Novel 1,2-disubstituted carbocyclic nucleoside analogues of purine with a cyclopentene ring

Article abstract of DOI:10.1055/s-2002-35239

A total and versatile synthesis of a new series of carbocyclic nucleoside analogues which are derivatives of purine with a 1,2-disubstituted cyclopentene ring (I) is described. The 6-chloropurine derivatives 3 and 9 were prepared by construction of the heterocyclic base about the primary amino group of the (±)-cis-2-amino-3-cyclopentenylmethanol (1), which was synthesized in good yield from cyclopentadiene in four steps. The substitution of a chlorine atom in the compounds 3 and 9 by an amino group (compounds 4 and 10) and by a hydroxyl group (compounds 5 and 11) was carried out with NH₄OH or with NaOH, respectively.

Full text of DOI:10.1055/s-2002-35239

PAPER
2445
Novel 1,2-Disubstituted Carbocyclic Nucleoside Analogues of Purine with a
Cyclopentene Ring
Carbocyclic
N
.
ucleoside
A
n
B
alogues of
P
urin
e
e
with
a
Cy
s
clopenten
a
e
R
ing da,a M. J. González-Moa,a C. Terán,*a L. Santana,b E. Uriarteb
a
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
Fax +34(986)812 262; E-mail: mcteran@uvigo.es
b
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Received 17 June 2002; revised 1 August 2002
analogues with interesting pharmacological properties
(Figure 1).
Abstract: A total and versatile synthesis of a new series of carbocy-
clic nucleoside analogues which are derivatives of purine with a
1,2-disubstituted cyclopentene ring (I) is described. The 6-chloro-
purine derivatives 3 and 9 were prepared by construction of the het-
erocyclic base about the primary amino group of the ( )-cis-2-
amino-3-cyclopentenylmethanol (1), which was synthesized in
good yield from cyclopentadiene in four steps. The substitution of a
chlorine atom in the compounds 3 and 9 by an amino group (com-
pounds 4 and 10) and by a hydroxyl group (compounds 5 and 11)
was carried out with NH4OH or with NaOH, respectively.
R1
O
N
N
N
N
NH
HO
N
N
R2
N
NH2
HO
Carbovir
I
Key words: amino alcohol, nucleosides, heterocycles, cyclization,
nucleophilic aromatic substitution
Figure 1 Carbovir and 1,2-disubstituted carbocyclic nucleoside
analogues (I).
We report here the synthesis of ( )-cis-9-[(2-hydroxyme-
thyl)-4-cyclopentenyl]purines that are 6-substituted (3–5)
or 2,6-disubstituted (9–11). These compounds were pre-
pared from the amino alcohol ( )-cis-2-amino-3-cyclo-
pentenylmethanol (1) by constructing a natural or
modified purine about the primary amino group of this
amino alcohol (Scheme 1).
The design and synthesis of nucleoside analogues as po-
tential antiviral and anticancer agents is a very active field
of research.1–4 Within this area, systems of particular in-
terest include carbocyclic nucleoside analogues and 2 ,3 -
dideoxynucleosides. Carbocyclic nucleosides are com-
pounds in which the furan ring has been replaced by a car-
bocyclic system and they possess increased metabolic
stability against nucleoside phosphorylases. This in-
creased stability results from the absence of a true glyco-
sidic bond, but such a modification does not prevent their
enzymatic conversion to nucleotide analogues.5 On the
other hand, the 2 ,3 -dideoxynucleoside analogues are of
interest because a simple chemical modification in the
sugar moiety can convert a normal substrate for nucleic
acid synthesis into a drug with potent activity to inhibit the
replication of the HIV. Indeed, six of these compounds
have been approved for the control of AIDS.6 In view of
the success of these two modifications, we became inter-
ested in exploring the potential of 1,2-disubstituted carbo-
nucleosides (OTCs) in which the usual 1,3-substitution
pattern of the carbocycle is replaced by a 1,2-pattern.
The key intermediate 1 was prepared with an overall yield
of 30%, as shown in Scheme 2, starting from cyclopenta-
diene and via lactam 12.9 The stereoespecific [2 + 2] cy-
cloaddition reaction between cyclopentadiene (2 mol) and
chlorosulfonyl isocyanate (CSI, 1 mol), in anhydrous di-
ethyl ether at –60 °C, was followed by reductive
hydrolysis10 at 0 °C of the N-chlorosulfonyl -lactam with
25% aqueous sodium sulfite. Then 10% aqueous potassi-
um hydroxide was added to give an alkaline pH and this
afforded the carbocyclic nucleoside precursor ( )-6-aza-
bicyclo[3.2.0]hept-3-en-7-one (12) as the main product
(46%) along with a small amount of the isomeric lactam
139 and compound 14, which resulted from coupling of
two molecules of CSI with one of cyclopentadiene. This
stereospecific cycloaddition gave rise to the cis stereo-
chemistry required in the target compounds. The conver-
sion of -lactam 12 to amino alcohol 1 was achieved in 3
steps: hydrolysis to ( )-cis-2-amino-3-cyclopentenecar-
boxylic acid (15) with 37% aqueous hydrochloric acid,
subsequent esterification with methanol via the acid chlo-
ride, to afford the amino ester hydrochloride salt 16,
which was converted into free 16 by ion-exchange chro-
matography and then reduced.11 The selective reduction
of amino ester 16 to amino alcohol 1 was achieved by
treatment with lithium borohydride in refluxing THF. The
amino alcohol 1 could be also a useful synthon for the syn-
In recent years our research group has developed a num-
ber of OTC-cyclopentane derivatives,7,8 and we have now
introduced an unsaturation into the 2 ,3 -position of the
carbocyclic ring. The double bond in that position is of in-
terest for itself but also for the posibility of easy funciona-
lization of the carbocycle. These compounds can be
considered as analogues of carbovir and other nucleoside
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2445,2449,ftx,en;T06802SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2446
P. Besada et al.
PAPER
alcohol 1 was first reacted with 2-amino-4,6-dichloro-
pyrimidine, and a second amino group was introduced at
position 5 of the pyrimidine ring by reaction with p-chlo-
robenzenediazonium chloride, followed by reduction of
the diazo linkage with Zn in an acid medium,8 to afford
the triamine 8 with an overall yield of 31% from 1. The
fused imidazole ring was then constructed in compounds
2 and 8 by reaction with ethyl orthoformate in hydro-
chloric acid, which afforded 6-chloropurine 3 (93%) and
2-amino-6-chloropurine 9 (55%), respectively.
Cl
R
N
HO
HO
iv
1
NH2
NH
N
NH2
iii
5
4
2
3
R = H
6
1
R = p-ClPh-N=N
7
i
v
Cl
N
Cl
H2N
NH
H2N
NH
N
HO
HO
Nucleophilic substitution of the 6-chloro substituentes of
3 and 9 by amino groups was achieved by treatment with
25% aqueous ammonium hydroxide, which gave 6-ami-
nopurinyl derivative 4 in 84% yield and 2,6-aminopurinyl
derivative 10 in 49% yield. Similarly, reaction of 3 and 9
with 0.5 M aqueous sodium hydroxide gave 6-hydroxy
derivative 5 and 2-amino-6-hydroxy derivative 11 in 61
and 93% yields, respectively.
N
NH2
N
8
2
ii
ii
R
6
R
N
7
N
5
N
N
N 1
HO
HO
N
8
2
2'
4
N
The preliminary biological testing showed that com-
pounds 3–5 and 9–11 did not present any significant anti-
viral activity whereas compound 3 did show moderate
antitumor activity against L1210, CEM and Molt4/C8
cells.
N
NH2
3'
4'
9
3
1'
5'
3 R = Cl
9 R = Cl
vi
vi
4 R = NH2
5 R = OH
10 R = NH2
11 R = OH
vii
vii
Mps are uncorrected and were determined in capillary tubes using a
Gallenkamp apparatus. IR spectra were recorded using a Bruker IFS
28 Equinox and a FTIR Bruker Vector 22 spectrometer. 1H and 13
C
Scheme 1 Reagents and conditions: (i) 5-amino-4,6-dichloropyri-
midine, BuOH, Et3N reflux; (ii) CH(OEt)3, aq HCl (12 M ), r.t.; (iii)
2-amino-4,6-dichloropyrimidine, BuOH, Et3N, reflux; (iv) 4-chloro-
benzenediazonium chloride, NaOAc 3H2O, HOAc, H2O, r.t.; (v) Zn,
HOAc, H2O–EtOH reflux; (vi) aq NH4OH (25%), reflux; (vii) aq
NaOH (0.5 M), reflux.
NMR spectra were recorded on a Bruker AMX-300, Bruker ARX-
400, and Bruker AMX-500 instruments, using TMS as internal stan-
dard [chemical shifts ( ) in ppm, J in Hz]. The complete assignment
of the signals was performed by NOE, DEPT, HMQC or HMBC ex-
periments. Mass spectra were recorded using a Hewlett–Packard
5988A spectrometer. Microanalyses were performed at the Mi-
croanalysis Service, University of Santiago, using a Perkin–Elmer
240B elemental analyser. Silica gel (Merck 60, 230–400 mesh) was
used for flash chromatography (FC). Analytical TLC was per-
formed on plates precoated with silica gel (Merck 60 F254, 0.25
mm).
thesis of other pharmacologically relevant compounds.12
The crude product 1 was used immediately in the next
steps.
Diamine 2 is the precursor of the 6-substituted purines 3–
5 and was obtained in 57% yield by reaction of 1 with 5-
amino-4,6-dichloropyrimidine.13 To obtain the triamine 8,
precursor of the 2,6-disubstituted purines 9–11, the amino
-6-Azabicyclo[3.2.0]hept-3-en-7-one (12)
A solution of freshly distilled cyclopentadiene (11 mL, 162.9
mmol) in anhyd Et2O (24 mL) was added dropwise to a solution of
chlorosulfonyl isocyanate (7.1 mL, 81.6 mmol) in anhyd Et2O (72
mL), with vigorous stirring at –60 °C. After stirring for 2 h at this
temperature the mixture was treated at 0 °C with a solution of aq
Na2SO3 (25%; 119 mL) and then with aq KOH (10%) to give pH 8.
After stirring the mixture for 30 min at 0 °C, the layers were sepa-
rated and the aq layer was extracted with CH2Cl2 (7 150 mL). The
combined organic layers were dried and evaporated in vacuo, and
the residue purified by FC (hexane–EtOAc, 2:1) to give 12.
O
O
O
7
6
5
7
4
NH
6
1
NH
5
i
8
2
+
+
3
NH
13
1
9
3
4
N 2
O
H
12
14
ii
Yield: 4.11 g (46%); colorless oil.
IR (KBr): 3263, 2920, 2853, 1741, 1443, 1352, 1311, 1180, 1012,
948, 713 cm–1.
1H NMR (300 MHz, CDCl3): = 6.35 (br s, 1 H, NH), 6.04–6.00
(m, 1 H, H-3), 5.99–5.91 (m, 1 H, H-4), 4.55–4.50 (m, 1 H, H-5),
3.89–3.81 (m, 1 H, H-1), 2.78–2.70 (m, 1 H, 1H-2), 2.51–2.43 (m,
1 H, 1H-2).
HO
CO2H
CO2CH3
NH2
1
iii
NH2
NH2
iv
5
2
4
3
1
15
16
Scheme 2 Reagents and conditions: (i) CSI, anhyd Et2O, –60 ºC, aq
Na2SO3 (25%), aq NaOH (10%) to pH 8, 0 ºC; (ii) aq HCl (37%), r.t.;
(iii) anhyd MeOH, Cl2SO, r.t., Amberlite IRA-400 (OH); (iv) LiBH4,
anhyd THF, reflux.
13C NMR (75 MHz, CDCl3): = 173.5 (CO), 137.2 (C-3), 131.1 (C-
4), 59.6 (C-5), 53.5 (C-1), 31.1 (C-2).
Anal. Calcd for C6H7NO: C, 66.05; H, 6.42; N, 12.84. Found: C,
66.25; H, 6.60; N, 12. 50.
Synthesis 2002, No. 16, 2445–2449 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Carbocyclic Nucleoside Analogues of Purine with a Cyclopentene Ring
2447
Subsequent fractions from the column gave small samples of the
A solution of 16 HCl (0.60 g, 7.56 mmol) in MeOH was adjusted to
pure compounds 139 and 14.
alkaline pH with Amberlite IRA-400 (OH) at r.t.. The resin was fil-
tered off and the filtrate was evaporated to dryness in vacuo to give
16 which was used immediately in the next step.
-2,4-Diazabicyclo[4.3.0]non-8-ene-3,5-dione (14)
Mp 242–244 °C.
Yield: 0.47 g (100%); brown oil.
IR (KBr): 3239, 3071, 2923, 2854, 1700, 1652, 1539, 1506, 1369,
1245, 875, 792, 677 cm–1.
-cis-2-Amino-3-cyclopentenylmethanol (1)
LiBH4 (0.44 g, 20.2 mmol) was added portionwise to a cooled (0
°C) solution of 16 (0.75 g, 5.30 mmol) in anhyd THF (40 mL) with
stirring under argon. The mixture was heated under reflux for 4 h,
cooled to 0 °C and quenched by slow addition of H2O–MeOH (1:1;
15 mL). After a further 30 min stirring at r.t., the resulting solid was
filtered off and the filtrate was extracted with CH2Cl2 (6 15 mL).
The combined organic layers were dried and evaporated to dryness
to give 1, which was used in the next step without further purifica-
tion.
1H NMR (300 MHz, DMSO-d6): = 10.05 and 7.71 (2 br s, 2 H
D2O exchange, 2 NH), 5.91–5.85 (m, 1 H, H-8), 5.67–5.61 (m, 1 H,
H-9), 4.41–4.32 (m, 1 H, H-1), 3.10–3.02 (m, 1 H, H-6), 2.67–2.56
(m, 2 H, H-7).
13C NMR (75 MHz, DMSO-d6): = 173.1 and 152.0 (2 CO), 132.5
(C-8), 131.6 (C-9), 55.7 (C-1), 40.0 (C-6), 35.1 (C-7).
MS: m/z = 153 ([M + 1]+, 4), 152 (M+, 32), 151 ([M – 1]+, 57), 110
([M + 1]+ – CHNO, 3), 109 (M+ – CHNO, 29), 108 ([M – 1]+ –
CHNO, 10), 82 ([M + 1]+ – C2HNO2, 7), 81 (M+ – C2HNO2, 24), 80
([M – 1]+ – C2HNO2, 59), 67 ([M + 1]+ – C2H2N2O2, 17), 66 (M+ –
C2H2N2O2, 100), 65 ([M – 1]+ – C2H2N2O2, 31).
Yield: 0.48 g (80%); oil. An analytical sample was obtained by dis-
tillation (bp 159–164 °C, 35 mmHg).
1H NMR (400 MHz, CDCl3): = 5.83–5.78 (m, 1 H, H-4), 5.69–
5.62 (m, 1 H, H-3), 4.14–4.09 (m, 1 H, H-2), 3.78–3.70 (m, 1 H,
HCHO), 3.69–3.60 (m, 1 H, HCHO), 2.78 (br s, 3 H, D2O exchange,
OH, NH2), 2.54–2.46 (m, 1 H, H-1), 2.39–2.31 (m, 1 H, 1H-5),
2.13–2.06 (m, 1 H, 1H-5).
Anal. Calcd for C7H8N2O2: C, 55.26; H, 5.26; N, 18.42. Found: C,
55.03; H, 5.45; N, 18.61.
-cis-2-Amino-3-cyclopentenecarboxylic Acid (15)
To compound 12 (1 g, 9.17 mmol) was slowly added, under ice-
cooling and stirring, aq HCl (37%; 25 mL). The reaction mixture
was stirred for 30 min at r.t. and then evaporated to dryness to give
the crude hydrochloride of 15 (1.8 g), which was used in the next
step without further purification. A small portion of this crude hy-
drochloride was submitted to ion exchange chromatography on
Dowex 50X8-100 resin: elution with aq NH4OH (1 M) afforded 15.
13C NMR (100 MHz, CDCl3): = 134.4 (C-4), 132.0 (C-3), 63.6
(CH2O), 58.6 (C-2), 41.1 (C-1), 33.9 (C-5).
-cis-2-[(5-Amino-6-chloro-4-pyrimidinyl)amino]-3-cyclo-
pentenylmethanol (2)
To a solution of 1 (217 mg, 1.92 mmol) in anhyd BuOH (10 mL)
was added 5-amino-4,6-dichloropyrimidine (437 mg, 2.66 mmol)
and anhyd Et3N (1.6 mL). The mixture was refluxed under an argon
atmosphere for 48 h. The solvent was evaporated in vacuo and the
solid residue was purified by FC (CH2Cl2 and then CH2Cl2–MeOH,
98:2) to yield 2.
Foamy brown solid.
1H NMR (400 MHz, D2O): = 6.21–6.17 (m, 1 H, H-4), 5.78–5.74
(m, 1 H, H-3), 4.28–4.22 (m, 1 H, H-2), 3.22 (q, 1 H, J = 8.3 Hz, H-
1), 2.72–2.65 (m, 1 H, 1H-5), 2.58–2.50 (m, 1 H, 1H-5).
13C NMR (100 MHz, D2O): = 179.4 (CO), 139.0 (C-4), 126.3 (C-
3), 56.0 (C-2), 45.7 (C-1), 34.7 (C-5).
Yield: 0.26 g (57%); white solid.
Mp 168–171 °C.
IR (KBr): 3352, 3255, 2923, 2859, 1651, 1584, 1474, 1021 cm–1.
Anal. Calcd for C6H9NO2: C, 56.69; H, 7.08; N, 11.02. Found: C,
56.82; H, 6.83, N, 11.23.
1H NMR (300 MHz, DMSO-d6): = 7.72 (s, 1 H, pyrimidine), 6.50
(d, 1 H, J = 7.9 Hz, D2O exchange, NH), 6.00–5.93 (m, 1 H, H-4),
5.74–5.68 (m, 1 H, H-3), 5.27–5.19 (m, 1 H, H-2), 5.08 (s, 2 H, D2O
exchange, NH2), 4.32–4.25 (m, 1 H, D2O exchange, OH), 3.43–3.16
(m, 2 H, CH2O), 2.53–2.42 (m, 1 H, H-1), 2.36–2.29 (m, 2 H, H-5).
13C NMR (75 MHz, DMSO-d6): = 151.5, 145.4, 136.8, 133.3 (C-
4), 130.9 (C-3), 123.4, 60.8 (C-6), 56.9 (C-2), 42.5 (C-1), 34.9 (C-
5).
-Methyl-cis-2-amino-3-cyclopentenecarboxylate (16)
Thionyl chloride (4.7 mL) was added dropwise and with stirring to
anhyd MeOH (18 mL) at –10 °C, under an argon atmosphere and
the mixture was stirred for 20 min. To this solution was added a so-
lution of crude hydrochloride 15 (1.8 g) in anhyd MeOH. The re-
sulting mixture was stirred for 22 h at r.t. and the solvent was
evaporated to dryness. The resulting residue was purified by FC
(CH2Cl2–MeOH, 97:3) to provide hydrochloride of 16.
MS: m/z = 242 ([M + 2]+, 7), 240 (M+, 18), 211 ([M + 2]+ – CH3O,
21), 209 (M+ – CH3O, 62), 146 ([M + 2]+ – C6H8O, 34), 144 (M+ –
C6H8O, 100), 117 (23), 79 (67), 67 (69).
Yield: 1.34 g (83% based on 12); white solid.
Mp 178–179 °C.
Anal. Calcd for C10H13ClN4O: C, 49.90; H, 5.41; N, 23.28. Found:
C, 50.12; H 5.25; N, 23.39.
IR (KBr): 3434, 3024, 2922, 1726, 1601, 1501, 1443, 1362, 1208,
1038, 729 cm–1.
1H NMR (300 MHz, MeOH-d4): = 6.39–6.31 (m, 1 H, H-4), 5.95–
5.87 (m, 1 H, H-3), 4.51–4.43 (m, 1 H, H-2), 3.85 (s, 3 H, CH3), 3.60
(q, 1 H, J = 8.3 Hz, H-1), 2.90–2.83 (m, 2 H, H-5).
13C NMR (75 MHz, MeOH-d4): = 173.5 (CO), 139.5 (C-4), 127.6
(C-3), 57.2 (CH3), 52.8 (C-2), 44.8 (C-1), 35.6 (C-5).
-cis-6-Chloro-9-[(2-hydroxymethyl)-4-cyclopentenyl]purine
(3)
A mixture of 2 (0.65 g, 2.72 mmol), triethyl orthoformate (39.7 mL,
238.98 mmol) and aq HCl (12 M; 0.175 mL) was stirred at r.t. for
16 h. The solvent was removed and the residue was dissolved in
THF (42 mL) and treated with aq HCl (0.5 M; 54 mL) for 2 h at r.t..
The mixture was neutralized with aq NaOH (0.5 M) and the solvents
were evaporated in vacuo. The residue was purified by FC
(CH2Cl2–MeOH, 98:2) to give 3.
MS: m/z = 141 (M+, 10), 126 (M+ – CH3, 8), 110 (M+ – CH3O, 9),
108 (12), 82 (M+ – C2H3O2, 100), 81 (31), 80 (42), 67 (M+
C2H4NO2, 35), 65 (12), 55 (15).
–
Anal. Calcd for C7H12ClNO2: C, 47.32; H, 6.76; N, 7.89. Found: C,
47.52; H, 6.48; N, 7.99.
Yield: 0.63 g (93%); white solid.
Mp 164–165 °C.
Synthesis 2002, No. 16, 2445–2449 ISSN 0039-7881 © Thieme Stuttgart · New York

2448
P. Besada et al.
PAPER
-cis-2-[(2-Amino-6-chloro-4-pyrimidinyl)amino]-3-cyclo-
IR (KBr): 3396, 3060, 2923, 2853, 1590, 1558, 1396, 1333, 1194,
1037, 955 cm–1.
pentenylmethanol (6)
To a solution of compound 1 (178 mg, 1.58 mmol) in anhyd BuOH
(7.8 mL) was added 2-amino-4,6-dichloropyrimidine (386 mg, 2.36
mmol) and anhyd Et3N (1.65 mL). The mixture was refluxed under
an argon atmosphere for 41 h. The solvent was evaporated in vacuo
and the solid residue was purified by FC (hexane–EtOAc, 1:1) to
give 6.
1H NMR (300 MHz, DMSO-d6): = 8.76 and 8.41 (2 s, 2 H, H-2
and H-8), 6.37–6.31 (m, 1 H, H-4 ), 5.94–5.88 (m, 1 H, H-5 ), 5.83–
5.78 (m, 1 H, H-1 ), 4.27 (t, 1 H, J = 4.6 Hz, OH), 3.16–3.09 (m, 1
H, HCHO), 2.99–2.92 (m, 1 H, HCHO) 2.84–2.72 (m, 1 H, H-2 ),
2.67–2.40 (m, 2 H, H-3 ).
13C NMR (75 MHz, DMSO-d6): = 152.5, 151.7, 149.1, 147.3,
138.3 (C-4 ), 131.2, 128.1 (C-5 ), 61.1 (C-1 ), 60.4 (C-6 ), 43.1 (C-
2 ), 34.8 (C-3 ).
Yield: 243 mg (51%); white solid.
Mp 189–190 °C.
MS: m/z = 252 ([M + 2]+, 1), 250 (M+, 4), 221 ([M + 2]+ – CH3O,
3), 219 (M+ – CH3O, 6), 157 ([M + 2]+ – C6H7O, 33), 155 (M+ –
C6H7O, 100), 119 (16), 96 (24), 79 (54), 67 (74).
IR (KBr): 3456, 3300, 3175, 2928, 1641, 1586, 1497, 1230, 1157,
892, 796 cm–1.
1H NMR (300 MHz, DMSO-d6): = 6.93 (d, 1 H, J = 8.0 Hz, D2O
exchange, NH), 6.43 (br s, 2 H, D2O exchange, NH2), 5.97–5.91 (m,
1 H, H-4), 5.75 (s, 1 H, pyrimidine), 5.69–5.61 (m, 1 H, H-3), 5.15–
5.02 (m, 1 H, H-2), 4.34 (br s, 1 H, D2O exchange, OH), 3.46–3.22
(m, 2 H, CH2-O), 2.45–2.05 (m, 3 H, H-1 and H-5).
13C NMR (75 MHz, DMSO-d6): = 163.7, 162.8, 157.3, 133.2 (C-
4), 131.1 (C-3), 92.6, 60.8 (C-6), 55.6 (C-2), 43.1 (C-1), 34.6 (C-5).
MS: m/z = 242 ([M + 2]+, 3), 240 (M+, 11), 223 (M+ – H3O, 4), 211
([M + 2]+ – CH3O, 34), 209 (M+ – CH3O, 100), 146 ([M + 2]+ –
C6H8O, 14), 144 (M+ – C6H8O, 32), 109 (19), 79 (11), 67 (24).
Anal. Calcd for C11H11ClN4O: C, 52.69; H, 4.39; N, 22.36. Found:
C, 52.87; H, 4.22; N, 22.49.
-cis-9-[(2-Hydroxymethyl)-4-cyclopentenyl]adenine (4)
A mixture of compound 3 (125 mg, 0.5 mmol) and aq NH4OH
(25%; 18 mL) was refluxed for 4 h. The mixture was concentrated
to dryness in vacuo and the residue was purified by FC (CH2Cl2–
MeOH, 96:4) to yield 4.
Yield: 97 mg (84%); white solid.
Mp 175–177 °C.
IR (KBr): 3356, 2924, 1682, 1613, 1419, 1304, 1039 cm–1.
Anal. Calcd for C10H13ClN4O: C, 49.90; H, 5.41; N, 23.28. Found:
C, 50.18; H, 5.60; N, 23.03.
1H NMR (300 MHz, DMSO-d6): = 8.14 and 7.83 (2 s, 2 H, H-2
and H-8), 7.23 (s, 2 H, D2O exchange, NH2), 6.31–6.26 (m, 1 H, H-
4 ), 5.93–5.88 (m, 1 H, H-5 ), 5.64–5.58 (m, 1 H, H-1 ), 4.39 (t, 1 H,
J = 4.8 Hz, OH), 3.21–2.97 (m, 1 H, HCHO), 2.93–2.87 (m, 1 H,
HCHO), 2.75–2.68 (m, 1 H, H-2 ), 2.58–2.40 (m, 2 H, H-3 ).
13C NMR (75 MHz, DMSO-d6): = 156.1, 152.6, 149.8, 139.9,
137.3 (C-4 ), 128.5 (C-5 ), 118.8, 60.5 (C-6 ), 59.7 (C-1 ), 43.4 (C-
2 ), 35.1 (C-3 ).
MS: m/z = 232 ([M + 1]+, 30), 231 (M+, 69), 214 (M+ – NH3, 27),
201 (M+ – CH2O, 42), 200 (M+ – CH3O, 33), 175 (30), 136 (M+ –
C6H7O, 97), 135 (M+ – C6H8O, 100), 108 (78), 96 (35), 79 (50), 67
(57).
-cis-2-{[2-Amino-6-chloro-5-(4-chlorophenylazo)-4-pyrimi-
dinyl]amino}-3-cyclopentenylmethanol (7)
NaNO2 (62 mg, 0.90 mmol) in H2O (0.75 mL) was added to a sus-
pension of 4-chloroaniline (105 mg, 0.82 mmol) in aq HCl (12 M;
0.5 mL) and H2O (1 mL) at 0 °C and this mixture was stirred for 30
min. The diazonium salt obtained was then added to a mixture of 6
(179 mg, 0.74 mmol), NaOAc 3 H2O (1.488 g, 10.94 mmol), HOAc
(3.54 mL), and H2O (3.54 mL) at 0 °C. The reaction mixture was
stirred for 16 h at r.t. and the resulting yellow precipitate was isolat-
ed by filtration, washed with cold H2O, and dried to afford 7 (179
mg). The filtrate was concentrated in vacuo and the residue was pu-
rified by FC (CH2Cl2–MeOH, 99.5:0.5) to give the yellow solid 7.
Yield: 58 mg (84%).
Anal. Calcd for C11H13N5O: C, 57.14; H, 5.63; N, 30.30. Found: C,
57.39; H, 5.29; N, 30.65.
Mp >300 °C (decomp).
IR (KBr): 3309, 3160, 2926, 1648, 1566, 1478, 1369, 1296, 1084,
786 cm–1.
-cis-9-[(2-Hydroxymethyl)-4-cyclopentenyl]hipoxantine (5)
A suspension of 3 (60 mg, 0.24 mmol) in aq NaOH (0.5 M; 3 mL)
was heated under reflux for 5 h. The solvent was evaporated to dry-
ness and the residue was purified by FC (CH2Cl2–MeOH, 92:8) to
provide 5.
1H NMR (300 MHz, DMSO-d6): = 10.38 (d, 1 H, J = 8.3 Hz, D2O
exchange, NH), 7.67 (d, 2 H, J = 8.7 Hz, ArH), 7.62 (br s, 2 H, D2O
exchange, NH2), 7.55 (d, 2 H, J = 8.7 Hz, ArH), 6.00–5.96 (m, 1 H,
H-4), 5.81–5.76 (m, 1 H, H-3), 5.41–5.34 (m, 1 H, H-2), 4.65 (t, 1
H, J = 4.8 Hz, D2O exchange, OH), 3.58–3.38 (m, 2 H, CH2O),
2.61–2.32 (m, 3 H, H-1 and H-5).
Yield: 30 mg (61%); white solid.
Mp 250–251 °C.
13C NMR (75 MHz, DMSO-d6): = 164.9, 161.1, 154.4, 150.8,
133.6 (C-4), 133.4, 131.1 (C-3), 129.5, 122.8, 118.7, 60.9 (C-6),
56.3 (C-2), 41.6 (C-1), 34.4 (C-5).
MS: m/z = 378 ([M – 1]+, 1), 254 ([M + 2]+ – C6H5ClN, 40), 252
(M+ – C6H5ClN, 100), 234 (47), 224 (18), 222 (29), 220 (34), 198
(28), 111 (75), 79 (45), 67 (70).
IR (KBr): 3383, 3103, 3050, 2924, 2851, 1711, 1597, 1550, 1418,
1217, 1136, 605 cm–1.
1H NMR (300 MHz, DMSO-d6): = 8.02 and 7.76 (2 s, 2 H, H-2
and H-8), 6.30–6.25 (m, 1 H, H-4 ), 5.89–5.82 (m, 1 H, H-5 ), 5.62–
5.58 (m, 1 H, H-1 ), 4.31 (br s, 1 H, D2O exchange, OH), 3.15–2.90
(m, 2 H, CH2O), 2.78–2.65 (m, 1 H, H-2 ), 2.57–2.33 (m, 2 H, H-3 ).
13C NMR (75 MHz, DMSO-d6): = 157.0, 148.8, 145.6, 139.7,
137.8 (C-4 ), 128.5 (C-5 ), 124.3, 60.5 (C-6 ), 60.2 (C-1 ), 43.4 (C-
2 ), 35.1 (C-3 ).
Anal. Calcd for C16H16Cl2N6O: C, 50.66; H, 4.22; N, 22.16. Found:
C, 50.87; H, 3.91; N, 22.31.
MS: m/z = 232 (M+, 11), 201 (M+ – CH3O, 3), 149 (9), 137 (M+ –
C6H7O, 100), 135 (M+ – C6H9O, 54), 109 (15), 97 (9), 79 (31), 78
(50), 67 (33), 63 (52), 58 (35).
-cis-2-[(2,5-Diamino-6-chloro-4-pyrimidinyl)amino]-3-cyclo-
pentenylmethanol (8)
Zn powder (194 mg, 2.97 mmol) and HOAc (0.12 mL) were added
to a suspension of 7 (109 mg, 0.29 mmol) in EtOH–H2O (1:1; 8.8
mL). The mixture was refluxed for 35 min under an argon atmos-
phere and the yellow solid disappeared during this time. The reac-
Anal. Calcd for C11H12N4O2: C, 56.90; H, 5.17; N, 24.14. Found: C,
56.75; H, 5.38; N, 24.32.
Synthesis 2002, No. 16, 2445–2449 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Carbocyclic Nucleoside Analogues of Purine with a Cyclopentene Ring
2449
tion mixture was filtered and the solvent was removed in vacuo. The
residue was purified by FC (CH2Cl2–MeOH, 97:3) to yield 8.
MS: m/z = 247 ([M + 1]+, 2), 246 (M+, 15), 151 (M+ – C6H7O, 17),
150 (M+ – C6H8O, 100), 133 (5), 108 (13), 67 (3).
Yield: 53 mg (72%); brown solid.
Mp 165–166 °C.
Anal. Calcd for C11H14N6O: C, 53.66; H, 5.69; N, 34.15. Found: C,
53.87; H, 5.46; N, 34.26.
1H NMR (300 MHz, DMSO-d6): = 6.19 (d, 1 H, J = 8.3 Hz, D2O
exchange, NH), 5.99–5.90 (m, 1 H, H-4), 5.78–5.61 (m, 3 H, two
D2O exchange, NH2 and H-3), 5.17–5.08 (m, 1 H, H-2), 4.35 (br s,
1 H, D2O exchange, OH), 3.99 (br s, 2 H, D2O exchange, NH2),
3.43–3.21 (m, 2 H, CH2O), 2.56–2.22 (m, 3 H, H-1 and H-5).
13C NMR (75 MHz, DMSO-d6): = 155.5, 154.7, 141.2, 133.2 (C-
4), 131.2 (C-3), 113.2, 60.8 (C-6), 56.6 (C-2), 42.7 (C-1), 34.6 (C-
5).
MS: m/z = 257 ([M + 2]+, 27), 256 ([M + 1]+, 12), 255 (M+, 85), 226
([M + 2]+ – CH3O, 11), 224 (M+ – CH3O, 32), 161 ([M + 2]+ –
C6H8O, 33), 160 ([M + 1]+ – C6H8O, 24), 159 (M+ – C6H8O, 100),
158 (M+ – C6H9O, 71), 79 (6), 67 (5).
-cis-9-[(2-Hydroxymethyl)-4-cyclopentenyl]guanine (11)
Prepared from 9 (30 mg, 0.11 mmol) in the same way as 5 from 3.
The crude product was purified by FC (CH2Cl2–MeOH, 94:6) to
give 11.
Yield: 26 mg (93%); white solid.
Mp 224–226 °C.
IR (KBr): 3341, 3136, 2926, 1687, 1604, 1531, 1377, 1118, 1038
cm–1.
1H NMR (300 MHz, DMSO-d6): = 10.55 (s, 1 H, D2O exchange,
OH), 7.35 (s, 1 H, H-8), 6.45 (s, 2 H, D2O exchange, NH2), 6.26–
6.21 (m, 1 H, H-4 ), 5.89–5.81 (m, 1 H, H-5 ), 5.39–5.31 (m, 1 H,
H-1 ), 4.38 (br s, 1 H, D2O exchange, OH), 3.12–3.01 (m, 1 H,
HCHO), 2.93–2.87 (m, 1 H, HCHO), 2.66–2.55 (m, 1 H, H-2 ),
2.55–2.42 (m, 1 H, 1H-3 ), 2.41–2.30 (m, 1 H, 1H-3 ).
Anal. Calcd for C10H14ClN5O: C, 46.97; H, 5.48; N, 27.40. Found:
C, 47.15; H, 5.19; N, 27.60.
-cis-2-Amino-6-chloro-9-[(2-hydroxymethyl)-4-cyclopente-
nyl]purine (9)
Prepared from 8 (90 mg, 0.35 mmol) in the same way as 3 from 2.
13C NMR (125 MHz, DMSO-d6): = 156.7, 153.5, 151.1, 137.0 (C-
4 ), 136.1 (C-8), 128.3 (C-5 ), 116.5, 60.3 (C-6 ), 58.9 (C-1 ), 43.2
(C-2 ), 34.9 (C-3 ).
The crude product was purified by FC (hexane–EtOAc, 1:2) to give
9.
MS: m/z = 247 (M+, 8), 152 (M+ – C6H7O, 28), 151 (M+ – C8H8O,
100), 134 (8), 109 (24), 79 (14), 67 (16).
Yield: 45 mg (55%); white solid.
Mp 77–79 °C.
Anal. Calcd for C11H13N5O2: C, 53.44; H, 5.26; N, 28.34. Found:
53.68; H, 5.03; N, 28.43.
1H NMR (300 MHz, DMSO-d6): = 7.80 (s, 1 H, H-8), 6.87 (s, 2
H, D2O exchange, NH2), 6.30–6.23 (m, 1 H, H-4 ), 5.90–5.82 (m, 1
H, H-5 ), 5.52–5.45 (m, 1 H, H-1 ), 4.35 (br s, 1 H, D2O exchange,
OH), 3.09–2.99 (m, 2 H, CH2-O), 2.68 (sextet, 1 H, J = 7.6 Hz, H-
2 ), 2.55–2.34 (m, 2 H, H-3 ).
13C NMR (75 MHz, DMSO-d6): = 159.7, 154.3, 149.2, 142.3 (C-
8), 137.5 (C-4 ), 128.1 (C-5 ), 123.4, 60.2 (C-6 ), 59.5 (C-1 ), 42.8
(C-2 ), 34.7 (C-3 ).
Acknowledgment
We thank the Universidad de Vigo and the Xunta de Galicia
(PGIDT01PX130114PR) for financial support, and the Universidad
de Vigo for the award of a fellowship to P. Besada. We are grateful
to the Rega Institute for Medical Research of the Katholieke Uni-
versiteit Leuven, for the preliminary biological study.
MS: m/z = 267 ([M + 2]+, 3), 265 (M+, 8), 172 ([M + 2]+ – C6H7O,
15), 171 ([M + 2]+ – C6H8O, 37), 170 (M+ – C6H7O, 46), 169 (M+ –
C6H8O, 100), 134 (47), 79 (19), 67 (20).
References
(1) Nucleosides and Nucleotides as Antitumor and Antiviral
Agents; Chu, C. K.; Baker, D. C., Eds.; Plenum Press: New
York, 1993.
Anal Calcd for C11H12ClN5O: C, 49.72; H, 4.52; N, 26.37. Found:
C, 49.95; H, 4.36; N, 26.05.
(2) Nucleoside Analogs in Cancer Therapy; Cheson, B. D.;
Keating, M. J.; Plunkett, W., Eds.; Marcel Dekker: New
York, 1997.
-cis-2,6-Diamino-9-[(2-hydroxymethyl)-4-cyclopentenyl]pu-
rine (10)
Prepared from 9 (54 mg, 0.20 mmol) in the same way as 4 from 3,
except that the reaction was conducted for 25 h. The crude product
was purified by FC (CH2Cl2–MeOH, 96:4) to yield 10.
(3) De Clercq, E. Clin. Microb. Rev. 1997, 10, 674.
(4) Ichikawa, E.; Kato, K. Synthesis 2002, 1.
(5) Marquez, V. E. Adv. Antiviral Drug Des. 1996, 2, 89.
(6) De Clercq, E. Nat. Rev. Drug Discovery 2002, 1, 13.
(7) Estrada, E.; Uriarte, E.; Montero, A.; Teijeira, M.; Santana,
L.; De Clercq, E. J. Med. Chem. 2000, 43, 1975.
(8) Santana, L.; Teijeira, M.; Terán, C.; Uriarte, E.; Viña, D.
Synthesis 2001, 1532.
Yield: 25 mg (49%); white solid.
Mp 232–233 °C.
IR (KBr): 3321, 3172, 2919, 2848, 1666, 1597, 1411, 1196, 1039,
795, 595 cm–1.
1H NMR (500 MHz, DMSO-d6): = 7.47 (s, 1 H, H-8), 6.70 (s, 2
H, D2O exchange, NH2), 6.30–6.20 (m, 1 H, H-4 ), 5.90–5.82 (m, 1
H, H-5 ), 5.42–5.39 (m, 1 H, H-1 ), 3.06 (dd, 1 H, J = 10.6, 6.6 Hz,
HCHO), 2.97 (dd, 1 H, J = 10.6, 7.7 Hz, HCHO), 2.64 (sextet, 1 H,
J = 7.5 Hz, H-2 ), 2.53–2.46 (m, 1 H, 1H-3 ), 2.39–2.30 (m, 1 H,
1H-3 ).
13C NMR (125 MHz, DMSO-d6): = 159.0, 155.3, 151.5, 136.6 (C-
4 ), 136.4 (C-8), 128.1 (C-5 ), 113.0, 60.1 (C-6 ), 58.7 (C-1 ), 43.4
(C-2 ), 34.5 (C-3 ).
(9) Malpass, J. R.; Tweddle, N. J. J. Chem. Soc., Perkin Trans.
1 1977, 874.
(10) Durst, T.; O’Sullivan, M. J. J. Org. Chem. 1970, 35, 2043.
(11) Evans, D. A.; Biller, S. A. Tetrahedron Lett. 1985, 26, 1907.
(12) (a) Francis, M. B.; Finney, N. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1996, 118, 8983. (b) Pecunioso, A.; Maffeis,
M.; Marchioro, C.; Rossi, L.; Tamburini, B. Tetrahedron:
Asymmetry 1997, 8, 775.
(13) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 12.
Synthesis 2002, No. 16, 2445–2449 ISSN 0039-7881 © Thieme Stuttgart · New York