Synthesis, antiviral and cytostatic activities, of carbocyclic nucleosides incorporating a modified cyclopentane ring. IV. Adenosine and uridine analogues

Article abstract of DOI:10.1081/NCN-120003289

Eight new carbocyclic nucleosides were prepared by mounting a purine (compounds 8-10), 8-azapurine (12 and 13) or pyrimidine (15, 16 and 17b) on the amino group of (1S,3R)-3-aminomethyl-2,2,3-trimethylcyclopentylmethanol (6). All the compounds were evaluated as antiviral and antitumor agents in a variety of assay systems. Only compound 8 showed any cytostatic activity against the tumor cell lines examined.

Full text of DOI:10.1081/NCN-120003289

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SYNTHESIS, ANTIVIRAL AND CYTOSTATIC ACTIVITIES,
OF CARBOCYCLIC NUCLEOSIDES INCORPORATING A
MODIFIED CYCLOPENTANE RING. IV. ADENOSINE AND
URIDINE ANALOGUES
M. Isabel Nieto a , Olga Caamaño a , Franco Fernández a , María Gómez a , Jan Balzarini b &
Erik De Clercq b
a Departamento de Química Orgánica , Facultad de Farmacia , Universidad de Santiago ,
E-15782, Santiago de Compostela, Spain
b Rega Institute for Medical Research , Katholieke Universiteit Leuven , Leuven, B-3000,
Belgium
Published online: 17 Aug 2006.
To cite this article: M. Isabel Nieto , Olga Caamaño , Franco Fernández , María Gómez , Jan Balzarini & Erik De Clercq
(2002) SYNTHESIS, ANTIVIRAL AND CYTOSTATIC ACTIVITIES, OF CARBOCYCLIC NUCLEOSIDES INCORPORATING A MODIFIED
CYCLOPENTANE RING. IV. ADENOSINE AND URIDINE ANALOGUES, Nucleosides, Nucleotides and Nucleic Acids, 21:3, 243-255,
DOI: 10.1081/NCN-120003289
To link to this article: http://dx.doi.org/10.1081/NCN-120003289
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 21(3), 243–255 (2002)
SYNTHESIS, ANTIVIRAL AND CYTOSTATIC
ACTIVITIES, OF CARBOCYCLIC NUCLEOSIDES
INCORPORATING A MODIFIED
CYCLOPENTANE RING. IV. ADENOSINE
AND URIDINE ANALOGUES
M. Isabel Nieto,1 Olga Caamano,1,* Franco Fernandez,1 Marıa
Gomez,1 Jan Balzarini,2 and Erik De Clercq2
1Departamento de Quımica Organica, Facultad de Farmacia,
Universidad de Santiago, E-15782-Santiago de Compostela, Spain
2Rega Institute for Medical Research, Katholieke Universiteit
Leuven, B-3000 Leuven, Belgium
ABSTRACT
Eight new carbocyclic nucleosides were prepared by mounting a purine
(compounds 8^10), 8-azapurine (12 and 13) or pyrimidine (15, 16 and
17b) on the amino group of (1S,3R)-3-aminomethyl-2,2,3-trimethyl-
cyclopentylmethanol (6). All the compounds were evaluated as antiviral
and antitumor agents in a variety of assay systems. Only compound 8
showed any cytostatic activity against the tumor cell lines examined.
INTRODUCTION
The development of nontoxic selective inhibitors of kinases and poly-
merases for control of viral diseases has been the focus of intense research1.
Despite significant progress, there is still a need for new viral replication
inhibitors, especially for the treatment of infection by human immunodefi-
ciency virus (HIV), herpes simplex virus (HSV), Epstein-Barr virus (EBV),
human cytomegalovirus (CMV) and hepatitis B virus (HBV). Nucleoside
analogues that are good substrates for cellular kinases but are resistant to
243
Copyright # 2002 by Marcel Dekker, Inc.
www.dekker.com

244
NIETO ET AL.
other host enzymes, such as phosphorylases, are essential for the develop-
ment of useful therapeutic agents.
The anomeric centre of natural nucleosides is essential for their con-
formational behaviour, and hence for their biological properties. One way of
eliminating this centre is to replace the endocyclic oxygen of the nucleoside
sugar moiety with a methylene unit. The resulting carbocyclic nucleoside
analogues have biological properties and structure-activity relationships that
differ radically from those of the starting furanose nucleosides2: in particular,
they are highly resistant to phosphorylases3 and have shown significant
antiviral and antitumoral activity4, including the inhibition of HIV replica-
tion by carbovir (1)5and abacavir (2)6.
The anomeric centre of natural nucleosides is also eliminated if a
methylene unit is introduced between the sugar ring and the base, giving rise
to homo-N-nucleosides (3). Guanine- and adenine-based members of this
class have been found to possess selective activity against type 1 and type 2
herpes simplex viruses7.
Both the above structural modifications – inclusion of a methylene
between sugar and base, and substitution of a methylene for endocyclic
oxygen of the sugar – are present in a number of trimethylcyclopentane
derivates 4 that we have found to possess moderate antiviral or cytostatic
activities8,9. To explore further the dependence of biological activity on
structural characteristics in derivatives of this kind, we have now synthesized
trimethylcyclopentane derivatives of type 5 and screened them for antiviral
and cytostatic activity. In these compounds the distance between the
hydroxymethyl oxygen and the pseudoglycosidic nitrogen is the same as in
compounds 4, but the absolute configuration of the pseudosugar moiety is
different (also, the non-geminal methyl group now lies on the a face instead
of the b face, but this not thought to be relevant).
RESULTS AND DISCUSSION
The carbocyclic homo-N-nucleosides here described were prepared by
construction of adenine, 8-azaadenine or uracil on the amino group of
amino alcohol 610 using the classical approach to carbonucleosides11–13
.
The first step in the preparation of the adenosine and 8-azaadenosine
analogues (Sch. 1) was condensation of 6 with 5-amino-4,6-dichloropyr-
imidine, which afforded diamine 7. Cyclization of this diamine with triethyl
orthoformate gave the 9-substituted-6-chloropurine 8, which was hydro-
lysed with dilute sodium hydroxide to the inosine analogue 9 or converted
to adenosine analogue 10 by heating in concentrated aqueous ammonia. To
obtain the corresponding 8-aza analogues, the triazole ring was formed by
diazotation of 7 with sodium nitrite in acetic acid, which afforded the
highly reactive 6-chloro-8-azapurine cyclization product 11 (not isolated).

CARBOCYCLIC NUCLEOSIDES. IV
245
Scheme 1.

246
NIETO ET AL.
This was converted to 8-azainosine analogue 12 by simply stirring the crude
reaction mixture at room temperature for 72 h, and to the 8-azaadenine
analogue 13 by treatment with concentrated aqueous ammonia followed by
4 h refluxing.
The uridine analogue 15 was obtained by a route based on the acry-
loylurea variant14 of the Shaw synthesis of 2,4-(1H,3H )-pyrimidinediones
(Sch. 2). Briefly, 3-ethoxypropenoyl isocyanate (prepared and used under
rigorously anhydrous conditions)15 was reacted with 6 to obtain the acry-
loylurea 14, which was then cyclized by refluxing in a basic medium,
affording 15 in 70% yield. The 5-iodouracil derivative 16 was prepared by the
method of Prusoff16, by treatment of the uracil 15 with iodine in dioxan in
the presence of nitric acid. The 5-bromouracil derivative 17b was prepared by
procedures similar to those used by Visser17 for the preparation of 5-bromo-
20-deoxyuridine (BrdUrd), by bromination of 15 in acetic anhydride and
deacylation of 17a.
The new carbocyclic nucleosides 8^10, 12, 13, 15, 16 and 17b were
evaluated for their antiviral activity in a wide variety of assay systems, as
follows.
At compound concentrations up to 400 mg=mL: type 1 herpes simplex
virus (strain KOS), type 2 herpes simplex virus (strain G), vaccinia virus and
Scheme 2.

CARBOCYCLIC NUCLEOSIDES. IV
247
vesicular stomatitis virus in human embryonic skin-muscle fibroblasts
(E6SM); vesicular stomatitis virus, respiratory syncytial virus and Coxsackie
B4 virus in human epithelial (HeLa) cells; and type 3 parainfluenza virus,
type 1 reovirus, sindbis virus, Coxsackie B4 and Punta Toro virus in African
green monkey (Vero) kidney cells. Brivudine, and ribavirin, acyclovir and
ganciclovir and=or (S)-9-(2,3-dihydroxypropyl)adenine were used in parallel
tests as reference drugs.
At compound concentrations up to 100 mg=mL: human immuno-
deficiency virus (HIV) (types 1 and 2) in CEM=0 T-lymphocytes (cytoxicity
against host cells was also evaluated).
At compound concentrations up to 50 mg=mL: cytomegalovirus (CMV,
strains AD-169 and DAVIS) and varicella-zoster virus (VZV, strains OKA,
YS, 07=1 and YS=R) in human embryonic lung (HEL) cells. Cidofovir and
ganciclovir, or brivudine and acyclovir, were used in parallel tests as refer-
ence drugs.
At subtoxic concentrations the new compounds generally showed no
activity or only marginal activity against the viruses tested. In tests of
cytostatic activity against tumour cell lines the most active compound was 8,
which was moderately effective in inhibiting the proliferation of human
T-lymphocytes [CEM (14 Æ 3 mg=mL) and MOLT 4=C8(9 Æ 1 mg=mL)] and
murine leukemia cells [L1210 (13 Æ 7 mg=mL)].
In conclusion, comparison of the above results with those obtained
previously for the corresponding isomeric compounds 49 suggests that quasi-
inversion of absolute configuration of the pseudosugar moiety eliminates
antiviral activity, and that among these carbocyclic homo-N-nucleosides
cytostatic activity is possessed by 6-chloropurines (regardless of carbocycle
structure) but no other members of this class.
EXPERIMENTAL SECTION
Silica gel (230 mesh) was purchased from Merck. All other chemicals
used were of reagent grade and were obtained from Aldrich Chemical Co.
Melting points were measured on a Reichert Kofler thermopan and are
uncorrected. Na D line polarimetry was carried out at 25ꢀC in a Perkin-
Elmer 241 polarimeter. Infrared spectra were recorded in a Perkin-Elmer
1
1640 FTIR spectrophotometer, H and 13C NMR spectra in a 300 MHz
Bruker AMX 300 spectrometer, and mass spectra on a Kratos MS-59
spectrometer.
(1)-(1S,3R)-3-[(5-Amino-6-chloropyrimidin-4-yl)aminomethyl]-2,2,3-tri-
methylcyclopentylmethanol (7). A solution of aminoalcohol 6 (0.73 g,
4.27 mmol) and 5-amino-4,6-dichloropyrimidine (0.87 g, 5.33 mmol) in dry
n-BuOH (40 mL) and dry Et3N (4.36 mL) was refluxed under argon for

248
NIETO ET AL.
72 h. Evaporation of the solvents under vacuum left 2.47 g of a residue
that was purified by column chromatography on silica gel with 15:1
CH2Cl2=MeOH and then pure MeOH as eluents, affording 7 as a
yellowish solid (0.94 g, 74%) that was recrystallized twice from AcOEt
25
containing active carbon as decolorant. Mp. 195–196ꢀC. [a]D þ31.3 (c
0.49; MeOH). IR (KBr) n (cmÀ1): 3344, 2960, 1579, 1458, 1433, 1362,
1
1296, 1087, 1057, 1024, 998, 893, 772. H NMR (DMSO-d6) d (ppm): 7.63
(s, 1H, pyrimidine 2-H); 6.28(t, 1H, J ¼ 5.79 Hz, D2O exchang., NH); 5.12
(s, 2H, D2O exchang., NH2); 4.25 (t, 1H, J ¼ 4.90 Hz, D2O exchang., OH);
3.51–3.42 (m, 2H); 3.28–3.24 (m, 2H); 1.97–1.94 (m, 1H); 1.76–1.67 (m,
2H); 1.37–1.29 (m, 2H); 0.92 (s, 3H, CH3); 0.88 (s, 3H, CH3), 0.77 (s, 3H,
CH3). 13C NMR (DMSO-d6) d (ppm): 152.96 (pyrimidine C6); 145.80
(pyrimidine C2); 137.18(pyrimidine C4); 123.75 (pyrimidine C5); 63.22
(OCH2); 49.83; (C1); 48.14 (C2); 46.82 (NCH2); 44.17 (C3); 34.79 (C4);
25.60 (C5); 23.86 (CH3); 20.97 (CH3); 18.57 (CH3). Anal. Calcd. for
C14H23ClN4O: C, 56.27, H, 7.76, N, 18.75. Found: C, 56.41, H, 8.01, N,
18.99.
(1)-(1S,3R)-3-(6-Chloro-9H-purin-9-ylmethyl)-2,2,3-trimethylcyclopentyl-
methanol (8). A mixture of 7 (0.84 g, 2.82 mmol), triethyl orthoformate
(15.50 mL, 138.11 mmol) and 12N HCl (0.19 mL) was stirred at room
temperature for 17 h and then concentrated under vacuum to obtain a
residue that was treated with 0.5 N HCl (59 mL) for 3 h at room
temperature. The resulting solution was brought to pH 8with 1N NaOH,
and evaporation of the solvents under reduced pressure left a residue that
was taken into MeOH (12 mL) and filtered to remove undissolved NaCl.
Evaporation of the MeOH under vacuum left a yellow solid (1.38g) that
upon purification by column chromatography on silica gel using 30:1
CH2Cl2=MeOH as eluent afforded 8 as a white solid (0.58g, 65%) that
25
was recrystallized from 2:1 hexane=EtOAc. Mp 153–155ꢀC. [a]D þ28.54 (c
0.48; MeOH). IR (KBr) n (cmÀ1): 3355, 2964, 2908, 2871, 1600, 1561,
1
1403, 1341, 1241, 1214, 944, 650. H NMR (DMSO-d6) d (ppm): 8.77 and
8.67 (2s, 2H, purine 2-Hþ8-H); 4.34 (s, 1H, D2O exchang., OH); 4.23 (s,
2H, NCH2); 3.50 (dd, 1H, J ¼ 10.28Hz, J ¼ 6.12 Hz, OCHH); 3.34–3.28(m,
1H, OCHH); 2.13–1.94 (m, 2H), 1.79–1.66 (m, 1H); 1.36–1.21 (m, 1H);
1.14–1.06 (m, 1H); 0.99 (s, 3H, CH3); 0.89 (s, 3H, CH3); 0.66 (s, 3H, CH3).
13C NMR (DMSO-d6) d (ppm): 153.06 (purine C4); 151.79 (purine C2);
149.40 (purine C6); 148.68 (purine C8); 130.71 (purine C5); 63.00 (OCH2);
50.33 (NCH2); 49.30 (C1); 49.06 (C2); 44.64 (C3); 35.03 (C4); 25.36 (C5);
þ
23.04 (CH3); 20.70 (CH3); 18.40 (CH3). EIMS m=z (%): 308(10, M ); 209
(20); 207 (11); 170 (23); 169 (14); 168(67); 167 (20); 157 (32); 155 (100);
123 (39); 95 (15); 81 (39); 79 (17); 77 (10); 71 (12); 69 (32); 68 (15); 67 (30);
58(17); 57 (18); 55 (36). Anal. Calcd. for C 15H21ClN4O: C, 58.34, H, 6.85,
N, 18.14. Found: C, 58.49, H, 6.98, N, 18.23.

CARBOCYCLIC NUCLEOSIDES. IV
249
(1)-(1R,3S)-6,9-Dihydro-9-[3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl-
methyl]-1H-purin-6-one (9). A mixture of 8 (0.53 g, 1.72 mmol) and 0.33N
NaOH (37 mL) was refluxed for 6.5 h. Subsequent concentration to dryness
by evaporation of the solvent afforded 1.65 g of a yellow solid that upon
purification by column chromatography on silica gel (41 g) with successive
30:1 and 10:1 mixtures of CH2Cl2 and MeOH as eluents gave 9 as a white
solid (0.44 g, 90%) that was recrystallized from MeOH, mp 286–288ꢀC.
25
[a]D þ35.46 (c 0,52; MeOH). IR (KBr) n (cmÀ1): 3219, 2967, 1676, 1576,
1
1541, 1508, 1458, 1026. H NMR (DMSO-d6) d (ppm): 12.23 (s, 1H, D2O
exchang., purine 1-H); 8.02 (2s, 2H, purine 2-Hþ8-H); 4.30 (t, 1H, D2O
exchang., J ¼ 4.78Hz, OH); 4.06 (s, 2H, NCH 2); 3.53–3.46 (m, 1H,
OCHH); 3.34–3.27 (m, 1H, OCHH); 2.08–2.01 (m, 2H); 1.80–1.67 (m, 1H);
1.33–1.22 (m, 1H); 1.15–1.07 (m, 1H); 0.97 (s, 3H, CH3); 0.86 (s, 3H,
CH3); 0.64 (s, 3H, CH3).13C NMR (DMSO-d6) d (ppm): 157.33 (purine
C6); 149.74 (purine C4); 145.84 (purine C8); 141.75 (purine C2); 124.13
(purine C5); 63.29 (OCH2); 50.02 (NCH2); 49.67 (C3); 49.23 (C2); 44.84
(C1); 35.38(C5); 25.63 (C4); 23.32 (CH ); 20.93 (CH3); 18.63 (CH3). EIMS
3
m=z (%): 290 (9, Mþ); 191 (14); 151 (9); 150 (82); 149 (33); 137 (100); 136
(28); 123 (17); 109 (9); 95 (11); 81 (25); 79 (10); 69 (22); 67 (24); 58 (15); 57
(19); 55 (36); 53 (12). Anal. Calcd. for C15H22N4O2: C, 62.05, H, 7.64, N,
19.30. Found: C, 62.25, H, 7.76, N, 19.48.
(1S,3R)-3-(6-Amino-9H-purin-9-ylmethyl)-2,2,3-trimethylcyclopentyl-
methanol (10). A mixture of 8 (100 mg, 0.32 mmol) and 14M NH4OH
(11 mL) was heated at 90ꢀC for 16 h and then concentrated to dryness,
affording 10 as a white solid (80 mg, 83%) that was washed with acetone,
mp 228–230ꢀC. IR (KBr) n (cmÀ 1) 3148, 1665, 1598, 1401, 1326, 1250,
1
1030, 796. H NMR (DMSO-d6) d (ppm): 8.12 and 8.07 (2s, 2H, purine 2-
Hþ8-H); 7.13 (s, H, D2O exchang., NH2); 4.32 (t, 1H, J ¼ 4.85 Hz, D2O
exchang., OH), 4.06 (d, 2H, J ¼ 3.19 Hz, NCH2); 3.51–3.46 (m, 1H,
OCHH); 3.33–3.26 (m, 1H, OCHH); 2.06–1.95 (m, 2H); 1.76–1.69 (m, 1H);
1.30–1.27 (m, 1H); 1.15–1.06 (m, 1H); 0.96 (s, 3H, CH3); 0.87 (s, 3H,
CH3); 0.65 (s, 3H, CH3). 13C NMR (DMSO-d6) d (ppm): 156.29 (purine
C6); 152.66 (purine C2); 150.68 (purine C4); 142.02 (purine C8); 118.67
(purine C5); 63.05 (HOCH2); 49.45 (C1); 49.30 (NCH2); 49.08(C2); 44.52
(C-3); 35.25 (C4); 25.42 (C5); 23.11 (CH3); 20.81 (CH3); 18.40 (CH3).
EIMS m=z (%): 289 (12, Mþ); 258(12); 190 (11); 18(11); 149 (94); 148
(64); 136 (49); 135 (100); 108(14); 81 (17); 79 (11); 69 (14); 67 (21); 58
(33); 57 (17); 55 (27); 53 (10). Anal. Calcd. for C15H23N5O: C, 62.26, H,
8.01, N, 24.20. Found: C, 62.43, H, 8.24, N, 24.29.
(1)-(1R,3S)-6,7-Dihydro-3-[3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl-
methyl]-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-7-one (12). A solution of NaNO2
(63 mg, 0.90 mmol) in water (1.5 mL) was added to a solution of 7 (0.20 g,

250
NIETO ET AL.
0.67 mmol) in AcOH (2.24 mL) and water (2.5 mL) in an ice-bath with salt.
After 10 min the ice-bath was removed and the suspension was left at
room temperature for 72 h, after which the solvents were evaporated under
reduced pressure. The solid residue (0.25 g) was purified by column
chromatography on silica gel with successive 30:1 and 10:1 mixtures of
CH2Cl2 and MeOH as eluents, affording 12 (0.14 g, 74%) as a white solid
25
that was recrystallized from EtOH, mp. 225–227ꢀC. [a]D þ 37.13 (c 0.53;
MeOH). IR (KBr) n (cmÀ 1): 3429, 2970, 1711, 1585, 1557, 1272, 1170,
1
1021, 609. H NMR (DMSO-d6) d (ppm): 12.66 (s an, 1H, D2O exchang.,
6-H); 8.23 (d, 1H, J ¼ 3.57 Hz, triazolopyrimidine 5-H); 4.40 (d, 2H,
J ¼ 2.99 Hz, NCH2); 4.31 (t, 1H, J ¼ 4.81 Hz, D2O exchang., OH); 3.50 (dd,
1H, J ¼ 10.25 Hz, J ¼ 6.06 Hz, OCHH); 3.31 (dd, 1H, J ¼ 10.25 Hz,
J ¼ 7.75 Hz OCHH ); 2.04–1.96 (m, 2H); 1.81–1.68 (m, 1H); 1.38–1.30 (m,
1H); 1.25–1.16 (m, 1H); 0.93 (s, 3H, CH3); 0.91 (s, 3H, CH3); 0.68(s, 3H,
CH3). 13C NMR (DMSO-d6) d (ppm): 156.01 (triazolopyrimidine C7);
150.08(triazolopyrimidine C3a); 149.96 (triazolopyrimidine C5); 129.74
(triazolopyrimidine C7a); 63.24 (OCH2); 53.43 (NCH2); 49.73 (C3); 49.36
(C2); 44.87 (C1); 35.62 (C5); 25.59 (C4); 23.44 (CH3); 21.10 (CH3); 18.68
(CH3). EIMS m=z (%): 291 (1, Mþ); 192 (8); 151 (15); 150 (7); 139 (15);
138 (100); 124 (21); 123 (26); 109 (6); 96 (17); 95 (16); 82 (8); 81 (34); 80
(6); 79 (22); 69 (26); 68(18); 67 (30); 58(12); 57 (19); 55 (37); 53 (12).
Anal. Calcd. for C14H21N5O2: C, 57.71, H, 7.27, N, 24.04. Found: C,
57.94, H, 7.36, N, 24.16.
(1)-(1S,3R)-3-(7-Amino-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl-
methyl)-2,2,3-trimethylcyclopentylmethanol (13). To a suspension of 7
(0.25 g, 0.83 mmol) in 1N HCl (2 mL) at 0ꢀC, a solution of NaNO2 (60 mg,
0.89 mmol) in water (7 mL) was added slowly enough to prevent the
temperature rising above 0ꢀC, and stirring was continued at this
temperature for a further 15 min. Then 14M NH4OH (4 mL) was added
and the mixture was refluxed for 4 h, after which the solvents were
removed. The resulting solid residue (0.2 g) was purified by column
chromatography on silica gel with 2:3 hexane=EtOAc as eluent, giving 13
as a white solid (0.1 g, 40%) that was recrystallized from EtOH. Mp. 248–
25
249ꢀC. [a]D þ 37.00 (c 0.86; MeOH). IR (KBr) n (cmÀ1): 3282, 2968,
1
1668, 1605, 1577, 1508, 1458, 1271, 1064, 1022. H NMR (DMSO-d6) d
(ppm): 8.35 (s, 1H, D2O exchang., NHH); 8.28 (s, 2H, triazolopyrimidine
5-H); 8.05 (s, 1H, D2O exchang., NHH); 4.42 (d, 2H, J ¼ 5.54 Hz, NCH2);
4.32 (t, 1H, D2O exchang., J ¼ 4.32 Hz, OH); 3.53–3.47 (m, 1H, OCHH);
3.35–3.28(m, 1H, OCH H); 2.07–1.95 (m, 2H); 1.78–1.70 (m, 1H); 1.37–
1.30 (m, 1H); 1.24–1.16 (m, 1H); 0.93 (s, 6H, 2CH3); 0.68(s, 3H, CH ).
3
13C NMR (DMSO-d6) d (ppm): 156.62 (triazolopyrimidine C7); 156.22
(triazolopyrimidine C5); 149.57 (triazolopyrimidine C3a); 123.37
(triazolopyrimidine C7a); 62.68(OCH ); 52.33 (NCH2); 49.15 (C1); 48.83
2

CARBOCYCLIC NUCLEOSIDES. IV
251
(C2); 44.16 (C3); 35.10 (C4); 24.98(C5); 22.82 (CH 3); 20.61 (CH3); 18.05
(CH3). EIMS m=z (%): 290 (8, Mþ); 275 (9); 259 (6); 191 (10); 150 (13);
149 (13); 137 (100); 123 (20); 95 (29); 94 (12); 81 (14); 79 (15); 69 (8); 67
(16); 55 (11). Anal. Calcd. for C14H22N6O: C, 57.91, H, 7.64, N, 28.94.
Found: C, 58.11, H, 7.72, N, 29.05.
(1)-(1R,3S)-N-[(3-Hydroxymethyl-1,2,2-trimethyl)cyclopentylmethyl]-N0-
(3-ethoxypropenoyl)urea (14). Silver cyanate (48.0 g, 320 mmol), previously
dried at 100ꢀC under vacuum over P2O5, was added to dry benzene
(321 mL) in the dark under argon, and the suspension was refluxed with
vigorous stirring for 0.5 h. A solution of 3-methoxypropenoyl chloride
(19.28g, 160 mmol) in dry benzene (60 mL) was then added dropwise, and
the resulting suspension was refluxed for a further 0.5 h with vigorous
stirring and then allowed to settle at room temperature for 3 h. A sample
of the supernatant (15 mL, theoretically containing 6.25 mmol of 3-
ethoxypropenoyl isocyanate) was transferred to a dry dropping funnel and
added dropwise to a solution of aminoalcohol 6 (0.72 g; 4.19 mmol) in dry
dimethylformamide (22 mL) at À15ꢀC. The mixture was allowed to warm
to room temperature over 1 h, stirred overnight at room temperature, and
concentrated under reduced pressure (oil pump) at a temperature below
40ꢀC by driving off the solvent by repeated co-evaporation with EtOH.
The residue (1.63 g) was chromatographed on silica gel with 5:3
EtOAc=hexane as eluent, and the pooled 14-containing fractions afforded a
white solid (0.89 g, 68%), a sample of which was recrystallized from
25
EtOAc=hexane. Mp. 98–100ꢀC. [a]D þ27.15 (c 0.50; MeOH). IR (KBr) n
(cmÀ 1): 3304, 3097, 2968, 1700, 1675, 1616, 1560, 1500, 1473, 1251, 1170,
1102, 816. 1H NMR (CDCl3) d (ppm): 8.63 (s, 1H, D2O exchang.,
CONHCO); 8.,10 (s, 1H, D2O exchang., CONHCH2); 7.65 (d, 1H,
J ¼ 12.13 Hz, CH3CH2OCH); 5.53 (d, 1H, J ¼ 12.13 Hz, COCH); 3.99 (c,
2H, J ¼ 7.03 Hz, CH3CH2); 3.76–3.71 (m, 1H, OCHH); 3.55–3.50 (m, 1H,
OCHH); 3.27 (d, 2H, J ¼ 5.82 Hz, NCH2); 2.13–2.08(m, 1H); 1.9–81.91
(m, 1H); 1.76–1.66 (m, 1H); 1.50–1.40 (m, 1H); 1.36 (t, 3H, J ¼ 7.05 Hz,
CH2CH3); 1.31–1.23 (m, 1H); 1.15 (s, 1H D2O exchang., OH); 1.01 (s, 3H,
CH3); 0.99 (s, 3H, CH3); 0.81 (s, 3H, CH3). 13C NMR (CDCl3) d (ppm):
168.33 (NHCOCH); 163.33 (CH3CH2OCH); 155.18(NHCONH); 9.828
(COCH); 68.04 (CH3CH2); 65.45 (OCH2); 50.62 (C1); 48.25 (C3); 46.42
(NCH2); 44.56 (C2); 35.18(C5); 25.64 (C4); 23.94 (CH ); 21.37 (CH3);
3
19.10 (CH3); 14.92 (CH3). Anal. Calcd. for C16H28N2O4: C, 61.51, H, 9.03,
N, 8.97. Found: C, 61.67, H, 9.15, N, 8.99.
(2)-(1R,3S)-1-[(3-Hydroxymethyl-1,2,2-trimethyl)cyclopentylmethyl]-1,2,3,
4-tetrahydropyrimidine-2,4-dione (15). A suspension of 14 (0.24 g, 0.77 mmol)
in 14M NH4OH (2.3 mL) was refluxed for 28h, and the solvent was removed.

252
NIETO ET AL.
The residual paste (0.23 g) was purified by column chromatography on silica
gel with 30:1 CH2Cl2=MeOH as eluent, affording 15 (0.14 g, 70%) as a
white solid that was recrystallized from EtOAc=hexane. Mp 161–163ꢀC.
25
[a]D À 11.74 (c 0.50; MeOH). IR (KBr) n (cmÀ 1): 3396, 2966, 1715, 1673,
1
1458, 1377, 1260, 1169, 1023, 550. H NMR (CDCl3) d (ppm): 7.95 (s, 1H,
D2O exchang., NH); 7.13 (d, 1H, J ¼ 7.94 Hz, pyrimidine 6-H); 5.66 (dd,
2H, J ¼ 7.94 Hz, J ¼ 2.40 Hz, pyrimidine 5-H); 3.92 and 3.54 (AB
system, 2H, J ¼ 13.85 Hz, NCH2); 3.81–3.76 (m, 1H, OCHH); 3.60–3.55
(m, 1H, OCHH); 2.15–2.10 (m, 1H); 2.00–1.87 (m, 2H); 1.49–1.40 (m, 2H);
1.16 (s, 1H, D2O exchang., HO); 1.04 (s, 3H, CH3); 0.86 (s, 3H, CH3);
0.84 (s, 3H, CH3). 13C NMR (CDCl3) d (ppm): 167.98(pyrimidine C4);
163.46 (pyrimidine C2); 145.58(pyrimidine C6); 102,00 (pyrimidine C5);
65.15 (OCH2); 54.52 (NCH2); 49.68(C-3); 49.49 (C1); 45.57 (C2); 35.94
(C5); 25.66 (C4); 23.15 (CH3); 19.91 (CH3); 18.69 (CH3). Anal. Calcd.
for C14H22N2O3: C, 63.14, H, 8.33, N, 10.52. Found: C, 63.31, H, 8.45,
N, 10.49.
(1)-(1R,3S)-1-[(3-Hydroxymethyl-1,2,2-trimethyl)cyclopentylmethyl]-5-
iodo-1,2,3,4-tetrahydropyrimidine-2,4-dione (16). A mixture of 15 (0.53 g,
1.99 mmol), dioxan (20 mL), I2 (0.51 g, 4.06 mmol) and 0.75N HNO3
(2.67 mL) was refluxed for 3 h. After cooling, the solvents were removed
under vacuum and the residual paste (0.76 g) was purified by column
chromatography on silica gel with 19:1 CH2Cl2=MeOH as eluent,
affording 16 as a white porous solid (0.52 g, 67%) that when washed
with ether (10 mL) was recovered as a white solid of mp 217–219ꢀC.
25
[a]D þ10.28( c 0.78; MeOH). IR (KBr) n (cmÀ 1): 3419, 2965, 1674, 1608,
1
1430, 1370, 1328, 1262, 1022. H NMR (CDCl3) d (ppm): 8.28 (s, 1H,
D2O exchang., NH); 7.57 (s, 1H, pyrimidine 6-H); 3.93 and 3.56 (AB
system, 2H, J ¼ 13,69 Hz, NCH2); 3.74 (dd, 1H, J ¼ 10,29 Hz, J ¼ 5.83 Hz,
OCHH); 3.58(dd, 1H, J ¼ 10.29 Hz, J ¼ 7.70 Hz, OCHH); 2.17–2.08(m,
1H); 2.04–1.84 (m, 2H); 1.52–1.24 (m, 3H one of them D2O exchang.,
OH); 1.04 (s, 3H, CH3); 0.87 (s, 3H, CH3); 0.84 (s, 3H, CH3). 13C NMR
(CDCl3) d (ppm): 160.49 (pyrimidine C2); 151.16 (pyrimidine C4); 150.02
(pyrimidine C6); 67.39 (pyrimidine C5); 65.10 (HOCH2); 54.97 (NCH2);
49.64 (C1); 49.47 (C3); 45.64 (C2); 35.77 (C5); 25.65 (C4); 23.16 (CH3);
19.90 (CH3); 18.68 (CH3). EIMS m=z (%): 392 (20, Mþ), 252 (64), 239
(36), 238 (24), 208 (33), 124 (12), 123 (100), 95 (17), 81 (38), 79 (11), 69
(21), 67 (18), 58 (15), 55 (24), 53 (21).
(1R,3S)-5-Bromo-1-[(3-hydroxymethyl-1,2,2-trimethyl)cyclopentylmethyl]-
1,2,3,4-tetrahydropyrimidine-2,4-dione acetate (17a). A mixture of acetic
anhydride (0.90 mL) and compound 15 (85 mg, 0.32 mmol) was refluxed
until the solid dissolved, cooled to room temperature, and then maintained

CARBOCYCLIC NUCLEOSIDES. IV
253
at 25ꢀC with stirring while a solution of bromine (80 mg, 0.50 mmol) in
acetic acid (0.10 mL) was added dropwise. The resulting solution was
stirred at room temperature for 3 h and then stored overnight at
about 5ꢀC. Volatile components were evaporated under reduced pressure,
and the crystalline residue (100 mg) was chromatographed on silica gel
with 10:0.1 CH2Cl2=MeOH as eluent, affording 17a (70 mg; 64%).
Mp. 214–215ꢀC. IR (KBr) n (cmÀ 1): 2967, 2835, 1744, 1682, 1615, 1464,
1
1431, 1374, 1257, 1045, 893, 750. H NMR (CDCl3) d (ppm): 8.17 (s, 1H,
D2O exchang., NH); 7.47 (s, 1H, pyrimidine 6-H); 4.12–4.00 (m, 2H,
NCH2), 3.95 and 3.55 (AB system, 2H, J ¼ 13.70 Hz, OCH2); 2.29–2.17 (m,
2H); 2.05 (s, 3H, COCH3); 1.99–1.86 (m, 2H); 1.50–1.44 (m, 2H,
one of them D2O exchang., OH); 1.03 (s, 3H, CH3); 0.87 (s, 3H, CH3);
0.85 (s, 3H, CH3). EIMS m=z (%): 388 (3), 386 (3), 247 (3), 206 (6), 205
(3), 204 (6), 192 (7), 191 (7), 162 (10), 136 (14), 124 (10), 123 (100), 121
(15), 107 (8), 105 (7), 95 (13), 93 (9), 82 (7), 81 (27), 79 (7), 69 (12), 67
(14), 55 (13), 53 (8).
(1)-(1R,3S)-5-Bromo-1-[(3-hydroxymethyl-1,2,2-trimethyl)cyclopentyl-
methyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione (17b). A solution of acetate
17a (57 mg, 0.15 mmol) in 20% methanolic ammonia (6 mL) was refluxed
for 72 h and then concentrated to dryness under reduced pressure. The
residue was dissolved in hot water and stored at about 5ꢀC, which afforded
17b as a white precipitate that was filtered out of solution and dried in
25
vacuo (40 mg; 79%). Mp. 189–191ꢀC. [a]D þ 4.72 (c 0.46; MeOH). IR
(KBr) n (cmÀ1): 2966, 2871, 1718, 1684, 1654, 1616, 1508, 1458, 1430,
1
1046, 630. H NMR (DMSOd6) d (ppm): 11.75 (s, 1H, D2O exchang.,
NH); 8.10 (s, 1H, pyrimidine 6-H); 4.28 (m, 1H, D2O exchang., OH);
3.77 and 3.57 (AB system, 2H, J ¼ 13.65 Hz, OCH2); 3.47–3.42 (m,
1H, NHH); 3.07–3.00 (m, 1H, NHH); 1.98–1.89 (m, 2H); 1.81–1.71 (m,
1
1H); 1.29–1.14 (m, 2H); 0.93 (s, 3H, CH3); 0.73 (2s, 6H, 2CH3). C NMR
(DMSOd6) d (ppm): 159.96 (pyrimidine C4); 151.28(pyrimidine C2);
146.41 (pyrimidine C6); 94.55 (pyrimidine C5), 63.06 (HOCH2);
53.37 (NCH2); 49.26 (C1); 48.95 (C3); 44.81 (C2); 34.62 (C5); 25.52
(C4); 22.95 (CH3); 19.68(CH ); 18.18 (CH3). EIMS m=z (%): 288 (1, Mþ),
3
206 (6), 204 (3), 193 (2), 123 (100), 95 (8), 82 (4), 81 (56), 79 (11), 78
(61), 69 (34), 67 (39), 63 (79), 58(60), 57 (15), 55 (40), 53 (14). Anal.
Calcd. for C15H23BrN2O3: C, 50.15, H, 6.45, N, 7.80. Found: C, 50.36, H,
6.58, N, 7.93.
ACKNOWLEDGMENTS
The authors thank the Xunta de Galicia (XUGA 20309B98) and the
European Commission (ISEP=FORTIS) for financial support.

254
NIETO ET AL.
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Received June 15, 2001
Accepted December 27, 2001