Synthesis and cytostatic activities of new 6-substituted purinylcarbonucleosides derived from indan

Article abstract of DOI:10.1055/s-2002-31956

A new series of 6-substituted purinylcarbonucleosides derivatives of indan, 8a-g and 10a-d, was synthesized from (±)-cis-1,3-indandimethanol acetate (5), which was prepared in three steps from benzonorbornadiene. 6-Chloropurine was introduced both by Mitsunobu reaction with 5 and by substitution of the mesylate 6. Suzuki-Miyaura reactions of the protected 6-chloropurine derivative 7 with substituted phenylboronic acids afforded 9a-d (protected purine derivatives with substituted phenyl rings at position 6); deprotection of the latter yielded the new series of purinylcarbonucleoside indan derivatives 10a-d. Treatment of compound 7 with R′H/NaOH afforded a parallel series 8a-g, with alkoxy or amino groups R′ at position 6 instead of substituted phenyl rings.

Full text of DOI:10.1055/s-2002-31956

1084
PAPER
Synthesis and Cytostatic Activities of New 6-Substituted
Purinylcarbonucleosides Derived from Indan1
Synthesis of
6r
ated Purinyl
n
c
arbonucleos
c
ides o Fernández,a Xerardo García-Mera,*a Melvin Morales,a José E. Rodríguez-Borges,b Eric De Clercqc
a
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782-Santiago de Compostela,
Spain
Fax +34(981)594912; E-mail: qoxgmera@usc.es
b
c
CIQ, Departamento de Química da Faculdade de Ciências do Porto, Rua do Campo Alegre, 687-4169007 Porto, Portugal
Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
Received 8 February 2002
which was prepared from benzonorbornadiene (2). The
classical Wittig method7 for the preparation of benzonor-
bornadiene consists in the [4+2] cycloaddition of ben-
zyne, generated in situ from 1-bromo-2-fluorobenzene
Abstract: A new series of 6-substituted purinylcarbonucleosides
derivatives of indan, 8a–g and 10a–d, was synthesized from ( )-cis-
1,3-indandimethanol acetate (5), which was prepared in three steps
from benzonorbornadiene. 6-Chloropurine was introduced both by
Mitsunobu reaction with 5 and by substitution of the mesylate 6. Su- (1), to cyclopentadiene in THF. In this work we achieved
zuki–Miyaura reactions of the protected 6-chloropurine derivative
7 with substituted phenylboronic acids afforded 9a–d (protected pu-
rine derivatives with substituted phenyl rings at position 6); depro-
trasound bath. Treatment of 2 with ozone and quenching
tection of the latter yielded the new series of
purinylcarbonucleoside indan derivatives 10a–d. Treatment of
a considerably improved yield of 66%, by using diethyl
ether instead of THF and carrying out the reaction in an ul-
with dimethyl sulphide afforded dialdehyde 3, which
upon treatment, without prior isolation, with lithium alu-
minum hydride, gave the diol 4 in 71% yield. Two meth-
ods were then compared for protection of the left-hand
hydroxyl of 4: reaction with acetic anhydride and pyri-
dine, and transesterification with vinyl acetate catalysed
by Novozym® 435. Both gave mixtures of 4 and 5 and the
diacetylated product containing almost the same amount
of 5 (around 55%), but with the enzymatic process, work-
up was easier and the recovery of 4 was greater (Scheme).
compound 7 with R H/NaOH afforded a parallel series 8a–g, with
alkoxy or amino groups R at position 6 instead of substituted phe-
nyl rings.
Key words: synthesis, antineoplastic agent, indan carbocyclic nu-
cleoside, Mitsunobu reaction, Suzuki–Miyaura cross-coupling re-
action
Purine bases and their nucleosides constitute an important
class of antineoplastic and antileukaemic agents.2 Efforts
to improve their performance in these roles have resulted
in the introduction of a variety of structural modifications
in both the base and the sugar moiety. In most cases an
oxo or amino group has been retained at purine position 6
because this group is essential for the formation of the hy-
drogen bonds through which the base gets subjected to the
action of key enzymes involved in nucleic acid metabo-
lism; but cytostatic activity has also been displayed by ar-
abinosides derived from 6-methoxypurine3 and by 6-alkyl
derivatives of mercaptopurines,4 and a number of 6-
arylpurine ribonucleosides have recently been reported to
be cytotoxic for certain cell lines.5 In view of these results,
we decided to investigate the effects of 6-substituents oth-
er than OH and NH2 on the properties of purine-based
members of the indan carbonucleoside family, whose an-
tineoplastic and antiviral activities are being explored by
us in recent years.6 We describe here the synthesis of two
series of 6-substituted purinylcarbonucleoside indan de-
rivatives, 8a–g and 10a–d (Scheme), and report their cy-
tostatic activities against a number of cell lines.
6-Chloropurine was first condensed with 5 by a standard
Mitsunobu reaction8 in the presence of triphenylphos-
phine and diethyl azodicarboxylate, but with this method
we were unable to achieve yields greater than 40%. More
satisfactory was an indirect route via mesylate 6 (obtained
from 5 in 93% yield by treatment at 0 °C with methane-
sulfonyl chloride, triethylamine and DMAP). Reaction of
crude 6 with 6-chloropurine in DMF in the presence of
NaH and 18-crown-6 ether9 gave the condensation prod-
uct 7 in 65% yield (60% from 5, i.e. 1.5 times the yield
obtained by the direct Mitsunobu route). Purinylcarbonu-
cleosides 8a–g, in which the purine 6-substituent is an
NHR or OR group, were obtained directly from 7 in 45–
75% yield by treatment with the corresponding nucleo-
philes NH2R or R OH (Scheme).
Following the observation of cytostatic activity for com-
pounds 8 (see below), synthesis of the 6-arylpurinyl car-
bonucleosides 10a–d was prompted by reports of
significant antineoplastic activity being displayed by 6-
arylpurine bases and nucleosides5 and acyclic nucleoside
analogues10 that have recently been prepared by Suzuki–
Miyaura cross-coupling of 6-halopurines with boronic ac-
ids.11 Treatment of 7 with boronic acids under Suzuki
conditions12 using potassium carbonate as base, tet-
rakis(triphenylphosphine)palladium as catalyst and tolu-
ene as solvent, afforded 9a–d in 63–87% yield, whose
The central step of the synthesis was the condensation of
6-chloropurine with ( )-cis-indandimethanol acetate (5),
Synthesis 2002, No. 8, 04 06 2002. Article Identifier:
1437-210X,E;2002,0,08,1084,1090,ftx,en;P00402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of 6-Substituted Purinylcarbonucleosides
1085
O
O
H
H
Mg
F
i) O3
ii) Me2S
95%
ultrasound
66%
Br
2
1
3
LiAlH4
74%
AcO
OSO2Me
AcO
OH
MeSO2Cl
HO
OH
NEt3/DMAP
OAc
Novozym® 435
55%
93%
6
4
5
Ph3P
DEAD
THF
Cl
Cl
N
NaH
N
18-crown-6
THF
N
N
N
N
H
R
R
N
N
H
65%
39%
R
Cl
N
N
N
N
N
N
N
N
N
N
N
N
AcO
AcO
HO
B
NaOMe
HO OH
MeOH
K2CO3
Pd(PPh3)4
87-95%
7
9
10
63-87%
R'-H
NaOH
Compound
10a
R
H
44-65%
10b
10c
CH3
OCH3
Cl
R'
N
10d
Compound
R'
OH
OCH3
OCH2CH3
NH2
NHCH2CH2CH3
NHCH(CH3)2
NHCH(CH2)2
N
8a
8b
8c
8d
8e
8f
N
N
HO
8g
8
Scheme
tography was performed on silica gel (Merck 60, 230–240 mesh)
and analytical TLC on pre-coated silica gel plates (Merck 60 F254,
0.25 mm).
deprotection with NaOMe/MeOH gave compounds
10a–d in 87–95% yield.
Compounds 8a–g and 10a–d were evaluated for cytostatic
activity using murine leukaemia cells (L1210/0) and hu-
man T-lymphocytes (Molt4/C8 and CEM/0).13 Com-
pounds 8a–g all showed moderate activity, while
compounds 10a–d showed much greater activity, espe-
cially 10d, which had IC50 values of 0.81 g/mL for
Molt4/C8 and 0.63 g/mL for CEM/0, and 10b (IC50 = 1.6
g/mL for Molt4/C8, 1.4 g/mL for CEM/0).
1,4-Dihydro-1,4-methanenaphthalene (Benzonorbornadiene, 2)
A solution of 1 (13 g, 75 mmol) and cyclopentadiene (4.9 g, 75
mmol) in Et2O (100 mL) was added over 45 min, under argon and
at r.t., to a stirred suspension of Mg (2 g, 83 mmol) in Et2O (50 mL)
placed in an ultrasound bath. After stirring for 3 h in the ultrasound
bath, the solvent was distilled off under reduced pressure and the
residue was treated with aq sat. NH4Cl solution (70 mL), Et2O (3
150 mL) and brine (100 mL). The organic layer was drawn off and
dried (Na2SO4), and the solvent was removed at reduced pressure.
The resulting oil was distilled in a Kugelrohr distillation apparatus
(80–85 °C/13–15 mm Hg) to afford 2 (10.68 g, 66%) as a colourless
oil.
Mps were determined in a Reichert Kofler Thermopan or in capil-
lary tubes in a Büchi 510 apparatus, and are uncorrected. IR spectra
1
were recorded in a Perkin-Elmer 1640-FT spectrometer. H NMR
spectra (300 MHz) and 13C NMR spectra (75.47 MHz) were record-
ed in a Bruker AMX spectrometer using TMS as internal standard
[chemical shifts ( ) in ppm, J in Hz]. Elemental analyses were ob-
tained on a Perkin-Elmer 240B microanalyser by the Microanalysis
Service of the University of Santiago de Compostela. Flash chroma-
IR (film): 3066, 2983, 2934, 2866, 1565, 1508, 1455, 1303, 1110,
830 cm–1.
1H NMR (CDCl3): = 2.29–2.32 (d, 1 H, J = 7.08 Hz, 9-H), 2.37–
2.39 (dt, 1 H, J(d) = 7.04 Hz, J(t) = 3.07 Hz, 9-H), 3.94 (t, 2 H,
Synthesis 2002, No. 8, 1084–1090 ISSN 0039-7881 © Thieme Stuttgart · New York

1086
F. Fernández et al.
PAPER
J = 1.76 Hz, 1-H and 4-H), 6.85 (t, 2 H, J = 1.80 Hz, 2-H and 3-H),
6.98–7.00 (m, 2 H, ArH), 7.27–7.30 (m, 2 H, ArH).
13C NMR (CDCl3): = 51.00 (CH), 70.81 (CH2), 122.21 (CH),
124.88 (CH), 143.63 (CH), 152.39 (C).
13C NMR (acetone-d6): = 21.24 (CH3), 33.84 (CH2), 44.16 (CH),
47.75 (CH), 66.97 (CH2), 68.80 (CH2), 125.26 and 125.61 (CH),
127.95 and 128.17 (CH), 145.39 and 146.65 (C), 171.50 (COOR).
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.66; H,
7.19.
Anal. Calcd for C11H10: C, 92.91; H, 7.09. Found: C, 93.04; H, 6.95.
( )-cis-3-(Methylsulfonyloxymethyl)indanylmethyl Acetate (6)
Mesyl chloride (8.5 mL, 110 mmol) was added dropwise to a solu-
tion of 5 (7.54 g, 36.6 mmol), Et3N (15 mL) and a catalyitic amount
of DMAP in CHCl3 (150 mL) at 0 °C. The mixture was refluxed for
12 h, then washed with H2O, and the organic layer was separated,
washed with 1 M aq NaOH (100 mL) and brine (100 mL), dried
(Na2SO4), and concentrated to dryness in a rotary evaporator. The
residue (10 g) was chromatographed on a column of silica gel
(300 g) with hexane–EtOAc (3:1) as eluent; light brown solid
(9.65 g, 93%); mp 40–43 °C.
cis-1,3-Indandimethanol (4)
Using a Fischer 503 ozone generator, ozone was bubbled for 30 min
at a rate of 6 g/h (60 L/h O2; according to the operating instructions
of the apparatus) through a vigorously stirred solution of 2 (10.68 g,
75 mmol) in MeOH–CHCl3 (1:1, 100 mL) at –78 °C. After the ad-
dition of Me2S (11.70 mL, 9.89 g, 85.16 mmol), the reaction mix-
ture was stirred for 12 h while returning to r.t. Concentration to
dryness then afforded 3 (12.47 g, 95.33%) as a colourless oil.
3
IR (film): 3420, 2822, 2725, 1718, 1477, 1457, 1388, 1160, 1059,
IR (KBr): 3450, 3025, 2975, 1733, 1466, 1296, 1285, 1250, 1170,
1045, 977, 954, 869, 825, 755 cm–1.
755 cm–1.
The crude 3 (12.47 g, 71.58 mmol) was then added dropwise to a
solution of LiAlH4 (8.5 g, 225 mmol) in anhyd THF (150 mL), and
after standing for 48 h at 0 °C, this mixture was poured over ice, and
left until all LiAlH4 had been destroyed. After the removal of organ-
ic solvents in a rotary evaporator, aluminum hydroxides were fil-
tered out, the filtrate was extracted with EtOAc (5 100 mL), and
the pooled organic layers were dried (Na2SO4) and concentrated to
dryness. Chromatography of the resulting white solid on silica gel
(250 g) using EtOAc–hexane (1:1) as eluent afforded an eluate,
from the middle fractions of which 4 was isolated as a white solid
(6.32 g, 74.5%); mp 99–100 °C.
1H NMR (CDCl3): = 1.62–1.72 (dt, 1 H, J(d) = 13.38 Hz, J(t) = 7.59
Hz, 2 -H), 2.15 (s, 3 H, OCOCH3), 2.62–2.72 (dt, 1 H, J(d) = 13.35
Hz, J(t) = 8.36 Hz, 2 -H), 3.07 (s, 3 H, OSO2CH3), 3.49 (m, 1 H, 1 -
H), 3.62 (m, 1 H, 3 -H), 4.27–4.34 (part A of an ABM system, 1 H,
JAB = 10.93 Hz, JAM = 6.95 Hz, CHHOAc), 4.40–4.46 (part B of an
ABM system, 1 H, JBA = 10.95 Hz, JBM = 5.90 Hz, CHHOAc),
4.39–4.45 (part A of an ABM system, 1 H, JAB = 9.61 Hz,
JAM = 7.23 Hz, CHHOSO2CH3), 4.54-4.61 (part B of an ABM sys-
tem, 1H, JBA = 9.70 Hz, JBM = 5.93 Hz, CHHOSO2CH3), 7.30–7.39
(m, 4 H, ArH).
13C NMR (CDCl3):
= 21.35 (CH3), 32.91 (CH2), 37.86
IR (KBr): 3276, 2918, 2864, 1474, 1456, 1091, 779, 745 cm–1.
(OSO2CH3), 43.21 (CH), 43.63 (CH), 67.77 (CH2), 72.72 (CH2),
124.59 and 124.81 (CH), 127.95 and 128.23 (CH), 142.54 and
144.09 (C), 171.50 (COOR).
1H NMR (CDCl3): = 1.75–1.84 (dt, 1 H, J(d) = 13.59 Hz, J(t) = 7.70
Hz, 2 -H), 2.03 (s, 2 H, exchang. with D2O, OH), 2.43–2.53 (dt, 1
H, J(d) = 13.37 Hz, J(t) = 8.96 Hz, 2 -H), 3.35–3.45 (m, 2 H, 1 -H
and 3 -H), 3.87–3.89 (m, 4 H, CH2OH), 7.21–7.30 (m, 4 H, ArH).
Anal. Calcd for C14H18O5S: C, 56.36; H, 6.08. Found: C, 56.54; H,
5.88.
13C NMR (CDCl3): = 31.66 (CH2), 46.52 (CH), 66.63 (CH2),
124.53 (CH), 127.57 (CH), 144.92 (C).
( )-cis-3-(6-Chloro-9H-purin-9-ylmethyl)indanylmethyl Ace-
tate (7)
Anal. Calcd for C11H14O2: C, 74.13; H, 7.92. Found: C, 74.02; H,
7.79.
Method A: Diethyl azodicarboxylate (1.32 mL, 8.40 mmol) was
added to a suspension of Ph3P (2.08 g, 7.94 mmol) and 6-chloropu-
rine (1.26 g; 8.15 mmol) in THF (55 mL) and the mixture was
stirred for 1 h. Following the slow addition of a solution of 5
(1.47 g, 6.68 mmol) in THF (20 mL), the stirring was continued for
36 h at r.t. and 24 h at 40 °C. Removal of the solvent under reduced
pressure gave a residue that was chromatographed on silica gel
(100 g) with hexane–EtOAc (3:2) as eluent; yellow solid (0.93 g,
39%).
( )-cis-1,3-Indandimethanol Acetate (5)
Novozym® 435 (8.18 g) was added to a solution of 4 (14.62 g, 82.1
mmol) in THF (200 mL), and after dropwise addition of vinyl ace-
tate (4.2 mL, 45.15 mmol), the mixture was stirred for 20 h at r.t.
The lipase was filtered out on a bed of Celite, the filtrate was con-
centrated to dryness, and the resulting oily residue was chromato-
graphed on silica gel (350 g) using hexane–EtOAc (1:1.5) as eluent.
The early-eluting fractions afforded 3 g of a solid identified as ( )-
cis-1,3-indandimethanol diacetate, the middle fractions 9.94 g
(55%) of an oil that crystallized spontaneously was identified as 5,
and the final fractions 3.74 g of a white solid was identified as the
starting diol 4; mp 101–103 °C.
Method B: A solution of 6-chloropurine (1.18 g, 7.53 mmol), NaH
(0.30 g, 7.53 mmol) and 18-crown-6 ether (1.35 g, 5.10 mmol) in
DMF (50 mL) was stirred at 55 °C for 30 min. A solution of 6
(1.50 g, 5.02 mmol) in DMF (25 mL) was slowly added and the stir-
ring was continued at the same temperature for a further 24 h. The
solvent was then removed under reduced pressure and the resulting
residue was chromatographed on silica gel (210 g) using hexane–
EtOAc (3:2); yellow solid (1.53 g, 65%); mp 112–114 °C (Et2O).
IR (KBr): 3420, 2948, 2871, 1654, 1479, 1457, 1385, 1365, 1244,
1035, 759 cm–1.
1H NMR (acetone-d6): = 1.59–1.69 (dt, 1 H, J(d) = 13.19 Hz,
IR (KBr): 3245, 3068, 2990, 1741, 1594, 1336, 1247, 1034, 772,
758 cm–1.
J(t) = 7.53 Hz, 2 -H), 2.03 (s, 3 H, OCOCH3), 2.40–2.49 (dt, 1 H,
J(d) = 13.09 Hz, J(t) = 8.30 Hz, 2 -H), 3.30 (m, 1 H, 3 -H), 3.44 (m,
1 H, 1 -H), 3.70 (m, 1 H, OH, exchange with D2O), 3.84 (m, 2 H,
CH2OH), 4.17–4.20 (part A of an ABM system, 1 H, JAB = 10.74
Hz, JAM = 7.36 Hz, CHHOAc), 4.28–4.35 (part B of an ABM sys-
tem, 1 H, JBA = 10.74 Hz, JBM = 6.26 Hz, CHHOAc), 7.17–7.38 (m,
4 H, ArH).
1H NMR (CDCl3): = 1.54–1.63 (dt, 1 H, J(d) = 13.47 Hz, J(t) = 7.30
Hz, 2 -H), 2.04 (s, 3 H, OCOCH3), 2.34–2.44 (dt, 1 H, J(d) = 13.30
Hz, J(t) = 8.30 Hz, 2 -H), 3.47 (m, 1 H, 1 -H), 3.88 (m, 1 H, 3 -H),
4.16–4.22 (part A of an ABM system, 1 H, JAB = 10.98 Hz,
JAM = 7.23 Hz, CHHOAc), 4.24–4.32 (part B of an ABM system, 1
H, JBA = 10.98 Hz, JBM = 7.09 Hz, CHHOAc), 4.38–4.45 (part A of
an ABM system, 1 H, JAB = 13.92 Hz, JAM = 8.30 Hz, CHHN),
4.71–4.77 (part B of an ABM system, 1 H, JBA = 13.92 Hz,
Synthesis 2002, No. 8, 1084–1090 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Substituted Purinylcarbonucleosides
1087
JBM = 6.87 Hz, CHHN), 7.07–7.32 (m, 4 H, ArH), 8.05 (s, 1 H, 2 -
crystallized from Et2O to afford 8c as a light brown solid (0.22 g,
H), 8.77 (s, 1 H, 8 -H).
73%); mp 127–129 °C (Et2O).
13C NMR (CDCl3): = 21.32 (CH3), 33.77 (CH2), 43.25 (CH),
44.10 (CH), 49.36 (CH2), 67.50 (CH2), 124.26, 125.09, 128.14 and
128.46 (CH), 131.95 (C), 142.99 (C), 143.91 (C), 145.70 (CH),
152.48 (CH), 171.49 [C(O)OR].
IR (KBr): 3314, 2903, 1654, 1609, 1575, 1474, 1381, 1341, 1319,
1239, 1111, 797, 741 cm–1.
1H NMR (CDCl3): = 1.48–1.53 (t, 3 H, J = 7.02 Hz, OCH2CH3),
1.69–1.77 (dt, 1 H, J(d) = 13.59 Hz, J(t) = 5.13 Hz, 2 -H), 2.26–2.37
(dt, 1 H, J(d) = 13.72 Hz, J(t) = 8.89 Hz, 2 -H), 3.32–3.36 (m, 1 H,
1 -H), 3.78–3.83 (m, 1 H, 3 -H), 3.85–3.91 (m, 2 H, CH2OH),
4.40–4.48 (part A of an ABM system, 1 H, JAB = 13.96 Hz,
Anal. Calcd for C18H17ClN4O2: C, 60.59; H, 4.80; N, 15.70. Found:
C, 60.44; H, 4.63; N, 15.55.
( )-cis-3-(6-Hydroxy-9H-purin-9-ylmethyl)indanylmethanol
(8a)
J
J
AM = 9.46 Hz, CHHN), 4.51–4.58 (part B of an ABM system, 1 H,
BA = 13.94 Hz, JBM = 6.10 Hz, CHHN), 4.62–4.69 (q, 2 H, J = 7.02
A solution of 7 (0.39 g, 1.09 mmol) in 0.25 N aq NaOH (25 mL) was
refluxed for 5 h. Removal of the solvent under reduced pressure us-
ing an azeotropic mixture with toluene afforded a brown solid. This
was chromatographed on silica gel (30 g) with EtOAc as eluent to
give 8a as a light brown solid (0.23 g 71%); mp 222–225 °C.
Hz, OCH2CH3), 7.02–7.05 (d, 1 H, J = 7.23 Hz, ArH), 7.15–7.30
(m, 3 H, ArH), 7.90 (s, 1 H, 2 -H), 8.50 (s, 1 H, 8 -H).
13C NMR (CDCl3): = 19.73 (CH3), 31.98 (CH2), 41.29 (CH),
42.37 (CH), 46.44 (CH2), 60.23 (CH2), 65.82 (CH2), 118.12 (C)
122.96, 1123.29, 126.23 and 126.35 (CH), 146.36 (C), 139.80
(CH), 142.79 (C), 151.22 (CH), 154.66 (C), 169.50 (C).
IR (KBr): 3450, 2861, 1699, 1587, 1549, 1475, 1414, 1342, 1201,
1128, 1030, 905, 790, 759 cm–1.
Anal. Calcd for C24H24N4O2: C, 71.98; H, 6.04; N, 13.99. Found: C,
72.15; H, 5.86; N, 14.09.
1H NMR (CDCl3): = 1.70–1.74 (dt, 1 H, J(d) = 13.53 Hz, J(t) = 7.79
Hz, 2 -H), 2.26–2.37 (dt, 1 H, J(d) = 13.52 Hz, J(t) = 8.74 Hz, 2 -H),
3.36–3.40 (m, 1 H, 1 -H), 3.83–3.88 (m, 1 H, 3 -H), 3.87–3.88 (d,
2 H, J = 4.77 Hz, CH2OH), 4.43–4.50 (part A of an ABM system, 1
H, JAB = 13.93 Hz, JAM = 8.95 Hz, CHHN), 4.65-4.71 (part B of an
ABM system, 1 H, JBA = 13.92 Hz, JBM = 7.90 Hz, CHHN), 7.02–
7.04 (d, 1 H, J = 7.35 Hz, ArH), 7.18–7.32 (m, 4 H, ArH), 8.10 (s,
1 H, 2 -H), 8.75 (s, 1 H, 8 -H).
( )-cis-3-(6-Amino-9H-purin-9-ylmethyl)indanylmethanol (8d)
A solution of 7 (0.35 g, 0.98 mmol) in MeOH (4 mL) and liquid
NH3 (3 mL) was heated in a bomb at 75 °C for 60 h. Once the reac-
tion mixture had cooled to r.t., the solvent was evaporated under re-
duced pressure and 8d was isolated as a white solid (0.18 g, 55%);
mp 226–228 °C (Et2O).
13C NMR (CDCl3): = 32.63 (CH2), 43.06 (CH), 45.54 (CH), 47.62
(CH2), 64.39 (CH2), 123.22, 123.56, 126.77 and 126.67 (CH),
124.06 (C), 140.05 (C), 144.93 (CH), 145.14 and 145.22 (C),
148.23 (CH), 156.33 (C).
IR (KBr): 3353, 1653, 1558, 1418, 1318, 1237, 1072, 796, 775
cm–1.
1H NMR (CDCl3): = 1.48–1.57 (dt, 1 H, J(d) = 13.14 Hz, J(t) = 7.56
Hz, 2 -H), 2.07–2.17 (dt, 1 H, J(d) = 13.05 Hz, J(t) = 8.22 Hz, 2 -H),
3.15 (m, 1 H, 1 -H), 3.48 (m, 1 H, 3 -H), 3.64–3.81 (m, 2 H,
CH2OH), 4.09–4.21 (part A of an ABM system, 1 H, JAB = 13.55
Hz, JAM = 8.95 Hz, CHHN), 4.55–4.68 (part B of an ABM system,
1 H, JBA = 13.59 Hz, JBM = 5.91 Hz, CHHN), 4.75 (s, 1 H, OH ex-
change with D2O), 7.03–7.33 (m, 4 H, ArH), 7.22 (s, 2 H, NH2 ex-
change with D2O), 8.10 (s, 1 H, 2 -H), 8.15 (s, 1 H, 8 -H).
13C NMR (CDCl3): = 33.46 (CH2), 43.54 (CH), 46.16 (CH), 48.01
(CH2), 65.01 (CH2), 123.96, 124.74, 127.01 and 127.37 (CH),
141.45 (C), 144.09 and 145.61 (C), 150.02 (CH), 152.81 (CH),
156.12 (C).
Anal. Calcd for C22H20N4O2: C, 70.95; H, 5.41; N, 15.04. Found: C,
70.73; H, 5.60; N, 15.19.
( )-cis-3-(6-Methoxy-9H-purin-9-ylmethyl)indanylmethanol
(8b)
A solution of 7 (0.30 g, 0.84 mmol) in MeOH (9 mL) was stirred at
r.t. for 24 h and then extracted with EtOAc (100 mL) and brine (100
mL). The pooled organic layers were dried (Na2SO4) and concen-
trated to dryness under reduced pressure to afford 8b as a pale yel-
low solid (0.17 g, 65%); mp 140–142 °C (hexane–Et2O).
IR (KBr): 3300, 2852, 1700, 1598, 1575, 1480, 1342, 1311, 1223,
1102, 799, 759 cm–1.
Anal. Calcd for C22H21N5O: C, 71.14; H, 5.70; N, 18.85. Found: C,
71.27; H, 5.48; N, 18.73.
1H NMR (CDCl3): = 1.70–1.78 (dt, 1 H, J(d) = 13.61 Hz, J(t) = 5.14
Hz, 2 -H), 2.28–2.38 (dt, 1 H, J(d) = 13.89 Hz, J(t) = 8.69 Hz, 2 -H),
2.98 (s, 1 H, OH exchang. with D2O), 3.33–3.38 (m, 1 H, 1 -H),
3.76–3.84 (m, 1 H, 3 -H), 3.88 (s, 2 H, CH2OH), 4.40–4.48 (part A
of an ABM system, 1 H, JAB = 13.96 Hz, JAM = 9.32 Hz, CHHN),
4.53–4.59 (part B of an ABM system, 1 H, JBA = 14.01 Hz,
( )-cis-3-(6-N-propylamino-9H-purin-9-ylmethyl)indanylmeth-
anol (8e)
A solution of 7 (0.30 g, 0.84 mmol) and propylamine (4 mL) in
MeOH (9 mL) was heated in a bomb at 75 °C for 60 h. Once the re-
action mixture had cooled to r.t., the solvent was evaporated under
reduced pressure, leaving a brown oil. This was chromatographed
on silica gel (15 g) using AcOH–MeOH (10:1) as eluent to afford
8e as a white solid (0.17 g, 60%); mp 116–118 °C (acetone–Et2O).
JBM = 6.17 Hz, CHHN), 7.04–7.06 (d, 1 H, J = 7.41 Hz, ArH),
7.17–7.32 (m, 3 H, ArH), 7.90 (s, 1 H, 2 -H), 8.53 (s, 1 H, 8 -H).
13C NMR (CDCl3): = 34.77 (CH), 47.62 (CH), 49.39 (CH), 51.71
(CH2), 57.25 (CH3), 68.51 (CH2), 127.06, 127.50, 130.23 y 130.83
(CH), 146.36 (C), 147.31 (C), 145.45 (CH), 155.00 (CH), 164.37
(C).
IR (KBr): 3273, 2952, 2862, 1618, 1577, 1540, 1476, 1339, 1248,
1224, 1082, 794, 758 cm–1.
1H NMR (CDCl3):
= 0.96–1.01 (t, 3 H, J = 7.66 Hz,
Anal. Calcd for C23H22N4O2: C, 71.48; H, 5.74; N, 14.50. Found: C,
71.33; H, 5.52; N, 14.72.
CH3CH2CH2N), 1.61–1.69 (sext, 2 H, J = 14.59, 7.44, 7.15 Hz,
CH3CH2CH2N), 1.71–1.77 (m, 1 H, 2 -H), 2.24–2.34 (dt, 1 H,
J(d) = 13.66 Hz, J(t) = 8.90 Hz, 2 -H), 3.28–3.34 (m, 1 H, 1 -H),
( )-cis-3-(6-Ethoxy-9H-purin-9-ylmethyl)indanylmethanol (8c)
A solution of 7 (0.33 g, 0.92 mmol) in EtOH (10 mL) was stirred at
r.t. for 24 h and then extracted with EtOAc (150 mL) and brine (100
mL). The pooled organic layers were dried (Na2SO4) and concen-
trated to dryness under reduced pressure. The solid obtained was re-
3.49–3.61 (m, 2 H, CH2OH), 3.71–3.79 (m, 1 H, 3 -H), 3.81–3.92
(m, 2 H, CH3CH2CH2N), 4.26–4.34 (part A of an ABM system, 1
H, JAB = 13.90 Hz, JAM = 9.70 Hz, CHHN), 4.43–4.50 (part B of an
ABM system, 1 H, JBA = 13.90 Hz, JBM = 6.22 Hz, CHHN), 4.70 (br
s, 1 H, OH exchange with D2O), 6.21 (br s, 1 H, NH exchange with
Synthesis 2002, No. 8, 1084–1090 ISSN 0039-7881 © Thieme Stuttgart · New York

1088
F. Fernández et al.
PAPER
D2O), 6.97–6.99 (d, 1 H, J = 6.96 Hz, ArH), 7.13–7.28 (m, 3 H,
ArH), 7.44 (s, 1 H, 2 -H), 8.34 (s, 1 H, 8 -H).
Anal. Calcd for C25H25N5O: C, 72.97; H, 6.12; N, 17.02. Found: C,
73.15; H, 5.98; N, 16.93.
13C NMR (CDCl3): = 14.33 (CH3), 24.91 (CH2), 34.78 (CH2),
44.85 (CH2), 47.65 (CH), 49.61 (CH), 51.49 (CH2), 68.32 (CH2),
127.06, 127.52, 130.04 and 130.69 (CH), 142.60 (CH), 146.58 (C),
147.55 (C), 156.12 (CH), 158.45 (C).
Suzuki–Miyaura Coupling of 7 with Substituted Arylboronic
Acids; General Procedure
A mixture of 7 (220 mg, 0.61 mmol), the appropriate arylboronic
acid (0.92 mmol), Pd(PPh3)4 (33.3 mg, 0.029 mmol) and K2CO3
(127.6 mg, 0.92 mmol) in toluene (30 mL) was stirred under argon
at 100 °C until the starting material had disappeared (TLC monitor-
ing). Once at r.t., the solvent was evaporated under reduced pressure
and the residue was chromatographed on silica gel (60 g) using hex-
ane–EtOAc (3:1) as eluent, affording fractions from which the cor-
responding 6-arylpurine derivative 9 was isolated by evaporation of
the solvent and drying.
Anal. Calcd for C25H27N5O: C, 72.61; H, 6.58; N, 16.94. Found: C,
72.83; H, 6.41; N, 16.71.
( )-cis-3-(6-N-isopropylamino-9H-purin-9-ylmethyl)indanyl-
methanol (8f)
A solution of 7 (0.10 g, 0.28 mmol) and isopropylamine (1 mL) in
MeOH (3 mL) was heated in a bomb at 75 °C for 60 h. Once the re-
action mixture had cooled to r.t., the solvent was evaporated under
reduced pressure leaving a brown oil. This was purified by chroma-
tography on silica gel (4 g) using AcOH–MeOH (10:1) as eluent to
furnish 8f as a light brown solid (0.045 g, 52%); mp 170–71 °C (ac-
etone).
( )-cis-3-(6-Phenyl-9H-purin-9-ylmethyl)indanylmethyl Ace-
tate (9a)
Yield: 73%; mp 96–99 °C.
IR (KBr): 2888, 1731, 1580, 1567, 1502, 1457, 1397, 1324, 1241,
1027, 928, 764 cm–1.
1H NMR (CDCl3): = 1.49–1.60 (dt, 1 H, J(d) = 13.20 Hz, J(t) = 7.38
Hz, 2 -H), 1.95 (s, H, CH3CO), 2.28–2.39 (dt, 1 H, J(d) = 13.20 Hz,
IR (KBr): 3260, 2951, 2857, 1684, 1653, 1576, 1474, 1337, 1225,
1082, 793, 758 cm–1.
1H NMR (CDCl3): = 1.30–1.31 (d, 6 H, J(d) = 2.5 Hz, 2 CH3),
1.72–1.80 (dt, 1 H, J(d) = 9.44 Hz, J(t) = 4.72 Hz, 2 -H), 2.26–2.36
(dt, 1 H, J(d) = 13.53 Hz, J(t) = 8.81 Hz, 2 -H), 3.35 (m, 1 H, 1 -H),
3.75 (m, 1 H, 3 -H), 3.80–3.90 (m, 2 H, CH2OH), 4.30–4.38 (part
A of an ABM system, 1 H, JAB = 14.05 Hz, JAM = 9.76 Hz, CHHN),
4.43–4.50 (part B of an ABM system, 1 H, JBA = 14.05 Hz,
JBM = 6.30 Hz, CHHN), 4.60 (s, 1 H, OH, exchang. with D2O), 6.00
(s, 1 H, NH exchang. with D2O), 7.02–7.05 (d, 1 H, ArH), 7.18–7.31
(m, 3 H, ArH), 7.55 (s, 1 H, 2 -H), 8.36 (s, 1 H, 8 -H).
13C NMR (CDCl3): = 20.79 (CH3), 27.12 (CH), 29.58 (CH2),
42.83 (CH), 44.60 (CH), 46.43 (CH2), 63.35 (CH2), 122.04, 122.50,
125.02 y 125.69 (CH), 137.55 (C), 141.51 y 142.49 (C), 151.09
(CH), 154.04 (C).
J
(t) = 8.34 Hz, 2 -H), 3.33–3.45 (m, 1 H, 1 -H), 3.79–3.90 (m, 1 H,
3 -H), 4.07–4.14 (part A of an ABM system, 1 H, JAB = 11.01 Hz,
AM = 7.04 Hz, CHHOAc), 4.19–4.26 (part B of an ABM system, 1
J
H, JBA = 11.01 Hz, JBM = 5.83 Hz, CHHOAc), 4.30–4.39 (part A of
an ABM system, 1 H, JAB = 13.98 Hz, JAM = 8.21 Hz, CHHN),
4.64–4.72 (part B of an ABM system, 1 H, JBA = 13.98 Hz,
JBM = 5.97 Hz, CHHN), 7.00–7.24 (m, 4 H, ArH), 7.44–7.53 (m, 3
H, ArH), 7.96 (s, 1 H, 2 -H), 8.70–8.74 (m, 2 H, ArH), 8.96 (s, 1 H,
8 -H).
13C NMR (CDCl3): = 21.32 (CH3), 33.88 (CH2), 43.25 (CH),
44.08 (CH3), 48.87 (CH2), 67.61 (CH2), 124.36, 125.01, 128.07 and
128.30 (CH), 129.10 (C), 130.19 (CH), 131.40 and 131.46 (CH),
136.00 (C), 143.42 (C), 143.99 (C), 144.89 (CH), 152.88 (CH),
153.14 (C), 155.36 (C), 171.43 (COO).
Anal. Calcd for C25H27N5O: C, 72.61; H, 6.58; N, 16.94. Found: C,
72.78; H, 6.69; N, 16.75.
Anal. Calcd for C24H22N4O2: C, 72.34; H, 5.57; N, 14.06. Found: C,
72.09; H, 5.71; N, 14.20.
( )-cis-3-(6-N-cyclopropylamino-9H-purin-9-ylmethyl)indanyl-
methanol (8g)
A solution of 7 (0.30 g, 0.84 mmol) and cyclopropylamine (3 mL)
in MeOH (9 mL) was heated in a bomb at 75 °C for 60 h. Once the
reaction mixture had cooled to r.t., the solvent was evaporated under
reduced pressure leaving a brown oil. Chromatography of this oil on
silica gel (15 g) using AcOH–MeOH (8:1) as eluent afforded 8g as
a light brown solid (0.125 g, 44%); mp 167–170 °C (acetone).
( )-cis-3-[6-(4 -Methyl)phenyl-9H-purin-9-ylmethyl]indanylm-
ethyl Acetate (9b)
Yield: 64%; mp 136–140 °C.
IR (KBr): 2889, 1733, 1579, 1560, 1514, 1455, 1325, 1304, 1231,
1204, 1179, 1025, 930, 799, 649 cm–1.
1H NMR (CDCl3): = 1.48–1.56 (dt, 1 H, J(d) = 13.36 Hz, J(t) = 7.15
Hz, 2 -H), 1.95 (s, H, CH3CO), 2.29–2.37 (dt, 1 H, J(d) = 13.36 Hz,
J(t) = 8.25 Hz, 2 -H), 2.36 (s, 3 H, CH3), 3.30–3.40 (m, 1 H, 1 -H),
3.75–3.85 (m, 1 H, 3 -H), 4.05–4.13 (part A of an ABM system, 1
H, JAB = 10.98 Hz, JAM = 7.14 Hz, CHHOAc), 4.18–4.25 (part B of
an ABM system, 1 H, JBA = 10.98 Hz, JBM = 5.85 Hz, CHHOAc),
4.26–4.35 (part A of an ABM system, 1 H, JAB = 13.89 Hz,
IR (KBr): 3319, 2920, 1717, 1615, 1578, 1477, 1356, 1285, 1235,
1075, 797, 759 cm–1.
1H NMR (CDCl3): = 0.59 (m, 2 H, cyclopropyl CH2) 0.86 (m, 2
H, cyclopropyl CH2), 1.64–1.74 (dt, 1 H, J(d) = 9.60 Hz, J(t) = 4.80
Hz, 2 -H), 2.19–2.31 (dt, 1 H, J(d) = 13.63 Hz, J(t) = 8.98 Hz, 2 -H),
2.96–2.98 (d, 1 H, J = 2.87 Hz, cyclopropyl CH), 3.26–3.31 (m, 1
H, 1 -H), 3.66–3.77 (m, 1 H, 3 -H), 3.84 (s, 2 H, CH2OH), 4.25–
4.34 (part A of an ABM system, 1 H, JAB = 13.90 Hz, JAM = 9.70
Hz, CHHN), 4.39–4.47 (part B of an ABM system, 1 H, JBA = 13.90
Hz, JBM = 6.32 Hz, CHHN), 4.70 (s, 1 H, OH exchang. with D2O),
6.30 (s, 1 H, NH exchang. with D2O), 6.95–6.98 (d, 1 H, J = 7.06
Hz, ArH), 7.10–7.25 (m, 3 H, ArH), 7.49 (s, 1 H, 2 -H), 8.40 (s, 1
H, 8 -H).
J
J
AM = 8.15 Hz, CHHN), 4.61–4.69 (part B of an ABM system, 1 H,
BA = 13.89 Hz, JBM = 5.97 Hz, CHHN), 7.00–7.19 (m, 4 H, ArH),
7.27–7.30 (d, 2 H, J(d) = 8.12 Hz, 3 -H and 5 -H), 7.92 (s, 1 H, 2 -
H), 8.61–8.64 (d, 2 H, J(d) = 8.26 Hz, 2 -H and 6 -H), 8.92 (s, 1 H,
8 -H).
13C NMR (CDCl3): = 21.31 (CH3), 22.02 (CH3), 33.88 (CH2),
43.23 (CH), 44.06 (CH), 48.78 (CH2), 67.70 (CH2), 124.35, 124.97,
128.04 and 128.25 (CH), 129.84 and 130.14 (CH), 131.16 (C),
133.30 (C), 141.87 (C), 143.46 and 143.99 (C), 144.63 (CH),
152.84 (CH), 153.00 (C), 155.35 (C), 171.42 (COO).
13C NMR (CDCl3): = 7.72 (CH2), 23.91 (CH), 32.28 (CH2), 45.15
(CH), 47.13 (CH), 49.01 (CH2), 66.01 (CH2), 124.55, 125.02,
127.58, 128.23 (CH), 140.46 (CH), 144.04 (C), 144.99 (C), 153.69
(CH), 156.22 (C).
Anal. Calcd for C25H24N4O2: C, 72.79; H, 5.86; N, 13.58. Found: C,
72.95; H, 5.69; N, 13.44.
Synthesis 2002, No. 8, 1084–1090 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Substituted Purinylcarbonucleosides
1089
( )-cis-3-[6-(4 -Methoxy)phenyl-9H-purin-9-ylmethyl]indanyl-
methyl Acetate (9c)
IR (KBr): 3365, 2919, 1684, 1654, 1581, 1476, 1399, 1325, 1259,
1209, 1029, 929, 802, 766, 694 cm–1.
Yield: 63%; mp 105-109 °C.
1H NMR (CDCl3): = 1.71–1.80 (dt, 1 H, J(d) = 13.60 Hz, J(t) = 5.40
Hz, 2 -H), 2.31–2.41 (dt, 1 H, J(d) = 13.60 Hz, J(t) = 8.88 Hz, 2 -H),
3.33–3.38 (m, 1 H, 1 -H), 3.81–3.90 (m, 3 H, 3 -H and CH2OH),
4.43–4.51 (part A of an ABM system, 1 H, JAB = 13.96 Hz,
IR (KBr): 2934, 1735, 1603, 1581, 1560, 1515, 1447, 1366, 1325,
1300, 1248, 1211, 1182, 1171, 1030, 927, 853, 806, 748 cm–1.
1H NMR (CDCl3): = 1.48–1.59 (m, 1 H, 2 -H), 1.96 (s, 3 H,
CH3CO), 2.28–2.36 (m, 1 H, 2 -H), 3.36–3.41 (m, 1 H, 1 -H),
3.76–3.86 (m, 1 H, 3 -H), 3.82 (s, 3 H, OCH3), 4.07–4.28 (m, 2 H,
CH2OAc), 4.29–4.37 (part A of an ABM system, 1 H, JAB = 13.51
Hz, JAM = 7.86 Hz, CHHN), 4.63–4.71 (part B of an ABM system,
1 H, JBA = 13.51 Hz, JBM = 5.47 Hz, CHHN), 6.98–7.02 (d, 2 H,
J(d) = 8.29 Hz, 3 -H and 5 -H), 7.02–7.19 (m, 4 H, ArH), 7.93 (s, 1
H, 2 -H), 8.73–8.76 (d, 2 H, J(d) = 8.29 Hz, 2 -H and 6 -H), 8.91 (s,
1 H, 8 -H).
JAM = 9.20 Hz, CHHN), 4.60–4.67 (part B of an ABM system, 1 H,
JBA = 13.96 Hz, JBM = 6.04 Hz, CHHN), 7.06–7.32 (m, 4 H, ArH),
7.52–7.60 (m, 3 H, ArH), 8.08 (s, 1 H, 2 -H), 8.77–8.80 (m, 2 H,
ArH), 9.01 (s, 1 H, 8 -H).
13C NMR (CDCl3): = 32.52 (CH2), 44.81 (CH), 46.83 (CH), 49.01
(CH2), 66.10 (CH2), 124.53, 124.99, 127.76 and 128.33 (CH),
129.11(C), 130.25 (CH), 131.45 (CH), 135.95 (C), 143.87 (C),
144.78 (C), 145.14 (CH), 152.70 (CH), 153.14 (C), 155.51 (C).
13C NMR (CDCl3): = 21.32 (CH3), 33.89 (CH2), 43.23 (CH),
44.06 (CH), 48.80 (CH2), 55.80 (CH3), 67.62 (CH2), 114.50 (CH),
124.37, 124.98, 128.05 and 128.26 (CH), 128.66 (C), 130.05 (C),
131.95 (CH), 143.47 (CH), 143.99 and 144.40 (C), 152.82 (CH),
154.98 (C), 162.48 (C), 171.44 (COO).
Anal. Calcd for C22H20N4O: C, 74.14; H, 5.66; N, 15.72. Found: C,
73.97; H, 5.81; N, 15.54.
( )-cis-3-[6-(4 -Methyl)phenyl-9H-purin-9-ylmethyl]indanyl-
methanol (10b)
Yield: 95%; mp 184–186 °C.
Anal. Calcd for C25H24N4O3: C, 70.08; H, 5.65; N, 13.08. Found: C,
69.96; H, 5.49; N, 12.91.
IR (KBr): 3373, 2876, 1581, 1477, 1444, 1396, 1326, 1214, 1183,
1020, 929, 798, 752, 650 cm–1.
( )-cis-3-[6-(4 -Chloro)phenyl-9H-purin-9-ylmethyl]indanylm-
ethyl Acetate (9d)
Yield: 87%; mp 127–130 °C.
1H NMR (CDCl3): = 1.65–1.74 (dt, 1 H, J(d) = 13.64 Hz, J(t) = 5.18
Hz, 2 -H), 2.23–2.32 (dt, 1 H, J(d) = 13.62 Hz, J(t) = 8.91 Hz, 2 -H),
2.38 (s, 3 H, CH3), 3.27–3.32 (m, 1 H, 1 -H), 3.73–3.82 (m, 3 H,
3 -H and CH2OH), 4.38–4.47 (part A of an ABM system, 1 H,
IR (KBr): 2966, 1725, 1578, 1558, 1498, 1447, 1382, 1326, 1244,
1174, 1032, 927, 855, 804, 763 cm–1.
JAB = 13.97 Hz, JAM = 9.22 Hz, CHHN), 4.51–4.59 (part B of an
ABM system, 1 H, JBA = 13.97 Hz, JBM = 6.13 Hz, CHHN), 7.02–
7.27 (m, 4 H, ArH), 7.29–7.32 (d, 2 H, J(d) = 8.12 Hz, 3 -H and 5 -
H), 8.02 (s, 1 H, 2 -H), 8.62–8.65 (d, 2 H, J(d) = 8.25 Hz, 2 -H and
6 -H), 8.92 (s, 1 H, 8 -H).
13C NMR (CDCl3): = 22.06 (CH3), 32.37 (CH2), 45.01 (CH),
46.88 (CH), 48.97 (CH2), 66.16 (CH2), 124.56, 125.00, 127.78 and
128.36 (CH), 129.89 and 130.19 (CH), 131.25 (C), 133.21 (C),
142.01 (C), 143.89 (CH), 144.76 and 144.83 (C), 152.68 (CH),
153.04 (C), 155.60 (C).
1H NMR (CDCl3): = 1.49–1.60 (dt, 1 H, J(d) = 13.27 Hz, J(t) = 7.11
Hz, 2 -H), 1.96 (s, 3 H, CH3CO), 2.28–2.40 (dt, 1 H, J(d) = 13.27
Hz, J(t) = 8.20 Hz, 2 -H), 3.34–3.46 (m, 1 H, 1 -H), 3.79–3.91 (m,
3 H, 3 -H), 4.07–4.14 (part A of an ABM system, 1 H, JAB = 11.00
Hz, JAM = 7.19 Hz, CHHOAc), 4.19–4.25 (part B of an ABM sys-
tem, 1 H, JBA = 11.00 Hz, JBM = 5.88 Hz, CHHOAc), 4.31–4.40
(part A of an ABM system, 1 H, JAB = 13.82 Hz, JAM = 8.16 Hz,
CHHN), 4.65–4.73 (part B of an ABM system, 1 H, JBA = 13.82 Hz,
JBM = 5.96 Hz, CHHN), 7.03–7.22 (d, 2 H, J(d) = 8.29 Hz, 3 -H and
5 -H), 7.44–7.47 (m, 4 H, ArH), 7.96 (s, 1 H, 2 -H), 8.71–8.75 (d,
2 H, J(d) = 8.71 Hz, 2 -H and 6 -H), 8.95 (s, 1 H, 8 -H).
Anal. Calcd for C23H22N4O: C, 74.57; H, 5.99; N, 15.12. Found: C,
74.39; H, 5.73; N, 15.35.
13C NMR (CDCl3): = 21.32 (CH3), 33.83 (CH2), 43.25 (CH),
44.09 (CH), 48.88 (CH2), 67.60 (CH2), 124.34, 125.04, 128.09 and
128.34 (CH), 129.33 and 131.51 (CH), 134.52 (C), 137.70 (C),
143.36 (C), 143.99 (C), 144.98 (CH), 152.85 (CH), 153.24 (C),
153.95 (C), 171.41 (COO).
( )-cis-3-[6-(4 -Methoxy)phenyl-9H-purin-9-ylmethyl]indanyl-
methanol (10c)
Yield: 88%; mp 172-176 °C.
IR (KBr): 3346, 2962, 1606, 1579, 1517, 1438, 1328, 1251, 1183,
1104, 1031, 872, 843, 802, 746, 646 cm–1.
Anal. Calcd for C24H21ClN4O2: C, 66.59; H, 4.89; N, 12.94. Found:
C, 66.41; H, 4.68; N, 13.15.
1H NMR (CDCl3): = 1.65–1.74 (dt, 1 H, J(d) = 13.65 Hz, J(t) = 5.10
Hz, 2 -H), 2.23–2.35 (dt, 1 H, J(d) = 13.65 Hz, J(t) = 8.92 Hz, 2 -H),
2.86 (br s, 1 H, OH, exchang. with D2O), 3.25–3.34 (m, 1 H, 1 -H),
3.70–3.76 (m, 3 H, 3 -H and CH2OH), 3.83 (s, 3 H, OCH3), 4.37–
4.47 (part A of an ABM system, 1 H, JAB = 13.99 Hz, JAM = 9.30
Hz, CHHN), 4.50–4.58 (part B of an ABM system, 1 H, JBA = 13.99
Hz, JBM = 6.18 Hz, CHHN), 6.99–7.26 (m, 6 H, ArH), 8.00 (s, 1 H,
2 -H), 8.73–8.77 (d, 2 H, J(d) = 8.91 Hz, 2 -H and 6 -H), 8.88 (s, 1
H, 8 -H).
13C NMR (CDCl3): = 32.33 (CH2), 45.05 (CH), 46.90 (CH), 48.95
(CH2), 55.83 (CH3), 66.17 (CH2), 114.51 (CH), 124.57, 125.00,
127.77 and 128.36 (CH), 128.61 (C), 130.09 (C), 132.01 (CH),
143.90 (CH), 144.58 and 144.77 (C), 152.65 (CH), 152.91 (C),
155.13 (C), 162.81 (C).
Cleavage of the Acetyl Group from Compounds 9a–d; General
Procedure
A 1 M solution of NaOMe (700 L, 0.7 mmol) was added to a solu-
tion of 9 (0.350 mmol) in MeOH (10 mL) and dioxane (10 mL) and
the mixture was stirred at r.t. overnight. Then the solution was neu-
tralized by addition of Dowex 50 8 (H+) (ca. 100 mg) and the re-
sultant solution was stirred for 1 h. The ion-exchanger was filtered
out and was washed with NH4OH 30% (5 mL) and MeOH (10 mL).
The combined filtrates were evaporated to dryness affording the
compounds 10a–d.
( )-cis-3-(6-Phenyl-9H-purin-9-ylmethyl)indanylmethanol
(10a)
Yield: 96%; mp 96–99 °C.
Anal. Calcd for C23H22N4O2: C, 71.48; H, 5.74; N, 14.50. Found: C,
71.35; H, 5.87; N, 14.36.
Synthesis 2002, No. 8, 1084–1090 ISSN 0039-7881 © Thieme Stuttgart · New York

1090
F. Fernández et al.
PAPER
Biological Applications, San Francisco, USA, September
( )-cis-3-[6-(4 -Chloro)phenyl-9H-purin-9-ylmethyl]indanyl-
methanol (10d)
Yield: 87%; mp 183–187 °C.
2000 and XII Congreso Nacional de la Sociedad Española de
Química Terapéutica, Sevilla, Spain, September 2001.
(2) (a) Cheson, B. D. Hematol. Cell. Ther. (Suppl. 2) 1996, 38,
109. (b) Bergmann, L. Leukemia (Suppl. 2) 1997, 11, 29.
(3) Lambe, C. U.; Averett, D. R.; Paff, M. T.; Reardon, J. E.;
Wilson, J. G.; Krenitsky, T. A. Cancer Res. 1995, 55, 3352.
(4) Gibboney, D. S.; French, B. T.; Patrick, D. E.; Trewin, R. W.
Cancer Chemother. Pharmacol. 1989, 25, 189.
(5) Hocek, M.; Hol, A.; Votruba, I.; Dvoráková, H. J. Med.
Chem. 2000, 43, 1817.
IR (KBr): 3376, 1654, 1583, 1559, 1506, 1447, 1328, 1213, 1015,
844, 801, 748, 644 cm–1.
1H NMR (CDCl3): = 1.72–1.80 (dt, 1 H, J(d) = 13.57 Hz, J(t) = 5.40
Hz, 2 -H), 2.32–2.43 (dt, 1 H, J(d) = 13.57 Hz, J(t) = 8.90 Hz, 2 -H),
2.58 (br s, 1 H, OH, exchang. with D2O), 3.35–3.40 (m, 1 H, 1 -H),
3.82–3.89 (m, 3 H, 3 -H and CH2OH), 4.46–4.54 (part A of an
ABM system, 1 H, JAB = 13.95 Hz, JAM = 9.19 Hz, CHHN), 4.62–
4.69 (part B of an ABM system, 1 H, JBA = 13.95 Hz, JBM = 6.01
Hz, CHHN), 7.08–7.33 (m, 4 H, ArH), 7.51–7.55 (d, 2 H, J(d) = 8.66
Hz, 3 -H and 5 -H), 8.10 (s, 1 H, 2 -H), 8.78–8.82 (d, 2 H,
J(d) = 8.63 Hz, 2 -H and 6 -H), 9.00 (s, 1 H, 8 -H).
13C NMR (CDCl3): = 32.46 (CH2), 44.88 (CH), 46.84 (CH), 49.03
(CH2), 66.14 (CH2), 124.53, 124.99, 127.82 and 128.41 (CH),
129.35 and 131.57 (CH), 134.70 (C), 137.80 (C), 143.82 (C),
144.68 (C), 145.19 (CH), 152.66 (CH), 153.21 (C), 154.08 (C).
(6) Fernández, F.; García-Mera, X.; Morales, M.; Rodríguez-
Borges, J. E. Synthesis 2001, 239.
(7) Wittig, G.; Knauss, E. Chem. Ber. 1958, 91, 895.
(8) (a) Mitsunobu, O.; Wata, M.; Sano, T. J. Am. Chem. Soc.
1972, 94, 679. (b) Mitsunobu, O. Synthesis 1981, 1.
(c) Girard, F.; Lee, M. G.; Agrofoglio, L. A. J. Heterocycl.
Chem. 1998, 35, 911.
(9) Borcherding, D. R.; Peet, N. P.; Munson, H. R.; Zhang, H.;
Hoffman, P. F.; Bowlin, T. L.; Edwards, C. K. J. Med. Chem.
1996, 39, 2615.
Anal. Calcd for C22H19ClN4O: C, 67.60; H, 4.90; N, 14.33. Found:
C, 67.95; H, 4.70; N, 14.17.
(10) Cesnek, M.; Hocek, M.; Hol, A. Collect. Czech. Chem.
Commun. 2000, 65, 1357.
(11) Havelková, M.; Dvorak, D.; Hocek, M. Synthesis 2001,
1704.
Acknowledgement
The authors thank the Xunta de Galicia for financial support of this
work under project PGIDT01PXI20302PR.
(12) Suzuki, A. J. Organomet. Chem. 1999, 576, 147; and
references therein.
(13) De Clercq, E. In Vivo and Ex Vivo Text Systems to
Rationalize Drug Design and Delivery; Cromelin, D.;
Couvreur, P.; Duchene, D., Eds.; Editions de Sante: Paris,
1994.
References
(1) Part of this work was presented at the XIV International
Round Table on Nucleosides, Nucleotides and their
Synthesis 2002, No. 8, 1084–1090 ISSN 0039-7881 © Thieme Stuttgart · New York