Carbocyclic analogues of nucleosides from bis-(Hydroxymethyl)-cyclopentane: synthesis, antiviral and cytostatic activities of adenosine, inosine and uridine analogues.

Article abstract of DOI:10.1248/cpb.51.1060

Six new carbocyclic nucleosides were prepared by constructing a purine base (in compounds 9-11) or pyrimidine base (in 6-8) on the amino groups of (+/-)-(1 beta,2 alpha,4 beta)-4-amino-1,2-cyclopentanedimethanol (4) and (+/-)-(1 beta,3 alpha,4 beta)-4-amino-1,3-cyclopentanedimethanol (5), and their activities against a variety of viruses and tumour cell lines were determined.

Full text of DOI:10.1248/cpb.51.1060

1060
Chem. Pharm. Bull. 51(9) 1060—1063 (2003)
Vol. 51, No. 9
Carbocyclic Analogues of Nucleosides from bis-(Hydroxymethyl)-
cyclopentane: Synthesis, Antiviral and Cytostatic Activities of
Adenosine, Inosine and Uridine Analogues
José Manuel BLANCO, ,a Olga CAAMAÑO,a Franco FERNÁNDEZ,a José Enrique RODRÍGUEZ-BORGES,b
*
c
Jan BALZARINI,c and Erik DE CLERCQ
a Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela; Santiago de
Compostela E-15782, Spain: b CIQ, Departamento de Química, Facultade de Ciencias do Porto; Rua do Campo Alegre,
687–4169007 Porto, Portugal: and c Rega Institute for Medical Research, Katholieke Universiteit Leuven; B-3000 Leuven,
Belgium. Received May 6, 2003; accepted July 2, 2003
Six new carbocyclic nucleosides were prepared by constructing a purine base (in compounds 9—11) or
pyrimidine base (in 6—8) on the amino groups of (؎)-(1b,2a,4b )-4-amino-1,2-cyclopentanedimethanol (4) and
(؎)-(1b,3a,4b)-4-amino-1,3-cyclopentanedimethanol (5), and their activities against a variety of viruses and tu-
mour cell lines were determined.
Key words carbocyclic nucleoside; adenosine analogue; uridine analogue; antiviral activity; cytostatic activity
Nucleoside analogues that inhibit the reverse transcrip- the inosine analogue 9, and the adenosine analogues 10 and
tase of human immunodeficiency virus (HIV) continue to be 11 (see Charts 1, 2)—have not been reported previously.
the cornerstone of AIDS therapy.1) Furthermore, although
Preparation of the uridine analogues was based on the
side effects limit the use of 3Ј-azido-3Ј-deoxythymidine propenoylurea variant of Shaw’s synthesis of pyrimidine-2,4-
(AZT), 2Ј,3Ј-dideoxyinosine (ddI) and 2Ј,3Ј-dideoxycytidine (1H,3H)-diones,20) to which end 3-ethoxypropenoyl iso-
(ddC),2—4) and resistance to single agents has emerged,5,6) nu- cyanate was prepared by means of a two-step procedure that
cleoside analogues are still the compounds attracting most at- for this kind of analogues has performed better21) than alter-
tention in the search for nontoxic agents capable of selec- native methods.22) Since the isocyanate is unstable, the result-
tively inhibiting the replication of HIV and other viruses. In ing reaction solution was added, without prior isolation of the
particular, carbocyclic analogues of nucleosides (CANs), isocyanate, to the amino alcohols 4 and 5. The resulting
which have no labile glycoside link between the base and the propenoylureas, 12 and 13, respectively, were then cyclized
carbocycle replacing the sugar of true nucleosides, could under conventional acidic conditions,22) affording compounds
offer an attractive in vivo stability advantage over the 2Ј,3Ј- 14 and 7 in practically quantitative yield. These compounds
dideoxynucleosides, as well as being more lipophilic (and were finally converted into their 5-iodo derivatives 6 and 8 by
hence potentially more readily absorbed) because of the re- treatment with iodine in a mixture of dioxane and nitric
placement of the endocyclic oxygen by a methylene group.
Among CANs with anti-HIV activity are the 2Ј,3Ј-unsatu-
acid.23)
Compounds 9—11 were prepared using standard chem-
rated compounds 2Ј,3Ј-didehydro-ddA,7) 2Ј,3Ј-didehydro- istry for purine CANs24) (Chart 1): amino alcohol 4 was con-
2Ј,3Ј-dideoxyguanosine (carbovir)8) (1) and abacavir densed with 5-amino-4,6-dichloropyrimidine, the resulting
(Ziagen® (2), which has better oral bioavailability and better diamine 15 was cyclized with ethyl orthoformate to obtain
penetration into the central nervous system than the other the key intermediate 16 (in 84% yield from 4), and this 9-
two and is currently being used in combination with other substituted 6-chloropurine was further transformed into the
antiretroviral drugs to treat HIV infection in adults.7,9—11)
final products in yields of 86—98%. Hydrolysis with 1 N HCl
However, reports of significant antiviral activity by nucleo- gave the inosine analogue 9; nucleophilic substitution by am-
side analogues with more than one hydroxymethyl group on monia gave the adenosine analogue 3; and treatment with cy-
the “sugar” ring (whether furan12,13) or cyclobutane14,15)) soon clopropylamine or isopropylamine in refluxing ethanol gave
led to investigation of a number of bis(hydroxymethyl)cyclo- the N-alkyladenosine analogues 10 and 11, respectively.
pentane derivatives.16—18) It was found that although (3S,4S)-
Using previously established procedures,25,26) the in vitro
and rac-bis(hydroxymethyl)cyclopentyl adenine 3 are inac- antiviral activities of compounds 6—11 were determined
tive against HIV-1,16,17) (3S,4S)-3 is active against type 1 her- against a variety of DNA and RNA viruses, and their cyto-
pes simplex virus (HSV-1), with an IC50 of less than toxicities for the host cell lines, were assayed in parallel with
0.0001 mg/ml.19)
In this work we extended the search for bis(hydroxy-
methyl)cyclopentanes with antiviral and antitumour activities
by preparing and screening seven that were chosen with a
view to analysing the influence of various structural parame-
ters on their biological activity. All these compounds were
prepared by construction of the heterocyclic base on the
amino group of either (Ϯ)-(1b,2a,4b)-4-amino-1,2-cyclo-
pentanedimethanol (4) or (Ϯ)-(1b,3a,4b)-4-amino-1,3-cy-
clopentanedimethanol (5). Six—the uridine analogues 6—8,
To whom correspondence should be addressed. e-mail: qojb@usc.es
© 2003 Pharmaceutical Society of Japan

September 2003
1061
the new compounds generally showed no activity against any
of these viruses. The antitumoral activities of compounds
6—11 were assayed against murine leukaemia cells
(L1210/0) and human T-lymphocytes (Molt4/C8 and CEM/0)
using procedures described elsewhere.26) The concentrations
required to reduce cell growth by 50% (IC50) were
Ͼ200 mg/ml in all cases.
Experimental
Melting points are uncorrected and were determined in a Reichert Kofler
Thermopan or in capillary tubes in a Büchi 510 apparatus. Infrared spectra
of samples in KBr discs (solids) or of films between NaCl plates (oils) were
recorded in a Perkin-Elmer 1640 FTIR spectrophotometer. 1H-NMR spectra
(300 MHz) and 13C-NMR spectra (75 MHz) were recorded in a Bruker AMX
300 spectrometer using tetramethylsilane (TMS) as internal reference
(chemical shifts in d values, J in Hz). Mass spectra were recorded on a
Kratos MS-59 spectrometer. Microanalyses were performed in a Perkin-
Elmer 240B element analyser by the Microanalysis Service of the University
of Santiago. Flash chromatography 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). Reagents and solvents were supplied by Aldrich Chemi-
cal Co. Starting materials 4 and 5 were prepared as previously described.27)
(؎)-(1b,2a,4b )-4-[(5-Amino-6-chloropyrimidin-4-yl)amino]-1,2-cy-
clopentanedimethanol (15) A solution of (Ϯ)-4 (0.1 g, 0.69 mmol), 5-
amino-4,6-dichloropyrimidine (0.17 g, 1.04 mmol) and triethylamine
(0.9 ml) in dry n-butanol (8 ml) was refluxed under argon for 48 h. After
cooling, the solvents were removed under reduced pressure and purification
of the residue by column chromatography with 10 : 1 CH2Cl2/MeOH as elu-
ent afforded (Ϯ)-15 as a viscous paste (0.19 g, 99%). IR (film) gmax: 3359,
3300, 2937, 1704, 1651, 1583, 1505, 1470, 1422, 1231 cmϪ1 1H-NMR
.
(DMSO-d6), as previously reported.16) 13C-NMR (DMSO-d6) d: 30.61 and
36.65 (C3ϩC5), 38.69 and 47.05 (C1ϩC2), 54.13 (C4), 63.04 (CH2O),
65.63 (CH2O), 123.71 (C5arom), 137.42 (C4arom), 145.82 (C2arom), 152.98
(C6arom). Electron impact (EI)-MS m/z (%): 273 (12, (Mϩ1)ϩ), 272 (30,
Mϩ), 256 (20), 241 (33), 144 (100), 127 (6). Anal. Calcd for C11H17ClN4O2:
C, 48.44; H, 6.28; Cl, 13; N, 20.54. Found: C, 48.55; H, 6.33; Cl, 12.88; N,
20.48.
(a) 5-Amino-4,6-dichloropyrimidine, n-BuOH, Et3N; (b) HC(OEt)3, 12 N HCl; (c)
1 N HCl, reflux; (d) 14 N NH4OH, reflux; (f) PrNH2, EtOH reflux; (g) ethoxypropenoyl
isocyanate, DMF, Ϫ15 °C; (h) 2 N H2SO4; (i) I2/HNO3.
i
Chart 1
(؎)-(1b,2a,4b)-4-(6-Chloro-9H-purin-9-yl)-1,2-cyclopentanedimethanol
(16) A mixture of (Ϯ)-15 (0.76 g, 2.79 mmol), triethyl orthoformate
(16.2 ml, 144.3 mmol) and 12 N HCl (0.84 ml) was stirred at room tempera-
ture for 18 h and then condensed to dryness under reduced pressure. The
residue was treated for 2 h with 0.5 N HCl (25 ml), this mixture was brought
to pH 7 with 1 N NaOH, the solvent was evaporated, and the semisolid
residue was chromatographed on silica gel with 10 : 1 CHCl3/MeOH as elu-
ent, affording (Ϯ)-16 as a viscous paste (0.67 g, 85%). IR (film) gmax: 3379,
1
2937, 1592, 1557, 1494, 1394, 1336, 1200 cmϪ1. H-NMR (DMSO-d6), as
previously reported.16) 13C-NMR (DMSO-d6) d: 29.99 and 36.08 (C3ϩC5),
38.74 and 45.33 (C1ϩC2), 58.90 (C4), 62.70 (CH2O), 65.28 (CH2O),
131.62 (C5arom), 147.10 (C8arom), 149.31 (C6arom), 151.49 (C2arom), 152.23
(C4arom). EI-MS m/z (%): 283 (1, (Mϩ1)ϩ), 282 (7, Mϩ), 251 (16), 222 (2),
181 (18), 155 (100), 119 (13). Anal. Calcd for C12H15ClN4O2: C, 50.98; H,
5.35; Cl, 12.54; N, 19.82. Found: C, 50.89; H, 5.39; Cl, 12.67; N, 19.68.
(؎)-6,9-Dihydro-9[(1b,3a,4b)-3,4-bis(hydroxymethyl)cyclopentyl]-
1H-purin-6-one (9) (Ϯ)-16 (0.15 g, 0.53 mmol) was refluxed for 4 h in 1 N
HCl (15 ml). After cooling, the solvent was removed under reduced pressure,
the solid residue (0.28 g) was suspended in water (10 ml), and this suspen-
sion was brought to pH 7 with 1 N NaOH. The solvents were then evapo-
rated, and the semisolid residue was chromatographed on silica gel with
10 : 3 CH2Cl2/MeOH as eluent, which afforded (Ϯ)-9 as a white solid
(0.12 g, 86%). An analytic sample was obtained by recrystallization from
ethanol. mp 208—210 °C. IR (KBr) gmax: 3384, 2868, 1694, 1591, 1546,
(a) Ethoxypropenoyl isocyanate, DMF, Ϫ15 °C; (b) 2 N H2SO4; (c) I2/HNO3.
Chart 2
those of standard drugs with known antiviral activities. The
viruses and cells used were type 1 herpes simplex virus
(strain KOS), type 2 herpes simplex virus (strain G), vaccinia
virus, vesicular stomatitis virus and thymidine-kinase-defi-
cient (TKϪ) KOS in E6SM cells; type 3 parainfluenza virus,
type 1 reovirus, Sindbis virus, Coxsackie B4 virus and Punta
Toro virus in Vero cells; respiratory syncytial virus in HeLa
1415, 1340, 1217 cmϪ1 1H-NMR (DMSO-d6) d: 1.73—1.76 (2H, m),
.
1.80—1.92 (1H, m), 2.20—2.29 (2H, m), 2.56—2.63 (1H, m), 3.34—3.49
(4H, m, 2ϫCH2O), 4.37—4.58 (3H, m, 1-Hϩ2ϫOH (D2O exchang.)), 8.07
and 8.22 (2H, 2s, (2-Hϩ8-H)arom), 12.30 (1H, br s, D2O exchang., 1-Harom).
cells; cytomegalovirus (strains AD-169 and DAVIS), vari- 13C-NMR (DMSO-d6) d: 35.46 and 41.85 (C2ϩC5), 44.03 and 51.07
(C3ϩC4), 63.04 (C1), 67.65 (CH2O), 70.61 (CH2O), 129.96 (C5arom),
cella zoster virus (strains OKA and YS) and thymidine-ki-
144.87 (C8arom), 150.69 (C4arom), 153.96 (C2arom), 162.31 (C6arom). EI-MS
nase-deficient (TKϪ) varicella zoster virus (strains 07/1 and
m/z (%): 265 (5, (Mϩ1)ϩ), 264 (33, Mϩ), 247 (3), 233 (21), 194 (18), 163
YS/R) in human embryonic lung (HEL) cells; and HIV-1 and
HIV-2 in human T-lymphocyte (CEM) cells (at compound
(26), 137 (100), 109 (25). Anal. Calcd for C12H16N4O3: C, 54.54; H, 6.10; N,
21.20. Found: C, 54.41; H, 5.99; N, 21.24.
(؎)-(1b,2a,4b)-4-(6-Amino-9H-purin-9-yl)-1,2-cyclopentanedimethanol
concentrations up to 100 mg/ml). At subtoxic concentrations

1062
Vol. 51, No. 9
(3) (Ϯ)-16 (0.24 g, 0.85 mmol) was refluxed for 15 min in concentrated Jϭ12.34 Hz, CHϭCH), 7.39 (1H, d, Jϭ12.29 Hz, CHϭCH), 8.43 (1H, d,
NH4OH (29 ml). After cooling, the solvent was removed under reduced pres- Jϭ6.71 Hz, D2O exchang., CONHCH), 9.84 (1H, br s, D2O exchang., CON-
sure and the residue was chromatographed on silica gel with 4 : 1 HCO). 13C-NMR (DMSO-d6) d: 14.50 (CH3), 30.24 and 36.51 (C2ϩC5),
EtOAc/MeOH as eluent, which afforded (Ϯ)-3 as a white solid (0.2 g, 91%).
38.63 and 47.67 (C3ϩC4), 52.52 (C1), 62.90 (CH2OH), 65.33 (CH2OH),
An analytic sample was obtained by recrystallization from ethanol. mp 67.34 (CH2O), 98.46 (COCH), 153.63 (NHCONH), 162.08 (EtOCH),
182—184 °C (lit.16) mp 182—183 °C). IR (KBr) gmax: 3370, 3254, 2933, 167.86 (NHCOCH). EI-MS m/z (%): 287 (1, (Mϩ1)ϩ), 286 (3, Mϩ), 211
1
1684, 1614, 1570, 1477, 1308, 1217 cmϪ1. H-NMR (DMSO-d6), as previ- (9), 159 (37), 99 (100), 71 (62). Anal. Calcd for C13H22N2O5: C, 54.53; H,
ously reported.16) 13C-NMR (DMSO-d6) d: 30.29 and 36.10 (C3ϩC5), 38.77 7.74; N, 9.78. Found: C, 54.68; H, 7.67; N, 9.90.
and 45.54 (C1ϩC2), 57.54 (C4), 62.42 (CH2O), 65.45 (CH2O), 119.23
(؎)-1-[(1b,3a,4b)-3,4-bis(Hydroxymethyl)cyclopentyl]-1,2,3,4-
(C5arom), 140.33 (C8arom), 149.20 (C4arom), 152.42 (C2arom), 156.32 (C6arom). tetrahydropyrimidine-2,4-dione (14) To a solution of (Ϯ)-12 (0.22 g,
EI-MS m/z (%): 264 (7, (Mϩ1)ϩ), 263 (44, Mϩ), 246 (38), 232 (52), 162
0.77 mmol) in dioxane (11 ml) was added 2 N H2SO4 (14 ml), and this mix-
(61), 136 (100), 108 (46). Anal. Calcd for C12H17N5O2: C, 54.74; H, 6.51; N, ture was refluxed for 30 min, allowed to cool, brought to pH 7 with
26.60. Found: C, 54.81; H, 6.65; N, 26.48.
2 N NaOH, and concentrated to dryness. The residue was extracted with
(؎)-(1b,2a,4b)-4-(6-Cyclopropylamino-9H-purin-9-yl)-1,2-cyclopen-
ethanol (3ϫ30 ml), and concentration of the extracts left a residue that upon
tanedimethanol (10) A mixture of (Ϯ)-16 (0.19 g, 0.67 mmol) and cyclo- purification on silica gel with 5 : 1 EtOAc/MeOH as eluent afforded (Ϯ)-14
propylamine (0.49 ml, 7.08 mmol) in dry ethanol (15 ml) was refluxed under (0.18 g, 97%) as a viscous paste. IR (film) gmax: 3382, 3100, 2939, 1684,
argon for 5 h and then condensed to dryness. The resulting residue was chro- 1466, 1385, 1268 cmϪ1. 1H-NMR (DMSO-d6), as previously reported.18) 13C-
matographed on silica gel with 4 : 1 EtOAc/MeOH as eluent, which afforded NMR (DMSO-d6) d: 30.15 and 34.58 (C2ϩC5), 38.08 and 44.39 (C3ϩC4),
(Ϯ)-10 as a white solid (0.2 g, 98%). An analytic sample was obtained by re- 58.56 (C1), 63.00 (CH2O), 65.37 (CH2O), 101.62 (CHϭCH), 143.12
crystallization from 3 : 1 EtOAc/ether. mp 78—80 °C. IR (KBr) gmax: 3258, (CHϭCH), 153.22 (NCONH), 163.21 (NHCOCH). EI-MS m/z (%): 241 (6,
3105, 2930, 2344, 1618, 1527, 1440, 1381, 1236, 1130 cmϪ1 1H-NMR (Mϩ1)ϩ), 240 (15, Mϩ), 192 (4), 151 (5), 113 (100). Anal. Calcd for
.
(DMSO-d6) d: 0.56—0.65 (2H, m, cyclopropyl CH2), 0.67—0.73 (2H, m, C11H16N2O4: C, 54.99; H, 6.71; N, 11.66. Found: C, 55.11; H, 6.80; N,
cyclopropyl CH2), 1.64—1.75 (2H, m), 1.89—1.93 (1H, m), 2.11—2.21
(2H, m), 2.59—2.61 (1H, m), 2.95—3.11 (1H, m), 3.27—3.33 (2H, m,
CH2O), 3.39—3.41 (2H, m, CH2O), 4.54—4.63 (3H, m, 4-Hϩ2ϫOH (D2O
exchang.)), 7.80—7.81 (1H, m, NH), 8.19 and 8.21 (2H, 2s, (2-Hϩ8-
11.60.
(؎)-1-[(1b,3a,4b)-3,4-bis(Hydroxymethyl)cyclopentyl]-5-iodo-1,2,3,4-
tetrahydropyrimidine-2,4-dione (6) mixture of (Ϯ)-14 (0.12 g,
0.5 mmol), dioxane (8 ml), I2 (0.26 g, 1.02 mmol) and 0.75 N HNO3 (0.68 ml)
A
H)arom). 13C-NMR (DMSO-d6) d: 7.81 (CH2–CH2), 23.94 (CHNH), 30.29 was refluxed for 2.5 h. After cooling, the solvents were removed under re-
and 36.10 (C3ϩC5), 38.77 and 45.55 (C1ϩC2), 57.56 (C4), 62.45 (CH2O), duced pressure and the residue was chromatographed on silica gel with
65.47 (CH2O), 120.01 (C5arom), 140.13 (C8arom), 149.11 (C6arom), 152.33 50 : 1 EtOAc/MeOH as eluent, which afforded (Ϯ)-6 (0.14 g, 78%) as a
(C2arom), 155.92 (C4arom). EI-MS m/z (%): 304 (13, (Mϩ1)ϩ), 303 (70, Mϩ), white solid that was washed with ether. mp 116—118 °C. IR (KBr) gmax
288 (100), 174 (47), 160 (77). Anal. Calcd for C15H21N5O2: C, 59.39; H,
6.98; N, 23.09. Found: C, 59.45; H, 6.87; N, 23.18.
:
3424, 1684, 1457, 1302, 1026 cmϪ1 1H-NMR (DMSO-d6) d: 1.42—1.68
.
(3H, m), 1.92—2.11 (2H, m), 2.21—2.41 (1H, m), 2.98—3.03 (2H, m,
(؎)-(1b,2a,4b)-4-(6-N-Isopropylamino-9H-purin-9-yl)-1,2-cyclopen-
CH2O), 3.08—3.12 (2H, m, CH2O), 4.48—4.56 (3H, m, 1-Hϩ2ϫOH (D2O
tanedimethanol (11) A mixture of (Ϯ)-16 (0.19 g, 0.67 mmol) and iso- exchang.)), 8.15 (1H, s, CHϭCI), 11.54 (1H, br s, D2O exchang., CON-
propylamine (0.5 ml, 7.63 mmol) in dry ethanol (15 ml) was refluxed under HCO). 13C-NMR (DMSO-d6) d: 30.01 and 34.55 (C2ϩC5), 38.03 and 44.31
argon for 8 h and then condensed to dryness under reduced pressure. The re- (C3ϩC4), 59.61 (C1), 63.19 (CH2O), 65.41 (CH2O), 68.93 (CI), 147.51
sulting residue was chromatographed on silica gel with 20 : 3 EtOAc/MeOH (CIϭCH), 150.90 (NCONH), 160.87 (NHCOCI). EI-MS m/z (%): 367 (53,
as eluent, which afforded (Ϯ)-11 as a white solid (0.19 g, 95%). An analytic (Mϩ1)ϩ), 366 (96, Mϩ), 336 (46), 274 (37), 239 (100), 195 (99), 128 (14),
sample was obtained by precipitation with ether. mp 135—136 °C. IR (KBr) 110 (98). Anal. Calcd for C11H15IN2O4: C, 36.08; H, 4.13; I, 34.66; N, 7.65.
g
max: 3348, 3258, 2967, 2867, 1614, 1574, 1471, 1404, 1365, 1297,
1164 cmϪ1 1H-NMR (DMSO-d6) d: 1.12 (6H, d, Jϭ6.49 Hz, 2ϫCH3),
1.58—1.79 (2H, m), 1.84—1.95 (1H, m), 2.08—2.21 (2H, m), 2.57—2.65
Found: C, 35.95; H, 4.30; I, 34.54; N, 7.76.
(؎)-N-[(1b,2a,4b)-2,4-bis(Hydroxymethyl)cyclopentyl]-N؅-(3-
ethoxypropenoyl)urea (13) A solution of 3-ethoxypropenoyl isocyanate
.
(1H, m), 3.25—3.27 (2H, m, CH2O), 3.35—3.37 (2H, m, CH2O), 4.19— in benzene (14 ml, theoretically containing 5.79 mmol) was added dropwise
4.34 (1H, m, CH(CH3)2), 4.53—4.69 (3H, m, 4-Hϩ2ϫOH (D2O exchang.)), under argon to a solution of (Ϯ)-5 (0.55 g, 3.79 mmol) in dry DMF (18 ml)
7.37 (1H, d, Jϭ8.12 Hz, NH), 8.07 and 8.11 (2H, 2s, (2-Hϩ8-H)arom). 13C- at Ϫ15 °C. A procedure analogous to that used to obtain (Ϯ)-12 left a
NMR (DMSO-d6) d: 23.51 (2ϫCH3), 30.29 and 36.12 (C3ϩC5), 38.73 and residue that upon purification by column chromatography afforded (Ϯ)-13
45.55 (C1ϩC2), 42.23 (CH(CH3)2), 57.53 (C4), 62.46 (CH2O), 65.46 (0.55 g, 51%) as a white solid. mp 113—115 °C. IR (KBr) gmax: 3280, 3089,
1
(CH2O), 120.02 (C5arom), 139.88 (C8arom), 149.13 (C6arom), 152.52 (C2arom), 2985, 1673, 1607, 1547, 1347, 1243, 1176, 1120 cmϪ1. H-NMR (DMSO-
154.32 (C4arom). EI-MS m/z (%): 306 (6, (Mϩ1)ϩ), 305 (30, Mϩ), 288 (32), d6) d: 1.19—1.22 (1H, m), 1.24 (3H, t, Jϭ7.02 Hz, CH3), 1.52—1.57 (1H,
274 (33), 177 (50), 162 (100), 135 (55). Anal. Calcd for C15H23N5O2: C,
m), 1.65—1.75 (2H, m), 1.79—1.84 (1H, m), 2.00—2.04 (1H, m), 3.27—
59.00; H, 7.59; N, 22.93. Found: C, 58.88; H, 7.46; N, 22.79.
3.36 (4H, m, 2ϫCH2O), 3.93 (2H, c, Jϭ7.13 Hz, CH2CH3), 3.99—4.01 (1H,
(؎)-N-[(1b,3a,4b)-3,4-bis(Hydroxymethyl)cyclopentyl]-N؅-(3- m, 1-H), 4.60—4.66 (2H, m, D2O exchang., 2ϫOH), 5.48 (1H, d,
ethoxypropenoyl)urea (12) Dry benzene (321 ml) was added in the dark, Jϭ12.92 Hz, CHϭCH), 7.54 (1H, d, Jϭ12.31 Hz, CHϭCH), 8.52 (1H, d,
under argon, to silver cyanate (48 g) that had previously been dried in vacuo
Jϭ7.38 Hz, D2O exchang., CONHCH), 9.99 (1H, br s, D2O exchang., CON-
over P2O5 at 100 °C. The resulting suspension was refluxed with vigorous HCO). 13C-NMR (DMSO-d6) d: 14.89 (CH3), 36.62 and 36.88 (C3ϩC5),
stirring for 30 min, after which a solution of 3-ethoxypropenoyl chloride 43.04 and 43.36 (C2ϩC4), 49.74 (C1), 64.74 (CH2OH), 65.00 (CH2OH),
(19.28 g, 160 mmol) in dry benzene (60 ml) was added dropwise. The result- 67.58 (CH2O), 98.72 (COCH), 153.72 (NHCONH), 162.30 (EtOCH),
ing mixture was refluxed with vigorous stirring for a further 30 min, vigor- 167.92 (NHCOCH). EI-MS m/z (%): 287 (1, (Mϩ1)ϩ), 286 (4, Mϩ), 257
ously stirred at room temperature for 3 h, and then left to settle. A sample of (11), 144 (45), 99 (100), 71 (67). Anal. Calcd for C13H22N2O5: C, 54.53; H,
the supernatant (16 ml, theoretically containing 6.62 mmol of 3- 7.74; N, 9.78. Found: C, 54.45; H, 7.88; N, 9.66.
ethoxypropenoyl isocyanate) was transferred to a dropping funnel and added
dropwise under argon to a solution of (Ϯ)-4 (0.64 g, 4.41 mmol) in dry DMF
(؎)-1-[(1b,2a,4b)-2,4-bis(Hydroxymethyl)cyclopentyl]-1,2,3,4-
tetrahydropyrimidine-2,4-dione (7) Crude (Ϯ)-7 was obtained from a so-
(21 ml) at Ϫ15 °C. The resulting mixture was left for 1 h to reach room tem- lution of (Ϯ)-13 (0.19 g, 0.66 mmol) in dioxane (8 ml) and 2 N H2SO4
perature and was then stirred overnight and concentrated under reduced (11 ml) by a procedure analogous to that described for the preparation of
pressure (oil pump) at a temperature below 40 °C. Removal of the solvents (Ϯ)-14 from (Ϯ)-12, and upon chromatography on silica gel afforded pure
by repeated co-evaporation with ethanol left a solid that when chro- (Ϯ)-7 (0.15 g, 94%) as a white solid. mp 141—142 °C. IR (KBr) gmax: 3326,
1
matographed on silica gel with 30 : 1 EtOAc/MeOH as eluent afforded com- 3042, 2881, 1683, 1465, 1393, 1268, 1198, 1080 cmϪ1. H-NMR (DMSO-
pound (Ϯ)-12 (0.58 g, 46%) as a white solid. An analytic sample was ob- d6) d: 1.45—1.56 (1H, m), 1.70—1.80 (3H, m), 1.94—2.02 (2H, m), 3.23—
tained by recrystallization from 4 : 1 cyclohexane/EtOAc. mp 92—95 °C. IR 3.46 (4H, m, 2ϫCH2O), 4.67—4.78 (3H, m, 1-Hϩ2ϫOH (D2O exchang.)),
(KBr) gmax: 3252, 3100, 2936, 1681, 1610, 1557, 1499, 1396, 1346, 1253, 5.56 (1H, d, Jϭ7.92 Hz, CHϭCH), 7.71 (1H, d, Jϭ7.97 Hz, CHϭCH),
1
1169, 1133 cmϪ1. H-NMR (DMSO-d6) d: 0.97—1.06 (1H, m), 1.10 (3H, t, 11.18 (1H, br s, D2O exchang., CONHCO). 13C-NMR (DMSO-d6) d: 34.80
Jϭ7.01 Hz, CH3), 1.31—1.42 (2H, m), 1.62—1.75 (1H, m), 1.83—2.05 and 36.45 (C3ϩC5), 44.33 and 45.17 (C2ϩC4), 57.03 (C1), 66.16 (CH2O),
(2H, m), 3.11—3.28 (4H, m, 2ϫCH2O), 3.52—3.68 (1H, m, 1-H), 3.79 (2H,
66.44 (CH2O), 102.97 (CHϭCH), 144.31 (CHϭCH), 153.89 (NCONH),
c, Jϭ7.04 Hz, CH2CH3), 4.35 (2H, br s, D2O exchang., 2ϫOH), 5.63 (1H, d, 166.75 (NHCOCH). EI-MS m/z (%): 241 (8, (Mϩ1)ϩ), 240 (19, Mϩ), 210

September 2003
1063
(17), 192 (66), 148 (6), 113 (100). Anal. Calcd for C11H16N2O4: C, 54.99; H,
6.71; N, 11.66. Found: C, 55.12; H, 6.79; N, 11.57.
Schultz R. H., Narayanan V. L., Mayo J. G., Shoemaker R. H., Boyd
M. R., Biochem. Biophys. Res. Commun., 156, 1046—1053 (1988).
9) Faletto M. B., Miller W. H., Garvey E. P., St Clair M. H., Daluge S.
M., Good S. S., Antimicrobs. Agents Chemother., 41, 1099—1107
(1977).
(؎)-1-[(1b,2a,4b)-2,4-bis(Hydroxymethyl)cyclopentyl]-5-iodo-1,2,3,4-
tetrahydropyrimidine-2,4-dione (8)
A
mixture of (Ϯ)-7 (0.14 g,
0.58 mmol), dioxane (9 ml), I2 (0.3 g, 1.18 mmol) and 0.75 N HNO3 (0.8 ml)
was refluxed for 3 h. After cooling, the solvents were removed under reduced 10) Graul A., Leeson P. A., Castaner J., Drugs Fut., 23, 1155—1167
pressure and the residue was chromatographed on silica gel with 50 : 1 (1998).
EtOAc/MeOH as eluent, which afforded (Ϯ)-8 (0.17 g, 85%) as a white 11) Foster R. H., Faulds D., Drugs, 55, 729—736 (1998).
solid. mp 80—82 °C. IR (KBr) gmax: 3433, 3404, 2927, 1684, 1604, 1448,
1345, 1271, 1044 cmϪ1 1H-NMR (DMSO-d6) d: 1.57—1.61 (1H, m),
1.74—1.78 (3H, m), 1.81—1.98 (2H, m), 3.33—3.43 (4H, m, 2ϫCH2O),
12) Tseng C. K.-H., Marquez V. E., Milne G. W. A., Wysocki R. J., Mit-
suya H., Shirasaki T., Driscoll J. S., J. Med. Chem., 34, 343—349
(1991).
.
4.64—4.72 (3H, m, 1-Hϩ2ϫOH (D2O exchang.)), 8.16 (1H, s, CHϭCI), 13) Bamford M. J., Coe P. L., Walker R. T., J. Med. Chem., 33, 2494—
11.57 (1H, br s, D2O exchang., CONHCO). 13C-NMR (DMSO-d6) d: 33.55
2501 (1990).
and 35.01 (C3ϩC5), 42.14 and 42.90 (C2ϩC4), 55.39 (C1), 64.36 (CH2O), 14) Nishiyama Y., Yamamoto N., Takahashi K., Shimada N., Antimicrob.
64.48 (CH2O), 69.11 (CI), 146.89 (CIϭCH), 150.57 (NCONH), 160.75
(NHCOCI). EI-MS m/z (%): 367 (4, (Mϩ1)ϩ), 366 (29, Mϩ), 336 (4), 239
(100), 195 (31). Anal. Calcd for C11H15IN2O4: C, 36.08; H, 4.13; I, 34.66; N,
7.65. Found: C, 36.17; H, 4.01; I, 34.52; N, 7.73.
Agents Chemother., 32, 1053—1056 (1988).
15) Norbeck D. W., Kern E., Hagashi S., Rosenbrook W., Sham H., Herrin
T., Plattner J. J., Erickson J., Clement J., Swanson R., Shipkowitz N.,
Hardy D., Marsh K., Arnett G., Shannon W., Broder S., Mitsuya H., J.
Med. Chem., 33, 1281—1285 (1990).
Acknowledgements The authors thank the Xunta de Galicia for 16) Boumchita H., Legraverend M., Bisagni E., Heterocycles, 32, 1785—
financial
support
under
projects
PGIDT01PXI20302PR
and
1792 (1991).
PGIDT02BTF20305PR.
17) Janson M., Svansson L., Svensson S. C. T., Kvarnstrom I., Nucleosides
& Nuleotides, 11, 1739—1747 (1992).
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