ,4Ј 3.7, J5Ј,5Љ 11.8, 5Љ-H), 5.80 (1H, d, J 4.6,
3Ј-OH), 6.25 (1H, dd, J1Ј,2Ј 2.0, 1Ј-H), 7.49–7.96 (7H, m, NH2
and PhCO), 8.38 (1H, s, 8-H); δC[(CD3)2SO] 41.4 (2Ј-C), 65.0
(5Ј-C), 70.2 (3Ј-C), 82.8 (4Ј-C), 83.6 (1Ј-C), 118.6 (5-C), 129.1–
134.3 (PhCO), 141.0 (8-C), 150.8 (4-C), 153.8 (2-C), 157.6
(6-C), 166.5 (PhCO); m/z (FAB > 0, GT) 390 (M ϩ H)ϩ, 170
(BH2)ϩ; m/z (FAB < 0, GT) 388 (M Ϫ H)Ϫ, 168 (B)Ϫ.
2-Chloro-9-[2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-
1,3-diyl)-ꢀ-L-threo-pentofuranosyl]adenine 10
To a stirred solution of 9 (3.00 g, 5.51 mmol) in dry acetonitrile
(100 cm3) were added DMAP (2.02 g, 16.5 mmol) and phenoxy-
(thiocarbonyl) chloride (1.14 cm3, 8.26 mmol) successively.
After 1 h, the solvent was removed under reduced pressure. The
residue was dissolved in dichloromethane (100 cm3) and the
organic layer was washed with 0.5 mol dmϪ3 hydrochloric acid
(2 × 100 cm3), dried over sodium sulfate and evaporated to dry-
ness. The resulting crude material was coevaporated with dry
toluene, then dissolved in the same solvent (85 cm3) and α,αЈ-
azoisobutyronitrile (0.362 g, 2.20 mmol) and tris(trimethyl-
silyl)silane (2.21 cm3, 7.16 mmol) were added. The resultant
2-Chloro-9-(2,3-dideoxy-ꢀ-L-glycero-pentofuranosyl)adenine 1
To a stirred solution of 12 (0.290 g, 0.74 mmol) in dry
2252
J. Chem. Soc., Perkin Trans. 1, 1999, 2249–2254

View Online
acetonitrile (10 cm3) were added DMAP (0.904 g, 7.40 mmol)
and phenoxy(thiocarbonyl) chloride (0.207 cm3, 1.48 mmol)
successively. Stirring was pursued for 68 h, and the solvent
was removed under reduced pressure. The residue was dis-
solved in dichloromethane (40 cm3) and the organic layer was
washed with 0.5 mol dmϪ3 hydrochloric acid (2 × 50 cm3) and
dried over sodium sulfate. The resulting crude material was
coevaporated with dry 1,4-dioxane, then dissolved in the
same solvent (10 cm3) and α,αЈ-azoisobutyronitrile (0.048 g,
0.30 mmol) and tris(trimethylsilyl)silane (0.456 cm3, 1.48
mmol) were added. The solution was heated under reflux for
2 h. After cooling to room temperature, the solvent was
removed under reduced pressure. The residue was purified by
silica gel column chromatography using a stepwise gradient
of methanol (0–3%) in dichloromethane. The appropriate
fractions were pooled and directly treated with methanolic
ammonia (17 cm3). After 18 h, solvent was removed and the
residue was purified by silica gel column chromatography
using a stepwise gradient of methanol (0–3%) in chloroform
to afford the title compound 1 (0.135 g, 75%), which was
crystallised from ethanol, mp 238 ЊC (lit.,12 240 ЊC) (Found:
C, 44.23; H, 4.63; N, 25.68. Calc. for C10H12ClN5O2: C, 44.54;
H, 4.49; N, 25.97%); [α]D20 ϩ21.0 (c 1.12 in Me2SO) [lit.,12
ϩ4.2 (c 0.15 in MeOH)]; λmax (95% EtOH)/nm 265 (ε 15 500)
[lit.,12 (MeOH) 266 (ε 18 000)]; δH[(CD3)2SO] 1.98–2.08 (2H,
m, 3Ј-H2), 2.30–2.47 (2H, m, 2Ј-H2), 3.48 (1H, m, 5Љ-H), 3.51
(1H, m, 5Ј-H), 4.09 (1H, m, 4Ј-H), 4.94 (1H, br s, 5Ј-OH),
6.13 (1H, dd, J1Ј,2Ј 3.5, J1Ј,2Ј 6.7, 1Ј-H), 7.77 (2H, br s, NH2),
8.36 (1H, s, 8-H); δC[(CD3)2SO] 26.3 (3Ј-C), 32.7 (2Ј-C), 63.5
(5Ј-C), 82.8 (4Ј-C), 85.2 (1Ј-C), 118.9 (5-C), 140.3 (8-C), 150.7
(4-C), 153.7 (2-C), 157.6 (6-C); m/z (FAB > 0, GT) 270
(M ϩ H)ϩ, 170 (BH2)ϩ; m/z (FAB < 0, GT) 268 (M Ϫ H)Ϫ,
168 (B)Ϫ.
2-Chloro-9-(2,3-dideoxy-ꢀ-L-glycero-pent-2-enofuranosyl)-
adenine 2
A solution of 13 (0.383 g, 1.00 mmol) in methanolic ammonia
(previously saturated at Ϫ10 ЊC and tightly stoppered) (20 cm3)
was stirred at ambient temperature for 18 h. After evaporation
to dryness under reduced pressure, the residue was purified by
silica gel column chromatography using a stepwise gradient of
methanol (0–5%) in chloroform to afford the title compound 2
(0.179 g, 67%), which was crystallised from methanol, mp
200–203 ЊC (lit.,31 200–205 ЊC for the -enantiomer) (Found:
C, 44.29; H, 3.86; N, 25.50. C10H10ClN5O2ؒ1/5H2O requires C,
44.28; H, 3.86; N, 25.82%); [α]D20 ϩ29 (c 1.02 in Me2SO); λmax
(95% EtOH)/nm 265 (ε 14 700); δH[(CD3)2SO] 3.58 (2H, m, 5Ј-H
and 5Љ-H), 4.89 (1H, m, 4Ј-H), 4.96 (1H, t, J 5.6, 5Ј-OH), 6.14
(1H, ddd, J3Ј,1Ј 1.5, J3Ј,4Ј 2.2, J3Ј,2Ј 6.0, 3Ј-H), 6.48 (1H, td, J2Ј,1Ј
1.7, 2Ј-H), 6.86 (1H, m, 1Ј-H), 7.83 (1H, br s, NH2), 8.18 (1H, s,
8-H); δC[(CD3)2SO] 63.4 (5Ј-C), 88.7 (1Ј-C), 89.1 (4Ј-C), 118.6
(5-C), 126.0 (3Ј-C), 135.5 (2Ј-C), 140.5 (8-C), 151.1 (4-C), 154.0
(2-C), 157.7 (6-C); m/z (FAB > 0, NBA) 268 (M ϩ H)ϩ, 170
(BH2)ϩ; m/z (FAB < 0, NBA) 266 (M Ϫ H)Ϫ, 168 (B)Ϫ.
2-Chloro-9-(2,3-dideoxy-3-fluoro-ꢀ-L-erythro-pentofuranosyl)-
adenine 3
DAST (0.200 cm3, 1.50 mmol) was added to a solution of
nucleoside 12 (0.390 g, 1.00 mmol) in dry dichloromethane (25
cm3) at 0 ЊC under argon and the mixture was stirred for 15
minutes before being poured into saturated aqueous sodium
hydrogen carbonate (50 cm3) at 0 ЊC. The organic phase was
washed with water (2 × 50 cm3), dried over sodium sulfate and
evaporated to dryness. The residue was purified on a silica
gel column with a stepwise gradient of methanol (0–4%) in
dichloromethane. The appropriate fractions were pooled, and
directly treated with methanolic ammonia for 18 h. After evap-
oration to dryness under reduced pressure, the residue was
purified by silica gel column chromatography using a stepwise
gradient of methanol (0–4%) in chloroform to afford the title
compound 3 (0.110 g, 38% overall yield from 12), which was
crystallised from ethanol, mp 204–205 ЊC (Found: C, 41.48;
H, 3.92; N, 24.35. C10H11ClFN5O2 requires C, 41.75; H, 3.85;
N, 24.34%); [α]D20 ϩ42 (c 1.06 in Me2SO); λmax (95% EtOH)/
nm 265 (ε 14 000); δH[(CD3)2SO] 2.66 (1H, m, 2Ј-H), 2.92 (1H,
m, 2Ј-H), 3.58 (2H, m, 5Ј-H and 5Љ-H), 4.21 (1H, td, J4Ј,3Ј 4.8,
J4Ј,F 26.7, 4Ј-H), 5.17 (1H, t, J 5.6, 5Ј-OH), 5.42 (1H, dd, J3Ј,2Ј
4.8, J3Ј,F 53.6, 3Ј-H), 6.30 (1H, dd, J1Ј,2Ј 5.7 , J1Ј,2Љ 9.1, 1Ј-H), 7.88
(2H, br s, NH2), 8.37 (1H, s, 8-H); δC[(CD3)2SO] 37.5 (d, J2Ј-C,F
20.6, 2Ј-C), 61.8 (d, J5Ј-C,F 11.0, 5Ј-C), 84.6 (1Ј-C), 86.4 (d,
J4Ј-C,F 22.0, 4Ј-C), 174.3 (d, J3Ј-C,F 20.6, 3Ј-C), 119.1 (5-C),
140.8 (8-C), 151.0 (4-C), 153.8 (2-C), 157.7 (6-C); m/z (FAB > 0,
GT) 575 (2M ϩ H)ϩ, 288 (M ϩ H)ϩ, 170 (BH2)ϩ; m/z (FAB <
0, GT) 573 (2M Ϫ H)Ϫ, 286 (M Ϫ H)Ϫ, 168 (B)Ϫ.
9-(5-O-Benzoyl-2,3-dideoxy-ꢀ-L-glycero-pent-2-enofuranosyl)-
2-chloroadenine 13
Methanesulfonyl chloride (0.36 cm3, 4.62 mmol) was added
to a solution of nucleoside 12 (0.60 g, 1.54 mmol) in dry
pyridine (23 cm3) at 0 ЊC under argon. The resultant solution
was stirred at room temperature for 18 h, and water was
added (3 cm3). After removal of solvents under reduced
pressure, the residue was dissolved in dichloromethane (100
cm3) and the organic phase was washed successively with
saturated aqueous sodium hydrogen carbonate (100 cm3)
and water (2 × 100 cm3). The organic layer was dried over
sodium sulfate and evaporated to dryness. The crude
material was dissolved in anhydrous THF (7 cm3) and a 1.1 mol
dmϪ3 solution of TBAF in THF (14 cm3, 13.6 mmol) was
added. The mixture was stirred for 1 h at ambient tem-
perature, then evaporated to dryness. Dichloromethane (150
cm3) and water (50 cm3) were added. The organic phase was
separated, dried and evaporated under reduced pressure. The
residue was subjected to silica gel column chromatography,
with a stepwise gradient of methanol (0–3%) in dichloro-
methane to afford the title compound 13 (0.485 g,
91% overall yield from 12), mp 173–174 ЊC (from MeOH)
(Found: C, 53.57; H, 3.93; N, 18.56. C17H14ClN5O3ؒ1/2H2O
requires C, 53.62; H, 3.97; N, 18.39%); [α]D20 ϩ77 (c 0.88 in
Me2SO); λmax (95% EtOH)/nm 265 (ε 17 000), 225 (15 500);
λmin 245 (ε 10 700); δH[(CD3)2SO] 4.46 (1H, dd, J5Ј,4Ј 5.4, J5Ј,5Љ
12.0, 5Ј-H), 4.52 (1H, dd, J5Љ,4Ј 3.2, 5Љ-H), 5.23 (1H, m, 4Ј-H),
6.28 (1H, ddd, J3Ј,1Ј 1.6, J3Ј,4Ј 2.3, J3Ј,2Ј 6.0, 3Ј-H), 6.59 (1H, td,
J2Ј,1Ј 2.1, 2Ј-H), 6.89 (1H, m, 1Ј-H), 7.48–7.89 (7H, m, NH2
and PhCO), 8.02 (1H, s, 8-H); δC[(CD3)2SO] 66.5 (5Ј-C), 85.6
(4Ј-C), 89.1 (1Ј-C), 118.8 (5-C), 126.9 (3Ј-C), 129.1–130.1
(PhCO), 134.0 (2Ј-C), 134.4 (PhCO), 139.9 (8-C), 151.1 (4-C),
154.1 (2-C), 157.7 (6-C); m/z (FAB > 0, GT) 268 (M Ϫ Ph-
CO ϩ 2H)ϩ, 170 (BH2)ϩ; m/z (FAB < 0, GT) 370 (M Ϫ H)Ϫ,
168 (B)Ϫ.
9-(3-Azido-2,3-dideoxy-ꢀ-L-erythro-pentofuranosyl)-2-chloro-
adenine 4
DEAD (0.472 cm3, 3.00 mmol) and DPPA (0.642 cm3, 3.00
mmol) in dry THF (18 cm3) were added to a solution of nucleo-
side 12 (0.390 g, 1.00 mmol) and triphenylphosphine (0.787 g,
3.00 mmol) in dry THF (12 cm3) at 0 ЊC under argon. The
resulting solution was stirred for 20 min at 0 ЊC. Solvent was
removed and the residue was subjected to silica gel column
chromatography with a stepwise gradient of methanol (0–3%)
in dichloromethane. The appropriate fractions were pooled and
directly treated with methanolic ammonia for 18 h. Evapor-
ation to dryness and column chromatography on silica gel using
a stepwise gradient of methanol (0–4%) in chloroform afforded
the title compound 4 (0.213 g, 68% overall yield from 12), mp
169–171 ЊC (from ethanol); [α]D20 ϩ8.0 (c 1.00 in Me2SO);
λmax (95% EtOH)/nm 265 (ε 17 100); δH[(CD3)2SO] 2.49 (1H, m,
2Ј-H), 2.88 (1H, m, 2Ј-H), 3.52–3.63 (2H, m, 5Ј-H and 5Љ-H),
J. Chem. Soc., Perkin Trans. 1, 1999, 2249–2254
2253

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3.90 (1H, m, 4Ј-H), 4.58 (1H, dd, J3Ј,4Ј 5.2, J3Ј,2Ј 11.6, 3Ј-H), 5.13
(1H, t, J 5.6, 5Ј-OH), 6.22 (1H, t, J1Ј,2Ј 6.3, 1Ј-H), 7.84 (2H, br s,
NH2), 8.37 (1H, s, 8-H); δC[(CD3)2SO] 37.0 (2Ј-C), 61.6 (3Ј-C),
61.9 (5Ј-C), 83.8 (1Ј-C), 85.5 (4Ј-C), 119.0 (5-C), 140.6 (8-C),
150.9 (4-C), 153.9 (2-C), 157.6 (6-C); m/z (FAB > 0, GT)
311 (M ϩ H)ϩ, 170 (BH2)ϩ; m/z (FAB < 0, GT) 309 (M Ϫ H)Ϫ,
168 (B)Ϫ.
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2-Chloro-9-(2-deoxy-ꢀ-L-erythro-pentofuranosyl)adenine 5
DEAD (0.364 cm3, 2.31 mmol) in dry THF (20 cm3) was added
to a stirred solution of nucleoside 12 (0.300 g, 0.77 mmol),
triphenylphosphine (0.605 g, 2.31 mmol) and benzoic acid
(0.282 g, 2.31 mmol) in dry THF (20 cm3) at 0 ЊC under argon.
The resulting solution was stirred for 15 min at 0 ЊC. Solvent
was removed and the residue was subjected to silica gel column
chromatography with a stepwise gradient of methanol (0–3%)
in dichloromethane to afford a mixture of compounds 13 and
14. The mixture was treated with methanolic ammonia for 18 h.
Evaporation to dryness and column chromatography (on silica
gel) of the residue using a stepwise gradient of methanol
(0–9%) in dichloromethane afforded successively the nucleoside
derivative 2 and the title compound 5.
Compound 2 (0.035 g, 17% overall yield from 12). The
physicochemical properties of 2 were identical with those
previously described.
Compound 5 (0.103 g, 47% overall yield from 12), mp 212–
214 ЊC (from ethanol) (lit.,13 210–215 ЊC for the -enantiomer)
(Found: C, 41.57; H, 4.26; N, 23.55. C10H12ClN5O3ؒ1/3H2O
requires C, 41.18; H, 4.38; N, 24.01%); [α]D20 ϩ20.0 (c 1.00
in Me2SO) {lit.,13 for the -enantiomer, [α]D26 Ϫ18.8 (c 1.00 in
DMF)}; λmax(95% EtOH)/nm 265 (ε 12 300); δH[(CD3)2SO] 2.26
(1H, m, 2Ј-H), 2.73 (1H, septuplet, J2Ј,1Ј 1.9, J2Ј,3Ј 5.4, J2Ј,2Ј 13.3,
2Ј-H), 3.49 (1H, m, 5Ј-H), 3.59 (1H, m, 5Љ-H), 3.84 (1H, m,
4Ј-H), 4.37 (1H, m, 3Ј-H), 4.97 (1H, t, J 5.4, 5Ј-OH), 5.32 (1H,
d, J 3.2, 3Ј-OH), 6.24 (1H, t, J1Ј,2Ј 6.5, 1Ј-H), 7.82 (2H, br s,
NH2), 8.34 (1H, s, 8-H); δC[(CD3)2SO] 40.1 (2Ј-C), 62.5 (5Ј-C),
71.5 (3Ј-C), 84.4 (1Ј-C), 88.8 (4Ј-C), 119.0 (5-C), 140.7 (8-C),
150.9 (4-C), 153.8 (2-C), 157.6 (6-C); m/z (FAB > 0, GT) 286
(M ϩ H)ϩ, 170 (BH2)ϩ; m/z (FAB < 0, GT) 284 (M Ϫ H)Ϫ,
168 (B)Ϫ.
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Acknowledgements
These investigations were supported by Grants from A.N.R.S.,
‘Agence Nationale de Recherche sur le SIDA,’ France. We
gratefully acknowledge Dr A.-M. Aubertin (Université Louis
Pasteur, Strasbourg, France) and Prof. J.-P. Sommadossi
(University of Alabama at Birmingham, Alabama, USA) for
the biological results. One of us (A. M.) is particularly grateful
to the Ministère de l’Education Nationale, de la Recherche et de
la Technologie, France, for a doctoral fellowship.
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