Synthesis of new 6-substituted purinyl-5′-nor-1′- homocarbanucleosides based on indanol

Article abstract of DOI:10.1016/j.tet.2004.07.054

A series of new 6-substituted purinyl-5′-nor-1′- homocarbanucleosides based on indanol were synthesized from (±)-cis-3- hydroxymethyl-1-indanol, an appropriately functionalized derivative of which was reacted with 6-chloropurine in the presence of NaH and

Full text of DOI:10.1016/j.tet.2004.07.054

Tetrahedron 60 (2004) 9245–9253
Synthesis of new 6-substituted
purinyl-50-nor-10-homocarbanucleosides based on indanol*
a
Franco Fernandez, Xerardo Garcıa-Mera, Melvin Morales, Leonardo Vilarino,
a,
a
a
*
´
´
˜
Olga Caaman˜oa and Eric De Clercqb
a
´ ´
Departamento de Quımica Organica, Facultade de Farmacia, Universidade de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
bRega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
Received 27 May 2004; revised 15 July 2004; accepted 22 July 2004
Available online 27 August 2004
Abstract—A series of new 6-substituted purinyl-50-nor-10-homocarbanucleosides based on indanol were synthesized from (G)-cis-3-
hydroxymethyl-1-indanol, an appropriately functionalized derivative of which was reacted with 6-chloropurine in the presence of NaH and
18-crown-6 ether to prepare a key intermediate that gave access to the target molecules, purinylcarbanucleosides in which position 6 is
occupied by a chloro, hydroxy, methoxy, amino or substituted phenyl group.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
C-1 of the pseudosugar moiety7 and a number of nor-
compounds in which and improved selectivity index has
been achieved by substituting an hydroxyl group for a
pseudosugar hydroxymethyl (e.g., the hydroxymethyls
on C-50 of aristeromycin8 and C-30 of carbocyclic
oxetanocin analogues9).
Of the many classes of nucleoside analogues that have
been synthesized with a view to clinical applications,
one of the most interesting is the class of carbocyclic
analogues (CANs), which continues to have great
potential for the development of new antitumour and
antiviral agents.2 CANs are compounds in which the
furan ring of natural nucleosides has been replaced by a
carbocyclic system. This modification endows them with
greater biostability than nucleosides by making them
more resistant to the hydrolytic action of phosphoryl-
ases.3,4 The anti-AIDS drug carbovir (I),5 which
selectively inhibits HIV reverse transcriptase, and its
equally potent but less toxic analogue abacavir (II),6 are
cyclopentenyl nucleosides CANs in which the sugar ring
of natural nucleosides has been replaced with a
cyclopentene ring. Variants of carbocyclic nucleosides
include 10-homonucleosides, in which further resistance
to enzymatic degradation has been sought by insertion
of a methylene group between the heterocyclic base and
In recent years our research group has prepared a
number of cyclopentenyl 10-homonucleoside derivatives
in which the cyclopentene ring is incorporated in an
indan system (III),10 our aim being to improve the
liposolubility of the compounds and thus facilitate its
access to the central nervous system, an important
reservoir of the HIV and other viruses.11 Some of these
compounds showed considerable cytostatic activity,12
particularly the 6-arylpurine derivatives (which is in
keeping with reports concerning 6-arylpurinyl ribonu-
cleosides).13,14
Here we describe a new series of this kind in which
both the variant features mentioned in the previous
paragraph have been introduced. Specifically, we report
the synthesis and antiviral activity of a series of indanyl
50-nor-10-homocarbanucleosides in which position 6 of
the purine system bears a Cl (12), OH (13a), OMe
(13b), NH2 (14a), cyclopropylamine (14b) or –PhR
(16a–d) group.
* See Ref. 1.
Keywords: Synthesis; Antiviral agents; Antineoplastic agents; Indan
carbanucleosides; Suzuki–Miyaura cross-coupling reaction.
* Corresponding author. Tel.: C34-981-563100; fax: C34-981-594912;
e-mail: qoxgmera@usc.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.054

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9246
which the desired acetate 5 was obtained only in
unsatisfactory yield and after laborious work-up
(accompanied by the diacetate and starting cis-4), we
resorted to lipase-catalysed transesterification from vinyl
acetate using Candida antarctica lipase (Novozymw 435),17
which afforded the desired monoacetate 5 as the only
product in 93% yield.
The secondary alcohol of 5 was efficiently protected by
reaction with tert-butyldimethylsilyl chloride and imidazole
in dichloromethane,18 and the primary alcohol of the
resulting compound 6, was then deprotected by treatment
with MeONa/MeOH. However, several attempts at Mitsu-
nobu coupling of 7 to 6-chloropurine (addition of DEAD to
a mixture of 7, PPh3 and 6-chloropurine followed by
reaction for times ranging from 12 to 36 h at temperatures
ranging from room temperature (rt) to 50 8C) were all
unsuccessful, only the starting compound ever being
recovered.
2. Results and discussion
Eventually, the purine was introduced on the diol by a more
classical method: treatment of 7 with mesyl chloride
provided mesylate 8, and heating 8 with 6-chloropurine in
DMF in the presence of NaH and 18-crown-6 ether19
afforded a 50% yield of the desired key intermediate 9 by
nucleophilic substitution.
Retrosynthetic analysis (Scheme 1) led to the choice of diol
cis-4 as starting compound. Appropriate functionalization
of cis-4 would allow it to be coupled to 6-chloropurine, and
the resulting key intermediate, 9, would afford purinylcar-
banucleosides 12, 13a–b and 14a–b by substitution of the
chlorine at position 6 (when necessary) and deprotection,
while its Suzuki–Miyaura cross-coupling with appropriate
boronic acids would give 6-arylpurinylcarbanucleosides
16a–d.
To obtain the 6-chloropurinyl carbanucleoside 12, com-
pound 9 was deprotected by distilling with FeCl3/water
(Scheme 3), a method that prevents the OH epimerization
that occurs when other deprotecting agents are employed.20
Treatment of 9 with 0.25 N NaOH in 1,4-dioxane afforded
the 6-hydroxypurinyl carbanucleoside 13a in one step and
75% yield, while treatment with methanol or amine,
followed by deprotection with FeCl3/water, gave the
6-methoxy and 6-amino compounds 13b, 14a and 14b.
Diol 4 was easily obtained from phenylsuccinic anhydride
by Friedel–Crafts reaction with aluminium trichloride in
1,2-dichloroethane15 followed by esterification with metha-
nol in an acidic medium and treatment of the resulting
ketoester 3 with lithium borohydride in tetrahydrofuran
(Scheme 2). The resulting 83:17 mixture of (G)-cis-4 and
(G)-trans-4 was efficiently resolved by chromatography on
silica gel.
Finally, following Hocek and co-workers,21 we introduced
substituted phenyls at position 6 of the purine by Suzuki–
Miyaura cross coupling reaction of 9 with the appropriate
arylboronic acids in dry toluene containing tetrakis(tri-
phenylphosphine)palladium as catalyst, potassium carbo-
nate as base. This procedure gave 50–96% yields of
compounds 15a–d, deprotection of which with FeCl3/
water afforded the 6-arylpurinyl carbanucleosides 16a–d
in yields of 71–87%.
We next acetylated the primary alcohol of cis-4 to prevent
its reaction during protection of the secondary alcohol with
a group that would subsequently withstand the conditions to
be employed for Mitsunobu coupling to 6-chloropurine.16
Since an attempt at acetylations by reaction with acetic
anhydride in pyridine afforded a complex mixture from
Scheme 1.

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F. Fernandez et al. / Tetrahedron 60 (2004) 9245–9253
9247
Scheme 2.
3. Antiviral activity
Bu¨chi 510 apparatus, and are uncorrected. Infrared spectra
were recorded in a Perkin–Elmer 1640-FT spectrometer. 1H
NMR spectra (300 MHz) and 13C NMR spectra
(75.47 MHz) were recorded in a Bruker AMX spectrometer,
using TMS as internal standard (chemical shifts (d) in ppm,
J in Hz). Elemental analyses were obtained on a Perkin–
Elmer 240B microanalyser by the Microanalysis Service of
the University of Santiago de Compostela. Flash chroma-
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).
Compounds 12, 13a–b, 14a–b and 16a–d were evaluated
for antiviral activity22 against a wide variety of viruses,
including herpes simplex virus type 1 (strain KOS), herpes
simplex virus type 2 (strain G), vaccinia virus, a thymidine
kinase-deficient HSV-1 strain (KOS, ACVR) and vesicular
stomatitis virus (VSV) in HEL cell cultures; respiratory
syncytial virus, Coxsackie virus B4 and vesicular stomatitis
virus in HeLa cell cultures; and type 3 parainfluenza virus,
type 1reovirus, Sindbis virus, Coxsackie virus B4 and Punta
Toro virus in Vero cell cultures. None of the compounds
showed inhibitory activity against any of the virus strains at
400 mg/mL.
5.1.1. Methyl 3-oxo-1-indanecarboxylate, 3. A solution of
phenylsuccinic anhydride (8 g, 45.41 mmol) in 1,2-dichloro-
ethane (65 mL) was added dropwise to a well-stirred
suspension of aluminium trichloride (13.6 g, 102 mmol) in
65 mL of the same solvent at 0 8C. The mixture was stirrred
for 40 min at rt, quenched with 100 mL of H2O at 0 8C, and
extracted with ethyl ether (3!75 mL). The pooled organic
layers were dried (Na2SO4), and removal of the solvent
under vacuum afforded 3-oxo-1-indanecarboxylic acid, 2,
which was dissolved in MeOH (20 mL) containing 5 drops
of sulphuric acid. This solution was refluxed for 16 h, the
solvent was removed under vacuum, and the resulting oil
was distilled in a Kugelrohr distillation apparatus (185 8C,
0.3 mm Hg), affording 3 (5.75 g, 29.94 mmol, yield 67%) as
an oil that crystallized spontaneously as white needles. Mp
40–42 8C. IR (KBr): nZ3009, 2954, 1736, 1715, 1654,
1598, 1342, 1209, 1170, 1049, 762 cmK1. 1H NMR (CDCl3):
dZ2.83 (d!d, 1H, JgemZ19.10 Hz, JvicZ8.0 Hz, 2-H),
3.14 (d!d, 1H, JgemZ19.1 Hz, JvicZ3.6 Hz, 2-H), 3.77 (s,
3H, CO2CH3), 4.29 (m, 1H, J3,2Z8.0 Hz, J3,2Z3.5 Hz,
1-H), 7.45 (t, 1H, JZ7.3 Hz, 5-H), 7.60–7.70 (m, 2H, 4-H
and 6-H), 7.76 (d, 1H, J4,5Z7.6 Hz, 7-H). 13C NMR
(CDCl3): dZ39.90, 44.01, 53.08, 124.35, 126.91, 129.21,
4. Conclusion
In conclusion, this paper describes a convenient synthetic
proce0dure for the preparation of 6-substituted purinyl-50-
nor-1 -homocarbanucleosides with a pseudosugar based on
indanol, 12, 13a–b, 14a–b and 16a–d, an interesting new
template in which the double bond of the cyclopentenyl
nucleosides is embedded in a benzene ring. However, none
of the members of this family that were synthesized exhibits
antiviral activity.
5. Experimental
5.1. General
Silica gel (230 mesh) was purchased from Merck. All other
chemicals used were of reagent grade and were obtained
from Aldrich Chemical Co. Melting points were determined
in a Reichert Kofler Thermopan or in capillary tubes in a

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F. Fernandez et al. / Tetrahedron 60 (2004) 9245–9253
9248
Scheme 3.
135.40, 136.75, 151.47, 172.63, 204.49. Anal. Calcd for
C11H10O3: C, 69.46; H, 5.30; found: C, 69.65; H, 5.13.
pooled organic phases were washed with saturated NaCl
solution, dried over anhydrous Na2SO4, and concentrated
under vacuum. Chromatography of the resulting yellow oil
on a column of silica gel (295 g) with 40:1 CH2Cl2/iPrOH as
eluent afforded cis-4 in the early fractions [as an oil that
underwent spontaneous solidification; 8.22 g, 50.06 mmol,
yield 78%. Mp 78–80 8C (Et2O/cyclohexane)] and trans-4
in the late fractions (as a yellow oil; 1.76 g, 10.71 mmol,
yield 15%). (G)-cis-4. IR (KBr): nZ3250, 2984, 2933, 1461,
1407, 1379, 1281, 1263, 1211, 1173, 1067, 1051, 1025, 777,
5.1.2. (G)-cis-3-Hydroxymethyl-1-indanol, 4. A solution
of 3 (12.48 g, 70.61 mmol) in dry THF was added dropwise
under argon to
a suspension of LiBH4 (8.09 g,
353.06 mmol) in the same solvent, and after 12 h stirring,
40 mL of saturated NH4Cl solution was added dropwise at
0 8C. The resulting mixture was filtered through celite, the
aqueous and organic phases were separated, the aqueous
phase was extracted with AcOEt (3!100 mL), and the
1
743, 577 cmK1. H NMR (CDCl3): dZ1.74–1.81 (m, 1H,

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F. Fernandez et al. / Tetrahedron 60 (2004) 9245–9253
9249
2b-H), 2.20–2.40 (m, 1H, –OH, exchang. with D2O), 2.49–
2.57 (m, 1H, 2a-H), 3.20–3.50 (m, 1H, 3b-H), 3.40–3.50
(b.s., 1H, –OH, exchang. with D2O), 3.72–3.83 (m, 2H,
CH2OH), 4.91–5.01 (m, 1H, 1b-H), 7.18–7.35 (m, 4H,
ArH). 13C NMR (CDCl3): dZ39.37 (CH2), 45.63 (CH),
65.60 (CH2), 74.83 (CH), 124.56, 125.24, 128.02 and
129.17 (CH), 143.77 and 146.43 (C). Anal. Calcd for
C10H12O2: C, 73.15; H, 7.37. Found: C, 73.41; H, 7.17. (G)-
trans-4. IR (NaCl): nZ3265, 2922, 1455, 1409, 1372, 1267,
NMR (CDCl3): dZK4.01 and K4.18 (CH3), 18.61 (C),
21.41 (CH3), 26.29 (CH3), 40.87 (CH2), 41.53 (CH), 67.94
(CH2), 75.39 (CH), 124.36, 124.58, 127.88 and 128.88
(CH), 142.34 and 146.44 (C), 171.50 (C). Anal. Calcd for
C18H28O3Si: C, 67.46; H, 8.81. Found: C, 67.19; H, 8.69.
5.1.5. (G)-cis-3-(tert-Butyldimethylsilyloxy)-1-indanyl-
methanol, 7. A solution of 6 (0.62 g, 1.93 mmol) and
NaOMe (0.22 g, 3.86 mmol) in MeOH (30 mL) was stirred
for 4 h at rt, after which concentration of the organic phase
under vacuum afforded an oil that upon chromatography on
silica gel with 4:1 hexane/AcOEt as eluent gave 7 as a
colourless oil (0.46 g, 1.65 mmol, yield 85%). IR (NaCl):
nZ3383, 3069, 3026, 2955, 2856, 1740, 1560, 1472, 1458,
1
1205, 1169, 1054, 1045, 768, 745, 573 cmK1. H RMN
(CDCl3): dZ2.02–2.13 (m, 1H, 2b-H), 2.24–2.34 (m, 1H,
2a-H), 3.43–3.50 (m, 1H, 3b-H), 3.68–3.70 (m, 2H,
CH2OH), 5.22–5.26 (m, 1H, 1a-H), 7.23–7.40 (m, 4H,
ArH). 13C RMN (CDCl3): dZ47.06 (CH2), 52.87 (CH),
73.73 (CH2), 82.85 (CH), 132.20, 132.38, 135.36 and
136.31 (CH), 151.12 and 153.27 (C). Anal. Calcd for
C10H12O2: C, 73.15; H, 7.37. Found: C, 73.36; H, 7.13.
1
1388, 1255, 1111, 1044, 866, 836, 774 cmK1. H NMR
(CDCl3): dZ0.18 and 0.20 (2s, 6H, 2CH3), 0.92 (1s, 9H,
–C(CH3)3), 1.70–1.80 (m, 1H, 2b-H), 2.10–2.20 (b.s., 1H,
–OH exchang. with D2O), 2.52–2.62 (m, 1H, 2a-H), 3.26–
3.34 (m, 1H, 1b-H), 3.79–3.95 (m, 2H, –CH2OH), 5.16–
5.21 (m, 1H, 3b-H), 7.28–7.36 (m, 4H, ArH). 13C NMR
(CDCl3): dZK4.08 and K1.43 (CH3), 18.56 (C), 26.24
(CH3), 40.46 (CH2), 45.50 (CH), 67.16 (CH2), 75.46 (CH),
124.50, 124.85, 127.78 and 128.83 (CH), 143.65 and 146.78
(C). Anal. Calcd for C16H26O2Si: C, 69.01; H, 9.41. Found:
C, 69.33; H, 9.74.
5.1.3. (G)-cis-3-Hydroxy-1-indanylmethyl acetate, 5.
Vinyl acetate (5.93 mL, 64.37 mmol) was added dropwise
under argon to a solution of lipase (Novozymw 435; 2.64 g,
16.36 mmol) and 4 (10.57 g, 64.37 mmol) in 100 mL of dry
THF at 0 8C. The mixture was stirred for 4 h at 0 8C and then
for 12 h at rt, after which it was filtered through celite.
Concentration of the filtrate under reduced pressure afforded
a yellow oil that upon chromatography on silica gel (525 g)
with 2:1 hexane/AcOEt as eluent gave 5 as a colourless oil
that spontaneously crystallized as a white solid (12.39 g,
60.07 mmol, yield 93%). Mp 81–83 8C (Et2O/cyclohexane).
IR (KBr): nZ3351, 3275, 2969, 1728, 1475, 1436, 1394,
5.1.6. (G)-cis-3-(tert-Butyldimethylsilyloxy)-1-indanyl-
methyl methanesulfonate, 8. Methoxysulphonyl chloride
(4 mL, 52.03 mmol) was added dropwise to a solution of 7
(4.83 g, 17.34 mmol), DMAP (catalytic amount) and TEA
(7.7 mL) in dry CHCl3, and the mixture was refluxed for
12 h and then poured onto ice. The organic phase was drawn
off and washed with 0.5 N NaOH (100 mL) and with
saturated NaCl solution, and the pooled aqueous phases
were extracted with CH2Cl2 (4!100 mL). The pooled
organic phases were dried over anhydrous Na2SO4 and
concentrated to dryness, and chromatography of the residue
on silica gel (234 g) with 5:1 hexane/AcOEt as eluent
afforded 8 as an oil (4.82 g, 13.52 mmol, yield 78%). IR
(NaCl): nZ3075, 3027, 2955, 2928, 2856, 1471, 1361,
1369, 1339, 1276, 1267, 1251, 1229, 1043, 775, 754 cmK1
.
1H NMR (CDCl3): dZ1.73–1.81 (dt, 1H, J(t)Z13.85 Hz,
J(d)Z5.90 Hz, 2b-H), 2.05 (s, 3H, –OC(O)CH3), 2.64–2.73
(dt, 1H, J(t)Z13.82 Hz, J(d)Z7.10 Hz, 2a-H), 3.36–3.41 (m,
1H, 1b-H), 4.27–4.37 (m, 2H, CH2OAc), 5.15–5.21 (m, 1H,
3b-H), 7.26–7.45 (m, 4H, ArH). 13C NMR (CDCl3): dZ
21.32 (CH3), 39.91 (CH2), 42.05 (CH), 68.06 (CH2), 75.32
(CH), 124.78, 124.86, 128.81 and 129.01 (CH), 143.07 and
145.80 (C), 171.39 (C). Anal. Calcd for C12H14O3: C, 69.88;
H, 6.84. Found: C, 70.04; H, 6.91.
1
1252, 11118, 1103, 1077, 865, 836, 775 cmK1. H NMR
(CDCl3): dZ0.17 and 0.18 (2s, 6H, 2CH3), 0.93 (1s, 9H,
–C(CH3)3), 1.70–1.80 (m, 1H, 2b-H), 2.52–2.62 (m, 1H,
2a-H), 2.97 (s, 3H, OSO2CH3), 3.41–3.51 (m, 1H, 1b-H),
4.34–4.40 (part A of an ABM system, 1H, JABZ9.67 Hz,
JAMZ7.40 Hz, CHHOSO2Me), 4.47–4.53 (part B of an
ABM system, 1H, JBAZ9.68 Hz, JBMZ6.48 Hz,
CHHOSO2Me), 5.15–5.25 (m, 1H, 1b-H), 7.28–7.35 (m,
4H, ArH). 13C NMR (CDCl3): dZK4.17 and K4.03 (CH3),
18.56 (C), 26.26 (CH3), 37.73 (OSO2CH3), 40.12 (CH2),
42.34 (CH), 73.18 (CH2), 75.26 (CH), 124.69, 124.99,
128.39 and 128.59 (CH), 141.20 and 146.36 (C). Anal.
Calcd for C17H28O4SSi: C, 57.27; H, 7.92. Found: C, 57.46;
H, 8.13.
5.1.4. (G)-cis-3-(tert-Butyldimethylsilyloxy)-1-indanyl-
methyl acetate, 6. A solution of 5 (12.39 g, 60.07 mmol)
in dry CH2Cl2 was added at 0 8C under argon to a
suspension of tert-butyldimethylsilyl chloride (13.7 g,
90.1 mmol) and imidazole (8.18 g, 120.14 mmol) in
80 mL of the same solvent, and the mixture was stirred
for 12 h, diluted with 100 mL of CH2Cl2, and extracted with
150 mL of saturated NaHCO3 solution. The aqueous phase
was in turn extracted with CH2Cl2 (3!50 mL), and the
pooled organic phases were washed with 100 mL of
saturated NH4Cl solution, dried over anhydrous Na2SO4,
and concentrated to dryness, affording 6 as a pale yellow oil
(18.36 g, 57.28 mmol, yield 95.3%). IR (NaCl): nZ3420,
2954, 2856, 1741, 1604, 1559, 1508, 1463, 1363, 1239,
1
1107, 1037, 864, 837, 762 cmK1. H NMR (CDCl3): dZ
5.1.7. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-inda-
nylmethyl]-6-chloro-9H-purine, 9. A solution of 6-chloro-
purine (0.338 g, 2.18 mmol), NaH (0.08 g, 2.18 mmol) and
18-crown-6 ether (0.389 g, 1.45 mmol) in dry DMF was
stirred at 70 8C under argon for 1 h and then allowed to cool.
A solution of 8 (0.52 g, 1.45 mmol) in dry DMF was slowly
added, and stirring was continues at 55 8C for 20 h, after
which the resulting solution was concentrated to dryness.
0.17 and 0.29 (2s, 6H, 2CH3), 0.95 (1s, 9H, –C(CH3)3),
1.70–1.80 (m, 1H, 2b-H), 2.10 (s, 3H, –OC(O)CH3), 2.50–
2.60 (m, 1H, 2a-H), 3.31–3.39 (m, 1H, 1b-H), 4.22–4.28
(part A of an ABM system, 1H, JABZ10.80 Hz, JAM
Z
7.01 Hz, CHHOAc), 4.36–4.42 (part B of an ABM system,
1H, JBAZ10.80 Hz, JBMZ6.39 Hz, CHHOAc), 5.18–5.23
(t, 1H, JZ6.90 Hz, 3b-H), 7.27–7.34 (m, 4H, ArH). 13C

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Chromatography of the residue on a column of silica gel
(75 g) with 4:1 hexane/AcOEt as eluent afforded 9 as a
white solid (0.3 g, 0.72 mmol, yield 50%). Mp 171–173 8C
(CHCl3/hexane). IR (KBr): nZ3656, 3281, 2959, 1722,
1708, 1594, 1566, 1497, 1438, 1339, 1240, 1214, 1187,
1068, 771, 655, 564 cmK1. 1H NMR (CDCl3): dZ0.13 and
0.16 (2s, 6H, 2CH3), 0.85 (1s, 9H, –C(CH3)3), 1.72–1.81 (dt,
1H, J(t)Z13.55 Hz, J(d)Z8.46 Hz, 20b-H), 2.40–2.48 (dt,
1H, J(t)Z13.55 Hz, J(d)Z6.61 Hz, 20a-H), 3.70–3.77 (m,
1H, 30b-H), 4.42–4.49 (part A of an ABM system, 1H,
JABZ13.79 Hz, JAMZ7.86 Hz, CHHN), 4.66–4.73 (part B
of an ABM system, 1H, JBAZ13.79 Hz, JBMZ6.57 Hz,
CHHN), 5.14–5.18 (m, 1H, 10b-H), 6.95–6.97 (d, 1H, JZ
7.12 Hz, ArH), 7.23–7.36 (m, 3H, ArH), 7.89 (s, 1H, 8-H),
8.77 (s, 1H, 2-H). 13C NMR (CDCl3): dZK4.12 and K4.07
(CH3), 18.53 (C), 26.25 (CH3), 40.66 (CH2), 42.97 (CH),
50.10 (CH2), 75.26 (CH), 124.44, 125.53, 128.61 and
128.90 (CH), 132.31 (C), 142.23 (C), 146.05 (CH), 146.10
(C), 152.37 (CH). Anal. Calcd for C21H27ClN4OSi: C,
60.78; H, 6.56; N, 13.50. Found: C, 60.44; H, 6.67; N, 13.72.
1H, J(t)Z13.22 Hz, J(d)Z7.28 Hz, 20a-H), 3.55–3.66 (m,
1H, 30b-H), 4.17–4.25 (part A of an ABM system, 1H,
JABZ13.71 Hz, JAMZ8.01 Hz, CHHN), 4.44–4.52 (part B
of an ABM system, 1H, JBAZ13.71 Hz, JBMZ6.83 Hz,
CHHN), 4.99–5.04 (m, 1H, 10b-H), 6.02 (s, 2H, NH2,
exchang. with D2O), 6.79–6.82 (d, 1H, JZ7.06 Hz, ArH),
7.06–7.22 (m, 3H, ArH), 7.49 (s, 1H, 8-H), 8.25 (s, 1H,
2-H). 13C NMR (CDCl3): dZK4.52 and K4.44 (CH3), 7.79
(CH2), 18.14 (C), 25.87 (CH3), 40.46 (CH2), 42.37 (CH),
49.28 (CH2), 74.87 (CH), 124.10, 124.89, 127.96 and
128.31 (CH), 141.33 (C), 142.15 (C), 145.75 (C), 152.16
(CH), 155.12 (C). Anal. Calcd for C21H29N5OSi: C, 63.76;
H, 7.39; N, 17.70. Found: C, 63.92; H, 7.19; N, 17.53.
5.1.10. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-inda-
nylmethyl]-6-N-cyclopropylamino-9H-purine, 11b. A
solution of 9 (0.42 g, 1.01 mmol) and N-cyclopropylamine
(3 mL) in MeOH was heated for 60 h at 75 8C in a reaction
bomb that had previously been purged with argon. The
resulting solution was concentrated to dryness, and
chromatography of the residue on silica gel (20 g) with
20:1 CH2Cl2/MeOH as eluent afforded solid 11b (0.3 g,
0.68 mmol, yield 68%). Mp 60–62 8C (CHCl3/hexane). IR
(KBr): nZ3420, 2954, 2926, 1635, 1617, 1577, 1474, 1385,
1355, 1250, 1111, 862, 835, 774 cmK1. 1H NMR (CDCl3):
dZ0.13 and 0.14 (2s, 6H, 2CH3), 0.69–0.72 (m, 2H,
cyclopropyl CH2), 0.75–0.77 (m, 2H, cyclopropyl CH2),
0.84 (1s, 9H, –C(CH3)3), 1.57–1.67 (dt, 1H, J(t)Z13.16 Hz,
J(d)Z5.06 Hz, 20b-H), 2.22–2.33 (dt, 1H, J(t)Z13.16 Hz,
J(d)Z7.23 Hz, 20a-H), 2.80–2.92 (m, 1H, cyclopropyl CH),
3.55–3.66 (m, 1H, 30b-H), 4.21–4.29 (part A of an ABM
system, 1H, JABZ13.72 Hz, JAMZ8.02 Hz, CHHN),
4.46–4.54 (part B of an ABM system, 1H, JBAZ13.72 Hz,
JBMZ6.94 Hz, CHHN), 4.99–5.04 (m, 1H, 10b-H), 5.80–
5.90 (b.s., 1H, NH, exchang. with D2O), 6.75–6.78 (d, 1H,
JZ7.23 Hz, ArH), 7.08–7.22 (m, 3H, ArH), 7.60 (s, 1H,
8-H), 8.44 (s, 1H, 2-H). 13C NMR (CDCl3): dZK4.13 and
K4.04 (CH3), 7.79 (CH2), 18.55 (C), 26.28 (CH3), 40.91
(CH2), 42.73 (CH), 49.61 (CH2), 75.30 (CH), 124.53,
125.23, 128.27 and 128.66 (CH), 142.69 (C), 146.16 (C),
153.67 (CH), 155.11 (C). Anal. Calcd for C24H33N5OSi: C,
66.17; H, 7.64; N, 16.08. Found: C, 66.33; H, 7.56; N, 16.21.
5.1.8. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-inda-
nylmethyl]-6-methoxy-9H-purine, 10. A solution of 9
(0.42 g, 1.01 mmol) and NaOMe (0.07 g, 1.23 mmol) in
MeOH (10 mL) was stirred at rt under argon for 24 h, and
then neutralized with acid resin (Dowex 50!8 (HC),
80 mg), stirred for a further 15 min., treated with 10 mL of
7:3 MeOH/NH3, and kept stirring for a further 15 minutes.
The resulting solution was filtered and concentrated to
dryness, and chromatography of the residue on silica gel
(17 g) with 1:1 hexane/AcOEt as eluent afforded 10 as a
white solid (0.3 g, 0.75 mmol, yield 72%). Mp 52–54 8C
(CH2Cl2). IR (KBr): nZ3063, 2929, 2855, 1718, 1599,
1576, 1478, 1405, 1312, 1232, 1111, 1059, 863, 834, 663,
1
649 cmK1. H NMR (CDCl3): dZ0.13 and 0.14 (2s, 6H,
2CH3), 0.91 (1s, 9H, –C(CH3)3), 1.73–1.80 (m, 1H, 20b-H),
2.40–2.50 (m, 1H, 20a-H), 3.70–3.80 (m, 1H, 30b-H), 4.21
(s, 3H, OCH3), 4.36–4.43 (part A of an ABM system, 1H,
JABZ13.76 Hz, JAMZ8.00 Hz, CHHN), 4.61–4.68 (part B
of an ABM system, 1H, JBAZ13.76 Hz, JBMZ6.93 Hz,
CHHN), 5.14–5.17 (m, 1H, 10b-H), 6.90–6.92 (d, 1H, JZ
7.46 Hz, ArH), 7.22–7.33 (m, 3H, ArH), 7.73 (s, 1H, 8-H),
8.57 (s, 1H, 2-H). 13C NMR (CDCl3): dZK4.13 and K4.05
(CH3), 18.54 (C), 26.27 (CH3), 40.91 (CH2), 42.81 (CH),
49.85 (CH2), 54.61 (CH3), 75.28 (CH), 124.49, 125.29,
128.36 and 128.72 (CH), 142.50 (C), 143.09 (CH), 146.13
(C), 152.39 (C), 152.49 (CH), 161.23 (C). Anal. Calcd for
C21H28N4O2Si: C, 63.60; H, 7.12; N, 14.13. Found: C,
63.84; H, 6.98; N, 14.26.
5.2. Suzuki–Miyaura coupling of 9 with substituted
arylboronic acids. General procedure
A mixture of 9 (0.83 mmol), the appropriate arylboronic
acid (0.92 mmol), Pd(PPh3)4 (0.035 mmol) and K2CO3
(1.24 mmol) in toluene (50 mL) was stirred under argon at
100 8C until the starting material has disappeared (TLC
monitoring). Once at rt, the solvent was evaporated under
reduced pressure anf the residue was chromatographed on
silica gel (50 g) using 4:1 hexane–EtOAc as eluent,
affording fractions from which the corresponding 6-aryl-
purine derivative 15 was isolated by evaporation of the
solvent and drying.
5.1.9. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-inda-
nylmethyl]-6-amino-9H-purine, 11a. A solution of 9
(100 mg, 0.24 mmol) and liquid NH3 (7 mL) in MeOH
(3 mL) was heated at 75 8C in a reaction bomb for 60 h.
After cooling to rt, removal of the solvent under vacuum left
a residue that upon chromatography on silica gel (17 g) with
3:1 hexane/AcOEt followed by 20:1 CH2Cl2/MeOH as
eluents afforded 11a as a white solid (83 mg, 0.21 mmol,
yield 87%). Mp 178–180 8C (CHCl3/hexane). IR (KBr): nZ
3430, 3154, 2928, 1661, 1601, 1475, 1361, 1309, 1246,
1115, 865, 836, 775 cmK1. 1H NMR (CDCl3): dZ0.11 and
0.12 (2s, 6H, 2CH3), 0.90 (1s, 9H, –C(CH3)3), 1.57–1.66 (dt,
1H, J(t)Z13.22 Hz, J(d)Z5.17 Hz, 20b-H), 2.24–2.35 (dt,
5.2.1. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-ind-
anylmethyl]-6-phenyl-9H-purine, 15a. Yield 50%. Mp
133–35 8C (CHCl3/hexane). IR (KBr): nZ3057, 2955,
2927, 2855, 1587, 1567, 1506, 1472, 1460, 1401, 1363,
1333, 1300, 1250, 1212, 1116, 1072, 835, 762, 650 cmK1
.
1H NMR (CDCl3): dZ0.14 (1s, 6H, 2CH3), 0.91 (1s, 9H,

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F. Fernandez et al. / Tetrahedron 60 (2004) 9245–9253
9251
–C(CH3)3), 1.61–1.71 (dt, 1H, J(t)Z13.16 Hz, J(d)
Z
Z
5.2.4. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-inda-
nylmethyl]-6-(40-chloro)phenyl-9H-purine, 15d. Yield
73%. Mp 167–71 8C (CHCl3/hexane). IR (KBr): nZ3070,
2958, 2927, 1585, 1560, 1500, 1329, 1316, 1250, 1115,
1082, 872, 846, 800, 770 cmK1. 1H NMR (CDCl3): dZ0.13
(s, 6H, 2CH3), 0.89 (s, 9H, C(CH3)3), 1.62–1.71 (dt, 1H,
J(t)Z13.25 Hz, J(d)Z4.83 Hz, 20b-H), 2.30–2.38 (dt, 1H,
J(t)Z13.30 Hz, J(d)Z7.25 Hz, 20a-H), 3.63–3.68 (m, 1H,
5.12 Hz, 20b-H), 2.26–2.37 (dt, 1H, J(t)Z13.16 Hz, J(d)
7.30 Hz, 20a-H), 3.70–3.80 (m, 1H, 30b-H), 4.42–4.49 (part
A of an ABM system, 1H, JABZ13.76 Hz, JAMZ7.96 Hz,
CHHN), 4.70–4.77 (part B of an ABM system, 1H, JBA
Z
13.73 Hz, JBMZ6.63 Hz, CHHN), 5.15–5.20 (m, 1H,
10b-H), 7.00–7.02 (d, 1H, JZ7.16 Hz, ArH), 7.25–7.35
(m, 3H, ArH), 7.52–7.60 (m, 3H, ArH), 7.93 (s, 1H, 8-H),
8.78–8.81 (m, 2H, ArH), 9.06 (s, 1H, 2-H). 13C NMR
(CDCl3): dZK4.12 and K4.04 (CH3), 18.55 (C), 26.28
(CH3), 40.86 (CH2), 42.83 (CH), 49.65 (CH2), 75.32 (CH),
115.80 (CH), 124.53, 125.38, 128.44 and 128.81 (CH),
130.01 and 131.42 (CH), 131.59 (C), 136.06 (CH), 142.52
(CH), 145.28 and 146.16 (C), 152.80 (CH), 152.99 and
155.37 (CH). Anal. Calcd for C27H32N4OSi: C, 71.01; H,
7.06; N, 12.27. Found: C, 70.86; H, 7.24; N, 12.13.
30b-H), 4.28–4.37 (part A of an ABM system, 1H, JAB
Z
13.76 Hz, JAMZ7.92 Hz, CHHN), 4.57–4.65 (part B of an
ABM system, 1H, JBAZ13.78 Hz, JBMZ6.58 Hz, CHHN),
5.02–5.06 (m, 1H, 10b-H), 6.86–6.89 (d, 1H, JZ6.90 Hz,
ArH), 7.09–7.25 (m, 3H, ArH), 7.38–7.41 (d, 1H, JZ
8.67 Hz, ArH), 7.78 (s, 1H, 8-H), 8.66–8.69 (d, 2H, JZ
8.67 Hz, ArH), 8.90 (s, 1H, 2-H). 13C NMR (CDCl3):
dZK4.12 and K4.05 (CH3), 18.53 (C), 26.26 (CH3), 40.80
(CH2), 42.86 (CH), 49.65 (CH2), 75.30 (CH), 124.50, 125.42,
128.47 and 128.82 (CH), 129.32 and 131.55 (CH), 134.52 (C),
137.81(C), 145.34(CH), 146.13(C), 152.74(CH), 152.99and
154.31 (C). Anal. Calcd for C27H31ClN4OSi: C, 66.03; H,
6.36; N, 11.41. Found: C, 66.19; H, 6.51; N, 11.20.
5.2.2. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-inda-
nylmethyl]-6-(40-methyl)phenyl-9H-purine, 15b. Yield
96%. Mp 123–25 8C (CHCl3/hexane). IR (KBr): nZ3109,
3030, 2961, 1560, 1515, 1445, 1398, 1358, 1310, 1184,
1
1110, 1067, 839, 802, 746 cmK1. H NMR (CDCl3): dZ
5.2.5. Cleavage of the tert-butyldimethylsilyl group from
compounds 15a–d. General procedure. A solution of 15
(0.21 mmol) in CH3CN was added dropwise with stirring
under argon to a solution of FeCl3$6H2O (0.32 mmol) in the
same solvent, and stirring was continued for 12 h. H2O and
CHCl3 (100 mL) were added, the aqueous and organic
phases were separated, the aqueous phase was extracted
with CHCl3 (3!100 mL), and the pooled organic phases
were dried over anhydrous Na2SO4 and concentrated under
vacuum. Chromatography of the residue on silica gel (5 g)
with 1:3 hexane/AcOEt as eluent afforded fractions that
were concentrated and dried to obtain the corresponding
indanol derivative 16.
0.10 (s, 6H, 2CH3), 0.77 (s, 9H, C(CH3)3), 1.62–1.71 (dt,
1H, J(t)Z13.20 Hz, J(d)Z4.78 Hz, 20b-H), 2.29–2.38 (dt,
1H, J(t)Z13.20 Hz, J(d)Z6.73 Hz, 20a-H), 2.31 (s, 3H,
CH3), 3.63–3.68 (m, 1H, 30b-H), 4.26–4.34 (part A of an
ABM system, 1H, JABZ13.78 Hz, JAMZ8.06 Hz, CHHN),
4.55–4.63 (part B of an ABM system, 1H, JBAZ13.78 Hz,
JBMZ6.60 Hz, CHHN), 5.01–5.06 (m, 1H, 10b-H), 6.86–6.89
(d, 1H, JZ6.94 Hz, ArH), 7.08–7.25 (m, 5H, ArH), 7.81 (s,
1H, 8-H), 8.56–8.59 (d, 2H, JZ8.24 Hz, ArH), 8.89 (s, 1H,
2-H). 13C NMR (CDCl3): dZK4.12 and K4.04 (CH3),
18.55 (C), 22.02 (CH3), 26.27 (CH3), 40.90 (CH2), 42.81
(CH), 49.61 (CH2), 75.31 (CH), 124.52, 125.35, 128.41 and
128.79 (CH), 129.85 and 130.15 (CH), 134.11 (C), 134.98
(C), 141.83 (C), 142.54 (C), 144.97 (CH), 146.18 (C) and
152.79 (CH). Anal. Calcd for C28H34N4OSi: C, 71.45; H,
7.28; N, 11.90. Found: C, 71.71; H, 7.11; N, 11.78.
5.2.6. (G)-cis-3-(6-Phenyl-9H-purin-9-ylmethyl)indanol,
16a. Yield 82%. Mp 168–70 8C (CHCl3/hexane). IR (KBr):
nZ3300, 3059, 2950, 1582, 1565, 1328, 1207, 1178, 1070,
926, 767, 753, 692, 652, 638 cmK1. 1H NMR (CDCl3): dZ
1.73–1.82 (dt, 1H, J(t)Z13.89 Hz, J(d)Z3.85 Hz, 2b-H),
2.29–2.31 (d, 1H, JZ5.02 Hz, OH exchang. with D2O),
2.49–2.59 (dt, 1H, J(t)Z13.88 Hz, J(d)Z6.77 Hz, 2a-H),
3.75–3.85 (m, 1H, 3b-H), 4.51–4.58 (part A of an ABM
system, 1H, JABZ13.96 Hz, JAMZ7.83 Hz, CHHN), 4.66–
5.2.3. (G)-cis-9-[3-(tert-Butyldimethylsilyloxy)-1-inda-
nylmethyl]-6-(40-methoxy)-phenyl-9H-purine, 15c.
Yield 50%. Mp 165–69 8C (CHCl3/hexane). IR (KBr): nZ
3424, 2926, 1604, 1579, 1560, 1513, 1460, 1440, 1301,
1
1256, 1119, 863, 832, 774 cmK1. H NMR (CDCl3): dZ
4.73 (part B of an ABM system, 1H, JBAZ13.96 Hz, JBM
Z
0.14 (s, 6H, 2CH3), 0.91 (s, 9H, C(CH3)3), 1.61–1.70 (dt,
1H, J(t)Z13.10 Hz, J(d)Z4.95 Hz, 20b-H), 2.25–2.36 (dt,
1H, J(t)Z13.10 Hz, J(d)Z6.97 Hz, 20a-H), 3.66–3.73 (m,
1H, 30b-H), 3.89 (s, 3H, OCH3), 4.39–4.46 (part A of an
ABM system, 1H, JABZ13.74 Hz, JAMZ8.01 Hz, CHHN),
4.68–4.75 (part B of an ABM system, 1H, JBAZ13.74 Hz,
JBMZ6.63 Hz, CHHN), 5.15–5.18 (m, 1H, 10b-H), 6.99–
7.02 (d, 1H, JZ7.25 Hz, ArH), 7.06–7.09 (d, 1H, JZ
9.01 Hz, ArH), 7.24–7.36 (m, 3H, ArH), 7.89 (s, 1H, 8-H),
8.81–8.84 (d, 2H, JZ9.06 Hz, ArH), 8.99 (s, 1H, 2-H). 13C
NMR (CDCl3): dZK4.12 and K4.04 (CH3), 18.54 (C),
26.28 (CH3), 40.88 (CH2), 42.79 (CH), 49.58 (CH2), 55.79
(CH3), 75.31 (CH), 114.49, 115.19 and 116.56 (CH),
124.53, 125.34, 128.39 and 128.78 (CH), 131.01 (C),
131.96 (CH), 142.55 (C), 144.76 (CH), 146.17 (C), 152.75
(CH), 154.97 and 162.44 (C). Anal. Calcd for
C28H34N4O2Si: C, 69.10; H, 7.04; N, 11.51. Found: C,
69.34; H, 6.86; N, 11.41.
6.98 Hz, CHHN), 5.18–5.25 (m, 1H, 1b-H), 6.97–7.01 (d,
1H, JZ7.24 Hz, ArH), 7.25–7.60 (m, 6H, ArH), 7.97 (s, 1H,
80-H), 8.78–8.81 (m, 2H, ArH), 9.03 (s, 1H, 20-H). 13C NMR
(CDCl3): dZ39.85 (CH2), 43.52 (CH), 49.61 (CH2), 75.10
(CH), 124.86, 125.47, 128.75 and 129.12 (CH), 129.35 and
130.22 (CH), 131.49 (C), 136.01 (CH), 143.14 (CH), 145.18
and 145.61 (C), 152.80 (CH), 153.05 and 155.40 (CH).
Anal. Calcd for C21H18N4O: C, 73.67; H, 5.30; N, 16.36.
Found: C, 73.79; H, 5.45; N, 16.09.
5.2.7.
(G)-cis-3-[6-(40-Methyl)phenyl-9H-purin-9-
ylmethyl)indanol, 16b. Yield 87%. Mp 166–69 8C
(CHCl3/hexane). IR (KBr): nZ3416, 3026, 1595, 1397,
1307, 1206, 1185, 783, 758, 639, 625 cmK1 1H NMR
.
(CDCl3–MeOD): dZ2.48 (s, 3H, CH3), 2.90–2.96 (d, 1H,
JZ14.93 Hz, 2b-H), 3.20–3.35 (m, 1H, 2a-H), 3.35–3.40
(m, 1H, OH exchang. with D2O), 4.10–4.20 (m, 1H, 3b-H),

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4.95–5.10 (m, 2H, CH2N), 6.60–6.62 (d, 1H, JZ6.42 Hz,
1b-H), 7.33–7.63 (m, 4H, ArH), 7.38–7.41 (d, 2H, JZ
8.41 Hz, ArH), 8.58 (s, 1H, 80-H), 8.82–8.86 (d, 2H, JZ
8.41 Hz, ArH), 9.69 (s, 1H, 20-H). 13C NMR (CDCl3–
MeOD): dZ21.36 (CH3), 37.66 (CH2), 40.03 (CH), 57.23
(CH2), 70.26 (CH), 124.70, 124.83, 129.43 and 129.67
(CH), 131.26 and 131.59 (CH), 133.52 (C), 137.83 (C),
142.69 (CH), 142.80 (C), 142.89 (C), 145.88 (C), 148.31
(CH) and 158.66 (CH). Anal. Calcd for C22H20N4O: C,
74.14; H, 5.66; N, 15.72. Found: C, 73.98; H, 5.83; N, 15.85.
of an ABM system, 1H, JABZ13.82 Hz, JAMZ7.63 Hz,
CHHN), 4.52–4.60 (part B of an ABM system, 1H, JBA
Z
13.82 Hz, JBMZ6.82 Hz, CHHN), 5.07–5.11 (m, 1H,
1b-H), 6.83–6.85 (d, 1H, JZ6.75 Hz, ArH), 7.14–7.31 (m,
2H, ArH), 7.59–7.62 (m, 1H, ArH), 7.79 (s, 1H, 80-H), 8.63
(s, 1H, 20-H). 13C NMR (CDCl3): dZ39.67 (CH2), 43.51
(CH), 50.10 (CH2), 75.06 (CH), 124.78, 125.48, 128.91 and
129.47 (CH), 132.29 (C), 142.25 (C), 145.99 (CH), 150.15
(C), 152.40 (CH). Anal. Calcd for C15H13ClN4O: C, 59.91;
H, 4.36; N, 18.63. Found: C, 60.12; H, 4.15; N, 18.44.
5.2.8. (G)-cis-3-[6-(40-Methoxy)phenyl-9H-purin-9-
ylmethyl)indanol, 16c. Yield 80%. Mp 142–44 8C
(CHCl3/hexane). IR (KBr): nZ3648, 2923, 1654, 1560,
1508, 1458, 1260, 1022, 804 cmK1. 1H NMR (CDCl3): dZ
1.75–1.84 (dt, 1H, J(t)Z13.88 Hz, J(d)Z3.82 Hz, 2b-H),
2.39–2.48 (m, 1H, 2a-H), 3.69–3.74 (m, 1H, 3b-H), 3.82 (s,
3H, OCH3), 4.39–4.48 (part A of an ABM system, 1H,
JABZ13.90 Hz, JAMZ7.86 Hz, CHHN), 4.55–4.63 (part B
of an ABM system, 1H, JBAZ13.90 Hz, JBMZ7.05 Hz,
CHHN), 5.11–5.15 (m, 1H, 1b-H), 6.88–6.91 (d, 1H, JZ
7.00 Hz, ArH), 6.98–7.02 (d, 2H, JZ8.91 Hz, ArH), 7.15–
7.26 (m, 2H,0 ArH), 7.36–7.39 (d, 1H, JZ6.92 Hz, ArH),
7.87 (s, 1H, 8 -H), 8.72–8.75 (d, 2H, JZ8.91 Hz, ArH), 8.87
(s, 1H, 20-H). 13C NMR (CDCl3): dZ38.42 (CH2), 42.05
(CH), 48.11 (CH2), 54.39 (CH3), 73.60 (CH), 113.06 (CH),
123.40, 124.01, 127.25 and 127.84 (CH), 129.46 (C), 130.53
(CH), 141.72 (C), 143.26 (CH), 144.23 (C), 151.29 (CH),
153.60 and 161.03 (C). Anal. Calcd for C22H20N4O2: C,
70.95; H, 5.41; N, 15.04. Found: C, 71.17; H, 5.23; N, 14.87.
5.2.11.
(G)-cis-9-(3-Hydroxy-1-indanylmethyl)-6-
hydroxy-9H-purine, 13a. A solution of 9 (100 mg,
0.24 mmol and 0.25 N NaOH (10 mL) in 1,4-dioxane
(4 mL) was refluxed for 5 h under argon. Removal of the
solvent under vacuum then left a solid (140 mg) that upon
chromatography on silica gel (10 g) with 30:1 CH2Cl2/
MeOH as eluent afforded 13a as a white solid (51 mg,
0.18 mmol, yield 75%). Mp 138–40 8C (CH2Cl2–Et2O). IR
(KBr): nZ3352, 2956, 1697, 1585, 1549, 1458, 1412, 1336,
1212, 1053, 908, 815, 760, 652 cmK1. H NMR (MeOH):
1
dZ1.58–1.68 (dt, 1H, J(t)Z13.40 Hz, J(d)Z5.40 Hz, 2b-H),
2.30–2.41 (dt, 1H, J(t)Z13.40 Hz, J(d)Z7.40 Hz, 2a-H),
3.57–3.63 (m, 1H, 3b-H), 4.27–4.36 (part A of an ABM
system, 1H, JABZ13.73 Hz, JAMZ8.14 Hz, CHHN), 4.53–
4.62 (part B of an ABM system, 1H, JBAZ13.73 Hz, JBM
Z
6.40 Hz, CHHN), 4.97–5.02 (m, 1H, 1b-H), 6.92–6.95 (d,
1H, JZ6.58 Hz, ArH), 7.13–7.27 (m, 2H, ArH), 7.29–7.32
(d, 1H, JZ6.60 Hz, ArH), 7.85 (s, 1H, 80-H), 7.94 (s, 1H,
20-H). 13C NMR (MeOH): dZ40.99 (CH2), 44.34(CH),
50.28 (CH2), 75.46 (CH), 125.48, 126.34, 129.31 and
129.74 (CH), 142.81 (CH), 144.01 (C), 147.02 (CH), 147.32
(C), 150.89 (C), 159.41 (C). Anal. Calcd for C15H14N4O2:
C, 63.82; H, 5.00; N, 19.85. Found: C, 64.03; H, 4.87; N,
19.67.
5.2.9.
(G)-cis-3-[6-(40-Chloro)phenyl-9H-purin-9-
ylmethyl)indanol, 16d. Yield 71%. Mp 176–78 8C
(CHCl3/hexane). IR (KBr): nZ3354, 3079, 2963, 1853,
1561, 1395, 1327, 1252, 1210, 1085, 802, 747, 647 cmK1
.
1H NMR (CDCl3): dZ1.23–1.27 (b.s., 1H, OH exchang.
with D2O), 1.82–1.89 (dt, 1H, J(t)Z13.90 Hz, J(d)
3.72 Hz, 2b-H), 2.48–2.57 (dt, 1H, J(t)Z13.89 Hz, J(d)
6.75 Hz, 2a-H), 3.75–3.84 (m, 1H, 3b-H), 4.48–4.56 (part A
of an ABM system, 1H, JABZ13.90 Hz, JAMZ7.79 Hz,
CHHN), 4.65–4.71 (part B of an ABM system, 1H, JBA
13.90 Hz, JBMZ6.92 Hz, CHHN), 5.19–5.22 (m, 1H,
1b-H), 6.97–6.99 (d, 1H, JZ7.14 Hz, ArH), 7.24–7.34 (m,
2H, ArH), 7.43–7.45 (d, 1H, JZ6.96 Hz, ArH), 7.51–7.53
(d, 2H, JZ8.62 Hz, ArH), 7.95 (s, 1H, 80-H), 8.76–8.79 (d,
2H, JZ8.65 Hz, ArH), 8.98 (s, 1H, 20-H). 13C NMR
(CDCl3): dZ39.82 (CH2), 43.51 (CH), 49.61 (CH2), 75.09
(CH), 124.83, 125.46, 128.78 and 129.35 (CH), 130.93 (C),
131.55 (CH), 134.48 (C), 137.74 (C), 143.09 (CH), 145.30
and 145.61 (C), 152.74 (C), 152.99 and 154.22 (C). Anal.
Calcd for C21H17ClN4O: C, 66.93; H, 4.55; N, 14.87.
Found: C, 67.12; H, 4.39; N, 14.69.
Z
Z
5.2.12. (G)-cis-3-(6-Methoxy-9H-purin-9-ylmethyl)in-
danol, 13b. Compound 13b was prepared from 10b by the
same general procedure as was used to prepare compounds
16 from 15. Yield 70%. Mp 152–156 8C (CH2Cl2–Et2O). IR
(KBr): nZ3567, 3387, 2954, 2883, 1654, 1600, 1576, 1478,
1405, 1312, 1250, 1111, 863, 835, 774, 649 cmK1. 1H NMR
(CDCl3): dZ1.18 (s, 1H, OH exchang. with D2O), 1.78–
1.85 (dt, 1H, J(t)Z13.86 Hz, J(d)Z7.80 Hz, 2b-H), 2.41–
2.51 (dt, 1H, J(t)Z13.81 Hz, J(d)Z7.22 Hz, 2a-H), 3.69–
3.76 (m, 1H, 3b-H), 4.17 (s, 3H, OCH3), 4.39–4.46 (part A
of an ABM system, 1H, JABZ13.91 Hz, JAMZ8.03 Hz,
Z
CHHN), 4.56–4.63 (part B of an ABM system, 1H, JBA
Z
13.91 Hz, JBMZ7.05 Hz, CHHN), 5.15–5.18 (m, 1H,
1b-H), 6.88–6.91 (d, 1H, JZ7.25 Hz, ArH), 7.18–7.29 (m,
2H, ArH), 7.40–7.43 (d, 1H, JZ7.17 Hz, ArH), 7.74 (s, 1H,
80-H), 8.49 (s, 1H, 20-H). 13C NMR (CDCl3): dZ38.29
(CH2), 42.08(CH), 48.28 (CH2), 53.26 (CH3), 73.46 (CH),
120.38 (C), 123.32, 124.03, 127.18 and 127.75 (CH), 141.59
(C), 144.31 (CH), 151.06 (CH), 160.11 (C). Anal. Calcd for
C16H16N4O2: C, 64.85; H, 5.44; N, 18.91. Found: C, 64.77;
H, 5.71; N, 19.01.
5.2.10. (G)-cis-3-(6-Chloro-9H-purin-9-ylmethyl)inda-
nol, 12. Compound 12 was prepared from 9 by the same
general procedure as was used to prepare compounds 16
from 15. Yield 65%. Mp 125–28 8C (CHCl3/hexane). IR
(KBr): nZ3566, 3279, 1594, 1560, 1497, 1476, 1398, 1339,
1215, 1187, 1098, 941, 772, 634, 564 cmK1
.
1H NMR
5.2.13. (G)-cis-3-(6-Amino-9H-purin-9-ylmethyl)inda-
nol, 14a. Compound 14a was prepared from 11a by the
same general procedure as was used to prepare compounds
16 from 15. Yield 79%. Mp 214–16 8C (CH3OH). IR (KBr):
nZ3293, 3146, 2943, 2880, 1693, 1606, 1572, 1424, 1338,
(CDCl3): dZ1.08–1.09 (d, 1H, JZ6.11 Hz, OH exchang.
with D2O), 1.68–1.77 (dt, 1H, J(t)Z13.95 Hz, J(d)
7.17 Hz, 2b-H), 2.34–2.42 (dt, 1H, J(t)Z13.95 Hz, J(d)
6.93 Hz, 2a-H), 3.62–3.66 (m, 1H, 3b-H), 4.35–4.44 (part A
Z
Z

´
F. Fernandez et al. / Tetrahedron 60 (2004) 9245–9253
9253
1
1300, 1223, 1077, 1012, 756, 744, 645 cmK1. H NMR
(e) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994,
50, 10611. (f) Borthwick, A. D.; Briggadike, K. Tetrahedron
1992, 48, 571.
(DMSO): dZ1.43–1.54 (dt, 1H, J(t)Z12.69 Hz, J(d)
5.52 Hz, 2b-H), 2.12–2.23 (dt, 1H, J(t)Z12.69 Hz, J(d)
Z
Z
7.18 Hz, 2a-H), 2.39 (s., 2H, NH2, exchang. with D2O),
3.48–3.60 (m, 1H, 3b-H), 4.12–4.21 (part A of an ABM
system, 1H, JABZ13.60 Hz, JAMZ8.52 Hz, CHHN),
4.50–4.58 (part B of an ABM system, 1H, JBAZ13.60 Hz,
JBMZ5.87 Hz, CHHN), 4.83–4.90 (q, 1H, JZ12.63,
6.52 Hz, 1b-H), 5.27–5.29 (d, 1H, JZ5.57 Hz, OH), 6.99–
7.02 (d, 1H, JZ6.16 Hz, ArH), 7.09–7.26 (m, 3H, ArH),
8.00 (s, 1H, 80-H), 8.05 (s, 1H, 20-H). 13C NMR (DMSO):
dZ40.60 (CH2), 41.89 (CH), 47.65 (CH2), 73.03 (CH),
119.04 (C), 123.89, 124.71, 127.50 and 127.85 (CH), 141.34
(CH), 142.52 (C), 147.21 (C), 150.10 (CH), 152.81 (CH),
156.33 (C). Anal. Calcd for C15H15N4O2: C, 64.04; H, 5.37;
N, 24.90. Found: C, 64.24; H, 5.15; N, 25.03.
3. Bricaud, H.; Herdewijn, P.; De Clercq, E. Biochem. Pharma-
col. 1983, 3583.
4. Cookson, R.; Dudfield, P.; Newton, R.; Ravenscroft, P.;
Scopes, D.; Cameron, J. Eur. J. Med. Chem. Chim. Ther. 1985,
20, 375.
5. (a) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17. (b) Vince,
R.; Brownell, J. J. Biochem. Biophys. Res. Commun. 1990,
168, 912.
6. Daluge, S. M.; Good, S. S.; Faleto, M. B.; Miller, W. H.; St.
Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon,
J. E.; Dornsife, R. E.; Averett, D. R.; Krenitsky, T. A.
Antimicrob. Agents Chemother. 1997, 41(5), 1082.
7. (a) Saladino, R.; Ciambecchini, U.; Hanessian, S. Eur. J. Org.
Chem. 2003, 4401. (b) Lamberth, C. Org. Prep. Proc. Int.
2002, 34, 151.
5.2.14. (G)-cis-3-(6-N-Cyclopropylamino-9H-purin-9-
ylmethyl)indanol, 14b. Compound 14b was prepared
from 11b by the same general procedure as was used to
prepare compounds 16 from 15. Yield 72%. Mp 95–98 8C
(CH3OH). IR (KBr): nZ3566, 3184, 2951, 1626, 1585,
1542, 1478, 1448, 1331, 1305, 1233, 1046, 1020, 796, 764,
8. (a) Patil, S. D.; Schneller, S. W.; Hosoya, M.; Snoeck, R.;
Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992,
35, 3372. (b) Siddiqui, S. M.; Chen, X.; Schneller, S. W.;
Ikeda, S.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.
J. Med. Chem. 1994, 37, 551.
647 cmK1 1H NMR (CDCl3): dZ0.64–0.67 (m, 2H,
.
cyclopropyl CH2), 0.89–0.92 (m, 2H, cyclopropyl CH2),
1.78–1.86 (dt, 1H, J(t)Z13.80 Hz, J(d)Z3.94 Hz, 2b-H),
2.43–2.54 (dt, 1H, J(t)Z13.80 Hz, J(d)Z7.57 Hz, 2a-H),
2.98–3.05 (m, 1H, cyclopropyl CH), 3.67–3.65 (m, 1H,
9. Wu, J.; Schneller, S. W.; Seley, K. L.; Snoeck, R.; Andrei, G.;
Balzarini, J.; De Clercq, E. J. Med. Chem. 1997, 40, 1401.
´ ´ ´
10. (a) Fernandez, F.; Garcıa-Mera, X.; Morales, M.; Rodrıguez-
Borges, J. E.; De Clercq, E. Synthesis 2002, 8, 1084.
3b-H), 4.34–4.43 (part A of an ABM system, 1H, JAB
Z
´ ´ ´
(b) Fernandez, F.; Garcıa-Mera, X.; Morales, M.; Rodrıguez-
Borges, J. E. Synthesis 2001, 2, 239.
13.92 Hz, JAMZ7.94 Hz, CHHN), 4.52–4.60 (part B of an
ABM system, 1H, JBAZ13.92 Hz, JBMZ6.87 Hz, CHHN),
5.17–5.21 (m, 1H, 1b-H), 6.25–6.35 (b.s., 1H, NH, exchang.
with D2O), 6.97–7.01 (d, 1H, JZ6.64 Hz, ArH), 7.21–7.46
(m, 3H, ArH), 7.54 (s, 1H, 80-H), 8.43 (s, 1H, 20-H). 13C
NMR (CDCl3): dZ7.27 (CH2), 23.69 (CH), 39.20 (CH2),
43.19 (CH), 48.91 (CH2), 74.45 (CH), 119.62 (C), 124.33,
125.01, 128.11 and 128.69 (CH), 140.12 (C), 142.74 (C),
145.38 (C), 149.23 (CH), 153.29 (CH), 155.78 (C). Anal.
Calcd for C18H19N5O: C, 67.27; H, 5.96; N, 21.79. Found:
C, 67.05; H, 5.89; N, 21.99.
11. 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, 12th World AIDS
Conference, 1998, Geneva.
´ ´
12. Yao, S.-W.; Lopez, V. H. C.; Fernandez, F.; Garcıa-Mera, X.;
´
´
Morales, M.; Rodrıguez-Borges, J. E.; Cordeiro, M. N. D. S.
Bioorg. Med. Chem. 2003, 11(23), 4999.
13. (a) Cheson, B. D. Hematol. Cell. Ther. 1996, 38(Suppl. 2),
109. (b) Bergmann, L. Leukemia 1997, 11(Suppl. 2), 29.
´ ´
14. Hocek, M.; Hol, A.; Votruba, I.; Dvorakova, H. J. Med. Chem.
2000, 43, 1817.
15. Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med. Chem. 1988,
31, 433.
Acknowledgements
16. (a) Mitsunobu, O.; Wata, M.; Sano, T. J. Am. Chem. Soc. 1972,
94, 679. (b) Toyota, A.; Katagiri, N.; Kaneko, C. Synth.
Commun. 1993, 23(9), 1295.
The authors thank the Xunta de Galicia for financial support
of this work under projects PGIDT01PXI20302PR and
PGIDT02BTF2030SPR.
´ ´ ´
17. Fernandez, F.; Garcıa-Mera, X.; Rodrıguez-Borges, J. E.
Tetrahedron: Asymmetry 2001, 12, 365.
18. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
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References and notes
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1. Part of this work was presented at the XIII Congreso Nacional
´ ´
de la Sociedad Espan˜ola de Quımica Terapeutica, Santiago de
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M.; Dvorak, D.; Hocek, M. Synthesis 2001, 1704.
´ ´
(c) Havelkova, M.; Hocek, M.; Cesnek, M.; Dvorak, D.
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