Synthesis and biological evaluation of 6-substituted purinylcarbanucleosides with a cyclopenta[b]thiophene pseudosugar

Article abstract of DOI:10.1055/s-0029-1216908

The first members of a new family of heterocarbobicyclic nucleoside analogues have been synthesized from the cis/trans mixture of (4-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)methanols (cis/trans-7). The separation of the cis and trans intermediates

Full text of DOI:10.1055/s-0029-1216908

2766
PAPER
Synthesis and Biological Evaluation of 6-Substituted Purinylcarbanucleosides
with a Cyclopenta[b]thiophene Pseudosugar
6
-Substituted P
a
urinylcar
b
u
anucleosidesla Abeijón,a José M. Blanco,*a Olga Caamaño,a Franco Fernández,a Marcos D. García,b Xerardo García-Mera,a
José E. Rodríguez-Borges,c Jan Balzarini,d Erik De Clercqd
a
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Fax +34(981)594912; E-mail: jm.blanco@usc.es
b
Departmento de Química Fundamental, Facultade de Ciencias, Campus da Zapateira s/n, 15701 A Coruña, Spain
c
CIQ, Departamento de Química, Facultade de Ciencias do Porto, Rua do Campo Alegre, 687-4169007 Porto, Portugal
d
Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
Received 16 April 2009
ficiency virus (HIV), and d4T is still in clinical use under
Abstract: The first members of a new family of heterocarbobicy-
clic nucleoside analogues have been synthesized from the cis/trans
mixture of (4-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-6-
yl)methanols (cis/trans-7). The separation of the cis and trans inter-
the commercial name Stavudine®.5 The antiviral activity
of these compounds is thought to be related to the confor-
mational restriction imposed on the pseudosugar moiety
mediates during the preparation of the 6-chloropurine derivatives by its double bond,6 which also increases the lipophilicity
allowed a separate preparation of the purine heterocarbanucleosides
cis-10 and trans-11, from which cis-12–14 and trans-16–18 were
obtained by replacement of the 6-chloro substituent with amino, hy-
droxy, and cyclopropylamino groups. Additionally, the 6-phe-
of the molecule and thereby facilitate its access to the cen-
tral nervous system, a major reservoir of the HIV virus.7
NH2
O
nylpurinyl analogues cis-15 and trans-19 were prepared from cis-10
and trans-11 using Suzuki–Miyaura methodology. In tests of anti-
viral and cytostatic activities, compound 11 showed cytostatic ac-
tivity against Molt4/C8 human T lymphoblastic leukemia cells.
Antiviral activity was shown by compounds 15 and 19 against
Punta Toro virus and Coxackie virus B4 (compound 11).
N
NH
N
O
N
O
O
O
HO
HO
1
2
Key words: heterobicyclic amino alcohol, cyclopenta[b]thiophene,
Suzuki–Miyaura cross-coupling reaction, purinylcarbanucleoside,
biological activity
Figure 1 Modified pyrimidine nucleosides d4C (1) and d4T (2)
In carbanucleosides (CNs),8 the D-ribose moiety of the
natural nucleosides is replaced by an aliphatic or aromatic
carbocycle. Carbanucleosides include the well-known
anti-HIV agents carbovir (3)9 and abacavir (4, marketed
as Ziagen®);10 the purine derivative BMS-200475 (5),11
which is active against hepatitis B virus (HBV); and the
pyrimidine derivative carba-BVDU (6), which is active in
vitro against herpes simplex virus 1 (HSV-1) (Figure 2).12
Once in a cell, they are active for a longer period than the
analogues with the endocyclic oxygen of natural nucleo-
sides because they resist the phosphorylases and hydro-
lases that cleave the glycoside bonds of the latter.
Furthermore, replacement of the endocyclic furanose ox-
ygen by a methylene group makes CNs less toxic than
their parent compounds.
The development of new antiviral drugs is a dynamic pro-
cess driven by the identification of new molecular targets
and the emergence of problems associated with drugs in
current clinical use (resistance, toxicity, etc.).1 In recent
decades, many research programs have sought nontoxic
antiviral drugs that act by selective inhibition of kinases or
polymerases.2 Among the most extensively and intensive-
ly studied compounds are the nucleoside analogues,
which become active when acted upon by kinases after
entry into a target cell. A number of these prodrugs have
been found to have antiviral activity and/or antitumoral
activity, and some are in clinical use.3
The many structural modifications that have been made to
natural nucleosides in the search for desired biological
properties include the introduction of a double bond be-
tween positions 2¢ and 3¢ of the sugar ring. The seminal
work of Balzarini et al.4 showed that when the parent com-
pound is a pyrimidine nucleoside the resulting cytosine
and thymidine analogues [d4C (1) and d4T (2), respec-
tively; see Figure 1] are active against human immunode-
In previous papers our research group reported the synthe-
sis of abacavir analogues in which a purine or pyrimidine
base was linked to an indane system.13 Some of these
compounds showed considerable cytostatic activity
against human T lymphoblastic leukemia cell lines
(Molt4/C8 and CEM/0) and murine leukemia cells
(L1210/0),14 and many of the active purine derivatives
featured an oxo or amino group at position 6 that would
allow hydrogen bonding between the nucleobase and the
polymerases and other enzymes involved in nucleic acid
metabolism.15
SYNTHESIS 2009, No. 16, pp 2766–2772
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.07.2009
DOI: 10.1055/s-0029-1216908; Art ID: P06109SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
6-Substituted Purinylcarbanucleosides
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X
N
O
N
Cl
NOH
MeO2C
H2N
N
N
N
N
N
NH
N
H
N
NH2
NH2
N
S
HO
HO
HO
AlH3
THF, Δ
85%
S
3: X = OH
4: X = c-PrNH
HO
cis-8
NH2
5
HO
O
N
5-amino-4,6-dichloropirimidine
n-BuOH, Et3N, Δ
Br
Cl
N
NH
S
77%
H2N
N
O
H
N
cis/trans-7
HO
HO
HO
6
S
trans-9
Figure 2 Carbanucleosides 3–6
Scheme 1
In the search for ways of increasing the lipophilicity and
polar interactions of the pseudosugar while maintaining
the rigidity of this moiety, our group has now begun to ex-
plore a new class of analogues in which the aromatic ring
of the indane system has been replaced by a heterocyclic
aromatic ring system.16 The results have been encourag-
ing: for example, preliminary biological assays of purinyl-
methyl derivatives of 2-benzylcyclopenta[c]pyrazoles
have found them to possess high activity against varicella
zoster virus and cytomegalovirus at subcytotoxic concen-
trations,17 and derivatives of 1-methylcyclopenta[c]pyra-
zoles have cytostatic activity.18 We are currently
exploring the case in which the pseudosugar is cyclopen-
ta[b]thiophene; in the work reported here, we examined
the dependence of the biological activity of some mem-
bers of this family on the stereochemistry of the pseu-
dosugar-nucleobase linkage.
ing hydroxy iminoester in refluxing THF with AlH3 that
had been freshly prepared in quantitative yield from
LiAlH4 and H2SO4.21 Reaction of cis/trans-7 for 45 hours
with 5-amino-4,6-dichloropyrimidine and Et3N in reflux-
ing n-BuOH afforded a mixture of cis-8 and trans-9 in
41% and 36% yield, respectively (the combined yield of
77% was less with shorter reaction times), and flash col-
umn chromatography of this mixture using 40:1 CHCl3–
MeOH as eluent efficiently separated cis-8 from trans-9
(in addition, a small amount of starting material was re-
covered and traces of 5-amino-4-chloro-6-hydroxypyrim-
idine were detected).
Treatment of cis-8 and trans-9 with triethyl orthoformate,
for the synthesis of the five-membered ring of purine22 af-
forded the corresponding 6-chloropurines, cis-10 and
trans-11, in 80% and 87% yield, respectively (Scheme 2).
In turn, these heterocarbanucleosides were directly con-
verted into the corresponding 6-amino, 6-cyclopropy-
lamino, and 6-hydroxy derivatives by reaction with the
appropriate nucleophile: reaction with NH4OH in dioxane
afforded cis-12 and trans-16 in 98% and 85% yield, re-
spectively; reaction with cyclopropylamine in refluxing
EtOH, cis-13 (88%) and trans-17 (73%); and reaction
with 0.25 N NaOH in dioxane for 24 hours at 50 °C, cis-
14 (59%) and trans-18 (52%).
Carbanucleosides are generally prepared either by con-
structing the nucleobase on the amino group of a suitable
amino alcohol,19 or by direct coupling of the heterocyclic
base with an appropriately functionalized carbocyclic
system16a,b,17 (e.g., by means of the Mitsunobu reac-
tion).13c,14a In this work, we chose the former approach not
only because it allows divergent synthesis of multiple
CNs from a single pseudosugar intermediate, but also be-
cause it would hopefully allow easy separation of stereo-
isomers with cis and trans pseudosugar-nucleobase
linkages (whereas in previous work20 direct separation of
the mixture of amino pseudosugar isomers cis/trans-7 had
been found to afford only moderate combined yields). Our
hopes in this respect were fulfilled; thus, flash column
chromatography of the heterocarbanucleoside precursors
cis-8 and trans-9 (Scheme 1) was accomplished more ef-
ficiently (96%). These CNs have been synthesized in its
racemic form, so the resolution of the enantiomers was
planned for a later work, once the biological activities of
the racemic mixtures were known.
The relative configuration of the heterocarbanucleoside
trans-18 was confirmed by means of X-ray crystallo-
graphic analysis of a single crystal obtained by recrystal-
lization of a pure sample from 9:1 EtOAc–MeOH
(Figure 3).23
In view of the high antineoplastic activities of certain 6-
arylpurinyl nucleosides15 and related acyclic nucleotide
analogues24 (including previous products of our
group),14a,b we also synthesized the 6-arylpurinyl hetero-
carbanucleosides cis-15 and trans-19, using Hocek’s
protocol25 to achieve Suzuki–Miyaura cross-coupling26
between 6-halopurines and boronic acids. Heating com-
pounds cis-10 and trans-11 at 100 °C with phenylboronic
acid, tetrakis(triphenylphosphine)palladium, and potassi-
The amino alcohol mixture cis/trans-7 was synthesized as
before,20 in spectroscopically determined 1:1 isomer ratio
and 55% combined yield, by reduction of the correspond-
Synthesis 2009, No. 16, 2766–2772 © Thieme Stuttgart · New York

2768
P. Abeijón et al.
PAPER
NH2
N
N
N
N
HO
NH
N
cis-12: 98%
trans-16: 85%
N
N
S
N
14 M NH4OH
dioxane, Δ
Cl
N
HO
H2N
N
Cl
N
H
N
cis-13: 88%
trans-17: 73%
c-PrNH2
S
N
N
N
HO
HC(OEt)3
12 N HCl
EtOH, Δ
O
HO
S
cis-8 or
trans-9
N
0.25 N NaOH
NH
dioxane, 50 °C
cis-10: 80%
trans-11: 87%
N
N
S
HO
Pd(PPh3)4 PhB(OH)3
Tol, Δ
cis-14: 59%
trans-18: 52%
S
K2CO3
Ph
N
N
N
N
HO
cis-15: 61%
trans-19: 77%
S
Scheme 2
vaccinia virus, vesicular stomatitis virus (VSV), and both
thymidine kinase-positive (TK+) and thymidine kinase-
deficient (TK–) strains of varicellazoster virus (VZV). In
HeLa cells: VSV, Coxsackie virus B4, and respiratory
syncytial virus. In Vero cells: reovirus 1, Sindbis virus,
Coxsackie virus B4, and Punta Toro virus. In HEL cells,
compound 10 had an EC50 of 52 mM against a TK+ VZV
(OKA); compounds 15 and 19 had EC50’s of 69 mM [eight
times less than their MCCs (MCC = minimum cytotoxic
concentration)] against vaccinia virus; and EC50’s of 115
and 122 mM (five times less than their MCCs) were shown
by compounds 13 and 19, respectively, against HSV-2 G.
Also, compounds 10 and 11 were both strong inhibitors of
HEL cell growth, with CC50’s of 32 and 4 mM, respective-
ly.
Figure 3 MERCURY projection (with 40% probability ellipsoids)
of the molecular structure of trans-18 (the atomic numbering is arbi-
trary)
In Vero cells, EC50’s of 23 mM (compounds 15 and 19)
and 26 mM (compound 11) (five times less than their
MCCs) were shown against Punta Toro virus and by com-
pound 11 against Coxsackie virus B4.
um carbonate in anhydrous toluene afforded the 6-phenyl
derivatives cis-15 and trans-19 in good yields. Attempts
to improve these results by using the Buchwald
methodology27 were unsuccessful.
Compounds 10–19 were evaluated for their cytostatic ac-
tivities against murine leukemia cells (L1210/0) and hu-
man T lymphoblastic leukemia cells (Molt4/C8 and CEM/
0). Activity was quantified as IC50, the concentration re-
quired to inhibit cell proliferation during the linear growth
phase by 50%.28 Against Molt4/C8 cells, compound 11
had an IC50 of 26 mM, and compounds 15 and 19 activities
of 46 and 37 mM, respectively. Against CEM/0 cells,
compounds 11 and 19 had IC50’s of 42 and 40 mM, respec-
tively. No compound had an IC50 of less than 40–50 mM
against L1210/0 cells.
Previously established procedures28 were employed to de-
termine the in vitro antiviral activities of compounds 10–
19 against a variety of DNA and RNA viruses. In human
embryonic lung (HEL) cells: cytomegalovirus (CMV;
strains AD-169 and Davis), herpes simplex virus 1 (HSV-
1; strain KOS and the thymidine-kinase-deficient strain
KOS ACVr), herpes simplex virus 2 (HSV-2; strain G),
Synthesis 2009, No. 16, 2766–2772 © Thieme Stuttgart · New York

PAPER
6-Substituted Purinylcarbanucleosides
2769
dine C-2), 137.43 (C-6a), 129.46 (C-3), 123.88 (C-3a), 122.19 (C-
2), 65.74 (CH2O), 51.81 (C-4), 43.51 (C-6), 41.16 (C-5).
In conclusion, we have reported the synthesis of the new
6-substituted purinyl heterocarbanucleosides cis-10, 12–
15 and trans-11, 16–19, which like the well-known bio- EIMS: m/z (%) = 297 (4, [M + 1]+), 296 (11, [M+]), 266 (3, [M+ –
CH2O]), 153 (100, [M+ – C4H4ClN4]), 135 (90, [M+ – C4H6ClN4O]),
125 (28), 121 (34).
logically active purinyl heterocarbanucleosides carbovir
and abacavir have a pseudosugar (in this case cyclopen-
Anal. Calcd for C12H13ClN4OS: C, 48.56; H, 4.42; Cl, 11.95; N,
18.88; S, 10.80. Found: C, 48.41; H, 4.51; Cl, 12.03; N, 18.72; S,
11.02.
ta[b]thiophenylmethanol) that features an endocyclic dou-
ble bond. The cis and trans isomers were efficiently
separated by flash column chromatography during con-
struction of the nucleobase on the pseudosugar, and their
relative stereochemistry was elucidated by X-ray crystal-
lography of the inosine derivative trans-18. Greatest cyto-
static activity was shown by compound 11, with an IC50 of
26 mM against Molt4/C8 cells, followed by compounds
15 and 19. Greatest antiviral activity was shown by com-
pounds 11, 15, and 19, which in Vero cells had EC50’s of
26 mM (11) and 23 mM (15 and 19) (five times less than
their MCCs) against Punta Toro virus and (in the case of
compound 11) Coxsackie virus B4.
( )-trans-9
An analytical sample was obtained by recrystallization from
EtOAc; white solid; mp 89–91 °C; Rf = 0.17 (CHCl3–MeOH, 20:1).
IR (KBr): 3442, 3346, 3245, 2924, 1649, 1575, 1466, 1421, 1089
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.78 (s, 1 H, pyrimidine 2-H),
7.35 (d, J = 5.1 Hz, 1 H, 2-H), 7.01 (d, J = 7.2 Hz, 1 H, D2O exch.,
NH), 6.86 (d, J = 4.9 Hz, 1 H, 3-H), 5.50–5.44 (m, 1 H, 4-H), 5.07
(br s, 2 H, D2O exch., NH2), 4.95–4.92 (m, 1 H, D2O exch., OH),
3.59–3.50 (m, 1 H, 6-H), 3.48–3.41 (m, 2 H, OCH2), 2.61–2.52 (m,
1 H, 5-H), 2.39–2.31 (m, 1 H, 5-H).
13C NMR (75 MHz, DMSO-d6): d = 151.54 (pyrimidine C-6),
146.85 (pyrimidine C-4), 146.60 (pyrimidine C-5), 145.83 (pyrimi-
dine C-2), 136.88 (C-6a), 129.49 (C-3), 123.91 (C-3a), 122.39 (C-
2), 65.47 (CH2O), 51.64 (C-4), 43.46 (C-6), 41.44 (C-5).
Melting points are uncorrected and were determined in a Reichert
Kofler Thermopan or in capillary tubes in a Büchi 510 apparatus. IR
spectra were recorded on a Perkin-Elmer 1640 FTIR spectropho-
1
tometer. H NMR spectra (300 MHz) and 13C NMR spectra (75
EIMS: m/z (%) = 296 (1, [M+]), 278 (1, [M+ – H2O]), 153 (65, [M+
– C4H4ClN4]), 135 (100, [M+ – C4H6ClN4O]), 125 (38), 121 (60), 97
(31).
MHz) were recorded in a Bruker AMX 300 spectrometer using
TMS as internal reference (chemical shifts in d values, J in Hz). EI
and FAB mass spectra were recorded on HP5988A and Micromass
Autospec spectrometers, respectively. Microanalyses were per-
formed using a Perkin-Elmer 240B elemental analyzer by the Mi-
croanalysis Service of the University of Santiago. X-ray diffraction
data were collected with an Enraf-Nonius CAD4 automatic diffrac-
tometer using the program CAD4-EXPRESS. Most reactions were
monitored by TLC on precoated silica gel plates (Merck 60 F254,
0.25 mm). Synthesized products were purified by flash column
chromatography on silica gel (Merck 60, 230–240 mesh), and were
crystallized, if necessary. Solvents were dried by distillation prior to
use.
Anal. Calcd for C12H13ClN4OS: C, 48.56; H, 4.42; Cl, 11.95; N,
18.88; S, 10.80. Found: C, 49.02; H, 4.38; Cl, 12.14; N, 18.67; S,
11.05.
( )-[cis-4-(6-Chloro-9H-purin-9-yl)-5,6-dihydro-4H-cyclopen-
ta[b]thiophen-6-yl]methanol (10)
A mixture of ( )-cis-8 (0.23 g, 0.78 mmol), triethyl orthoformate
(4.3 mL, 38.3 mmol), dioxane (10 mL), and aq 12 N HCl (0.27 mL)
was stirred at r.t. for 22 h. Once the reaction was judged to have ter-
minated, the solvents were removed under reduced pressure. The re-
sulting residue was dissolved in dioxane (5 mL) and treated with aq
0.5 N HCl (16 mL) for 2 h. The organic solvent was evaporated un-
der reduced pressure, the aqueous layer was brought to pH 8 by the
addition of aq 2 N NaOH (8 mL), and the resulting mixture was ex-
tracted with EtOAc (3 × 50 mL). The combined organic layers were
dried (Na2SO4) and concentrated to dryness. Column chromatogra-
phy of the residue on silica gel (8 g) using 80:1 CH2Cl2–MeOH as
eluent yielded ( )-cis-10 (0.19 g, 80%) as a white solid; mp 162–
164 °C; Rf = 0.25 (CHCl3–MeOH, 40:1).
( )-{cis-4-[(5-Amino-6-chloropyrimidin-4-yl)amino]-5,6-di-
hydro-4H-cyclopenta[b]thiophen-6-yl}methanol (8) and
( )-{trans-4-[(5-Amino-6-chloropyrimidin-4-yl)amino]-5,6-di-
hydro-4H-cyclopenta[b]thiophen-6-yl}methanol (9)
5-Amino-4,6-dichloropyrimidine (1.04 g, 6.38 mmol) was added to
a solution of the amino alcohol mixture ( )-cis/trans-7 (0.6 g, 3.55
mmol) in anhyd n-BuOH (60 mL) and Et3N (4 mL). This mixture
was refluxed under argon for 45 h, cooled to r.t., and the solvents
were removed under reduced pressure. Chromatography of the solid
residue on silica gel (60 g) using 40:1 CHCl3–MeOH as eluent af-
forded first ( )-cis-8 (0.43 g, 41%) and then ( )-trans-9 (0.38 g,
36%).
IR (KBr): 3373, 3277, 1595, 1564, 1445, 1397, 1341, 1126, 1089
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.74 (s, 1 H, purine 8-H), 8.10 (s,
1 H, purine 2-H), 7.36 (d, J = 5.0 Hz, 1 H, 2-H), 6.74 (d, J = 5.0 Hz,
1 H, 3-H), 6.12 (dd, J = 8.6, 4.1 Hz, 1 H, 4-H), 3.95 and 3.77 (AB
part of an ABM system, JAB = 10.5, JAM = 5.4 and JBM = 4.4 Hz, 2
H, OCH2), 3.66–3.59 (m, 1 H, 6-H), 3.51–3.41 (m, 1 H, 5-H), 2.95
(t, J = 4.5 Hz, 1 H, D2O exch., OH), 2.47 (dt, J = 14.2, 4.3 Hz, 1 H,
5-H).
( )-cis-8
An analytical sample was obtained by recrystallization from
EtOAc; white solid; mp 197-198 °C; Rf = 0.23 (CHCl3–MeOH,
20:1).
IR (KBr): 3256, 2991, 2934, 1582, 1505, 1482, 1425, 1059 cm–1.
13C NMR (75 MHz, CDCl3): d = 152.16 (purine C-2), 151.88 (pu-
rine C-6), 151.22 (purine C-4), 148.93 (purine C-5), 144.82 (purine
C-8), 142.35 (C-6a), 132.18 (C-3a), 131.94 (C-3), 121.26 (C-2),
65.74 (CH2O), 55.51 (C-4), 43.79 (C-6), 41.70 (C-5).
1H NMR (300 MHz, DMSO-d6): d = 7.77 (s, 1 H, pyrimidine 2-H),
7.35 (d, J = 4.9 Hz, 1 H, 2-H), 7.00 (d, J = 7.3 Hz, 1 H, D2O exch.,
NH), 6.83 (d, J = 4.9 Hz, 1 H, 3-H), 5.48–5.46 (m, 1 H, 4-H), 5.09
(br s, 2 H, D2O exch., NH2), 4.98-4.95 (m, 1 H, D2O exch., OH),
3.69–3.59 (m, 1 H, 6-H), 3.43–3.41 (m, 1 H, OCHH), 3.35–3.25 (m,
1 H, OCHH), 3.02–2.97 (m, 1 H, 5-H), 1.90–1.86 (m, 1 H, 5-H).
FABMS: m/z (%) = 307 (15, [M + 1]+), 306 (1, [M+]), 288 (11, [M+
– H2O]), 155 (35), 154 (100, [M+ – C5HClN4]), 153 (14), 137 (99,
[M+ – C5H2ClN4O]), 109 (24).
13C NMR (75 MHz, DMSO-d6): d = 151.60 (pyrimidine C-6),
146.67 (pyrimidine C-4), 146.02 (pyrimidine C-5), 145.84 (pyrimi-
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P. Abeijón et al.
PAPER
Anal. Calcd for C13H11ClN4OS: C, 50.90; H, 3.61; Cl, 11.56; N,
18.26; S, 10.45. Found: C, 50.68; H, 3.69; Cl, 11.70; N, 18.23; S,
10.52.
( )-6,9-Dihydro-9-[cis-(6-hydroxymethyl)-5,6-dihydro-4H-cy-
clopenta[b]thiophen-4-yl)]-1H-purin-6-one (14)
Aq 0.25 N NaOH (8 mL) was added to a solution of ( )-cis-10
(0.1 g, 0.33 mmol) in dioxane (15 mL). The mixture was heated at
50 °C for 24 h and cooled to r.t. The solvents were removed under
reduced pressure and the solid residue (0.23 g) was purified by col-
umn chromatography on silica gel (10 g) using 30:1 CH2Cl2–MeOH
as eluent to give ( )-cis-14 (0.055 g, 59%) as a white solid; mp 219–
221 °C; Rf = 0.08 (CH2Cl2–MeOH, 20:1).
( )-[cis-4-(6-Amino-9H-purin-9-yl)-5,6-dihydro-4H-cyclopen-
ta[b]thiophen-6-yl]methanol (12)
Concd NH4OH (40 mL) was added to a solution of ( )-cis-10
(0.06 g, 0.196 mmol) in dioxane (5 mL) and the mixture was re-
fluxed for 42 h. After cooling to r.t., the solvents were evaporated
under reduced pressure and the residue was chromatographed on
silica gel (9 g) using 20:1 CH2Cl2–MeOH as eluent to give ( )-cis-
12 (0.055 g, 98%) as a yellowish solid. An analytical sample was
obtained by recrystallization from EtOH; mp 213–215 °C; Rf = 0.11
(CH2Cl2–MeOH, 30:1).
IR (KBr): 3108, 2923, 2875, 1705, 1607, 1584, 1506, 1348, 1206,
1137, 1039 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.30 (br s, 1 H, D2O exch.,
purine OH), 8.05 (s, 1 H, purine 8-H), 7.80 (s, 1 H, purine 2-H), 7.47
(d, J = 5.0 Hz, 1 H, 2-H), 6.77 (d, J = 5.0 Hz, 1 H, 3-H), 5.95 (dd,
J = 8.1, 5.7 Hz, 1 H, 4-H), 5.01 (t, J = 4.9 Hz, 1 H, D2O exch.,
CH2OH), 3.66–3.59 (m, 1 H, 6-H), 3.53–3.36 (m, 2 H, OCH2),
3.25–3.15 (m, 1 H, 5-H), 2.27 (dt, J = 13.6, 5.6 Hz, 1 H, 5-H).
IR (KBr): 3097, 2923, 2821, 1687, 1608, 1526, 1468, 1299, 1080
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.14 (s, 1 H, purine 8-H), 7.85
(s, 1 H, purine 2-H), 7.46 (d, J = 4.95 Hz, 1 H, 2-H), 7.22 (br s, 2 H,
D2O exch., NH2), 6.76 (d, J = 5.0 Hz, 1 H, 3-H), 5.96 (dd, J = 8.1,
5.7 Hz, 1 H, 4-H), 5.01 (t, J = 4.8 Hz, 1 H, D2O exch., OH), 3.66–
3.60 (m, 1 H, OCHH), 3.54–3.47 (m, 1 H, OCHH), 3.45–3.39 (m, 1
H, 6-H), 3.25–3.15 (m, 1 H, 5-H), 2.33–2.24 (m, 1 H, 5-H).
13C NMR (75 MHz, DMSO-d6): d = 157.21 (purine C-6), 148.54
(purine C-4), 148.10 (purine C-5), 145.89 (purine C-2), 142.88 (C-
6a), 138.43 (purine C-8), 131.10 (C-3), 124.75 (C-3a), 121.29 (C-
2), 64.93 (CH2O), 54.65 (C-4), 43.64 (C-6), 40.96 (C-5).
FABMS: m/z (%) = 289 (35, [M + 1]+), 288 (3, [M+]), 262 (11), 231
(53), 156 (10), 155 (32, [C8H11OS]+), 154 (90, [C8H10OS]+), 137
(100, [C8H9S]+), 135 (13, [C5H3N4O]+), 109 (32), 105 (13).
13C NMR (75 MHz, DMSO-d6): d = 156.00 (purine C-6), 152.36
(purine C-2), 149.36 (purine C-4), 147.47 (purine C-5), 143.03 (C-
6a), 138.64 (purine C-8), 130.62 (C-3), 120.96 (C-2), 119.01 (C-
3a), 64.63 (CH2O), 53.82 (C-4), 43.29 (C-6), 40.34 (C-5).
Anal. Calcd for C13H12N4O2S: C, 54.15; H, 4.20; N, 19.43; S, 11.12.
Found: C, 54.25; H, 4.31; N, 19.24; S 11.08.
FABMS: m/z (%) = 288 (19, [M + 1]+), 287 (1, [M+]), 155 (35,
[C8H11OS]+), 154 (95, [C8H10OS]+), 137 (100, [C8H9S]+), 135 (11,
[C5H5N5]+), 109 (26), 105 (11).
( )-[cis-4-(6-Phenyl-9H-purin-9-yl)-5,6-dihydro-4H-cyclopen-
ta[b]thiophen-6-yl]methanol (15)
Anal. Calcd for C13H13N5OS: C, 54.34; H, 4.56; N, 24.37; S, 11.16.
Found: C, 54.21; H, 4.65; N, 24.59; S, 11.01.
A mixture of ( )-cis-10 (0.068 g, 0.22 mmol), phenylboronic acid
(0.041 g, 0.33 mmol), Pd(PPh3)4 (0.012 g, 0.011 mmol), and K2CO3
(0.046 g, 0.33 mmol) in anhyd toluene (10 mL) was stirred under ar-
gon at 100 °C for 48 h, after which it was allowed to reach r.t. and
the solvent was removed under reduced pressure. The solid residue
was chromatographed on silica gel (13 g) using 2:1 hexane–EtOAc
as eluent, and the product obtained after removal of the solvent was
washed with Et2O, yielding ( )-cis-15 (0.047 g, 61%) as a white
solid; mp 138–140 °C; Rf = 0.38 (hexane–EtOAc, 1:1).
( )-[cis-4-(6-Cyclopropylamino-9H-purin-9-yl)-5,6-dihydro-
4H-cyclopenta[b]thiophen-6-yl]methanol (13)
A mixture of ( )-cis-10 (0.06 g, 0.20 mmol) and c-PrNH2 (0.14 mL,
2.02 mmol) in anhyd EtOH (5 mL) was refluxed under argon for 3
h and then concentrated to dryness. The residue was chromato-
graphed on silica gel (9 g) using 30:1 CH2Cl2–MeOH as eluent,
yielding ( )-cis-13 as a white solid (0.056 g, 88%). An analytical
sample was obtained by recrystallization from EtOAc; mp 135–137
°C; Rf = 0.18 (CH2Cl2–MeOH, 30:1).
IR (KBr): 3322, 2925, 1683, 1566, 1438, 1317, 1208, 1026 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.01 (s, 1 H, purine 8-H), 8.77 (dd,
J = 7.9, 1.7 Hz, 2 H, 2¢ + 6¢-Harom), 8.07 (s, 1 H, purine 2-H), 7.59–
7.52 (m, 3 H, 3¢ + 4¢ + 5¢-Harom), 7.37 (d, J = 5.1 Hz, 1 H, 2-H), 6.78
(d, J = 5.0 Hz, 1 H, 3-H), 6.18 (dd, J = 8.5, 4.7 Hz, 1 H, 4-H), 3.97
and 3.77 (AB part of an ABM system, JAB = 10.4, JAM = 5.3 and
JBM = 4.7 Hz, 2 H, OCH2), 3.67–3.61 (m, 1 H, 6-H), 3.53–3.42 (m,
1 H, 5-H), 2.51 (dt, J = 14.1, 4.8 Hz, 1H, 5-H), 2.42–2.35 (m, 1 H,
D2O exch., OH).
IR (KBr): 3242, 1738, 1618, 1474, 1309, 1265, 1053 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.44 (s, 1 H, purine 8-H), 7.62 (s,
1 H, purine 2-H), 7.32 (d, J = 5.0 Hz, 1 H, 2-H), 6.72 (d, J = 5.0 Hz,
1 H, 3-H), 6.11 (br s, 1 H, D2O exch., NH), 5.99 (dd, J = 8.6, 4.7 Hz,
1 H, 4-H), 3.94–3.89 (m, 1 H, OCHH), 3.77–3.71 (m, 1 H, OCHH),
3.61–3.55 (m, 2 H, one of them D2O exch., 6-H + OH), 3.46–3.35
(m, 1 H, c-Pr CH), 3.02–3.01 (m, 1 H, 5-H), 2.49 (dt, J = 14.1, 4.8
Hz, 1 H, 5-H), 0.94–0.88 (m, 2 H, c-Pr CH2), 0.66–0.60 (m, 2 H, c-
Pr CH2).
13C NMR (75 MHz, CDCl3): d = 155.88 (purine C-6), 152.56 (pu-
rine C-2), 148.23 (purine C-4), 143.56 (C-6a), 142.94 (purine C-8),
136.04 (purine C-5), 132.01 (C-1¢arom), 131.74 (CHarom), 131.40 (C-
3), 130.19 and 129.08 (4 × CHarom), 121.41 (C-2), 120.93 (C-3a),
66.15 (CH2O), 55.20 (C-4), 43.83 (C-6), 41.50 (C-5).
13C NMR (75 MHz, CDCl3): d = 156.23 (purine C-6), 153.42 (pu-
rine C-2), 149.18 (purine C-4), 148.12 (purine C-5), 143.21 (C-6a)
138.97 (purine C-8), 131.46 (C-3), 121.44 (C-2), 120.87 (C-3a),
66.10 (CH2O), 55.26 (C-4), 43.90 (C-6), 41.45 (C-5), 30.05 (c-Pr
CH2), 24.67 (c-Pr CH), 7.79 (c-Pr CH2).
FABMS: m/z (%) = 349 (19, [M + 1]+), 348 (1, [M+]), 309 (17), 278
(26), 263 (16), 231 (74), 197 (17, [C11H9N4]+), 156 (11), 155 (36,
[C8H11OS]+), 154 (94, [C8H10OS]+), 137 (100, [C8H9S]+), 109 (26),
105 (12).
FABMS: m/z (%) = 328 (50, [M + 1]+), 327 (4, [M+]), 309 (23), 278
(27), 263 (15), 231 (68), 176 (16, [C8H10N5]+), 156 (11), 155 (37,
[C8H11OS]+), 154 (98, [C8H10OS]), 137 (100, [C8H9S]), 135 (10,
[C5H5N5]), 109 (23), 105 (10).
Anal. Calcd for C19H16N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20.
Found: C, 65.34; H, 4.78; N, 15.91; S, 9.44.
Anal. Calcd for C16H17N5OS: C, 58.70; H, 5.23; N, 21.39; S, 9.79.
Found: C, 58.51; H, 5.36; N, 21.48; S, 9.98.
( )-[trans-4-(6-Chloro-9H-purin-9-yl)-5,6-dihydro-4H-cyclo-
penta[b]thiophen-6-yl]methanol (11)
A mixture of ( )-trans-9 (0.2 g, 0.68 mmol), triethyl orthoformate
(3.8 mL, 33.8 mmol), dioxane (10 mL), and aq 12 N HCl (0.23 mL)
Synthesis 2009, No. 16, 2766–2772 © Thieme Stuttgart · New York

PAPER
6-Substituted Purinylcarbanucleosides
2771
was stirred at r.t. for 3.5 h. Once the reaction was judged to have ter-
minated, the mixture was concentrated to dryness under reduced
pressure, and the residue was dissolved in dioxane (10 mL) and
treated for 1.5 h with aq 0.5 N HCl (14 mL). ( )-trans-11 was ob-
tained as a white solid (0.18 g, 87%) in the same way as ( )-cis-10.
An analytical sample was obtained by recrystallization from
EtOAc; mp 134–136 °C; Rf = 0.24. (CHCl3–MeOH, 40:1).
+ 6-H), 3.02–2.82 (m, 3 H, one of them D2O exch., OH + 5-H + c-
Pr CH), 2.69–2.62 (m, 1 H, 5-H), 1.05–0.84 (m, 2 H, c-Pr CH2),
0.66–0.60 (m, 2 H, c-Pr CH2).
13C NMR (75 MHz, CDCl3): d = 156.20 (purine C-6), 153.59 (pu-
rine C-2), 148.95 (purine C-4), 148.84 (purine C-5), 142.90 (C-6a),
138.25 (purine C-8), 131.35 (C-3), 121.63 (C-2), 120.48 (C-3a),
66.15 (CH2O), 54.90 (C-4), 43.85 (C-6), 42.73 (C-5), 24.10 (c-Pr
CH), 7.77 (2 × c-Pr CH2).
IR (KBr): 3372, 2926, 1590, 1560, 1485, 1395, 1334, 1202, 1042
cm–1.
FABMS: m/z (%) = 328 (25, [M + 1]+), 327 (2, [M+]), 309 (16), 278
(16), 263 (12), 231 (59), 176 (11, [C8H10N5]+), 156 (10), 155 (33,
[C8H11OS]+), 154 (100, [C8H10OS]+), 137 (98, [C8H9S]+), 135 (10,
[C5H5N5]+), 109 (23), 105 (9).
1H NMR (300 MHz, CDCl3): d = 8.75 (s, 1 H, purine 8-H), 7.82 (s,
1 H, purine 2-H), 7.37 (d, J = 5.0 Hz, 1 H, 2-H), 6.82 (d, J = 5.0 Hz,
1 H, 3-H), 6.17 (dd, J = 7.9, 2.4 Hz, 1 H, 4-H), 3.93–3.89 (m, 1 H,
OCHH), 3.79–3.72 (m, 2 H, OCHH + 6-H), 3.05–2.96 (m, 1 H, 5-
H), 2.75–2.67 (m, 1 H, 5-H), 2.28 (br s, 1 H, D2O exch., OH).
Anal. Calcd for C16H17N5OS: C, 58.70; H, 5.23; N, 21.39; S, 9.79.
Found: C, 58.77; H, 5.42; N, 21.32; S, 9.68.
13C NMR (75 MHz, CDCl3): d = 152.30 (purine C-2), 151.90 (pu-
rine C-6), 151.45 (purine C-4), 149.14 (purine C-5), 143.78 (purine
C-8), 142.19 (C-6a), 132.43 (C-3a), 131.91 (C-3), 121.36 (C-2),
66.22 (CH2O), 55.82 (C-4), 43.84 (C-6), 42.44 (C-5).
( )-6,9-Dihydro-9-[trans-(6-hydroxymethyl-5,6-dihydro-4H-cy-
clopenta[b]thiophen-4-yl)]-1H-purin-6-one (18)
Aq 0.25 N NaOH (7 mL) was added to a solution of ( )-trans-11
(0.1 g, 0.33 mmol) in dioxane (15 mL), and the mixture was heated
at 50 °C for 24 hours. ( )-trans-18 (0.049 g, 52%) was isolated as a
white solid following a procedure similar to that used for ( )-cis-14.
An analytical sample was obtained by recrystallization from 9:1
EtOAc–MeOH; mp 225–227 °C; Rf = 0.10 (CH2Cl2–MeOH, 20:1).
FABMS: m/z (%) = 307 (61, [M + 1]+), 306 (2, [M+]), 288 (2, [M+
– H2O]), 155 (51), 154 (100, [M+ – C5HClN4]), 153 (45), 137 (91,
[M+ – C5H2ClN4O]), 109 (25).
Anal. Calcd for C13H11ClN4OS: C, 50.90; H, 3.61; Cl, 11.56; N,
18.26; S, 10.45. Found: C, 50.72; H, 3.57; Cl, 11.74; N, 18.18; S,
10.54.
IR (KBr): 3747, 3662, 2923, 1857, 1694, 1581, 1543, 1459, 1206,
1099, 1039 cm–1.
( )-[trans-4-(6-Amino-9H-purin-9-yl)-5,6-dihydro-4H-cyclo-
penta[b]thiophen-6-yl]methanol (16)
1H NMR (300 MHz, DMSO-d6): d = 12.29 (br s, 1 H, D2O exch.,
purine OH), 8.03 (s, 1 H, purine 8-H), 7.78 (s, 1 H, purine 2-H),
7.44 (d, J = 4.9 Hz, 1 H, 2-H), 6.81 (d, J = 5.0 Hz, 1 H, 3-H), 5.96
(dd, J = 7.3, 3.2 Hz, 1 H, 4-H), 5.03 (t, J = 4.5 Hz, 1 H, D2O exch.,
CH2OH), 3.73–3.60 (m, 2 H, OCH2), 3.45–3.37 (m, 1 H, 6-H),
2.81–2.66 (m, 2 H, 5-H).
Concd NH4OH (22 mL) was added to a solution of ( )-trans-11
(0.07 g, 0.23 mmol) in dioxane (5 mL), and the mixture was re-
fluxed for 23 h. ( )-trans-16 (0.055 g, 85%) was obtained as a beige
solid by a procedure similar to that used for ( )-cis-12; mp 100–
102 °C; Rf = 0.22 (CH2Cl2–MeOH, 20:1).
13C NMR (75 MHz, DMSO-d6): d = 156.88 (purine C-6), 148.43
(purine C-4), 148.22 (purine C-5), 145.85 (purine C-2), 143.86 (C-
6a), 138.55 (purine C-8), 130.96 (C-3), 124.78 (C-3a), 121.31 (C-
2), 65.02 (CH2O), 54.81 (C-4), 43.72 (C-6), 41.07 (C-5).
IR (KBr): 3319, 3172, 2923, 2854, 1646, 1579, 1471, 1409, 1369,
1329, 1299, 1207, 1037 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.14 (s, 1 H, purine 8-H), 7.83
(s, 1 H, purine 2-H), 7.43 (d, J = 4.9 Hz, 1 H, 2-H), 7.20 (br s, 2 H,
D2O exch., NH2), 6.81 (d, J = 5.0 Hz, 1 H, 3-H), 5.98–5.95 (m, 1 H,
4-H), 5.03 (t, J = 4.7 Hz, 1 H, D2O exch., OH), 3.75–3.61 (m, 2 H,
OCH2), 3.50–3.41 (m, 1 H, 6-H), 2.80–2.66 (m, 2 H, 5-H).
FABMS: m/z (%) = 289 (5, [M + 1]+), 288 (5, [M+]), 263 (13), 231
(65), 156 (10), 155 (37, [C8H11OS]+), 154 (81, [C8H10OS]+), 137
(100, [C8H9S]+), 135 (11, [C5H3N4O]+), 110 (11), 109 (25), 105
(11).
13C NMR (75 MHz, DMSO-d6): d = 157.01 (purine C-6), 152.79
(purine C-2), 149.88 (purine C-4), 148.01 (purine C-5), 144.06 (C-
6a), 139.07 (purine C-8), 130.84 (C-3), 121.38 (C-2), 118.93 (C-
3a), 65.07 (CH2O), 54.32 (C-4), 43.78 (C-6), 41.02 (C-5).
Anal. Calcd for C13H12N4O2S: C, 54.15; H, 4.20; N, 19.43; S, 11.12.
Found: C, 53.97; H, 4.28; N, 19.31; S, 11.30.
( )-[trans-4-(6-Phenyl-9H-purin-9-yl)-5,6-dihydro-4H-cyclo-
penta[b]thiophen-6-yl]methanol (19)
FABMS: m/z (%) = 288 (12, [M + 1]+), 287 (1, [M+]), 155 (36,
[C8H11OS]+), 154 (100, [C8H10OS]+), 137 (99, [C8H9S]+), 135 (10,
[C5H5N5]+), 109 (22), 105 (10).
A mixture of ( )-trans-11 (0.125 g, 0.41 mmol), phenylboronic acid
(0.075 g, 0.62 mmol), Pd(PPh3)4 (0.023 g, 0.02 mmol), and K2CO3
(0.086 g, 0.62 mmol) in anhyd toluene (17 mL) was stirred under ar-
gon at 100 °C for 38 h. ( )-trans-19 (0.11 g, 77%) was isolated as a
white solid by a procedure similar to that used for ( )-cis-15; mp
166–168 °C; Rf = 0.21 (hexane–EtOAc, 1:1).
Anal. Calcd for C13H13N5O5: C, 54.34; H, 4.56; N, 24.37; S, 11.16.
Found: C, 54.40; H, 4.62; N, 24.17; S, 11.08.
( )-[trans-4-(6-Cyclopropylamino-9H-purin-9-yl)-5,6-dihydro-
4H-cyclopenta[b]thiophen-6-yl]methanol (17)
IR (KBr): 3321, 2916, 1567, 1496, 1407, 1323, 1206, 1127, 1024
cm–1.
A solution of ( )-trans-11 (0.084 g, 0.27 mmol) and c-PrNH2 (0.2
mL, 2.89 mmol) in anhyd EtOH (7 mL) was refluxed under argon
for 6 h. ( )-trans-17 (0.056 g, 73%) was obtained as a white solid
by a method similar to that used for ( )-cis-13. An analytical sample
was obtained by recrystallization from 1:1 hexane–EtOAc; mp 73–
75 °C; Rf = 0.16 (CH2Cl2–MeOH, 30:1).
1H NMR (300 MHz, DMSO-d6): d = 8.99 (s, 1 H, purine 8-H),
8.83–8.81 (m, 2 H, 2¢ + 6¢-Harom), 8.42 (s, 1 H, purine 2-H), 7.59–
7.57 (m, 3 H, 3¢ + 4¢ + 5¢-Harom), 7.44 (d, J = 4.9 Hz, 1 H, 2-H), 6.85
(d, J = 4.9 Hz, 1 H, 3-H), 6.20–6.17 (m, 1 H, 4-H), 5.07 (t, J = 4.9
Hz, 1 H, D2O exch., OH), 3.81–3.79 (m, 1 H, OCHH), 3.70–3.66
(m, 1 H, OCHH), 3.50–3.45 (m, 1 H, 6-H), 2.85–2.81 (m, 2 H, 5-H).
IR (KBr): 3256, 2923, 1619, 1469, 1354, 1314, 1297, 1220, 1042
cm–1.
13C NMR (75 MHz, DMSO-d6): d = 153.02 (purine C-6), 152.40
(purine C-4), 152.11 (purine C-2), 149.07 (C-6a), 145.02 (purine C-
8), 143.16 (purine C-5), 135.80 (C-1¢arom), 131.37 (C-3), 131.13
(CHarom), 131.00 (C-3a), 129.70 and 129.01 (4 × CHarom), 121.39
(C-2), 65.07 (CH2O), 54.89 (C-4), 43.89 (C-6), 40.79 (C-5).
1H NMR (300 MHz, CDCl3): d = 8.48 (s, 1 H, purine 8-H), 7.39 (s,
1 H, purine 2-H), 7.32 (d, J = 4.9 Hz, 1 H, 2-H), 6.81 (d, J = 4.9 Hz,
1 H, 3-H), 6.31 (br s, 1 H, D2O exch., NH), 6.07 (dd, J = 7.5, 2.6 Hz,
1 H, 4-H), 3.91–3.84 (m, 1 H, OCHH), 3.73–3.69 (m, 2 H, OCHH
Synthesis 2009, No. 16, 2766–2772 © Thieme Stuttgart · New York

2772
P. Abeijón et al.
PAPER
FABMS: m/z (%) = 349 (40, [M + 1]+), 348 (1, [M+]), 309 (13), 278
(17), 263 (13), 231 (68), 197 (37, [C11H9N4]+), 156 (9), 155 (27,
[C8H11OS]+), 154 (89, [C8H10OS]+), 137 (100, [C8H9S]+), 109 (30),
105 (12).
A.; Merchant, Z.; Slusarchyk, W. A.; Sundeen, J. E.; Young,
M. G.; Colonno, R.; Zahler, R. Bioorg. Med. Chem. Lett.
1997, 7, 127.
(12) Wyatt, P. G.; Anslow, A. S.; Coomber, B. A.; Cousins, R. P.
C.; Evans, D. N.; Gilbert, V. S.; Humber, D. C.; Paternoster,
I. L.; Sollis, S. L.; Tapolczay, D. J.; Weingarten, G. G.
Nucleosides Nucleotides 1995, 14, 2039.
Anal. Calcd for C19H16N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20.
Found: C, 65.28; H, 4.81; N, 16.18; S, 9.31.
(13) (a) Fernández, F.; García-Mera, X.; Morales, M.;
Rodríguez-Borges, J. E. Synthesis 2001, 239.
Acknowledgment
(b) Fernández, F.; García-Mera, X.; Morales, M.; Vilariño,
L.; Caamaño, O.; De Clercq, E. Tetrahedron 2004, 60,
9245. (c) Fernández, F.; García-Mera, X.; López, C.;
Morales, M.; Rodríguez-Borges, J. E. Synthesis 2005, 3549.
(14) (a) Fernández, F.; García-Mera, X.; Morales, M.;
Rodríguez-Borges, J. E.; De Clercq, E. Synthesis 2002,
1084. (b) Yao, S.-W.; Lopes, V. H. C.; Fernández, F.;
García-Mera, X.; Morales, M.; Rodríguez-Borges, J. E.;
Cordeiro, M. N. D. S. Bioorg. Med. Chem. 2003, 11, 4999.
(15) Hocek, M.; Hol, A.; Votruba, I.; Dvoráková, H. J. Med.
Chem. 2000, 43, 1817.
(16) (a) García, M. D.; Caamaño, O.; Fernández, F.; Abeijón, P.;
Blanco, J. M. Synthesis 2006, 73. (b) Caamaño, O.; Gómez,
G.; Fernández, F.; García, M. D.; García-Mera, X.;
De Clercq, E. Synthesis 2004, 2855. (c) Hergueta, A. R.;
López, C.; García-Mera, X.; Fernández, F. Tetrahedron
2004, 60, 10343. (d) García, M. D.; Caamaño, O.;
Fernández, F.; Figueira, M. J.; Gómez, G. Synthesis 2003,
2138. (e) López, C.; Caamaño, O.; Hergueta, A. R.; García,
M. D.; Fernández, F. Tetrahedron Lett. 2002, 43, 5311.
(17) García, M. D.; Caamaño, O.; Fernández, F.; López, C.;
De Clercq, E. Synthesis 2005, 925.
The authors thank the Xunta de Galicia for financial support under
project PGIDIT02BTF20305PR.
References
(1) (a) Vermeire, K.; Schols, D.; Bell, T. W. Curr. Med. Chem.
2006, 13, 731. (b) De Clercq, E. J. Med. Chem. 2005, 48,
1297. (c) De Clercq, E. Front. Med. Chem. 2004, 1, 543.
(d) Lazzarin, A.; Clotet, B.; Cooper, D.; Reynes, J.; Arastéh,
D.; Nelson, M.; Katlama, C.; Stellbrink, H.-J.; Delfraissy,
J.-F.; Lange, J.; Huson, L.; DeMasi, R.; Wat, C.; Delehanty,
J.; Drobnes, C.; Salgo, M. N. Engl. J. Med. 2003, 348, 2186.
(2) Mansour, T. S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227.
(3) (a) Nucleoside Analogs in Cancer Therapy; Cheson, B. D.;
Keating, M. J.; Plunkett, W., Eds.; Marcel Dekker: New
York, 1997. (b) De Clercq, E. Clin. Microb. Rev. 1997, 10,
674. (c) De Clercq, E. Curr. Med. Chem. 2001, 8, 1543.
(d) Ena, J.; Pasquau, F. Clin. Infect. Dis. 2003, 36, 1186.
(e) Louie, M.; Hogan, C.; Di Mascio, M.; Hurley, A.; Simon,
V.; Rooney, J.; Ruiz, N.; Brun, S.; Sun, E.; Perelson, A. S.;
Ho, D. D.; Markowitz, M. J. Infect. Dis. 2003, 187, 896.
(4) Balzarini, J.; Kang, G.-J.; Dala, M.; Herdewijn, P.;
De Clercq, E.; Broker, S.; Johns, D. G. Mol. Pharmacol.
1987, 32, 162.
(18) García, M. D.; Caamaño, O.; Fernández, F.; García-Mera,
X.; Pérez-Castro, I. Synthesis 2006, 3967.
(19) (a) Blanco, J. M.; Caamaño, O.; Fernández, F.; Rodríguez-
Borges, J. E.; Balzarini, J.; De Clercq, E. Chem. Pharm.
Bull. 2003, 51, 1060. (b) Guan, H.-P.; Ksebati, M. B.;
Cheng, Y. C.; Drach, J. C.; Kern, E. R.; Zemlicka, J. J. Org.
Chem. 2000, 65, 1280.
(5) Lea, A. P.; Faulds, D. Drugs 1996, 51, 846.
(6) Krayevsky, A. A.; Watanabe, K. A. Modified Nucleosides
as Anti-AIDS Drugs: Current Status and Perspectives;
Bioinform: Moscow, 1993.
(20) Abeijón, P.; Blanco, J. M.; Fernández, F.; García, M. D.;
López, C. Eur. J. Org. Chem. 2006, 759.
(21) Yoon, N. M.; Brown, H. C. J. Am. Chem. Soc. 1968, 90,
2927.
(22) (a) Daluge, S.; Vince, R. J. Org. Chem. 1978, 43, 2311.
(b) Patil, S. D.; Schneller, S. W.; Hosoya, M.; Snoeck, R.;
Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992,
35, 3372.
(23) CCDC-636456 contains the supplementary crystallographic
data for compound trans-18 reported in this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(7) Thomas, S.; McDowall, J. E.; Cheah, V.; Bye, A.; Segal, M.
B. The Entry of Abacavir into the Guinea Pig Brain:
Comparison with Other Reverse Transcriptase Inhibitors;
Presented at the 12th World AIDS Conference, Geneva:
Italy, 1998.
(8) For recent reviews of the biological properties of CNs, see:
(a) Cho, J. H.; Bernard, D. L.; Sidwell, R. W.; Kern, E. R.;
Chu, C. K. J. Med. Chem. 2006, 49, 1140. (b) Schneller, S.
W. Curr. Top. Med. Chem. 2002, 2, 1087. (c) Rodríguez, J.
B.; Comin, M. J. Mini Rev. Med. Chem. 2003, 3, 95.
(d) Ichicawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385.
(e) Zhu, X.-F. Nucleosides, Nucleotides Nucleic Acids 2000,
19, 651. (f) Agrofoglio, L.; Challand, S. R. Acyclic,
Carbocyclic and L-Nucleosides; Klewer Academic:
Dordrecht, 1998.
(24) Cesnek, M.; Hocek, M.; Holy, A. Collect. Czech. Chem.
Commun. 2000, 65, 1357.
(25) (a) Hocek, M. Eur. J. Org. Chem. 2003, 245.
(b) Havelková, M.; Dvorak, D.; Hocek, M. Synthesis 2001,
1704. (c) Havelková, M.; Hoces, M.; Cesnek, M.; Dovorák,
D. Synlett 1999, 1145.
(26) Suzuki, A. J. Organomet. Chem. 1999, 576, 147; and
references cited therein.
(27) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S.
L. Angew. Chem. Int. Ed. 2004, 43, 1871.
(28) De Clercq, E. In Vitro and Ex Vivo Test Systems to
Rationalize Drug Design and Delivery; Cromelin, D.;
Couvreur, P.; Duchene, D., Eds.; Editions de Sante: Paris,
1994, 108.
(9) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192.
(10) (a) Foster, R. H.; Faulds, D. Drugs 1998, 55, 729.
(b) Daluge, S. M.; Martín, M. T.; Sickles, B. R.; Livingston,
D. A. Nucleosides, Nucleotides Nucleic Acids 2000, 19,
297. (c) Mahony, W. B.; Domin, B. A.; Daluge, S. M.;
Zimmerman, T. P. Biochem. Pharmacol. 2004, 68, 1797.
(d) Opravil, M.; Hirschel, B.; Lazzarin, A.; Furrer, H.;
Chave, J.-P.; Yerly, S.; Bisset, L. R.; Fischer, M.; Vernazza,
P.; Benasconi, E.; Battegay, M.; Ledergerber, B.; Günthard,
H.; Howe, C.; Weber, R.; Perrin, L. J. Infect. Dis. 2002, 185,
1251.
(11) Bisacchi, G. S.; Chao, S. T.; Bachard, C.; Daris, J. P.;
Innaimo, S.; Jacobs, G. A.; Kocy, O.; Lapointe, P.; Martel,
Synthesis 2009, No. 16, 2766–2772 © Thieme Stuttgart · New York