Synthesis of new nucleoside analogues comprising a methylenecyclobutane unit

Article abstract of DOI:10.1016/j.tet.2005.04.023

Synthesis of eight nucleoside analogues 3-10 with a methylene cyclobutane unit is described. Wittig or Peterson reactions with protected 2-hydroxycyclobutanones 12 and 13 gave E- and Z-derivatives, respectively. After functional modifications the heterocyclic moieties were introduced via a Mitsunobu reaction either on the lateral chain or on the cycle. When adenine was used in this reaction only the N-9 substitution products were obtained. Removal of the protecting groups provided the target products.

Full text of DOI:10.1016/j.tet.2005.04.023

Tetrahedron 61 (2005) 5782–5787
Synthesis of new nucleoside analogues comprising a
methylenecyclobutane unit
b
Sophie Danappe,a Ashutosh Pal,a Christian Alexandre,a, Anne-Marie Aubertin,
*
Nathalie Bourgougnonc and Franc¸ois Hueta,
*
a
` ´ ´
Laboratoire de Synthese Organique, UMR CNRS 6011, Faculte des Sciences, Universite du Maine, Avenue Olivier Messiaen,
F-72085 Le Mans Cedex 9, France
b
´ ´ ´ ´
Institut de Virologie, INSERM U 544, Faculte de Medecine, Universite Louis Pasteur, 3 Rue Koeberle, F-67000 Strasbourg, France
´
c
Laboratoire de Biologie et Chimie Moleculaires, Centre de recherche et d’enseignement Yves Coppens, Campus de Tohannic, BP 573,
F-56017 Vannes, France
Received 7 February 2005; revised 1 April 2005; accepted 14 April 2005
Available online 11 May 2005
Abstract—Synthesis of eight nucleoside analogues 3–10 with a methylene cyclobutane unit is described. Wittig or Peterson reactions with
protected 2-hydroxycyclobutanones 12 and 13 gave E- and Z-derivatives, respectively. After functional modifications the heterocyclic
moieties were introduced via a Mitsunobu reaction either on the lateral chain or on the cycle. When adenine was used in this reaction only the
N-9 substitution products were obtained. Removal of the protecting groups provided the target products.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
moderated effect of 1 against EBV was established but was
not separated from cytotoxicity. The methylenecyclobutane
system is a rigid linker between the hydroxymethyl group
and base residue so that a modification of this system could
lead to more active compounds. And thus we examined
different geometries in this series, keeping the same distance
between the two active parts but with different positions of
double bond and cyclobutane.
Nucleoside analogues are at the center of current interest
because they display a wide range of biological activities
especially as antiviral and antitumor agents.1 Several
analogues have been prepared and evaluated in order to
obtain compounds with better properties particularly
towards enzymatic cleavage. Products with good activity
were found among a large number of structures,2–6 and it is
difficult to predict which compounds will be sufficiently
active and selective against viral enzymes. Structures of
these analogues could be close of nucleosides as the HIV
drug 30-azido-20,30-dideoxythymidine (AZT) or very differ-
ent as the acyclic analogues gancyclovir. Among these
products, several compounds with a methylenecyclobutane
In the course of our research program towards nucleoside
analogues, we have already synthesized some carbocyclic
compounds with double bonds in endocyclic7a,b,d,e or
exocyclic7c position and acyclic dienic8a and methylenic8b
compounds. We then planned to synthesize products related
to 1 and 2 but not bearing the base in the vinylic position.
We thus selected compounds 3–10 (Fig. 2) as targets and we
describe here a short route to these compounds from
2-hydroxycyclobutanone 11.
unit 1 and 2 (Fig. 1) were described by Zemlicka.5
A
Figure 1.
Keywords: Nucleoside analogues; Methylenecyclobutane; Mistsunobu
conditions.
*
Corresponding authors. Tel.: C33 2 4383 3338; fax: C33 2 4383 3902
(F.H.); tel.: C33 2 4383 3096; fax: C33 2 4383 3902 (C.A.); e-mail
addresses: calexan@univ-lemans.fr; fhuet@univ-lemans.fr
Figure 2.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.023

S. Danappe et al. / Tetrahedron 61 (2005) 5782–5787
5783
2. Results and discussion
The starting material for the synthesis of Z- and E-methyl-
enecyclobutane analogues was 2-hydroxycyclobutanone
119 (Scheme 1). This ketol was first protected as silyl
ether. The resulting compounds 12 and 1310 were treated by
two different methods. The first one was the Wittig reaction
with ethoxycarbonylmethylene phosphorane, which led to
E-isomers 14 as sole product. The other one was the
Peterson reaction with ethyl trimethylsilylacetate in basic
medium, which led to a mixture of E- and Z-isomers 14 and
16 (ratio 1/12) or 15 and 17 (ratio 1/18).
Scheme 2. Reagents and conditions: (a) Adenine, DIAD, Ph3P, THF, rt, 7
days; (b) (nBu)4NF, THF, rt, 2.5 h; (c) N3-benzoyl thymine, DIAD, Ph3P,
THF, rt, 7 days; (d) sat NH3/MeOH, rt, 48 h.
Scheme 1. Reagents and conditions: (a) tBuR2SiCl, imidazole, DMF, rt,
20 h; (b) Ph3P]CHCOOEt, C6H6, rt, 72 h; (c) LDA, (Me)3SiCH2COOEt,
THF K78 8C, 1 h; (d) DIBALH, CH2Cl2, toluene K60 8C, 2 h.
These compounds were separated by column chromato-
graphy. The NOE experiments were used to distinguish the
two isomers. Thus, Z isomer 14 showed NOE enhancement
of the olefinic signal after irradiation of the H2, similar effect
was absent in E isomer 16. Reduction of esters with
DIBALH gave, respectively, alcohol 18 from ester 14 and
alcohol 20 from ester 17. With these key compounds in our
hands, two different methods were used to obtain the target
products either 3–6 or 7–10 (Fig. 3).
Scheme 3. Reagents and conditions: (a) (nBu)4NF, THF, rt, 2.5 h;
(b) Ac2O, pyridine, rt, 14 h; (c) Adenine, DIAD, Ph3P, THF, rt, 7 days;
(d) sat NH3/MeOH, rt, 15 h; (e) N3-benzoyl thymine, DIAD, Ph3P, THF, rt,
7 days.
Figure 3. NOE enhancements of 14 and 16.
To access the series 3–6 (Scheme 2) with the nucleic base in
allylic position, direct substitutions with protected thymine
and free adenine were performed, in Mitsunobu conditions,
separately from alcohols 18 (E) or 20 (Z). The reactions
were carried out with triphenylphosphine and DIAD in THF
and led to good results. It is worth mentioning that reaction
with adenine only led to the N-9 substitution products. We
could not detect any other isomer by NMR analysis of the
nucleic base by substitution in Mitsunobu conditions with
alcohol 27 resulting from removal of the silyl group on 14.
Unfortunately, in these conditions, benzoyl thymine led to
several products including the expected product in low yield
and another one resulting from Michael addition to the
conjugated double bond. As to adenine, it did not react. We
thought that these difficulties could be avoided by using
compounds 30 and 31. Both of these products were prepared
from alcohols 18 and 19 by acetylation providing com-
pounds 28 and 29, followed by desilylation. These very
volatile compounds can only be obtained in good yield if
suitable precautions were taken for solvent evaporation
stage. The subsequent Mitsunobu reactions provided
compounds 32 to 35 and cleavage of acetyl group only
(from 32 and 33) or of acetyl and benzoyl groups (from 34
crude products. These assignments were proved by H/13C
1
HMBC NMR spectra. In the adenine series the target
products 3 and 5 were obtained after desilylation with
TBAF. For the thymine analogs 4 and 6, an additional mild
treatment with NH3/MeOH was necessary to remove the
benzoyl group. In every case the final product was obtained
as single isomer.
For obtaining compounds 7–10 (Scheme 3) with base
directly linked to the cycle, we first tried to introduce the

5784
S. Danappe et al. / Tetrahedron 61 (2005) 5782–5787
and 35) with NH3/MeOH gave the target molecules in
satisfying overall yields.
71.4, 109.8, 127.2, 129.4, 132.8, 133.1, 135.1, 166.1, 167.3.
Anal. Calcd for C24H30SiO3: C, 73.05; H, 7.66. Found C,
73.49; H, 7.74.
Compounds 3 to 10 were tested against HIV-1 and HSV-1,
none of them had a significant antiviral activity.
3.1.4. (Z)-2-{(tert-Butyldiphenylsilyl)oxycyclobutyl-
idene}ethyl acetate 16. To a solution of diisopropylamine
(0.21 mL, 1.5 mmol) in THF (0.5 mL) at 0 8C was added a
1.6 M solution of BuLi in hexane (0.98 mL). The resulting
mixture was stirred 30 min at 0 8C before cooling at
K78 8C. At this temperature ethyl trimethylsilylacetate
(0.275 mL, 1.5 mmol) was added. After 45 min a solution of
ketone 12 (0.487 g, 1.5 mmol) in THF (2 mL) was added
slowly. After 1 h the reaction mixture was allowed to warm
to rt, and hydrolyzed with a 3 M solution of HCl (2 mL).
The aqueous layer was extracted with dichloromethane and
the organic layer was dried and concentrated under reduced
pressure. The crude product (mixture Z/E 12/1) was purified
by column chromatography on silica gel to give isomer Z 16
(0.377 g, 69%) as a colorless oil. IR (film, cmK1): 1724,
3. Experimental
3.1. General
NMR spectra were recorded at 400 and 100 MHz for 1H and
13C, respectively. IR spectra were recorded with a FT
infrared spectrophotometer. Melting points are uncorrected.
Elemental analyses were performed by the service of
microanalyses, CNRS ICSN, Gif sur Yvette. High-
resolution mass measurements were performed at the
CRMPO (Rennes). The column chromatographies were
run on silica gel Gerudan SI 60, 230–400 mesh, under
1–2 bars.
1
1687, 1190, 1112, 703. H NMR (CDCl3) d: 1.05 (9H, s),
1.20 (3H, t, JZ6.9 Hz), 1.82 (2H, m), 2.26 (1H, m), 2.50
(1H, m), 3.96 (1H, dq, JZ14.4, 6.9 Hz), 4.16 (1H, dq, JZ
14.4, 6.9 Hz), 5.17 (1H, m), 5.63 (1H, m), 7.38 (6H, m), 7.74
(4H, m). 13C NMR(CDCl3) d: 14.3, 19.2, 25.3, 16.9, 59.9,
72.5, 114.0, 127.5, 127.6, 129.5, 129.6, 133.8, 134.4, 135.7,
135.9, 163.5, 165.5. Anal. Calcd for C24H30SiO3: C, 73.05;
H, 7.66. Found C, 73.04; H, 7.68.
3.1.1. 2-{(tert-Butyldiphenylsilyl)oxycyclobutanone} 12.
To a solution of alcohol 11 (1.50 g, 17.5 mmol) in DMF
(4 mL) were added imidazole (1.43 g, 21 mmol) and tertio-
butylchlorodiphenylsilane (5.4 mL, 21 mmol). The result-
ing mixture was stirred 20 h at rt. Water (15 mL) was added
and the aqueous layer was extracted with diethyl ether. The
combinated organic layers were dried and evaporated under
reduced pressure. The residue was purified by column
chromatography on silica gel to give 12 (5.1 g, 90%) as a
3.1.5. (Z)-2-{(tert-Butyldimetylsilyl)oxycyclobutyl-
idene}ethyl acetate 17. With the same procedure as
above from 13 (1 g, 5 mmol), (Z) ester 17 (1.05 g, 78%)
was obtained as a colorless oil. IR (film, cmK1: 1726, 1686,
1192, 1083. 1H NMR (CDCl3) d: 0.09 (3H, s), 0.13 (3H, s),
0.87 (9H, s), 1.24 (3H, t, JZ7.5 Hz), 1.99 (1H, m), 2.35
(1H, m), 2.41 (1H, m), 2.62 (1H, m), 4.07 (1H, m), 4.17 (1H,
m), 5.05 (1H, m), 5.61 (1H, m). 13C NMR (CDCl3) d: K5.3,
K4.9, 2.3, 14.4, 18.2, 25.1, 26.1, 29.8, 59.8, 71.5, 114.3,
165.1. Anal. Calcd for C14H26O3Si: C, 62.18; H, 9.69.
Found C, 62.41, H, 9.64.
1
colorless oil. IR (film, cmK1): 1793, 1170, 1113, 704. H
NMR (CDCl3) d: 1.08 (9H, s), 1.92 (1H, m), 2.19 (1H, m),
2.61 (2H, m), 4.82 (1H, dtt, JZ8.1, 1.7 Hz), 7.40 (6H, m),
7.68 (2H, m), 7.77 (2H, m). 13C NMR (CDCl3) d: 19.3, 22.4,
26.7, 38.4, 82.3, 127.91, 127.93, 130.1, 132.8, 133.4, 135.6,
135.7, 206.6. Anal. Calcd for C20H24SiO2: C, 74.03; H,
7.45. Found C, 73.77; H, 7.54.
3.1.2. 2-{(tert-Butyldimethylsilyl)oxycyclobutanone}
13.10 With the same procedure as above from 11 (1.17 g,
14 mmol), imidazole (1.295 g, 19 mmol) and tertio-butyl-
chlorodimethylsilane (1.38 g, 19 mmol) in DMF (3 mL), 13
3.1.6. (E)-2-{(tert-Butyldiphenylsilyl)oxycyclobutyl-
idene}ethanol 18. To a stirred solution of the ester 14
(1.3 g, 3.34 mmol) in dry dichloromethane (185 mL) at
K60 8C was added dropwise a 1 M solution of DIBALH in
toluene (16.85 mL). The mixture was stirred for 2 h at this
temperature. A solution of 10% citric acid (150 mL) was
added at K20 8C, the aqueous layer was extracted with
toluene (2!50 mL) then the combinated organic layers
were dried and evaporated under reduced pressure. The
residue was purified by column chromatography on silica
gel to afford 18 (1.01 g, 87%) as a colorless oil. IR (film,
cmK1): 3378, 1428, 1112, 703. 1H NMR (CDCl3) d: 1.07 (s,
9H), 1.60 (1H, br s), 1.99 (3H, m), 2.45 (1H, m) 4.10 (2H,
m), 4.70 (1H, m), 5.64 (1H, m), 7.39 (6H, m), 7.67 (4H, m).
13C NMR (CDCl3) d: 18.7, 21.2, 26.3, 29.8, 59.1, 71.1,
117.3, 127.2, 129.2, 133.5, 135.1, 147.9. Anal. Calcd for
C22H28SiO2: C, 74.95; H, 8.01. Found C, 74.64; H, 7.98.
1
(2.36 g, 87%) was obtained as a colorless oil. H NMR
(CDCl3) d: 0.10 (3H, s), 0.12 (3H, s), 0.91 (9H, s), 1.86 (1H,
m), 2.37 (1H, m), 3.72 (2H, m), 4.88 (1H, m). 13C NMR
(CDCl3) d: K4.7, K4.5, 18.5, 22.5, 25.8, 26.0, 38.5, 82.2,
207.3.
3.1.3. (E)-2-{(tert-Butyldiphenylsilyl)oxycyclobutyl-
idene}ethyl acetate 14. To a solution of ketone 12
(0.953 g, 2.94 mmol) in benzene (6 mL) was added
carbethoxymethylene triphenylphosphorane (1.637 g,
4.70 mmol). The resulting mixture was stirred for 3 days
at rt. The solvent was removed under reduced pressure and
the residue was diluted with petroleum ether. After filtration
the solid was washed with petroleum ether and the filtrate
was evaporated under reduced pressure. The resulting oil
was purified by column chromatography on silica gel to give
14 (1.109 g, 96%) as a colorless oil. IR (film, cmK1): 1716,
3.1.7. (Z)-2-{(tert-Butyldiphenylsilyl)oxycyclobutyl-
idene}ethanol 19. With the same procedure as above
from ester 16 (0.5 g, 1.27 mmol), 19 (0.405 g, 91%) was
obtained as a colorless oil. IR (film, cmK1): 3421, 1428,
1112, 704. 1H NMR (CDCl3) d: 1.09 (9H, s), 1.62 (1H, m),
1
1685, 704. H NMR (CDCl3) d: 1.07 (9H, s); 1.28 (3H, d,
JZ7.4 Hz), 1.99 (2H, m), 2.40 (1H, m), 2.95 (1H, m), 4.18
(2H, m), 4.75 (1H, m), 5.87 (1H, m), 7.40 (6H, m), 7.65 (3H,
m). 13C NMR (CDCl3) d: 13.9, 18.7, 24.8, 26.3, 29.4, 59.4,

S. Danappe et al. / Tetrahedron 61 (2005) 5782–5787
5785
1.76 (1H, m), 2.04 (1H, m), 2.23 (1H, m), 2.94 (1H, br s),
4.20 (1H, dd, JZ13.1, 4.3 Hz), 4.33 (1H, dd, JZ13.1,
5.3 Hz), 4.95 (1H, m), 5.46 (1H, m), 7.40 (6H, m), 7.71 (4H,
m). 13C NMR (CDCl3) d: 18.9, 23.0, 26.8, 29.5, 59.5, 72.4,
121.4, 127.6, 127.7, 129.8, 132.9, 133.6, 135.6, 135.7,
145.5. Anal. Calcd for C22H28SiO2$0.2 H2O: C, 74.19; H,
8.04. Found C, 74.19; H, 8.11.
231.1133. Anal. Calcd for C11H13N5O: C, 57.13, H, 5.66,
N, 30.28. Found C, 56.66, H, 5.52, N, 30.12.
3.1.12. (Z)-2-[2-(6-Amino-purin-9-yl)-ethylidene]-cyclo-
butanol 5. With the same procedure as above from
protected alcohol 22 (0.15 g, 0.434 mmol), alcohol 5 was
obtained (0.098 g, 98%) as a white powder, mp 196.8–
197.5 8C (methanol). IR (film, cmK1): 3427, 3290, 1688,
1
3.1.8. (Z)-2-{(tert-Butyldimethylsilyl)oxycyclobutyl-
idene}ethanol 20. With the same procedure as above
from ester 17 (1.3 g, 4.82 mmol), 20 (0.94 g, 86%) was
obtained as a colorless oil. IR (film, cmK1): 3374, 1254,
1614, 1576, 1159. H NMR (DMSO-d6) d: 1.78 (1H, m),
2.20 (3H, m), 4.80 (1H, m), 4.89 (1H, m), 5.35 (1H, m), 6.09
(1H, d, JZ8 Hz), 7.16 (2H, br s), 8.10 (1H, s), 8.15 (1H, s).
13C NMR 22.9, 29.3, 39.8, 70.4, 115.3, 119.1, 140.7, 149.2,
150.8, 152.3, 156.2. Anal. Calcd for C11H13N5O: C, 57.13,
H, 5.66, N, 30.28. Found C, 57.02, H, 5.71, N, 30.11.
1
1131. H NMR (CDCl3) d: 0.08 (3H, s), 0.10 (3H, s), 0.89
(9H, s), 1.88 (1H, m), 2.20 (2H, m), 2.33 (1H, m), 3.10 (1H,
br s), 4.07 (1H, m), 4.15 (1H, m), 4.86 (1H, m), 5.42 (1H,
m). 13C NMR (CDCl3) d: K5.1, K4.7, 2.1, 17.9, 23.1, 25.7,
29.9, 59.7, 71.4, 121.6, 145.4. HRMS Calcd for C8H15O2Si
[MKtBu] 171.08413. Found 171.0843.
3.1.13. (E)-Benzoyl-1-{2-[2-(tert-butyldiphenyl-silanyl-
oxy)-cyclobutylidene]-ethyl}-5-methyl-1H-pyrimidine-
2,4-dione 23. With the same procedure as for 21 from
alcohol 18 (0.45 g, 1.27 mmol) and N-3-benzoylpyrimidine
(0.585 g, 2.55 mmol) 23 was obtained (0.591 g, 82%) as a
white powder, mp 68.8–69.7 8C. IR (film, cmK1): 1748,
3.1.9. (E)-{2-[2-(tert-Butyldiphenyl-silanyloxy)-cyclo-
butylidene]-ethyl}-9H-purin-6-ylamine 21. To a solution
of alcohol 18 (0.61 g, 1.73 mmol), triphenylphosphine
(0.99 g) and adenine (0.495 g) in THF (10 mL), was
added for 2.5 h a solution of DIAD (0.55 mL) in THF
(10 mL). The mixture was stirred at rt for 1 week. The
solvent was removed under reduced pressure and the residue
was purified by column chromatography on silica gel to give
21 (0.374 g, 46%) as white needles, mp 174–175 8C. IR
(film, cmK1): 3301, 3147, 1670, 1601, 1144, 1109. 1H NMR
(CDCl3) d: 1.05 (9H,s), 1.99 (1H, m), 2.10 (2H, m), 2.44
(1H, m), 4.70 (2H, d, JZ7 Hz), 4.74 (1H, m), 5.60 (1H, m),
5.81 (2H, br s), 7.36 (6H, m), 7.62 (4H, m), 7.76 (1H,s), 8.36
(1H, s). 13C NMR (CDCl3) d: 19.1, 21.6, 26.8, 29.9, 41.1,
71.5, 112.1, 119.6, 127.7, 129.8, 133.7, 135.5, 140.0, 150.0,
151.6, 153.0, 155.4. Anal. Calcd for C27H31N5SiO: C,
69.05; H, 6.65, N, 14.91. Found C, 68.90; H, 6.64, N, 14.88.
1
1699, 1656, 1234, 1110. H NMR (CDCl3) d: 1.07 (9H, s),
1.98 (3H, s), 2.12 (3H, m), 2.50 (1H, m), 4.25 (2H, m), 4.73
(1H, m), 5.40 (1H, m), 7.03 (1H, s), 7.40 (5H, m), 7.48 (4H,
m), 7.63 (4H, m), 7.92 (2H, d, JZ7 Hz). 13C NMR(CDCl3)
d: 12.3, 15.1, 18.9, 21.6, 26.6, 29.7, 45.1, 71.3, 100.5, 111.6,
127.5, 128.9, 129.6, 130.3, 131.5, 133.5, 134.8, 135.4,
139.1, 149.7, 152.1, 162.9, 169.0.
3.1.14. (Z)-Benzoyl-1-{2-[2-(tert-butyldimethyl-silanyl-
oxy)-cyclobutylidene]-ethyl}-5-methyl-1H-pyrimidine-
2,4-dione 24. With the same procedure as for 23 from
alcohol 20 (0.40 g, 1.75 mmol), 24 was obtained (0.678 g,
88%) as a white powder, mp 130–131.2 8C. IR (film, cmK1):
1
1701, 1658, 1599, 1252. H NMR (CDCl3) d: 0.16 (6H, s),
0.97 (9H, s), 1.97 (3H, s), 1.98 (1H, m), 2.30 (2H, m), 2.43
(1H, m), 4.25 (1H, dd, JZ13.8, 9.8 Hz), 4.73 (1H, dd, JZ
13.8, 5.3 Hz), 4.96 (1H, m), 5.26 (1H, m), 7.50 (2H, dd, JZ
7, 7 Hz), 7.56 (1H, s), 7.63 (2H, t, JZ7.7 Hz) 7.94 (2H, d,
JZ7 Hz). 13C NMR (CDCl3) dK4.7, K4.2, 12.5, 18.2,
23.6, 26.0, 30.4, 44.0, 71.6, 110.5, 115.1, 129.3, 130.6,
132.0, 140.3, 150.2, 151.0, 163.5, 169.6.
3.1.10. (Z)-{2-[2-(tert-Butyldimethyl-silanyloxy)-cyclo-
butylidene]-ethyl}-9H-purin-6-ylamine 22. With the
same procedure as above from ester 20 (0.47 g,
2.06 mmol), 22 (0.305 g, 43%) was obtained as white
powder, mp 178.6–180 8C (methanol). IR (film, cmK1):
1
3430, 3293, 3148, 1671, 1604, 1135. H NMR (CDCl3) d:
0.11 (3H, s), 0.12 (3H, s), 0.89 (9H, s), 1.96 (1H, m), 2.26
(2H, m), 2.37 (1H, m), 4.92 (2H, d, JZ7 Hz), 4.98 (1H, m),
6.20 (2H, br s), 8.01 (1H, s), 8.37 (1H, s). 13C NMR(CDCl3)
d: K5.0, K4.5, 17.9, 23.2, 25.7, 29.9, 40.1, 71.4, 115.17,
119.5, 140.9, 149.8, 150.1, 152.8, 155.5. HRMS Calcd for
C17H27N5OSi 345.1985. Found 345.1964.
3.1.15. (E)-1-{2-[2-(tert-Butyldiphenyl-silanyloxy)-cyclo-
butylidene]-ethyl}-5-methyl-1H-pyrimidine-2,4-dione
25. A solution of 23 (0.34 g, 0.60 mmol) in methanol
saturated with ammonia (9.5 mL) was stirred for 48 h at rt.
After removal of the volatile substances, the residue was
purified by column chromatography on silica gel to give 25
(0.22 g, 80%) as a white powder, mp 58.8–59.8 8C. IR (film,
1
cmK1): 3170, 1680, 1112, 702. H NMR (CDCl3) d: 1.08
3.1.11. (E)-2-[2-(6-Amino-purin-9-yl)-ethylidene]-cyclo-
butanol 3. To a solution of protected alcohol 21 (0.32 g,
0.68 mmol) in THF (5.5 mL) was added tetrabutylammonium
fluoride (1 M, 1.3 mL) and the mixture was stirred for 2.5 h
at rt. The solvent was removed under reduced pressure and
the residue was purified by column chromatography on
silica gel to give alcohol 3 (0.26 g, 95%). IR (film, cmK1):
3272, 1678, 1605, 1577, 1298. 1H NMR (DMSO-d6) d: 1.75
(1H, m), 2.22 (2H, m), 2.55 (1H, m), 4.57 (1H, m), 4.74 (2H,
d, JZ7.0 Hz), 5.47 (1H, m), 5.64 (1H, m), 7.30 (2H, br s),
8.21 (1H, s), 8.23 (1H, s). 13C NMR (DMSO-d6) d: 21.2,
29.2, 40.6, 69.9, 112.7, 118.7, 140.5, 149.4, 151.3, 152.5,
156.0. HRMS Calcd for C11H13ON5 231.1120. Found
(9H, s), 1.94 (3H, s), 1.98 (1H, m), 2.10 (2H, m), 2.48 (1H,
m), 4.25 (2H, m), 4.72 (1H, m), 5.39 (1H, m), 6.96 (1H, s),
7.38 (6H, m), 7.68 (4H, m) 10.05 (1H, br s). 13C NMR
(CDCl3) d: 12.4, 19.1, 21.8, 26.7, 26.8, 29.9, 44.9, 71.5,
110.7, 112.3, 127.6, 127.8, 129.7, 129.8, 133.7, 133.8,
135.5, 139.6, 151.2, 151.5, 164.7. HRMS Calcd for
C27H32N2O3Si 460.2182. Found 460.2169.
3.1.16. (Z)-1-{2-[2-(tert-Butyldimethyl-silanyloxy)-cyclo-
butylidene]-ethyl}-5-methyl-1H-pyrimidine-2,4-dione
26. With the same procedure as above from protected
alcohol 24 (0.33 g, 0.75 mmol), 26 was obtained (0.219 g,

5786
S. Danappe et al. / Tetrahedron 61 (2005) 5782–5787
87%) as a white powder, mp 134.8–135.9 8C (petroleum
ether/ether 2/1). IR (film, cmK1): 3464, 3414, 1695, 1681,
1640, 1134. 1H NMR (CDCl3) d: 0.12 (6H, s), 0.91 (9H, s),
1.91 (3H, s), 1.92 (1H, m), 2.27 (2H, m), 2.39 (1H, m), 4.19
(1H, dd, JZ14.0, 10.3 Hz), 4.73 (1H, dd, JZ14.0, 4.3 Hz),
4.94 (1H, m), 5.25 (1H, m), 7.42 (1H, s), 9.75 (1H, br s). 13C
NMR(CDCl3) d: K4.5, 12.3, 18.0, 23.3, 25.8, 30.2, 43.5,
71.4, 110.4, 115.5, 140.3, 150.1, 151.4, 164.7. HRMS Calcd
for C17H28O3N2Si 336.1869. Found 336.1849.
m), 4.80 (2H, dd, JZ1.4, 0.8 Hz), 4.91 (1H, m), 5.35 (1H,
m), 7.38 (6H, m), 7.68 (4H, m). 13C NMR (CDCl3) d: 18.9,
21.0, 23.2, 26.8, 29.5, 61.0, 72.1, 115.7, 127.5, 127.7, 129.6,
133.4, 134.0, 135.7, 135.8, 149.9, 170.9. Anal. Calcd for
C24H30O3Si$0.2 H2O: C, 72.39, H, 7.70. Found C, 72.15, H,
7.53.
3.1.21. (E)-Acetic acid 2-(2-hydroxy-cyclobutylidene)-
ethyl ester 30. With the same procedure as for alcohol 3
from acetate 28 (0.177 g, 0.45 mmol), alcohol 30 was
obtained as a colorless oil (0.64 g, 91%). IR (film, cmK1):
3.1.17. (E)-1-[2-(2-Hydroxy-cyclobutylidene)-ethyl]-5-
methyl-1H-pyrimidine-2,4-dione 4. With the same pro-
cedure as for 3 from protected alcohol 25 (0.17 g,
0.369 mmol), alcohol 4 was obtained (0.074 g, 91%) as a
white powder, mp 137.6–138.4 8C (methanol/ether 1/4). IR
(film, cmK1): 3406, 1696, 1673, 1117. 1H NMR (CD3OD) d:
1.72 (1H, m), 1.77 (3H, s), 2.19 (2H, m), 2.45 (1H, m), 4.18
(2H, d, JZ7.5 Hz), 4.49 (1H, m), 5.36 (1H, m), 7.28 (1H, s).
13C NMR (CD3OD) d: 14.0, 24.3, 32.1, 48.1, 73.4, 113.1,
115.8, 144.5, 154.2, 154.7, 168.8. Anal. Calcd for
C11H14N2O: C, 59.45, H, 6.35, N, 12.61. Found C, 59.01,
H, 6.30, N, 12.22. HRMS Calcd for C11H14O3N2Si
222.1004. Found 222.0094.
1
3399, 1744, 1251. H NMR (CDCl3) d: 1.85 (1H, m), 2.06
(3H, s), 2.28 (1H, m), 2.37 (1H, m), 2.57 (1H, m), 4.53 (2H,
m), 4.69 (1H, m), 5.60 (1H, m). 13C NMR (CDCl3) d: 20.9,
21.7, 30.0, 60.9, 70.9, 113.4, 151.4, 171.0. HRMS: calcd for
C6H10O [MKC2H2O] 114.06808, found 114.0688.
3.1.22. (Z)-Acetic acid 2-(2-hydroxy-cyclobutylidene)-
ethyl ester 31. With the same procedure as for alcohol 3
from acetate 29 (1.53 g, 3.88 mmol), alcohol 31 was
obtained as a colorless oil (0.549 g, 91%). IR (film, cmK1
)
3443, 1735, 12441H NMR (CDCl3) d: 1.83 (1H, m), 2.08
(3H, s), 2.30 (3H, m), 3.92 (1H, dd, JZ8.9 Hz), 4.39 (1H,
m), 4.82 (1H, m), 5.07 (1H, dd, JZ12.3, 9.8 Hz), 5.26 (1H,
m). 13C NMR (CDCl3) d: 21.2, 23.3, 29.6, 61.3, 71.3, 115.7,
150.7, 171.9. HRMS Calcd for C6H10O [MK C2H4O]
112.05243. Found 112.0515.
3.1.18. (Z)-1-[2-(2-Hydroxy-cyclobutylidene)-ethyl]-5-
methyl-1H-pyrimidine-2,4-dione 6. With the same pro-
cedure as for 3 from protected alcohol 26 (0.16 g,
0.48 mmol), alcohol 6 was obtained (0.096 g, 91%) as a
white powder, mp 129–130 8C (methanol/ether 1/4). IR
(film, cmK1): 3452, 1680, 1640, 1104. 1H NMR (CD3OD) d:
1.88 (3H, s), 1.90 (1H, m), 2.30 (2H, m), 2.40 (1H, m), 4.39
(1H, dd, JZ14.2, 8.3 Hz), 4.48 (1H, dd, JZ14.2, 7.0 Hz),
4.85 (2H, br s), 5.26 (1H, m), 7.50 (1H, s). 13C NMR
(CD3OD) d: 14.0, 25.7, 31.8, 47.8, 73.5, 113.0, 118.5, 144.5,
144.6, 153.8, 154.7, 168.7. Anal. Calcd for C11H14N2O: C,
59.45, H, 6.35, N, 12.61. Found C, 59.39, H, 6.41, N, 12.69.
3.1.23. (E)-Acetic acid 2-[2-(6-amino-purin-9-yl)-cyclo-
butylidene]-ethyl ester 32. With the same procedure as for
21 from 30 (0.047 g, 0.3 mmol), alcohol 32 was obtained
(0.03 g, 37%) as a white powder, mp 155–157 8C (metha-
1
nol). IR (film, cmK1): 1727, 1675, 1606, 1571, 1240. H
NMR (CDCl3) d: 2.06 (3H, s), 2.49 (1H, m), 2.74 (2H, m),
2.93 (1H, m), 4.56 (2H, m), 5.44 (1H, m), 5.71 (1H, m), 5.93
(2H, br s), 7.98 (1H, s), 8.36 (1H, s). 13C NMR (CDCl3) d:
20.6, 24.7, 27.7, 53.1, 60.4, 117.5, 119.4, 138.7, 145.1,
149.8, 152.9, 155.7, 170.7. Anal. Calcd for C13H15N5O2: C,
57.13, H, 5.53, N, 25.63. Found C, 57.14, H, 5.65, N, 25.11.
3.1.19. (E)-Acetic acid 2-[2-(tert-butyldiphenyl-silanyl-
oxy)-cyclobutylidene]-ethyl ester 28. To a solution of
alcohol 18 (0.252 g, 0.71 mmol) in pyridine (10 mL) at 0 8C
acetic anhydride (0.3 mL, 3.18 mmol) was added slowly.
After 10 min at this temperature the mixture was stirred for
one night at rt. Dichloromethane (15 mL) was added and the
organic layer was washed with water, the aqueous layer was
extracted with dichloromethane (2!20 mL) and the
combinated organic layers were dried (MgSO4) then
evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel to afford
28 (0.245 g, 87%) as a colorless oil. IR (film, cmK1): 1744,
3.1.24. (Z)-Acetic acid 2-[2-(6-amino-purin-9-yl)-cyclo-
butylidene]-ethyl ester 33. With the same procedure as for
21 from 31 (0.384 g, 2.46 mmol), alcohol 33 was obtained
(0.296 g, 44%) as a white powder, mp 155–157 8C
1
(methanol). IR (film, cmK1). H NMR (CDCl3) d: 1.88
(3H, s), 2.47 (1H, m), 2.74 (2H, m), 2.90 (1H, m), 4.07 (1H,
ddd, JZ12.8, 7.4, 1.0 Hz), 4.21 (1H, ddd, JZ12.8, 6.8,
1.5 Hz), 5.63 (1H, m), 5.81 (1H, m), 5.85 (1H, br s), 7.98
(1H, s), 8.38 (1H, s). 13C NMR (CDCl3) d: 20.6, 26.3, 27.3,
53.0, 59.6, 119.7, 119.9, 139.0, 144.4, 149.5, 153.0, 155.9,
170.5. Anal. Calcd for C13H15N5O2: C, 57.13, H, 5.53, N,
25.63. Found C, 57.16, H, 5.56, N, 25.41.
1
1237, 1117, 704. H NMR (CDCl3) d: 1.07 (9H, s), 2.03
(3H, m), 2.07 (3H, s), 2.48 (1H, m), 4.51 (2H, m), 4.69 (1H,
m), 5.58 (1H, m), 7.39 (6H, m), 7.67 (4H, m). 13C NMR
19.1, 21.0, 21.7, 26.8, 30.0, 61.1, 71.5, 112.8, 127.5, 127.6,
129.6, 133.7, 134.0, 135.5, 150.9, 170.9. Anal. Calcd for
C24H30O3Si: C, 73.05, H, 7.66. Found C, 72.96, H, 7.76.
3.1.25. (E)-2-[2-(6-Amino-purin-9-yl)-cyclobutylidene]-
ethanol 7. A solution of 32 (0.112 g, 0.41 mmol) in
methanol saturated with ammonia (9.5 mL) was stirred for
15 h at rt. After removal of the volatile substances, the
residue was purified by column chromatography on silica
gel to give 7 (0.095 g, 100%) as a white powder, mp 192 8C.
IR (film, cmK1): 3120, 1684, 1614, 1571. 1H NMR (DMSO-
d6): d: 2.57 (3H, m), 2.80 (1H, m), 3.90 (2H, m), 4.53 (1H,
br s), 5.23 (1H, m), 5.56 (1H, m), 7.18 (2H, s), 8.15 (1H, s),
8.25 (1H, s). 13C NMR (DMSO-d6): 24.2, 26.0, 52.9, 57.3,
3.1.20. (Z)-Acetic acid 2-[2-(tert-butyldiphenyl-silanyl-
oxy)-cyclobutylidene]-ethyl ester 29. With the same
procedure as above from alcohol 19 (1.473 g, 4.18 mmol),
pyridine (30 mL) and acetic anhydride (1 mL, 10.6 mmol),
29 (1.548 g, 94%) was obtained as a colorless oil. IR (film,
1
cmK1): 1742, 1233, 1114, 705. H NMR (CDCl3) d: 1.07
(9H, s), 1.80 (2H, m), 2.06 (3H, s), 2.09 (1H, m), 2.28 (1H,

S. Danappe et al. / Tetrahedron 61 (2005) 5782–5787
5787
118.7, 122.3, 139.1, 140.9, 149.3, 152.3, 155.9. Anal. Calcd
for C11H13N5O$0.1 H2O: C, 56.69, H, 5.71, N, 30.05. Found
C, 56.53, H, 5.73, N, 29.67.
methyl-1H-pyrimidine-2,4-dione 10. With the same pro-
cedure as for 25 from acetate 35 (0.118 g, 0.32 mmol),
alcohol 10 was obtained (0.065 g, 91%) as a white powder,
mp 177 8C (methanol). IR (film, cmK1) 3450, 3165, 1739,
1
3.1.26. (Z)-2-[2-(6-Amino-purin-9-yl)-cyclobutylidene]-
ethanol 9. With the same procedure as above from acetate
33 (0.29 g, 1.06 mmol), alcohol 9 was obtained (0.245 g,
100%) as a white powder, mp 159.5–160.5 8C (methanol).
1675, 1641, 1226. H NMR (CD3OD) d: 1.89 (3H, d, JZ
1 Hz), 2.21 (1H, m), 2.44 (1H, m), 2.59 (1H, m), 2.69 (1H,
m), 3.84 (2H, m), 5.54 (1H, m) 5.69 (1H, m), 7.54 (1H, q,
JZ1 Hz). 13C NMR (CD3OD) d: 12.4, 26.3, 26.5, 56.1,
58.9, 111.9, 125.8, 139.6, 141.7, 152.5, 166.5. Anal. Calcd
for C11H14N2O3: C, 59.45, H, 6.35, N, 12.60. Found C,
59.36, H, 6.42, N, 12.57.
1
IR (film, cmK1): 3271, 3120, 1683, 1612, 1573, 1000. H
NMR (DMSO-d6) d: 2.52 (2H,m), 2.62 (1H, m), 2.77 (1H, m),
3.36 (1H, m), 3.45 (1H, m), 4.39 (1H, m), 5.42 (1H, m), 5.66
(1H, m), 7.17 (1H, s), 8.14 (1H, s), 8.22 (1H,s). 13C NMR
(DMSO-d6): 25.4, 26.0, 52.3, 56.5, 118.7, 125.2, 139.3, 139.5,
149.0, 152.3, 155.9. Anal. Calcd for C11H13N5O: C, 57.13, H,
6.67, N, 30.28. Found C, 56.81, H, 5.59, N, 30.23.
Acknowledgements
We acknowledge Dr. Tran Thy Thu Thui for preliminary
works.
3.1.27. (E)-Acetic acid 2-[2-(3-benzoyl-5-methyl-2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-cyclobutylidene]-
ethyl ester 34. With the same procedure as for 21 from 31
(0.086 g, 0.55 mmol), alcohol 34 was obtained (0.151 g,
74%) as a white powder, mp 124–125 8C (methanol). IR
(film, cmK1): 1751, 1725, 1691, 1655, 1646, 1229. 1H NMR
(CDCl3) d: 1.97 (3H, s), 2.07 (3H, s), 2.21 (1H, m), 2.51
(1H, m), 2.60 (1H, m), 2.79 (1H, m), 4.51 (1H, ddd, JZ12.7,
6.1, 1.5 Hz), 4.61 (1H, ddd, JZ12.7, 7.4, 0.8 Hz), 5.45 (1H,
m), 5.68 (1H, m), 7.30 (1H, s), 7.49 (2H, m), 7.64 (1H, m),
7.92 (2H, m). 13C NMR (CDCl3) d: 12.5, 20.8, 24.2, 26.2,
54.6, 60.4, 111.1, 117.9, 129.0, 130.3, 131.5, 134.9, 136.4,
144.4, 149.6, 162.6, 168.9, 170.7. Anal. Calcd for
C20H20N2O5: C, 65.21, H, 5.47, N, 7.60. Found C, 65.33,
H, 5.65, N, 7.41.
References and notes
1. For reviews see for instance: Huryn, D. M.; Okabe, M. Chem.
Rev. 1992, 92, 1745–1768. Borthwick, A. D.; Biggadike, K.
Tetrahedron 1992, 48, 571–623. Agrofoglio, L.; Suhas, E.;
Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R.
Tetrahedron 1994, 50, 10611–10670. Herdewijn, P. Drug
Discov. Today 1997, 2, 235–242. Crimmins, M. T.
Tetrahedron 1998, 54, 9229–9272. De Clercq, E. Collect.
Czech. Chem. Commun. 1998, 63, 449–479. Agrofoglio, L. A.;
Challand, S. R. In Acycllic, carbocyclic and L-nucleosides;
Kluwer Academic: Dordrecht, 1998. Ichikawa, E.; Kato, K.
Synthesis 2002, 1–28. De Clercq, E.; Neyts, J. Rev. Med. Virol.
2004, 14, 289–300.
3.1.28. (Z)-Acetic acid 2-[2-(3-benzoyl-5-methyl-2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-cyclobutylidene]-
ethyl ester 35. With the same procedure as for 21 from 31
(0.052 g, 0.33 mmol), alcohol 35 was obtained (0.104 g,
86%) as a white powder, mp 127–130 8C (methanol). IR
(film, cmK1): 1732, 1686, 1641, 1598, 1230. 1H NMR
(CDCl3) d: 1.99 (3H, s), 2.01 (3H, s), 2.21 (1H, m), 2.54
(1H, m), 2.64 (1H, m), 2.71 (1H, m), 4.41 (2H, m), 5.64 (1H,
m), 5.77 (1H, m), 7.32 (1H, s), 7.51 (2H, m), 7.65 (1H, m),
7.95 (2H, m). 13C NMR (CDCl3) d: 12.4, 20.5, 25.5, 25.6,
54.6, 59.6, 111.1, 119.7, 129.0, 130.3, 131.4, 134.8, 136.6,
144.0, 149.3, 162.5, 168.8, 170.3. Anal. Calcd for
C20H20N2O5$0.2 H2O: C, 64.58, H, 5.53, N, 7.53. Found
C, 64.52, H, 5.54, N, 7.81.
2. Qiu, Y.-L.; Ksebati, M. B.; Zemlicka, J. Nucleosides
Nucleotides Nucleic Acids 2000, 19, 31–37.
3. Panda, J.; Ghosh, S.; Ghosh, S. J. Chem. Soc., Perkin Trans. 1
2001, 3013–3016.
4. Guan, H.-P.; Ksebati, M. B.; Cheng, Y.-C.; Drach, J. C.; Kern,
E. R.; Zemlicka, J. J. Org. Chem. 2000, 65, 1280–1290.
5. Guan, H.-P.; Ksebati, M. B.; J, C.; Kern, E. R.; Zemlicka, J.
J. Org. Chem. 2000, 65, 5177–5184.
6. Demaison, C.; Hourioux, C.; Roingeard, P.; Agrofoglio, L. A.
Tetrahedron Lett. 1998, 39, 9175–9178.
7. (a) Gourdel-Martin, M.-E.; Huet, F. J. Org. Chem. 1997, 62,
2166–2172. (b) Gourdel-Martin, M.-E.; Huet, F. Nucleosides
Nucleotides 1999, 18, 645–648. (c) Gauvry, N.; Bhat, L.;
3.1.29. (E)-1-[2-(2-Hydroxy-ethylidene)-cyclobutyl]-5-
methyl-1H-pyrimidine-2,4-dione 8. With the same pro-
cedure as for 25 from acetate 34 (0.163 g, 0.44 mmol),
alcohol 8 was obtained (0.085 g, 87%) as a white powder,
mp 133–139 8C (methanol). IR (film, cmK1): 3422, 3022,
´
Mevellec, L.; Zucco, M.; Huet, F. Eur. J. Org. Chem. 2000,
2717–2722. (d) Gauvry, N.; Huet, F. J. Org. Chem. 2001, 66,
583–588. (e) Hubert, C.; Alexandre, C.; Aubertin, A.-M.;
Huet, F. Tetrahedron 2002, 58, 3575–3578.
1
1673, 1636, 1265. H NMR (CD3OD) d: 1.89 (3H, d, JZ
1 Hz), 2.24 (1H, m), 2.41 (1H, m), 2.56 (1H, m), 2.75 (1H,
m), 4.06 (2H, m), 5.37 (1H, m), 5.61 (1H, m), 7.57, (1H, q,
JZ1 Hz). 13C NMR(CD3OD) d: 12.4, 24.8, 26.8, 56.2, 59.1,
111.8, 123.2, 139.4, 143.4, 152.9, 166.5. Anal. Calcd for
C11H14N2O3: C, 59.45, H, 6.35, N, 12.60. Found C, 59.21,
H, 6.44, N, 12.28.
8. (a) Hubert, C.; Alexandre, C.; Aubertin, A.-M.; Huet, F.
Tetrahedron 2003, 59, 3127–3130. (b) Guillarme, S.;
Legoupy, S.; Bourgougnon, N.; Aubertin, A.-M.; Huet, F.
Tetrahedron 2003, 59, 9635–9639.
9. Bloomfield, J. J.; Nelke, J. M. In Organic syntheses, Collect.
Vol. 6; Wiley: New York, 1988; p 167.
10. Kazunori, T.; Akio, M. Tetrahedron Lett. 1992, 33,
4345–4348.
3.1.30. (Z)-1-[2-(2-Hydroxy-ethylidene)-cyclobutyl]-5-