A short and convenient synthesis of new 1,2-disubstituted carbocyclic nucleoside analogues of pyrimidine based on a cyclopentene ring

Article abstract of DOI:10.1055/s-2004-815975

The synthesis of a new series of 1,2-disubstituted carbonucleoside analogues, pyrimidines of general structure I, is reported. These compounds were prepared in good yield from (±)-6-azabicyclo[3.2.0]hept-3-en-7-one (1) via two synthetic routes that involve NaBH₄-mediated C-N bond cleavage as the key step. The uracil derivative Ia was halogenated with Cl, Br, and I at position 5 by treatment with the corresponding N-halosuccinimide.

Full text of DOI:10.1055/s-2004-815975

PAPER
543
A Short and Convenient Synthesis of New 1,2-Disubstituted Carbocyclic Nu-
cleoside Analogues of Pyrimidine Based on a Cyclopentene Ring
Carbocyclic
N
ucleosid
.
e
A
nalogues
J
of
P
yrimi
.
dine Based
o
G
n a Cyclopentene
o
Ring nzález-Moa,a P. Besada,a M. Teijeira,a C. Terán,*a E. Uriarteb
a
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
Fax +34(986)812262; E-mail: mcteran@uvigo.es
b
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Received 23 October 2003; revised 7 January 2004
d, Scheme 3) are not only of interest for their potential
chemotherapeutic properties13 but also as synthetic inter-
mediates in the formation of new carbon–carbon or car-
bon–heteroatom bonds.14 Our usual approach to the
Abstract: The synthesis of a new series of 1,2-disubstituted carbo-
nucleoside analogues, pyrimidines of general structure I, is report-
ed. These compounds were prepared in good yield from ( )-6-
azabicyclo[3.2.0]hept-3-en-7-one (1) via two synthetic routes that
involve NaBH4-mediated C–N bond cleavage as the key step. The synthesis of uracil-based OTCs is to construct the hetero-
uracil derivative Ia was halogenated with Cl, Br, and I at position 5
by treatment with the corresponding N-halosuccinimide.
cyclic base on an appropriate amino alcohol by reaction
with a -alkoxyacryloyl isocyanate followed by acid-cat-
alyzed cyclization according to published procedures.15,16
Key words: nucleosides, reductions, amino alcohols, carbocycles,
heterocycles
The preparation of the uracil derivative Ia, which is the
precursor for the other compounds in the series, employed
-lactam 1 as the starting material. Compound 1 was ob-
Nucleoside analogues display a wide range of biological tained in 46% yield by a [2 + 2]-cycloaddition between
activities and have attracted particular attention as antivi- cyclopentadiene and chlorosulfonyl isocyanate,12 two
ral and antitumor agents.1–4 The synthesis of new modi- commercially available compounds, and Ia was subse-
fied nucleosides represents an important and increasingly quently prepared following the two synthetic routes out-
active area of interest for organic chemists in the search lined in Scheme 1. The first route represents the
for compounds with improved biological properties.5,6 conventional methodology for the construction of the het-
Within this area, systems of particular interest include car- erocyclic base using the amino group of the amino alco-
bocyclic nucleosides and 2 ,3 -dideoxynucleosides. Car- hol. This path required the initial synthesis of ( )-cis-2-
bocyclic nucleosides are compounds in which the amino-3-cyclopentenylmethanol (2), which was previous-
furanose oxygen atom of a classical nucleoside is replaced ly described by us.12 The second route involves initial re-
by a methylene group. These compounds possess greater action of 1 with 3-methoxyacryloyl isocyanate17 or with
metabolic stability toward the nucleoside phosphorylases 3-ethoxyacryloyl isocyanate18 in anhydrous benzene af-
and a higher lipophilicity,7 two properties that are poten- fording the corresponding carbamoyl derivatives 3a–b.
tially beneficial in terms of increased in vivo half life, oral Reduction of compounds 3 with an excess of NaBH4 in
efficiency and cell wall penetration.8 On the other hand, a methanol gave the corresponding acyclic ureides with cis
number of 2 ,3 -dideoxynucleosides are currently the stereochemistry (4a–b) and subsequent acidic ring clo-
drugs of choice for the treatment of certain viral infections sure afforded the desired uracil derivative Ia. The key step
(including AIDS).9 Indeed, the potent HIV-1 inhibitor in the second route is the reductive opening of the amide
carbovir and its prodrug, abacavir, combine the two types bond of 1 using an open-chain uracil precursor as the re-
of structural modification described above.
quisite electron-withdrawing N-substituent.19 Such an ap-
proach has not been used previously with -lactam
systems. This strategy allows the transformation of 1 into
the uridine analogue Ia in three steps with overall yields
in the range 30–33% and gives rise to the desired precur-
sor Ia in a more direct way. It also avoids the preparation
of amino alcohol 2, which is an unstable compound that is
difficult to isolate and purify.
On the basis of the factors outlined above, and as part of
our study of the therapeutic potential of 1,2-disubstituted
carbonucleosides (OTCs),10–12 we describe now the syn-
thesis of ( )-cis-1-(2-hydroxymethyl-4-cyclopentenyl)-
2,4-pyrimidinediones of structure I (Schemes 1 and 3).
We previously developed another series of pyrimidine-
based OTCs in which the pseudosugar is a cyclopentane
ring,11 and in this present study unsaturation has now been This approach also proved suitable for the preparation of
incorporated into the 2 ,3 -position of the carbocycle.12 amino alcohol 2 from -lactam 1. In this case the ethoxy-
Such a structural modification also allows versatility in carbonyl group was selected as the labile electron-with-
the functionalization of the ring. 5-Halopyrimidines (Ib– drawing group (Scheme 2).20 The LDA-assisted
ethoxycarbonylation of 1 with ethoxycarbonyl chloride
afforded carbamate 5 and subsequent reductive amide
bond cleavage of 5 gave the cis-1,2-disubstituted cyclo-
pentene derivative 6 as the major product. The ethoxycar-
SYNTHESIS 2004, No. 4, pp 0543–0548
Advanced online publication: 12.02.2004
DOI: 10.1055/s-2004-815975; Art ID: T11203SS.pdf
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4

544
M. J. González-Moa et al.
PAPER
O
O
ly. However, as one would expect, iodination of Ia under
the same conditions was not possible and it was necessary
to replace DMF with acetic acid and heat the reaction at
80 ºC for 8 h. These reaction conditions gave rise to a mix-
ture of three products in similar proportions due to simul-
taneous esterification of the hydroxyl group. The products
formed were identified as the 5-iodouridine analogue Id
(41%), its acetyl derivative 7 (24%) and the acetylated
product 8 (34%). These products were separated by col-
umn chromatography. Better results were obtained by car-
rying out an in situ deacetylation on the reaction mixture
by treatment with NaOH (0.5 M) at room temperature.
This approach allowed the iodinated product Id to be iso-
lated in 67% yield. The use of the synthetic strategy out-
lined above should allow the synthesis of a wide variety
of pyrimidine derivatives for pharmacological evaluation.
O
NH
N
O
NH
a
route 2
RO
3a R = CH3
3b R = C2H5
1
route 1
(scheme 2)
b
H
N
H
HO
HO
HO
O
O
O
N
O
NH2
NH
N
c
d
OR
2
4a R = CH3
4b R = C2H5
Ia
Scheme 1 Reagents and conditions: a) 3-methoxyacryloyl isocya-
nate or 3-ethoxyacryloyl isocyanate, anhyd benzene, 60 °C, 60–68%;
b) NaBH4, MeOH, r.t., 74–75%; c) 3-methoxyacryloyl isocyanate,
anhyd DMF–benzene, –20 °C to r.t., 29%; d) H2SO4 (2 M) reflux, 68–
65%.
H
H
HO
O
N
O
X
HO
O
N
O
N
a or b
N
bonyl group was removed by treatment with aqueous
KOH in methanol. Although this new synthetic approach
does not represent a reduction in the number of steps com-
pared to the previously reported method for the synthesis
of amino alcohol 2 from 1,12 it is far more convenient in
terms of the isolation, manipulation and purification of the
products and intermediates. Furthermore, the new route
allows the synthesis of amino alcohol 2 in good overall
yield (43%).
X = Cl (Ib); X = Br (Ic)
Ia
c or d
H
RO
O
N
O
X
N
R = H, X = I (Id)
R = CH3CO, X = I (7)
R = CH3CO, X = H (8)
Scheme 3 Reagents and conditions: a) NCS, DMF, 50 °C (Ib,
71%); b) NBS, DMF, r.t. (Ic, 99%); c) NIS, HOAc, reflux (Id, 41%;
7, 24%; 8, 34%); d) NIS, HOAc, reflux, NaOH (0.5 M), r.t. (Id, 67%).
O
HO
HO
H
NCO2Et
N
OEt
NH2
a
b
c
1
O
Mps are uncorrected and were determined in capillary tubes using a
Gallenkamp apparatus. IR spectra were recorded using a Bruker IFS
5
6
2
28 Equinox and a FTIR Bruker Vector 22 spectrometer. 1H and 13
C
Scheme 2 Reagents and conditions: a) LDA, THF, ClCO2Et, –78 °C
to r.t., 86%; b) NaBH4, MeOH, r.t. (83%); c) KOH (10 M), MeOH,
reflux (62%).
NMR spectra were recorded on a Bruker ARX-400 instrument, us-
ing TMS as internal standard [chemical shifts ( ) in ppm, J in Hz].
Complete assignment of the signals was performed by NOE, DEPT,
HMQC or HMBC experiments. Mass spectra were recorded using
a Hewlett–Packard 5988A spectrometer. Microanalyses were per-
formed at the Microanalysis Service, University of Santiago, using
a Perkin–Elmer 240B elemental analyzer. Silica gel (Merck 60,
230–400 mesh) was used for flash chromatography (FC). Analytical
TLC was performed on plates precoated with silica gel (Merck 60
F254, 0.25 mm).
The synthesis of pyrimidine analogue Ia using the amino
alcohol leads to a longer synthetic strategy, but it also al-
lows greater versatility given that amino alcohol 2 can be
converted into a range of different heterocyclic bases. On
the other hand, the second synthetic strategy is more direct
for compound Ia and allows access to a diverse series of
pyrimidine-based OTCs.
( )-6-Aza-6-ethoxycarbonylbicyclo[3.2.0]hept-3-en-7-one (5)
A solution of 1 (200 mg, 1.83 mmol) in anhyd THF (3.3 mL) was
added dropwise to a stirred mixture of LDA–hexane suspension
(10%; 3.34 mL, 3.12 mmol) and anhyd THF (3.3 mL) at –78 ºC un-
der Ar. The mixture was stirred at –78 ºC for 1 h and ethyl chloro-
formate (0.23 mL, 2.44 mmol) was added. The reaction temperature
was raised gradually to r.t. and the mixture stirred for 12 h. The sol-
vent was evaporated under vacuum and the residue was purified by
FC (hexane–EtOAc, 6:1) to give 5.
We proceeded to investigate the halogenation at position
5 of the uracil in compound Ia, bearing in mind that the
presence of the double bond in the carbocycle could inter-
fere with this reaction. Given this possibility, the use of
the corresponding N-halosuccinimide was investigated
and found to be suitable for the generation of the electro-
phile (Scheme 3).11,21 The chlorination reaction was car-
ried out with NCS in DMF at 50 ºC and the bromination
was carried out with NBS in DMF at room temperature.
These reactions gave yields of 71% and 99%, respective-
Yield: 272 mg (82%); colourless oil.
IR (KBr): 2980, 1799, 1717, 1320, 1178, 1060, 907, 875, 781, 732
cm–1.
Synthesis 2004, No. 4, 543–548 © Thieme Stuttgart · New York

PAPER
Carbocyclic Nucleoside Analogues of Pyrimidine Based on a Cyclopentene Ring
545
1H NMR (CDCl3): = 6.14–6.07 (m, 2 H, H-3, H-4), 4.89–4.85 (m,
1 H, H-5), 4.28 (q, 2 H, J = 7.1 Hz, OCH2), 3.85–3.78 (m, 1 H, H-
1), 2.85–2.70 (m, 1 H, 1H-2), 2.60–2.48 (m, 1 H, 1H-2), 1.33 (t, 3
H, J = 7.1 Hz, CH3).
13C NMR (CDCl3): = 168.5 (C-7), 149.2 (COO), 138.4 (C-3),
129.1 (C-4), 63.1 (C-5), 62.8 (OCH2), 51.8 (C-1), 31.5 (C-2), 14.8
(CH3).
MS: m/z = 182 ([M + 1]+, 1), 153 (M+ – CO, 3), 108 (M+ – C3H5O2,
6), 93 ([M + 1]+ – C3H5NO2, 5), 80 (M+ – C4H5O3, 11), 66 (M+ –
C4H5NO3, 100), 53 (8), 65 (15).
4.96 (m, 1 H, H-5), 3.94–3.89 (m, 1 H, H-1), 3.76 (s, 3 H, OCH3),
2.81–2.75 (m, 1 H, 1H-2), 2.63–2.55 (m, 1 H, 1H-2).
13C NMR (CDCl3):
= 170.3 (C-7), 166.2 (NHCO), 165.4
(CHOCH3), 146.1 (NCONH), 138.2 (C-3), 128.4 (C-4), 97.6
(COCH=), 62.7 (C-5), 57.7 (OCH3), 51.6 (C-1), 30.8 (C-2).
MS: m/z (%) = 236 (M+, 1), 205 (M+ – CH3O, 8), 170 (M+ – C5H6,
5), 138 (4), 85 (M+ – C7H7N2O2, 100), 66 (M+ – C6H6N2O4, 47).
Anal. Calcd for C11H12N2O4: C, 55.93; H, 5.12; N, 11.86. Found: C,
56.05; H, 5.28; N, 11.65.
Anal. Calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C,
59.51; H, 5.98; N, 7.83.
( )-6-Aza-6-(3-ethoxyacryloylaminocarbonyl)bicyclo-
[3.2.0]hept-3-en-7-one (3b)
According to the procedure described for the preparation of 3a, a so-
lution of 3-ethoxyacryloyl isocyanate19 (5.86 g, 41.51 mmol) in an-
hyd benzene (140 mL) was treated with a solution of 1 (3.02 g,
27.69 mmol) in anhyd benzene (30 mL). The solid residue was pu-
rified by FC (hexane–EtOAc, 4:1) to give 3b.
( )-cis-2-Ethoxycarbonylamino-3-cyclopentenylmethanol (6)
To a stirred solution of 5 (272 mg, 1.5 mmol) in anhyd MeOH (14
mL) at 0 °C was added NaBH4 (596 mg, 15.77 mmol) portionwise.
The mixture was stirred for 1 h at r.t. and the excess reducing re-
agent was destroyed by the addition of of MeOH–HOAc (10:1; 3
mL). The solvent was evaporated under reduced pressure and the
residue was purified by FC (hexane–EtOAc, 4:1) to afford 6.
Yield: 4.73 g (68%); white solid; mp 94–96 ºC.
1H NMR (CDCl3): = 8.65 (s, 1 H, D2O exchange, CONHCO),
7.76 (d, 1 H, J = 12.4 Hz, CHOC2H5), 6.32 (d, 1 H, J = 12.4 Hz,
COCH), 6.16–6.12 (m, 1 H, H-3), 6.10–6.07 (m, 1 H, H-4), 4.96–
4.94 (m, 1 H, H-5), 3.97 (q, 2 H, J = 7.1 Hz, OCH2CH3), 3.91–3.86
(m, 1 H, H-1), 2.79–2.72 (m, 1 H, 1H-2), 2.60–2.53 (m, 1 H, 1H-2),
1.33 (t, 3 H, J = 7.1 Hz, OCH2CH3).
Yield: 230 mg (83%), mp 64–66 ºC.
IR (KBr): 3311, 1684, 1539, 1249, 1076, 1044 cm–1.
1H NMR (CDCl3): = 6.03–6.01 (m, 1 H, H-4), 5.80–5.78 (m, 1 H,
H-3), 4.73–4.68 (m, 1 H, H-1), 4.57 (br s, 1 H, D2O exchange, NH),
4.15 (q, 2 H, J = 7.1 Hz, CH2CH3), 3.66–3.63 (m, 2 H, CH2OH),
3.42 (br s, 1 H, D2O exchange, OH), 2.58–2.46 (m, 1 H, H-2), 2.38–
2.28 (m, 1 H, 1H-5), 2.04–1.94 (m, 1 H, 1H-5), 1.26 (t, 3 H, J = 7.1
Hz, CH3).
13C NMR (CDCl3):
= 170.3 (C-7), 166.4 (NHCO), 164.6
(CHOC2H5), 146.1 (NHCOCH), 138.1 (C-3), 128.4 (C-4), 98.0
(COCH=), 67.2 (OCH2CH3), 62.6 (C-5), 51.6 (C-1), 30.8 (C-2),
14.3 (OCH2CH3).
13C NMR (CDCl3): = 157.9 (CO), 136.6 (C-4), 130.9 (C-3), 61.8
(CH2OH), 61.2 (OCH2), 57.7 (C-2), 45.9 (C-1), 33.3 (C-5), 14.9
(CH3).
MS: m/z = 185 (M+, 0.5), 167 (M+ – H2O, 19), 156 (M+ – C2H5, 26),
155 (M+ – C2H6, 36), 154 (M+ – CH3O, 25), 149 (33), 126 (26), 112
(M+ – C3H5O2, 82), 97 (M+ – C3H6NO2, 18), 94 (M+ – C3H9NO2,
41), 95 (22), 90 (21), 83 (20), 82 (M+ – C4H7O3, 100), 80 (29), 79
(26), 67 (M+ – C4H8NO3, 52), 66 (M+ – C4H9NO3, 27), 65 (19), 57
(20), 55 (22).
MS: m/z = 250 (M+, 9), 221 (M+– C2H5, 11), 206 ([M + 1]+
–
C2H5O, 27), 205 (M+ – C2H5O, 41), 185 (M+ – C5H5, 9), 184 (M+ –
C5H5, 9), 178 (M+ – C4H8O, 11), 176 (M+ – C4H10O, 14), 99 (M+ –
C7H7N2O2, 100), 93 (M+ – C6H9N2O3, 35), 71 (M+ – C8H7N2O3, 38),
66 (M+ – C7H8N2O4, 42).
Anal. Calcd for C12H14N2O4: C, 57.59; H, 5.64; N, 11.19. Found: C,
57.49; H, 5.82; N, 10.98.
( )-cis-N-(2-Hydroxymethyl-4-cyclopentenyl)-N -(3-methoxy-
acryloyl)urea (4a)
Method A
To a stirred solution of 2 (692 mg, 6.12 mmol) in anhyd DMF (20
mL) at –20 ºC was added dropwise a solution of 3-methoxyacryloyl
isocyanate (857 mg, 6.75 mmol) in anhyd benzene (30 mL). The
mixture was allowed to warm up to r.t., stirred overnight and fil-
tered. The filtrate was concentrated under reduced pressure and the
residue purified by FC (hexane–EtOAc, 1:2) to give 4a.
Anal. Calcd for C9H15NO3: C, 58.36; H, 8.16; N, 7.56. Found: C,
58.44; H, 7.98; N, 7.63.
( )-cis-2-Amino-3-cyclopentenylmethanol (2)
To a solution of 6 (434 mg, 2.34 mmol) in MeOH (14 mL) was add-
ed aq KOH (10 M; 14 mL) and the mixture was heated under reflux
for 20 h. The solvent was evaporated under vacuum and the aq res-
idue was extracted with EtOAc (6 × 15 mL). The combined organic
layers were dried and evaporated to dryness to give 2.12
Yield: 431 mg (29%); white solid; mp 139–142 ºC.
Yield: 165 mg (62%); colourless oil.
IR (KBr): 3239, 3110, 2944, 1684, 1615, 1544, 1255, 1190, 1153,
1122, 808 cm–1.
( )-6-Aza-6-(3-methoxyacryloylaminocarbonyl)bicyclo-
[3.2.0]hept-3-en-7-one (3a)
1H NMR (DMSO-d6): = 10.07 (s, 1 H, D2O exchange, CONHCO),
8.45 (d, 1 H, J = 8.9 Hz, D2O exchange, CONH), 7.55 (d, 1 H,
J = 12.3 Hz, CHOCH3), 5.94–5.92 (m, 1 H, H-4), 5.69–5.67 (m, 1
H, H-5), 5.52 (d, 1 H, J = 12.3 Hz, COCH), 4.83–4.81 (m, 1 H, H-
1), 4.43 (t, 1 H, J = 4.9 Hz, D2O exchange, OH), 3.66 (s, 3 H,
OCH3), 3.49–3.42 (m, 1 H, HCHOH), 3.34–3.25 (overlapped with
the H2O signal) (m, 1 H, HCHOH), 2.38–2.22 (m, 2 H, H-2, 1H-3),
2.19–2.14 (m, 1 H, 1H-3).
A solution of 1 (936 mg, 8.57 mmol) in anhyd benzene (10 mL) was
added dropwise to a solution of 3-methoxyacryloyl isocyanate18 in
benzene (60 mL, 12.86 mmol). The mixture was stirred at 60 ºC for
3 h, filtered and evaporated to dryness. The solid residue was puri-
fied by FC (hexane–EtOAc, 4:1) to give 3a.
Yield: 1.22 g (60%); white solid; mp 94–96 ºC.
IR (KBr): 3304, 1768, 1714, 1681, 1607, 1517, 1305, 1250, 1200,
1146, 834, 633 cm–1.
1H NMR (CDCl3): = 8.69 (s, 1 H, D2O exchange, CONHCO),
7.82 (d, 1 H, J = 12.3 Hz, CHOCH3), 6.35 (d, 1 H, J = 12.3 Hz,
COCH), 6.18–6.15 (m, 1 H, H-3), 6.13–6.10 (m, 1 H, H-4), 4.99–
13C NMR (DMSO-d6): = 167.5 (NHCO), 162.7 (CHOCH3), 153.5
(NHCONH), 133.5 (C-4), 130.9 (C-5), 97.8 (COCH), 60.8
(CH2OH), 57.9 (CH3), 55.1 (C-1), 41.9 (C-2), 34.4 (C-3).
MS: m/z = 240 (M+, 9), 225 (M+ – CH3, 6), 222 (M+ – H2O), 210 ([M
+ 1]+ – CH3O, 6), 145 ([M + 2]+ – C6H9O, 21), 112 (M+ – C5H6NO3,
Synthesis 2004, No. 4, 543–548 © Thieme Stuttgart · New York

546
M. J. González-Moa et al.
PAPER
75), 102 (22), 94 (15), 85 (M+ – C7H11N2O2, 100), 82 (24), 80
(M+ – C5H8N2O4, 15), 75 (30), 67 ([M + 1]+ – C6H10N2O4, 23), 66
(M+ – C6H10N2O4, 20).
([M + 1]+ – C5H6N2O3, 82), 66 (M+ – C5H6N2O3, 33), 63 (21), 53
(25).
Anal. Calcd for C10H12N2O3: C, 57.68; H, 5.81; N, 13.45. Found: C,
57.72; H, 6.01; N, 13.41.
Anal. Calcd for C11H16N2O4: C, 54.99; H, 6.71; N, 11.66. Found: C,
55.12; H, 6.58; N, 11.41.
Method D
Method B
According to the procedure described in Method C, 4b (2.15 g, 8.63
mmol) was treated with aq H2SO4 (2 M; 69.10 mL). The solid resi-
due was purified by FC (CH2Cl2–MeOH, 98:2) to give Ia.
NaBH4 (75 mg, 1.99 mmol) was carefully added to a stirred solution
of 3a (94 mg, 0.398 mmol) in anhyd MeOH (5 mL) at 0 °C. The
suspension was stirred at r.t. for 20 min. Excess NaBH4 was decom-
posed by the addition of H2O (3 mL) and the stirring was continued
for 20 min. The mixture was extracted with CH2Cl2 (5 × 3 mL). The
extract was dried (Na2SO4), the solvent was removed and the resi-
due purified by FC (hexane–EtOAc, 1:1) to afford 4a.
Yield: 802 mg (65%).
( )-cis-5-Chloro-1-(2-hydroxymethyl-4-cyclopentenyl)uracil
(Ib)
To a solution of compound Ia (150 mg, 0.720 mmol) in anhyd DMF
(7 mL) was added dropwise a solution of NCS (110 mg, 0.821
mmol) in anhyd DMF (3 mL). The reaction mixture was stirred at
50 ºC for 5 h. After evaporation of the solvent under vacuum the res-
idue was purified by FC (CH2Cl2–MeOH, 99:1) to give Ib.
Yield: 71 mg (74%).
( )-cis-N-(2-Hydroxymethyl-4-cyclopentenyl)-N -(3-ethoxy-
acryloyl)urea (4b)
According to the procedure described for the preparation of 4a
(Method B), a solution of 3b (1.01 g, 4.03 mmol) in MeOH (50 mL)
was treated with NaBH4 (763 mg, 20.17 mmol). The solid residue
was purified by FC (hexane–EtOAc, 2:1) to give 4b.
Yield: 124 mg (71%); white solid; mp 194–196 ºC.
IR (KBr): 3473, 3054, 1692, 1618, 1461, 1245, 743 cm–1.
1H NMR (DMSO-d6): = 11.68 (br s, 1 H, D2O exchange, NH),
7.30 (s, 1 H, H-6), 6.19–6.17 (m, 1 H, H-4 ), 5.63–5.61 (m, 1 H, H-
5 ), 5.44–5.42 (m, 1 H, H-1 ), 4.46 (t, 1 H, J = 4.6 Hz, D2O ex-
change, OH), 3.21–3.17 (m, 2 H, CH2OH), 2.59–2.50 (m, 1 H, H-
2 ), 2.38–2.34 (m, 1 H, 1H-3 ), 2.26–2.19 (m, 1 H, 1H-3 ).
13C NMR (DMSO-d6): = 159.1 (C-4), 150.4 (C-2), 139.9 (C-6),
138.2 (C-4 ), 127.6 (C-5 ), 105.5 (C-5), 62.2 (C-1 ), 60.0 (CH2OH),
40.8 (C-2 ), 34.4 (C-3 ).
MS: m/z = 244 ([M + 2]+, 4), 242 (M+, 14), 225 ([M + 2]+ – H3O, 1),
223 (M+ – H3O, 4), 212 (M+ – CH2O, 4), 149 ([M + 2]+ – C6H7O,
13), 148 ([M + 2]+ – C6H8O, 12), 147 (M+ – C6H7O, 37), 146 (M+ –
C6H8O, 31), 79 (M+ – C4H4ClN2O3, 100), 67 (M+ – C5H4ClN2O3,
33), 66 (M+ – C5H5ClN2O3, 78), 53 (25) 52 (12), 51 (16).
Yield: 772 mg (75%); white solid; mp 113–116 ºC.
1H NMR (CDCl3): = 9.59 (s, 1 H, D2O exchange, CONHCO),
8.47 (d, 1 H, J = 7.5 Hz, D2O exchange, CONH), 7.61 (d, 1 H,
J = 12.2 Hz, CHOC2H5), 6.05–6.03 (m, 1 H, H-4), 5.80–5.78 (m, 1
H, H-5), 5.27 (d, 1 H, J = 12.2 Hz, COCH), 4.84–4.80 (m, 1 H, H-
1), 3.94 (q, 2 H, J = 7.1 Hz, OCH2CH3), 3.72–3.41 (m, 3 H,
CH2OH), 2.57–2.53 (m, 1 H, H-2), 2.33–2.27 (m, 1 H, 1 H-3), 2.04–
1.97 (m, 1 H, 1H-3), 1.33 (t, 3 H, J = 7.1 Hz, OCH2CH3).
13C NMR (CDCl3): = 168.3 (NHCO), 163.3 (CHOEt), 156.2 (NH-
CONH), 136.2 (C-4), 130.0 (C-5), 100.1 (COCH), 67.5
(OCH2CH3), 61.7 (CH2OH), 55.8 (C-1), 45.6 (C-2), 32.8 (C-3),
14.4 (OCH2CH3).
MS: m/z = 254 (M+, 22), 225 (M+ – CH2CH3, 23), 159 (M+ – C6H7O,
Anal. Calcd for C10H11ClN2O3: C, 49.50; H, 4.57; N, 11.54. Found:
C, 49.72; H, 4.36; N, 11.41.
25), 116 (M+ – C7H8NO2, 27), 113 (14), 112 (M+ – C8H14O2, 100),
99 (M+ – C7H11N2O2, 80), 82 (M+ – C6H8N2O4, 24), 80 (M+
–
C6H10N2O4, 7), 79 (M+ – C6H11N2O4, 8), 71 (M+ – C8H11N2O3, 54),
67 (M+ – C7H11N2O4, 12), 66 (M+ – C7H12N2O4, 10).
( )-cis-5-Bromo-1-(2-hydroxymethyl-4-cyclopentenyl)uracil
(Ic)
To a solution of Ia (200 mg, 0.96 mmol) in anhyd DMF (8 mL) was
added a solution of NBS (195 mg, 1.095 mmol) in anhyd DMF (4
mL). The reaction mixture was stirred at r.t. for 2 h. After evapora-
tion of the solvent under vacuum the residue was purified by FC
(CH2Cl2–MeOH, 98:2) to give Ic.
Anal. Calcd for C12H18N2O4: C, 56.68; H, 7.13; N, 11.02. Found: C,
56.79; H, 6.95; N, 11.21.
( )-cis-1-(2-Hydroxymethyl-4-cyclopentenyl)uracil (Ia)
Method C
Yield: 275 mg (99%); white solid; mp 214–216 ºC.
IR (KBr): 3454, 3038, 1684, 1611, 1457, 1244, 1042 cm–1.
1H NMR (DMSO-d6): = 11.72 (s, 1 H, D2O exchange, NH), 7.39
(s, 1 H, H-6), 6.22–6.20 (m, 1 H, H-4 ), 5.67–5.65 (m, 1 H, H-5 ),
5.47–5.45 (m, 1 H, H-1 ), 4.53 (t, 1 H, J = 4.6 Hz, D2O exchange,
OH), 3.22–3.19 (m, 2 H, CH2OH), 2.63–254 (m, 1 H, H-2 ), 2.45–
2.37 (m, 1 H, 1H-3 ), 2.29–2.26 (m, 1 H, 1H-3 ).
A solution of compound 4a (226 mg, 0.94 mmol) in aq H2SO4 (2 M;
7.57 mL) was heated under reflux for 3 h and the mixture was neu-
tralized with aq NaOH (2 M). The residue obtained after evapora-
tion of the solvent was purified by FC (CH2Cl2–MeOH 98:2) to give
Ia.
Yield: 133 mg (68%); white solid; mp 153–155 ºC.
IR (KBr): 3361, 3033, 1686, 1471, 1260, 1073, 805 cm–1.
13C NMR (DMSO-d6): = 159.3 (C-4), 150.6 (C-2), 142.2 (C-6),
138.2 (C-4 ), 127.6 (C-5 ), 93.9 (C-5), 62.2 (C-1 ), 60.0 (CH2OH),
40.8 (C-2 ), 34.4 (C-3 ).
1H NMR (DMSO-d6): = 11.18 (br s, 1 H, D2O exchange, NH),
7.14 (d, 1 H, J = 8.0 Hz, H-6), 6.23–6.20 (m, 1 H, H-4 ), 5.69–5.66
(m, 1 H, H-5 ), 5.51–5.46 (m, 1 H, H-1 ), 5.47 (d, 1 H, J = 8.0 Hz,
H-5), 4.50 (s, 1 H, OH), 3.23–3.17 (m, 2 H, CH2OH) 2.66–2.55 (m,
1 H, H-2 ), 2.45–2.41 (m, 1 H, HCH), 2.27–2.19 (m, 1 H, HCH).
13C NMR (DMSO-d6): = 163.4 (C-4), 151.3 (C-2), 143.2 (C-6),
138.0 (C-4 ), 128.5 (C-5 ), 100.6 (C-5), 61.3 (C-1 ), 60.6 (CH2OH),
41.8 (C-2 ), 35.2 (C-3 ).
MS: m/z = 288 ([M + 1]+, 5), 286 ([M – 1]+, 7), 193 ([M + 1]+ –
C6H7O, 23), 192 ([M + 1]+ – C6H8O, 20), 191 ([M – 1]+ – C6H7O,
23), 190 ([M – 1]+ – C6H8O, 19), 149 (15), 120 (15), 97 (M+ –
C4H2BrN2O2, 16), 96 (M+ – C4H3BrN2O2, 20), 84 (38), 79 (M+ –
C4H4BrN2O3, 76), 67 (M+ – C5H4BrN2O3, 61), 66 (M+
C5H5BrN2O3, 100), 65 (29), 53 (34), 52 (15).
–
MS: m/z = 210 ([M + 2]+, 3), 209 ([M + 1]+, 3), 208 (M+, 23), 190
(M+ – H2O, 19), 189 (M+ – H3O, 49), 178 ([M + 1]+ – CH3O, 26),
134 (33), 113 ([M + 2]+ – C6H9O, 66), 79 (M+ – C4H5N2O3, 100), 67
Anal. Calcd for C10H11BrN2O3: C, 41.83; H, 3.86; N, 9.76. Found:
C, 41.69; H, 3.62; N, 9.60.
Synthesis 2004, No. 4, 543–548 © Thieme Stuttgart · New York

PAPER
Carbocyclic Nucleoside Analogues of Pyrimidine Based on a Cyclopentene Ring
547
( )-cis-1-(2-Hydroxymethyl-4-cyclopentenyl)-5-iodouracil (Id)
Method E
Anal. Calcd for C12H14N2O4: C, 57.59; H, 5.64; N, 11.19. Found: C,
57.68; H, 5.49; N, 11.27.
To a solution of compound Ia (250 mg, 1.20 mmol) in HOAc (20
mL) was added dropwise a solution of NIS (297 mg, 1.32 mmol) in
HOAc (12 mL). The mixture was heated at 80 ºC for 8 h. After
evaporation of the solvent under vacuum the residue was purified
by FC (CH2Cl2–MeOH, 98:2) to give 7, 8 and Id.
Method F
According to the procedure described in Method E, a solution of
compound Ia (1.95 g, 9.37 mmol) in HOAc (100 mL) was treated
with a solution of NIS (2.32 g, 10.30 mmol) in HOAc (80 mL). The
residue was treated with aq NaOH (0.5 M; 100 mL), neutralized
with aq HCl (0.5 M) and purified by FC (CH2Cl2–MeOH, 98:2) to
give Id.
Compound Id
Yield: 163 mg (41%); yellow solid; mp 202–204 ºC (decomp).
IR (KBr): 3448, 3027, 1668, 1601, 1455, 1245, 1044, 447 cm–1
Yield: 2.11 g (67%).
1H NMR (DMSO-d6): = 11.58 (s, 1 H, D2O exchange, NH), 7.41
(s, 1 H, H-6), 6.25–6.23 (m, 1 H, H-4 ), 5.70–5.68 (m, 1 H, H-5 ),
5.48–5.46 (m, 1 H, H-1 ), 4.52 (t, 1 H, J = 4.3 Hz, D2O exchange,
OH), 3.23–3.20 (m, 2 H, CH2OH), 2.64–2.56 (m, 1 H, H-2 ), 2.45–
2.40 (m, 1 H, 1H-3 ), 2.27–2.23 (m, 1 H, 1H-3 ).
13C NMR (DMSO-d6): = 160.7 (C-4), 151.0 (C-2), 146.9 (C-6),
138.1 (C-4 ), 127.8 (C-5 ), 67.3 (C-5), 62.4 (C-1 ), 60.5 (CH2OH),
40.9 (C-2 ), 34.5 (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 fellowships to M. J. González-Moa and P.
Besada.
MS: m/z = 334 (M+, 9), 239 (M+ – C6H7O, 36), 238 (M+ – C6H8O,
37), 195 (16), 127 (M+ – C10H11N2O3, 18), 97 (M+ – C4H2IN2O2,
11), 96 (M+ – C4H3IN2O2, 29), 84 (54), 79 (M+ – C4H4IN2O3, 63),
78 (M+ – C4H5IN2O3, 16), 77 (M+ – C4H6IN2O3, 17), 67 (M+ –
C5H4IN2O3, 50), 66 (M+ – C5H5IN2O3, 100), 53 (26).
References
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Antitumor and Antiviral Agents; Plenum Press: New York,
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(2) Cheson, D. K.; Keating, M. J.; Plunkett, W. Nucleoside
Analogs in Cancer Therapy; Marcel Dekker: New York,
1997.
Anal. Calcd for C10H11IN2O3: C, 35.95; H, 3.32; N, 8.38. Found: C,
36.13; H, 3.25; N, 8.43.
(3) Mansour, T. S.; Storer, R. Curr. Pharm. Design 1997, 3,
227.
(4) Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385.
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L.; De Clercq, E. J. Med. Chem. 2000, 43, 1975.
(11) Santana, L.; Teijeira, M.; Terán, C.; Uriarte, E.; Viña, D.
Synthesis 2001, 1532.
( )-cis-1-(2-Acetyloxymethyl-4-cyclopentenyl)-5-iodouracil (7)
Yield: 109 mg (24%); yellow solid; mp 103–105 ºC.
1H NMR (CDCl3): = 8.86 (s, 1 H, D2O exchange, NH), 7.46 (s, 1
H, H-6), 6.36–6.33 (m, 1 H, H-4 ), 5.72–5.68 (m, 2 H, H5 , H-1 ),
4.08 (dd, 1 H, J = 11.9, 4.6 Hz HCHO), 3.98 (dd, 1 H, J = 11.9, 7.4
Hz HCHO), 3.03–2.94 (m, 1 H, H-2 ), 2.68–2.61 (m, 1 H, 1H-3 ),
2.32–2.27 (m, 1 H, 1H-3 ), 1.98 (s, 3 H, CH3).
13C NMR (DMSO-d6): = 170.5 (CH3CO), 159.9 (C-4), 150.9 (C-
2), 146.6 (C-6), 139.2 (C-4 ), 127,4 (C-5 ), 66.9 (C-5), 62.5 (CH2O),
62.4 (C-1 ), 39.0 (C-2 ), 34.4 (C-3 ), 20.8 (CH3).
MS: m/z = 377 ([M + 1]+, 1), 376 (M+, 9), 315 (M+ – C2H5O2, 3),
239 ([M + 1]+ – C8H11O2, 5), 238 (M+ – C8H11O2, 8), 195 (6),
139 (M+ – C4H4IN2O2, 21), 80 ([M + 1]+ – C6H6IN2O4, 9), 79
([M + 1]+ – C6H7IN2O4, 100), 78 (M+ – C6H7IN2O4, 28), 77 (M+ –
C6H8IN2O4, 15), 66 (M+ – C7H7IN2O4, 11), 53 (10).
(12) Besada, P.; González-Moa, M. J.; Terán, C.; Santana, L.;
Uriarte, E. Synthesis 2002, 2445.
(13) (a) Bridges, G. S.; Ahmed, S. P.; Sunkara, P. S.; McCarty, J.
R.; Tyms, A. S. Antivir. Res. 1995, 27, 325. (b) Foye, W. O.
Cancer Chemotherapeutic Agents; American Chemical
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(14) (a) Farina, V.; Hauck, S. I. Synlett 1991, 157. (b) Robins,
M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854.
(c) Tsvetkov, A. V.; Latyshev, G. V.; Lukashev, N. V.;
Beletskaya, I. P. Tetrahedron Lett. 2002, 43, 7267.
(15) Sheally, Y. F.; O’Dell, C. A. J. Heterocycl. Chem. 1976, 13,
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(17) Santana, L.; Teijeira, M.; Uriarte, E. J. Heterocycl. Chem.
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1079. (b) Fernández, F.; García-Mera, X.; Morales, M.;
Rodríguez-Borges, J. E. Synthesis 2001, 239.
Anal. Calcd for C12H13IN2O4: C, 38.32; H, 3.48; N, 7.45. Found: C,
38.15; H, 3.29; N, 7.37.
( )-cis-1-(2-Acetyloxymethyl-4-cyclopentenyl)uracil (8)
Yield: 104 mg (34%); white solid; mp 78–80 ºC.
1H NMR (CDCl3): = 9.39 (s, 1 H, D2O exchange, NH), 7.04 (d, 1
H, J = 8.03 Hz, H-6), 6.27–6.24 (m, 1 H, H-4 ), 5.73 (d, 1 H,
J = 8.03 Hz, H-5), 5.66–5.61 (m, 2 H, H-1 , H-5 ), 4.06 (dd, 1 H,
J = 11.7, 5.4 Hz, HCHO), 3.87 (dd, 1 H, J = 11.7, 8.2 Hz HCHO),
2.99–2.94 (m, 1 H, H-2 ), 2.64–2.16 (m, 1 H, 1H-3 ), 1.95 (s, 3 H,
CH3).
13C NMR (DMSO-d6): = 170.4 (CH3CO), 163.6 (C-4), 151.5 (C-
2), 142.9 (C-6), 137.9 (C-4 ), 128.3 (C-5 ), 101.2 (C-5), 63.0
(CH2O), 61.9 (C-2 ), 38.4 (C-1 ), 34.6 (C-3 ), 20.8 (CH3).
MS: m/z = 252 ([M + 2]+, 1), 250 (M+, 4), 190 (16), 189 (43), 149
(17), 113 (21), 79 (M+ – C6H7N2O4, 100), 78 (M+ – C6H8N2O4, 93),
77 (M+ – C6H9N2O4, 19), 65 (M+ – C7H9N2O4, 11), 63 (M+
C7H11N2O4, 71), 61 (M+ – C7H13N2O4, 11).
–
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548
M. J. González-Moa et al.
PAPER
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Kaneko, C. Chem. Pharm. Bull. 1991, 39, 1112.
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Tsuruo, T. J. Med. Chem. 1992, 35, 1882.
Synthesis 2004, No. 4, 543–548 © Thieme Stuttgart · New York