1,2-Disubstituted cyclohexane nucleosides: Comparative study for the synthesis of cis and trans adenosine analogues

Article abstract of DOI:10.1016/j.tet.2004.10.076

A new class of adenosine analogues with 1,2-disubstituted carbocycles (with cis and trans stereochemistry) have been synthesized. Construction of the base on the amino group of (±)-cis-(2-aminocyclohexyl)methanol was more efficient than the Mitsunobu cond

Full text of DOI:10.1016/j.tet.2004.10.076

Tetrahedron 61 (2005) 473–478
1,2-Disubstituted cyclohexane nucleosides: comparative study for
the synthesis of cis and trans adenosine analogues
a,
Dolores Vina, Lourdes Santana, Eugenio Uriarte and Carmen Teran
a
a
b
*
´
˜
a
´ ´
Departamento de Quımica Organica, Facultad de Farmacia, Universidad de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
b
´
´
Departamento de Quımica Organica, Universidad de Vigo, E-36200 Vigo, Spain
Received 19 February 2004; revised 21 September 2004; accepted 21 October 2004
Available online 11 November 2004
Abstract—A new class of adenosine analogues with 1,2-disubstituted carbocycles (with cis and trans stereochemistry) have been
synthesized. Construction of the base on the amino group of (G)-cis-(2-aminocyclohexyl)methanol was more efficient than the Mitsunobu
condensation between the purine base and protected (G)-trans-(2-hydroxymethyl)cyclohexanol. The latter strategy gave the final compound
with cis stereochemistry in a short number of steps with the overall yield depending on the nature of the protecting group on the
hydroxymethyl group of the diol. However, Mitsunobu condensation between a purine base and the protected (G)-cis-(2-
hydroxymethyl)cyclohexanol is not an ideal method to obtain trans purine derivatives because the elimination reaction is faster than the
substitution reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
hydoxymethyl group and the heterocyclic base attached to
contiguous positions of the carbocycle, being the pseudo-
sugar a cyclopentane or cyclopentene ring. Some of them
have shown an interesting profile of activity against the
proliferation of murine leukaemia cells (L1210/0) and
human T-lymphocyte cells (Molt4/C8 and CEM/0).6–8
Carbanucleosides are compounds in which the endocyclic
oxygen of the nucleoside sugar ring has been replaced by a
methylene group. Such compounds have recently been the
focus of a great deal of attention in the development of new
antiviral and antitumoral therapeutic agents.1 This modifi-
cation reduces phosphorylase- and hydrolase-catalyzed
reactivity (thereby increasing the in vivo half life)2 and
increases lipophilicity (thus favouring absorption and
penetration of the cell membrane).
Despite the fact that carbocyclic nucleosides have been
extensively studied, little effort has been directed toward the
synthesis of six-membered carbocyclic analogues. How-
ever, recent publications have described the potent antiviral
activity of such compounds.9,10
On the other hand, removal of the hydroxyl groups in the 20-
and 30-positions of the carbocycle has generated drugs of
choice for treatment of certain viral infections, including
human immunodeficiency virus (HIV) infection, which
works by blocking viral reproduction, thus inhibiting
reverse transcriptase.3
In view of the success obtained on carrying out these
modifications, we became interested in exploring the
potential of 1,2-disubstituted cyclohexane nucleoside
analogues. In the target compounds the usual 1,3-substi-
tution pattern of the heterocyclic base and hydroxymethyl
group on the carbocycle is replaced by a 1,2-pattern.
Additionally, transposition of the base or the 50-hydro-
xymethyl group from their normal 10- or 40-position to non-
natural or isomeric positions has generated significant
interest in the synthesis of non-natural nucleosides.4,5 For
some year, we have been examining a group of 20,30-
dideoxy-cyclopentyl analogues which have the
2. Results and discussion
As a preliminary study to the synthesis of a large series of
this kind of compound, we investigated the efficiency with it
was possible to prepare a representative purine (adenosine
analogue) as a racemic mixture, with either the cis or trans
stereochemistry, using the two routes that have been most
widely employed in this field.11 These two routes are (i)
Keywords: Carbanucleosides; Aminocyclohexanemethanol; Hydroxycy-
clohexanemethanol; Adenine; Mitsunobu reaction.
* Corresponding author. Fax: C34 981 594912; e-mail: qovina@usc.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.076

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D. Vin˜a et al. / Tetrahedron 61 (2005) 473–478
construction of the heterocyclic base on the primary amino
group of an appropriate aminoalcohol12,13 and (ii) direct
condensation between the heterocyclic base and an appro-
priately functionalized carbocyclic moiety, in this case
Mitsunobu condensation of 6-chloropurine with the corre-
sponding protected diol and subsequent nucleophilic
substitution of the 6-chloro atom to afford the adenosine
analogue.14–16
orthoformate in an acidic medium and, finally, nucleophilic
exchange of the 6-chloro atom to give an amino group. This
route afforded compound 4 in 50% overall yield (Scheme 1).
Alternatively, compound 4 was obtained from the alcohol 6
in two steps in 23% overall yield by following route (ii):
direct condensation of 6-chloropurine and (G)-trans-(2-
hydroxy)cyclohexylmethyl benzoate (6) in the presence of
triphenylphosphine and diethyl azodicarboxylate gave 3b,
which was converted into 4 by treatment with saturated
methanolic ammonia (Scheme 1).
Route (i), starting from the aminoalcohol 1, involved a
sequence of three steps: condensation of 1 with 5-amino-
4,6-dichloropyrimidine to give the substituted diamino-
pyrimidine 2, reaction of the product with ethyl
Furthermore, whereas aminoalcohol 1 was prepared in 20%
overall yield from cyclohexene, the starting compound for
the Mitsunobu reaction (compound 6) was prepared from
ethyl 2-oxocyclohexanecarboxylate in 23% overall yield
using an easier and more direct procedure. Aminoalcohol 1
was obtained by a (2C2) cycloaddition between cyclo-
hexene and chlorosulphonylisocyanate followed by
hydrolysis of the resulting lactam, esterification of the
amino acid and subsequent reduction with LiAlH4.17
Compound 6 was obtained by reduction of ethyl 2-oxo-
cyclohexanecarboxylate with NaBH4 to give a mixture of
(G)-cis/trans diols 5. Subsequent benzoylation of the
primary hydroxyl group using benzoyl chloride gave a
mixture of (G)-cis/trans-(2-hydroxy)cyclohexylmethyl
benzoate, which could be separated by silica gel column
chromatography (1.2:1 ratio of compounds 6 and 7).
Treatment of (G)-cis-(2-hydroxy)cyclohexylmethyl benzo-
ate (7) with 6-chloro-purine under Mitsunobu conditions
afforded the dehydratation compound 8a, a reaction that
proceeds by anti E2 elimination.18
The use of tert-butyldimethylsilyl as a protecting group was
necessary to obtaining the trans purine derivative 11
through a Mitsunobu reaction (Scheme 2). Silyl derivative
919 was obtained in 77% yield, starting from compound 5,
by treatment with tert-butyldimethylsilyl chloride and
imidazole in anhydrous THF. The cis and trans isomers of
9 could not be separated and the mixture was used in the
reaction with 6-chloropurine under Mitsunobu conditions
giving the (G)-cis-derivative 3c (41% yield), the (G)-
trans-derivative 10a (10% yield) and the dehydratation
compound 8b (30% yield) which could be separated by
silica gel column chromatography. Compounds 3c and 10a
must arise from the trans and cis isomers of 9 respectively,
whereas the compound 8b must arise from the cis isomer of
9 by dehydratation reaction, such as compound 7 had
yielded 8a.
Deprotection of silyl derivatives 3c and 10a was performed
by treatment with an acidic medium20 (CH3COOH, H2O,
THF) to afford (G)-cis- and (G)-trans-6-chloropurine
derivatives 3a and 10b, respectively in quantitative yield.
cis/trans Assignment was made in an unequivocal way (by
comparison) because compound 3a had been also obtained
following the stereoespecific route (i). Moreover, when
NOE experiments were performed, NOE effects were more
intensive between the protons 10 and 60 for the compound 3a
(cis) than for compound 10b (trans). Finally, substitution of
the 6-chloro atom by an amino group in both compounds, 3a
and 10b, was performed by treatment with NH4OH to give
Scheme 1. Reagents and conditions: (a) 5-amino-4,6-dichloropyrimidine,
Et3N, n-BuOH, reflux, 24 h, 71%; (b) CH(OEt)3, 12 M HCl, reflux, 12 h,
71%; (c) from 3a: NH4OH, reflux, 4 h, 99%; from 3b: NH3/MeOH, 80 8C,
20 h, 75%; (d) NaBH4, EtOH, rt, 3 h, 71%; (e) BzCl, Et3N, CH2Cl2, rt, 3 h,
6: 32%, 7: 27%; (f) 6-chloropurine, Ph3P, N2(CO2Et), THF, rt, 60 h, 3b:
30%, 8a: 80%.

D. Vin˜a et al. / Tetrahedron 61 (2005) 473–478
475
Scheme 2. Reagents and conditions: (a) TBDMSCl, imidazole, THF, rt, 4.5 h, 77%; (b) 6-chloropurine, Ph3P, N2(CO2Et)2, THF, rt, 24 h, 3c: 41%, 10a: 10%,
8b: 30%; (c) CH3COOH/H2O/THF, rt, 5 h, 3a: 99%, 10b: 95%; (d) NH4OH, reflux, 4 h, 99%.
1
in almost quantitative yield the final compounds 4 and 11,
respectively.
spectrophotometer (y in cmK1). H and 13C NMR spectra
were recorded on Bruker DPX (250 MHz) and Bruker AMX
(500 MHz) spectrometers, using TMS as internal standard
(chemical shifts as d in ppm, J in Hz). The complete
assignment of the signals was performed by DEPT, HMQC
or HMBC experiments and comparison with analogues of
these compounds previously synthesized in our group. Mass
spectra and HRMS (EI) were obtained using a Hewlett
Packard 5988A spectrometer and Micromass Autospec
spectrometer, respectively. Elemental analyses were per-
formed on a Perkin–Elmer 240B microanalyser. UV/Vis
spectra were measured by means of a Kontron UVICON-
810P spectrophotometer. Silica gel (Merck 60, 230–400
mesh) was used for flash chromatography (FC). Analytical
thin layer chromatography (TLC) was performed on plates
precoated with silica gel (Merck 60 F254, 0.25 mm).
In summary, novel cyclohexyl nucleosides, in which the
base and the hydroxymethyl group have a 1,2-relationship,
have been synthesized using two different methodologies.
The first route (i) gave the final carbanucleoside compounds
in an acceptable overall yield, although numerous steps are
required. The other route (ii) involved the Mitsunobu
reaction and is a more direct procedure. However, the
common use of benzoate as a protecting group for the
primary hydroxyl group of 5 only allowed the cis-derivative
to be obtained (in a low yield) and not the trans derivative.
This drawback arises because the protected diol cis 7
afforded only the dehydration product. Nevertheless, when
tert-butyldimethylsilyl is used as the protecting group for
the hydroxymethyl group of the diol, both cis and trans
derivatives (4 and 11) could be synthesized. In this case, the
cis derivative was obtained with a higher yield whereas the
yield of the trans derivative was low due to the persistence
in the formation of the elimination compound from the
protected cis diol.
3.1.1. (G)-cis-5-Amino-6-chloro-4-[2-(hydroxymethyl)-
cyclohexylamino]pyrimidine (2). A mixture of amino-
alcohol
1
(320 mg, 2.48 mmol), 5-amino-4,6-
dichloropyrimidine (426 mg, 2.60 mmol), Et3N (1.43 mL)
and n-BuOH (8.55 mL) was heated under reflux for 24 h
under Ar. The solvent was evaporated under vacuum and the
solid residue was redissolved in ethyl acetate by stirring
with IRA-420 (OH) until all turbidity had disappeared. The
resin was filtered off, the solvent was evaporated under
vacuum and the residue was purified by FC using CH2Cl2/
MeOH (98:2) as eluent, which gave pure 2 (450 mg, 71%).
Mp: 177–179 8C (acetonitrile). IR (KBr): 3246, 2932, 1654,
1576, 1472, 1364, 1015. 1H NMR (DMSO-d6) d: 1.24–1.90
(m, 9H, (–CH2–)4C–CH–C–O), 3.30 (m, 2H, –CH2–O),
4.93 (m, 2H, –CH–N– and –OH), 5.24 (s, 2H, –NH2), 6.10
(d, 1H, –NH–, JZ7.7 Hz), 7.70 (s, 1H, H-2). 13C NMR
(DMSO-d6) d: 22.0, 23.7, 24.0, 29.6, 41.6, 48.2, 61.7, 123.8,
137.2, 145.9, 151.9. MS m/z (%): 258 ((MC2)C, 3), 256
(MC, 9), 146 ((MC2)CKC7H12O, 33), 144 (MCKC7H12O,
100), 117 (100). HRMS (EI): (MC) calcd for C11H17ClN4O:
256.1090, found 256.1092.
Preliminary assays of antiviral activity showed that
compound
4 presenting moderate activity against
respiratory syncytial virus at concentrations of 3.2 mg/mL
(1.92 mg/mL for Rivabirin). An extensive series of these
compounds is currently being synthesized for pharmaco-
logical evaluation.
3. Experimental
3.1. General
Melting points were determined using a Stuart Scientific
melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin–Elmer 1640 FT

476
D. Vin˜a et al. / Tetrahedron 61 (2005) 473–478
3.1.2. (G)-cis-6-Chloro-9H-9-[2-(hydroxymethyl)cyclo-
hexyl]purine (3a). A mixture of compound 2 (450 mg,
1.75 mmol), CH(OEt)3 (9.6 mL) and 12 M HCl (0.11 mL)
was stirred for 12 h at room temperature. The solvent was
evaporated under vacuum and the solid residue was
redissolved in tetrahydrofuran (THF) (28 mL) and 0.5 M
HCl (36.7 mL). The mixture was stirred for 2 h at room
temperature and neutralized with 0.5 M NaOH. The solvent
was evaporated under vacuum (forming an azeotropic
mixture with ethanol/toluene) and the solid residue was
purified by FC using CH2Cl2/MeOH (98:2) as eluent, which
gave pure 3a (330 mg, 71%). Mp: 160–162 8C (hexane/
CHCl31). IR (KBr): 3285, 3092, 2930, 1594, 1568, 1397,
1340. H NMR (CDCl3) (d): 1.50–2.40 (m, 9H, (–CH2–)4
C–CH–C–O), 2.90 (bs, 1H, –OH), 3.14 (m, 1H, –HCH–O),
3.50 (m, 1H, –HCH–O), 5.10 (m, 1H, –CH–N), 8.37 (s, 1H,
(–CH2–)4), 2.15 (m, 1H, –CH–CH2–OBz), 3.99 (m, 1H,
CH–OH), 4.12 (dd, 1H, –HCH–OBz, JZ11.1, 5.7 Hz), 4.53
(dd, 1H, HCH–OBz, JZ11.1, 9.1 Hz), 7.45 (m, 2 Ar-H.),
7.56 (m, 1 Ar-H), 8.05 (m, 2 Ar-H). 13C NMR (Cl3CD) (d):
20.4, 23.4, 25.5, 32.9, 41.7, 66.2, 66.8, 128.8, 130.0, 130.5,
133.5, 167.6. MS m/z (%): 235 ((MC1)C, 82), 217 ((MC
1)CKH2O, 100), 123 (34), 95 (C7H5O, 84). Compound 6:
IR (KBr): 3434, 2921, 2846, 1713, 1446, 1275, 1114, 708.
1H NMR (CDCl3) (d): 1.31 (m, 2H, –CH2–), 1.75 (m, 5H,
(–CH2–)2C–HCH–), 2.03 (m, 1H, –HCH–), 2.65 (m, 1H,
–CH–CH2–OBz), 3.38 (m, 1H, –CH–OH), 4.27 (dd, 1H,
–HCH–OBz, JZ11.2, 4.3 Hz), 4.70 (dd, 1H, –HCH–OBz,
JZ11.2, 4.7 Hz), 7.43 (m, 2 Ar-H), 7.58 (m, 1 Ar-H), 8.05
(m, 2 Ar-H). 13C NMR (CDCl3) (d): 25.2, 25.7, 28.7, 35.3,
45.9, 67.1, 71.5, 128.8, 130.0, 130.4, 133.5, 166.8. MS m/z
(%): 235 ((MC1)C, 100), 217 ((MC1)CKH2O, 92), 123
(45), 105 (86), 95 (C7H5O, 64).
13
H-8), 8.73 (s, 1H, H-2). C NMR (CDCl3) (d): 23.3 (40),
24.5 (30), 25.6 (50), 28.9 (60), 42.6 (20), 54.2 (10), 62.5 (70),
131.8 (5), 144.9 (8), 151.8 (4), 152.0 (2), 152.6 (6). UV/Vis
(CH3OH): lmaxZ270 nm. MS m/z (%): 268 ((MC2)C, 4),
266 (MC, 12), 157 ((MC2)CKC7H11O, 33), 155 (MCK
C7H13O, 100), 119 (14). Anal. calcd for C12H15ClN4O: C,
54.0; H, 5.7; N, 21.0. Found: C, 54.0; H, 5.7, N, 20.9.
Compound 3a was also obtained in 99% yield by hydrolysis
of the tert-butyldimethylsilyloxymethyl derivative 3c with
CH3COOH/H2O/THF (1.8:0.6:0.6 mL) at room temperature
for 5 h.
3.1.5. (G)-cis-6-Chloro-9H-9-[2-(benzoyloxymethyl)-
cyclohexyl]purine (3b). 6-Chloropurine (299 mg,
1.94 mmol) was added at 0 8C to a solution of Ph3P
(515 mg, 1.94 mmol) and diethyl azodicarboxylate
(0.30 mL, 1.94 mmol) in anhydrous THF (10 mL) and the
mixture was stirred for 10 min. Alcohol 6 (278 mg,
1.19 mmol) in anhydrous THF (5 mL) was added and the
mixture was stirred at room temperature for 60 h. The
solvent was evaporated under vacuum and the residue
purified by FC using CH2Cl2/MeOH (95:5) as eluent, which
gave pure 3b (132 mg, 30%) as a colourless oil. IR (KBr):
3.1.3. (G)-cis-9-[2-(Hydroxymethyl)cyclohexyl]adenine
(4). A mixture of compound 3a (120 mg, 0.45 mmol),
NH4OH (16 mL) and a few drops of dioxane (sufficient to
obtain a solution of 3a) was heated under reflux for 6 h. The
solvent was evaporated under vacuum and the solid residue
was purified by FC using CH2Cl2/MeOH (95:5) as eluent,
which gave pure 4 (110 mg, 99%). Mp: 278–280 8C
(CHCl3). IR (KBr): 3344, 3199, 2928, 2868, 1667, 1606,
1
3409, 3123, 3058, 2931, 2856, 1712, 1589, 1557, 1269. H
NMR (CDCl3) (d): 1.22–2.19 (m, 8H, (–CH2–)4), 2.38 (m,
1H, –CH–C–O), 4.30 (m, 2H, –CH2–O), 4.98 (m, 1H, –CH–
N), 7.32 (m, 2 Ar-H), 7.48 (m, 3 Ar-H), 8.23, 8.67 (2s, 2H,
H-2 and H-8). 13C NMR (CDCl3) (d): 23.45, 24.87, 27.92,
28.65, 29.63, 58.23, 67.65, 109.36, 122.87, 124.18, 125.66,
128.42, 129.22, 132.11, 143.37, 151.06, 165.93. HRMS
(EI): (MC) calcd for C19H19ClN4O2: 370.1197, found
370.1196.
1
1586, 1480, 1322, 1052, 653. H NMR (DMSO-d6) (d):
1.55–2.25 (m, 9H, (–CH2–)4C–CH–CO), 2.97 (m, 1H,
–HCH–O), 3.42 (m, 1H, –HCH–O), 4.29 (t, 1H, –OH, JZ
5.1 Hz), 4.65 (m, 1H, –CH–N), 7.15 (s, 2H, –NH2), 8.11,
8.14 (2s, 2H0, H-2 and H-8). 13C NMR (DMSO-d6) (d): 20.8
(400), 24.9 (3 ), 25.7 (50), 27.0 (60), 40.6 (20), 54.5 (10), 58.6
(7 ), 118.7 (5), 139.8 (8), 149.8 (4), 152.5 (2), 156.4 (6). UV/
Vis (CH3OH): lmaxZ261 nm. MS m/z (%): 247 (MC, 30),
230 (MCKOH, 15), 217 (MCKCH2O, 12), 162 (35), 135
(MCKC7H12O, 100), 108 (32), 66 (34). Anal. calcd for
C12H17N5O: C, 58.3; H, 6.9; N, 28.3. Found: C, 58.1; H, 6.9;
N, 28.1. Compound 4 was also obtained in 75% yield from
3b (130 mg, 0.35 mmol) by heating a solution in saturated
methanolic ammonia (15 mL) at 80 8C for 20 h.
3.1.6. (Cyclohexen-1-yl)methyl benzoyl ester (8a). Reac-
tion of (G)-cis-(2-hydroxy)cyclohexylmethyl benzoate (7,
398 mg, 1.70 mmol) with 6-chloropurine under Mitsunobu
conditions, in an analogous way to the procedure described
for 3b, gave a residue that was purified by FC using hexane/
iprOH (95:5) as eluent to afford 8a as a colourless oil
(294 mg, 80%). IR (KBr): 2931, 2835, 1718, 1269, 1109. 1H
NMR (CDCl3) (d): 1.66 (m, 4H, (–CH2–)2), 2.06 (m, 4H,
(–CH2–)2), 4.69 (s, 2H, –CH2–O), 5.84 (s, 1H, –CH]), 7.43
(t, 2 Ar-H, JZ7.4 Hz), 7.55 (t, 1 Ar-H, JZ7.4 Hz), 8.05 (dd,
2 Ar-H, JZ1.4, 7.4 Hz). 13C NMR (CDCl3) (d): 21.1, 21.3,
25.4, 26.2, 69.7, 125.9, 126.6, 128.7, 129.4, 130.0, 133.3,
165.5. MS m/z (%): 105 (C7H5O, 100), 94 (53), 79 (40), 77
(35).
3.1.4. (G)-trans-(2-Hydroxy)cyclohexylmethyl benzoate
(6) and (G)-cis-(2-hydroxy)cyclohexylmethyl benzoate
(7). Benzoyl chloride (0.5 mL) was added to a solution of
diol 5 (500 mg, 3.84 mmol) and Et3N (1.8 mL) in anhydrous
CH2Cl2 (10 mL) under Ar. The mixture was stirred at room
temperature for 3 h. The organic layer was washed with
NaHCO3, dried (Na2SO4) and the solvent was evaporated
under vacuum. The residue was purified by FC using
hexane/EtOAc (85:15) to give firstly compound 7 (240 mg,
27%) and then compound 6 (290 mg, 32%) as colourless
oils. Compound 7: IR (KBr): 3477, 2932, 2857, 1718, 1702,
3.1.7.
(G)-cis/trans-2-(tert-Butyldimethylsilyloxy-
methyl)cyclohexanol (9). TBDMSCl (2.2 g, 15.12 mmol)
was slowly added to a solution of diol 5 (1.30 g, 9.98 mmol)
and imidazole (1.68 g, 23.95 mmol) in anhydrous THF
(30 mL) at 0 8C. The mixture was stirred at room
temperature for 4.5 h and the solvent was evaporated
under vacuum. The residue was redissolved in Et2O and
washed with water (3!30 mL). The organic layer was dried
(Na2SO4) and the solvent was evaporated under vacuum.
1
1275, 1114, 708. H NMR (CDCl3) (d): 1.18–1.90 (m, 8H,

D. Vin˜a et al. / Tetrahedron 61 (2005) 473–478
477
The residue was distilled under vacuum (0.15 mbar,
138–140 8C) to give 919 (1.87 g, 77%) as a colourless oil.
0.22 mmol) in an analogous way to 4 from 3a. The crude
product was purified by FC using CH2Cl2/MeOH (95:5) as
eluent to give pure 11 (55 mg, 99%). Mp: 266–268 8C
(Hexane/CHCl3). IR (KBr): 3300, 2950, 2871, 1687, 1610,
3.1.8. Mitsunobu reaction of 9 with 6-chloropurine.
6-Chloropurine (1.06 g, 8.47 mmol) was added at 0 8C to a
solution of Ph3P (2.25 g, 8.47 mmol) and diethyl azodi-
carboxylate (1.32 mL, 8.47 mmol) in anhydrous THF
(10 mL) and the mixture was stirred for 10 min. Alcohol 9
(1.26 g, 5.16 mmol) in anhydrous THF (5 mL) was added
and the mixture was stirred for 24 h at room temperature.
The solvent was evaporated under vacuum and the residue
purified by FC using hexane/EtOAc (85:15) as eluent to give
compound 8b (350 mg, 30%), compound 10a (197 mg,
10%) and finally compound 3c (800 mg, 41%), all of them
as colourless oils.
1
1567, 1477, 1419, 1303, 651. H NMR (CDCl3) (d): 1.48–
2.13 (m, 8H, (–CH2–)4), 2.50 (m, 1H, –CH–C–O), 3.36 (m,
2H, –CH2–O), 4.58 (m, 2H, –CH–N, –OH), 7.14 (bs, 2H,
–NH2), 8.11, 8.17 (2s, 2H, H-2, H-8). 13C NMR (CDCl3)
(d): 23.45 (40), 24.87 (30), 26.76 (50), 27.06 (60), 34.54 (20),
56.67 (10), 60.14 (70), 118.20 (5), 140.98 (8), 152.10 (2),
152.77 (6), 155.85 (4). UV/Vis (CH3OH): lmaxZ261 nm.
MS m/z (%): 247 (MC, 25), 230 (MCKNH3, 15), 217
(MCKCH2O, 9), 162 (13), 135 (MCKC7H12O, 100), 108
(22), 66 (14). Anal. calcd for C12H17N5O: C, 58.3; H, 6.9; N,
28.3. Found: C, 58.2; H, 6.9; N, 28.4.
3.1.9. (Cyclohexen-1-yl)methyl-tert-butyldimethylsilyl
ether (8b). H NMR (CDCl3) (d): K0.02 (s, 6H, (–CH3–)2
–Si), 0.84 (s, 9H, (–CH3–)3–C), 1.10–2.20 (m, 8H, (–CH2–)4),
3.92 (s, 2H, –CH2–O), 5.52 (m, 1H, –CH]).
1
Acknowledgements
We thank the Spanish Ministry of Science and
Technology (SAF 2003-02222) and the Xunta de Galicia
(PGIDT00PXI20317PR) for financial support. D.V. is
grateful to the Spanish Ministry of Science and Technology
for a predoctoral grant (FPU). We also thank Professor Eric
De Clercq for the biological assays.
3.1.10. (G)-trans-6-Chloro-9H-9-[2-(tert-butyldimethyl-
silyloxymethyl) cyclohexyl]purine (10a). IR (KBr): 2932,
2852, 1580, 1545, 1318, 1244, 1188, 1097, 784. H NMR
1
(CDCl3) (d): 0.00 (s, 6H, (–CH3)2), 0.99 (s, 9H, (–CH3)3),
1.46–2.58 (m, 9H, (–CH2–)4CCH–C–O), 3.30 (m, 1H,
–HCH–O), 3.47 (m, 1H, –HCH–O), 4.63 (m, 1H, CH–N),
8.28, 8.89 (2s, 2H, H-2 and H-8). 13C NMR (CDCl3) (d):
18.5, 25.5, 26.0, 26.2, 26.2, 29.5, 32.9, 43.9, 57.9, 64.4,
132.4, 145.5, 151.3, 151.7, 152.1. HRMS (EI): (MC) calcd
for C18H29ClN4OSi: 380.1799, found 380.1801.
References and notes
1. Marquez, V. E. Adv. Antivir. Drug Des. 1996, 2, 89–146.
2. Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1966, 88,
3885–3887.
3.1.11. (G)-cis-6-Chloro-9H-9-[2-(tert-butyldimethyl-
silyloxymethyl) cyclohexyl]purine (3c). IR (KBr): 2966,
2864, 1585, 1551, 1335, 1250, 1193, 1102, 943, 841, 773.
1H NMR (CDCl3) (d): 0.00 (s, 6H, (–CH3)2), 0.89 (s, 9H,
(–CH3)3), 1.81–2.20 (m, 8H, (–CH2–)4), 2.55 (m, 1H, –CH–
C–O), 3.69 (d, 2H, –CH2–O, JZ5.7 Hz), 5.20 (m, 1H,
–CH–N), 8.44, 8.92 (2s, 2H, H-2 and H-8). 13C NMR
(CDCl3) (d): 18.4, 22.3, 24.9, 26.1, 27.8, 28.4, 40.7, 55.6,
63.0, 126.3, 131.9, 144.6, 151.2, 151.9, 152.4. HRMS (EI):
(MC) calcd for C18H29ClN4OSi: 380.1799, found 380.1795.
3. Balzarini, J.; De Clercq, E. Nucleoside and non nuclease
reverse transcriptase inhibitors active against HIV. In
Textbook of AIDS Medicine; Merigan, T. C., Bartlett, J. G.,
Bolognesi, D., Eds.; Williams and Wilkings: Baltimore, 1999;
pp 815–847.
4. Nair, V.; Nuesca, Z. M. J. Am. Chem. Soc. 1992, 114,
7951–7953.
5. Nair, V.; St Clair, M. H.; Reardon, J.; Krasny, H. C.; Hazen,
R. C.; Paff, M. T.; Boone, L. R.; Tisdale, M.; Najera, I.;
Dornsife, R. E.; Averett, D. R.; Borroto-Esoda, K.; Yale, J. L.
Antimicrob. Agents Chemother. 1995, 39, 1993–1999.
6. Santana, L.; Uriarte, E.; Balzarini, J.; De Clercq, E. Bioorg.
Med. Chem. Lett. 1998, 8, 1349–1352.
3.1.12. (G)-trans-6-Chloro-9H-9-[2-(hydroxymethyl)-
cyclohexyl]purine (10b). This compound was prepared
from 10a (70 mg, 0.184 mmol) in an analogous way to 3a
from 3c. The crude product was purified by FC using
CH2Cl2/MeOH (98:2) as eluent to give pure 10b (46 mg,
95%). Mp: 148–150 8C (hexane/CHCl3). IR (KBr): 3341,
2943, 2868, 1597, 1557, 1330. 1H NMR (CDCl3) (d): 1.47–
2.17 (m, 9H, (–CH2–)4C–CH–C–O), 2.88 (s, 1H, OH), 3.13
(dd, 1H, –HCH–O, JZ1.8, 9.3 Hz), 3.33 (dd, 1H, –HCH–O,
JZ1.8, 11.2 Hz), 4.55 (m, 1H, CH–N), 8.22, 8.75 (2s, 2H,
7. Estrada, E.; Uriarte, E.; Montero, A.; Teijeira, M.; Santana, L.;
De Clercq, E. J. Med. Chem. 2000, 43, 1975–1985.
´ ´
8. Besada, P.; Gonzalez-Moa, M. J.; Teran, C.; Santana, L.;
Uriarte, E. Synthesis 2002, 16, 2445–2449.
9. Wang, J.; Herdewijn, P. J. Org. Chem. 1999, 64, 7820–7827.
10. Wang, J.; Froeyen, M.; Hendrix, C.; Andrei, G.; Snoeck, R.;
De Clercq, E.; Herdewijn, P. J. Med. Chem. 2000, 43,
736–745.
13
H-8 and H-2). C NMR (CDCl3) (d): 26.7 (40), 27.1 (30),
30.6 (50), 34.0 (60), 45.3 (20), 59.3 (10), 64.8 (70), 131.3 (5),
148.1 (8), 151.5 (2), 153.0 (4), 153.6 (6). UV/Vis (CH3OH):
lmaxZ270 nm. MS m/z (%): 268 ((MC2)C, 2), 266 (MC,
6), 235 (4), 181 (9), 155 (MCKC7H13O, 100), 119 (16).
Anal. calcd for C12H15ClN4O: C, 54.0; H, 5.7; N, 21.0.
Found: C, 53.8; H, 5.7, N, 21.1.
´
11. Santana, L.; Teijeira, M.; Teran, C.; Uriarte, E.; Vina, D.
Synthesis 2001, 10, 1532–1538.
˜
12. Szakonyi, Z.; Martinek, T.; Hetenyi, A.; Fulop, F.
Tetrahedron: Asymmetry 2000, 11, 4571–4579.
13. Katagiri, N.; Nomura, N.; Sato, H.; Kaneko, C.; Yusa, K.;
Tsuro, T. J. Med. Chem. 1992, 35, 1882–1886.
3.1.13. (G)-trans-9-[2-(Hydroxymethyl)cyclohexyl]ade-
nine (11). This compound was prepared from 10b (60 mg,
14. Kinast, G.; Tietze, L.-F. Chem. Ber. 1976, 109, 3626–3639.
15. (a) Schlessinger, R. H.; Lopes, A. J. Org. Chem. 1981, 46,

478
D. Vin˜a et al. / Tetrahedron 61 (2005) 473–478
5252–5253. (b) Theil, F.; Ballschuh, S. Tetrahedron:
Asymmetry 1996, 7, 3565–3572.
18. Takamasa, I.; Yasuo, O.; Takeshi, O. Tetrahedron Lett. 1991,
32, 1209–1212.
16. Girard, F.; Lee, M.-G.; Agrofoglio, L. A. J. Heterocycl. Chem.
1998, 35, 911–913.
19. Osamu, K.; Isao, K. Tetrahedron 2000, 56, 5639–5648.
20. Theil, F.; Ballschuh, S.; Flatan, S.; von Janta-Lipinski, M.;
Matthes, E. Bioorg. Med. Chem. 1998, 6, 701–706.
17. Vin˜a, D.; Santana, L.; Uriarte, E.; Quezada, E.; Valencia, L.
Synthesis 2004, 2517–2522.