Efficient synthesis of new nucleoside analogues with a methylenecyclobutane unit

Article abstract of DOI:10.1080/00397910600908918

Synthesis of eight nucleoside analogues 4-11 with a methylenecyclobutane unit is described. Wittig reaction with 2-hydroxymethylcyclobutanone 12 gave a mixture of Z (13) and E (14) derivatives, which was separated before functional modifications. The hete

Full text of DOI:10.1080/00397910600908918

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Efficient Synthesis of New Nucleoside
Analogues with a Methylenecyclobutane Unit
Sophie Danappe a , Fabien Boeda a , Christian Alexandre a , Anne‐Marie
Aubertin b , Nathalie Bourgougnon c & François Huet a
a Laboratory of Organic Synthesis, Faculty of Sciences , University of Maine ,
Le Mans, France
b Institute of Virology, Faculty of Medicine , University Louis Pasteur ,
Strasbourg, France
c Laboratory of Molecular Biology and Chemistry, Research and Teaching
Center Yves Coppens , Campus de Tohannic, Vannes, France
Published online: 24 Nov 2006.
To cite this article: Sophie Danappe , Fabien Boeda , Christian Alexandre , Anne‐Marie Aubertin ,
Nathalie Bourgougnon & François Huet (2006) Efficient Synthesis of New Nucleoside Analogues with a
Methylenecyclobutane Unit, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:21, 3225-3239, DOI: 10.1080/00397910600908918
To link to this article: http://dx.doi.org/10.1080/00397910600908918
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Synthetic Communicationsw, 36: 3225–3239, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600908918
Efficient Synthesis of New Nucleoside
Analogues with a Methylenecyclobutane
Unit
Sophie Danappe, Fabien Boeda, and Christian Alexandre
Laboratory of Organic Synthesis, Faculty of Sciences, University of
Maine, Le Mans, France
Anne-Marie Aubertin
Institute of Virology, Faculty of Medicine, University Louis Pasteur,
Strasbourg, France
Nathalie Bourgougnon
Laboratory of Molecular Biology and Chemistry, Research and Teaching
Center Yves Coppens, Campus de Tohannic, Vannes, France
Franc¸ois Huet
Laboratory of Organic Synthesis, Faculty of Sciences, University of
Maine, Le Mans, France
Abstract: Synthesis of eight nucleoside analogues 4–11 with a methylenecyclobutane
unit is described. Wittig reaction with 2-hydroxymethylcyclobutanone 12 gave a
mixture of Z (13) and E (14) derivatives, which was separated before functional
modifications. The heterocyclic moieties were introduced via a Mitsunobu reaction
either on the saturated chain or on the unsaturated chain. When adenine was used
in this reaction, only the N-9 substitution products were obtained. Removal of the
protecting groups provided the target products.
Keywords: Mitsunobu reaction, nucleoside analogues, total synthesis, Wittig reaction
Received in Poland March 29, 2006
Address correspondence to Franc¸ois Huet, Laboratory of Organic Synthesis, UMR
CNRS 6011, Faculty of Sciences, University of Maine, Le Mans, France. E-mail:
fhuet@univ-lemans.fr or calexan@univ-lemans.fr
3225

3226
S. Danappe et al.
INTRODUCTION
Among nucleoside analogues synthesized in recent years, some displayed
significant antiviral activity. The most important modifications concerned the
sugar part of the nucleoside. In many cases, the oxygen in the furanose ring
was substituted by a methylene group to stabilize the structure toward
hydolysis.[1] A large number of solutions were proposed to link the two
important groups that are necessary to confer antiviral activity, the heterocyclic
base and the hydroxyl group. The spacers may be rigid as in thymallene[2] or
adenallen[3] or flexible as in acyclovir.[4] Other compounds with various
arrangements of a double bond and the cycle were also prepared. For
example, the methylenecyclopropane derivative 1[5] is an efficient anti-HIV
agent. Our group has already synthesized methylenecyclobutane analogues 2
and 3,[6] but none of them had significant antiviral activity (Fig. 1).
Another factor that may influence antiviral activity is the distance between
the two functional groups. The structure modifications that were proposed
covered increasing the length of the chain and modification of the flexibility
of this one. This chain flexibility allowed the synthetic substance to improve
interaction with enzymes.[7] In continuation of our efforts to synthesize nucleo-
side analogues, we explore the synthetic feasibility of analogues with a sup-
plementary methylene group. In this article, synthesis of eight compounds,
4–11 with a methylenecyclobutane unit is described (Fig. 2).
RESULTS AND DISCUSSION
For the synthesis of all compounds 4–11, 2-hydroxymethylcyclobutanone 12[8]
was a convenient starting material (Scheme 1). Reaction of alcohol 12 with
Figure 1. Examples of nucleoside analogues.
Figure 2. Target compounds.

Nucleoside Analogues with Methylenecyclobutane
3227
Scheme 1. Synthesis of methylenecyclobutane unit: Ph3P ¼ CHCOOEt, toluene,
808C, 3 d.
carbethoxymethylene–triphenylphosphorane gave a mixture of isomers 13 (Z)
and 14 (E) in 74% total yield (ratio Z/E, 1/1). The mixture was separated by
column chromatography on silica gel to afford pure alcohols 13 and 14. Con-
figurations of double bonds were established by nuclear Overhauser effect
(NOE) experiments.
These two products, 13 and 14, were precursors for the series Z (4, 5, 8, and
9) and E (6, 7, 10, and 11) respectively. The sequence was the same in both
cases (Scheme 2). Protection of alcohol 13 with t-butylchlorodimethylsilane
gave ester 15, which was reduced with diisobutylaluminium hydride
(DIBAL-H)[9] to afford alcohol 17. Under Mitsunobu conditions, 17 reacted
Scheme 2. Synthesis of the nucleoside analogues 4–7: (a) tBuMe2SiCl, imidazole,
DMF, 20 h, rt; (b) DIBAL-H, CH2Cl2/toluene, 2 608C, 2 h; (c) adenine, Ph3P,
DIAD, THF, 7 d; (d) TBAF, THF 2.5 h, rt; (e) N-3-benzoylthymine, Ph3P, DIAD,
THF, 7 d; and (f) NH3/MeOH, 48 h, rt.

3228
S. Danappe et al.
Scheme 3. Synthesis of the nucleoside analogues 8–11. (a) Ac2O, pyridine, 14 h, rt;
(b) TBAF, THF 2.5 h, rt; (c) adenine, Ph3P, DIAD, THF, 7 d; (d) NH3/MeOH, 14 h, rt;
and (e) N-3-benzoylthymine, Ph3P, DIAD, THF, 7 d.
with adenine to give 19. It is worth mentioning that reaction with adenine only
led to the N-9 substitution product, and it was the same in the three other cases
of coupling with adenine. We could not detect any other isomer by NMR
analysis of the crude product. This assignement was proved by 1H/13C hetero-
nuclear multiple bond correlation (HMBC) NMR spectra. A final deprotection
step with tetrabutylammonium fluoride (TBAF) led to nucleoside analogue 4.
This straightforward route yielded the target molecule in 16% yield from
alcohol 12.
Under the same conditions, 17 reacted with N-3-benzoyl thymine to give 21,
which, after two deprotection steps (removal of the benzoyl group with NH3/
MeOH and of the silyl group with tetrabutylammonium fluoride), afforded the
nucleoside analogue 5 in 23% overall yield from 12. Similarly, 18 was
converted into the nucleoside analogues 6 in 15% overall yield from 12, and 7
in 25% overall yield from 12.
Alcohols 17 and 18 were also used to obtain the other nucleoside
analogues in which positions of the base and the hydroxyl group were
inverted (Scheme 3).
Acetylation of alcohol 17 gave acetate 25, which was then deprotected to
give alcohol 27. Under the Mitsunobu condition, 27 reacted with adenine to
afford acetate 29. Deacetylation with NH3/MeOH gave the nucleoside

Nucleoside Analogues with Methylenecyclobutane
3229
analogue 8 in 21% overall yield from 12. N-3-Benzoyl thymine and 27 reacted
in the same conditions to give acetate 31. Treatment of 31 with NH3/MeOH
simultaneously allowed deacetylation and debenzoylation to afford nucleoside
analogue 9 in 31% overall yield from 12. Similarly, alcohol 18 led to the
nucleoside analogues 10 and 11 (27 and 37% overall yield from 12).
Compounds 4 to 11 were tested against HIV-1 and HSV-1; none of them
had a significant antiviral activity.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker AC 400 spectrometer at
400 and 100.6 MHz, respectively. All melting points are uncorrected.
Elemental analyses were performed by the service of microanalyses,
National Center of Scientific Research, Institute of Chemistry of Natural Sub-
stances, Gif sur Yvette. High-resolution mass spectra (HRMS) were recorded
on a Varian Mat 311 or ZabSpec TOF micromass spectrometer at the Regional
Center of Physical measurements of Ouest, Rennes. Infrared spectra were
measured with a FT infrared spectrometer Genesis Matteson instrument.
3-(2-Hydroxymethyl-cyclobutylidene)-Acetic Acid Ethyl Ester
(13) and (14)
Carbethoxymethylene triphenylphosphorane (6.548 g, 18.8 mmol) was added
to a solution of ketone 12 (1.2 g, 12 mmol) in toluene (6 mL). The resulting
mixture was stirred for 3 d at 808C. 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 evap-
orated under reduced pressure to give a mixture of 13 and 14. The resulting oil
was purified by column chromatography on silica gel to give 13 and 14 [(Z) 13
Rf ¼ 0.31, (E) 14 Rf ¼ 0.21, ethyl acetate/toluene 2:8] in a 1/1 ratio (global
yield: 1.517 g, 74%).
1
Isomer (Z) 13 obtained as a colorless oil: H NMR (400 MHz, CDCl3):
d ¼ 1.28 (t, J ¼ 7.2 Hz, 3H), 1.73 (m, 1H), 2.25 (m, 1H), 2.72 (m, 1H),
2.88 (m, 1H), 3.62 (m, 1H), 3.84 (2H, m), 4.17 (m, 3H), 5.72 (m, 1H) ppm.
13C NMR (100.6 MHz, CDCl3) d ¼ 14.0, 20.4, 30.1, 48.0, 60.2, 65.0,
113.7, 167.2, 167.8 ppm. IR (n cm21): 3435, 1716, 1673, 1194. Isomer (E)
14 obtained as a colorless oil: 1H NMR (400 MHz, CDCl3): d ¼ 1.27
(t, J ¼ 7.2 Hz, 3H), 1.93 (m, 1H), 2.22 (m, 1H), 3.07 (m, 2H), 3.29
(m, 1H), 3.70 (dd, J ¼ 10.8, 6.4 Hz, 1H), 3.78 (dd, J ¼ 10.8, 6.4 Hz, 1H),
4.15 (q, J ¼ 7.2 Hz, 2H), 5.73 (m, 1H) ppm. 13C NMR (100.6 MHz,
CDCl3) d ¼ 14.2, 20.6, 31.0, 46.5, 59.7, 63.9, 112.5, 166.5, 167.7 ppm. IR
(n cm21): 3450, 1713, 1673, 1191. Anal. calcd. for C9H14O3, 0.15 H2O: C,
62.52; H, 8.34. Found: C, 62.49; H, 8.37.

3230
S. Danappe et al.
(Z)-3-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutylidene]-
acetic Acid Ethyl Ester (15)
Imidazole (192 mg, 2.83 mmol) and tertio-butylchlorodimethylsilane
(409 mg, 2.71 mmol) were added to a solution of alcohol 13 (384 mg,
2.26 mmol) in DMF (2 mL). The resulting mixture was stirred for 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
1
silica gel to give 15 (562 mg, 87%) as a colorless oil. H NMR (400 MHz,
CDCl3): d ¼ 0.03 (s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.27 (t, J ¼ 7.2 Hz,
3H), 2.08 (m, 1H), 2.17 (m, 1H), 2.62 (m, 1H), 2.84 (m, 1H), 3.53 (m, 1H),
3.90 (m, 2H), 4.14 (q, J ¼ 7.2 Hz, 2H), 5.61 (m, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 25.4, 14.3, 18.3, 20.6, 30.5, 25.9, 47.9, 59.5,
63.2, 113.6, 165.9, 167.8 ppm. IR (n cm21): 1718, 1676, 1189, 1090, 838.
Anal. calcd. for C15H28O3Si: C, 63.33; H, 9.92. Found: C, 63.31; H, 10.03.
(E)-3-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutylidene]-
acetic Acid Ethyl Ester (16)
With the same procedure as before from alcohol 14 (1.645 g, 9.66 mmol), 16
was obtained as a colorless oil (2.521 g, 92%). 1H NMR (400 MHz, CDCl3):
d ¼ 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.27 (t, J ¼ 7.2 Hz, 3H), 1.83
(m, 1H), 2.17 (m, 1H), 3.03 (m, 2H), 3.22 (m, 1H), 3.67 (dd, J ¼ 11.3,
6.9 Hz, 1H), 3.70 (dd, J ¼ 11.3, 6.4 Hz, 1H), 4.14 (q, J ¼ 7.2 Hz, 2H), 5.70
(m, 1H) ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 25.4, 14.3, 18.2, 20.7,
31.0, 25.8, 46.6, 59.5, 64.7, 112.5, 166.5, 168.2 ppm. IR (n cm21): 1716,
1676, 1189, 1084, 838. Anal. calcd. for C15H28O3Si: C, 63.33; H, 9.92.
Found: C, 63.31; H, 10.03.
(Z)-2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutylidene]-
ethanol (17)
A 1 M solution of DIBAL-H in toluene (26 mL) was added dropwise to a
stirred solution of ester 15 (2.513 g, 8.83 mmol) in dry dichloromethane
(185 mL) at –608C. The mixture was stirred for 2 h at this temperature.
A solution of 10% citric acid (150 mL) was added at 2208C, the aqueous
layer was extracted with toluene (2 ꢀ 50 mL), and 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
(1.987 g, 93%) as a colorless oil. H NMR (400 MHz, CDCl3): d ¼ 0.10
(s, 3H), 0.11 (s, 3H), 0.92 (s, 9H), 1.53 (m, 1H), 2.14 (m, 1H), 2.57
(m, 1H), 2.72 (m, 1H), 3.13 (br s, 1H), 3.29 (m, 1H), 3.67 (dd, J ¼ 9.8,

Nucleoside Analogues with Methylenecyclobutane
3231
9.3 Hz, 1H), 3.77 (dd, J ¼ 9.8, 5.4 Hz, 1H), 4.06 (m, 2H), 5.44 (m, 1H) ppm.
13C NMR (100.6 MHz, CDCl3) d ¼ 25.5, 18.4, 19.8, 28.7, 25.9, 44.4, 59.9,
66.1, 122.0, 143.4 ppm. IR (n cm21): 3367, 1255, 1089, 843. Anal. calcd.
for C13H26O2Si: C, 64.41; H, 10.81. Found: C, 64.41, H, 11.01.
(E)-2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutylidene]-
ethanol (18)
With the same procedure as before from ester 16 (2.496 g, 8.77 mmol), 18 was
obtained as a colorless oil (2.054, 97%). 1H NMR (400 MHz, CDCl3):
d ¼ 0.05 (s, 6H), 0.89 (s, 9H), 1.18 (t J ¼ 4.9 Hz, 1H), 1.74 (m, 1H), 2.08
(m, 1H), 2.63 (m, 2H), 3.10 (m, 1H), 3.63 (dd, J ¼ 10.3, 6.9 Hz, 1H), 3.68
(dd, J 10.3, 6.9 Hz, 1H), 4.03 (m, 2H), 5.45 (m, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 25.3, 18.3, 20.6, 26.5, 25.9, 45.5, 59.3, 65.6,
119.7, 146.0 ppm. IR (n cm21): 3343, 1259, 1088, 841. Anal. calcd. for
C13H26O2Si: C, 64.41; H, 10.81. Found: C, 64.08; H, 10.93.
(Z)-9-f2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethylg-9H-purin-6-ylamine (19)
A solution of DIAD (0.34 mL) in THF (8 mL) was added dropwise to a
solution of alcohol 17 (250 mg, 1.03 mmol), triphenylphosphine (580 mg)
and adenine (295 mg) in THF (8 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 19 (140 mg,
38%) as a white solid. Mp: 159–1618C. 1H NMR (400 MHz, CDCl3):
d ¼ 0.05 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 1.69 (m, 1H), 2.14 (m, 1H),
2.60 (m, 1H), 2.73 (m, 1H), 3.32 (m, 1H), 3.78 (m, 2H), 4.74 (dd, J ¼ 14.5,
7.4 Hz, 1H), 4.86 (dd, J ¼ 14.5, 7.4 Hz, 1H), 5.44 (m, 1H), 5.76 (br s, 2H),
7.87 (s, 1H), 8.37 (s, 1H) ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 25.8,
17.9, 19.0, 28.0, 25.4, 41.2, 65.1, 44.6, 115.3, 119.2, 148.1, 149.5, 155.1,
139.8, 152.3 ppm. IR (n cm21): 1672, 1601, 1569, 1307, 1033. Anal. calcd.
for C18H29N5OSi: C, 60.13; H, 8.13. Found: C, 60.22; H, 8.28.
(E)-9-f2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethylg-9H-purin-6-ylamine (20)
With the same procedure as before from alcohol 18 (250 mg, 1.03 mmol), 20
was obtained as a colorless oil (119 mg, 32%). 1H NMR (400 MHz, CDCl3):
d ¼ 0.02 (2s, 6H), 0.87 (s, 9H), 1.80 (m, 1H), 2.11 (m, 1H), 2.67 (m, 2H), 3.14
(m, 1H), 3.65 (dd, J ¼ 12.3, 6.9 Hz, 1H), 3.67 (dd, J ¼ 12.3, 6.4 Hz, 1H), 4.66
(d, J ¼ 7.4 Hz, 2H), 5.53 (m, 1H), 5.73 (br s, 2H), 7.81 (s, 1H), 8.38 (s, 1H)

3232
S. Danappe et al.
ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 25.4, 18.3, 20.0, 26.6, 25.8, 41.1,
65.2, 45.4, 113.8, 119.7, 149.5, 150.0, 155.4, 140.1, 152.9 ppm. IR (n
cm21): 3125, 1673, 1603, 1572, 1083, 833. Anal. calcd. for C18H29N5OSi:
C, 60.13; H, 8.13; N, 19.48. Found: C, 60.12; H, 8.16; N, 19.41.
(Z)-f2-[2-(6-Amino-purin-9-yl)-ethylidene]-cyclobutylg-
methanol (4)
Tetrabutylammonium fluoride (1M, 0.57 mL) was added to a solution of the
protected alcohol 19 (127 mg, 0.37 mmol) in THF (4 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
1
give alcohol 4 (78 mg, 90%) as a white solid. Mp: 173–1748C. H NMR
(400 MHz, CDCl3): d ¼ 1.65 (m, 1H), 2.02 (m, 1H), 2.48 (m, 1H), 2.63
(m, 1H), 3.27 (m, 1H), 3.62 (dd, J ¼ 6.9, 5.4 Hz, 2H), 4.66 (dd, J ¼ 14.8,
7.9 Hz, 1H), 4.74 (dd, J ¼ 14.8, 7.4 Hz, 1H), 5.09 (t, J ¼ 5.4 Hz, 1H), 5.35
(m, 1H), 7.21 (br s, 2H), 8.10 (s, 1H), 8.13 (s, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 19.3, 27.9, 41.2, 44.9, 63.3, 116.3, 118.8, 140.4,
146.9, 149.2, 152.3, 156.0 ppm. IR (n cm21): 3118, 1687, 1607, 1576,
1302, 1062. Anal. calcd. for C12H15N5O: C, 58.76, H, 6.16, N, 28.55.
Found: C, 58.61, H; 6.28; N, 28.43.
(E)-f2-[2-(6-Amino-purin-9-yl)-ethylidene]-cyclobutylg-
methanol (6)
With the same procedure as before from the protected alcohol 20 (111 mg,
0.31 mmol), 6 was obtained as a white solid (70 mg, 92%). Mp: 190–192 8C.
1H NMR (400 MHz, CDCl3): d ¼ 1.68 (m, 1H), 1.99 (m, 1H), 2.62 (m, 2H),
2.99 (m, 1H), 3.42 (m, 2H), 4.56 (t, J ¼ 5.4 Hz, 1H), 4.58 (d, J ¼ 7.9 Hz, 2H),
5.46 (m, 1H), 7.20 (br s, 2H), 8.10 (s, 1H), 8.13 (s, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 20.1, 26.1, 40.5, 45.3, 63.5, 114.7, 118.7, 140.5,
147.5, 149.3, 152.4, 155.9 ppm. IR (n cm21): 3100, 1679, 1603, 1576, 1305,
1033. Anal. calcd. for C12H15N5O: C, 58.76; H, 6.16. Found: C, 58.49; H, 6.27.
(Z)-3-Benzoyl-1-f2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethylg-5-methyl-1H-pyrimidine-2,4-dione (21)
With the same procedure as for 19, from the protected alcohol 17 (250 mg,
1.03 mmol) and N3-benzoylthymine (502 mg, 2.18 mmol), 21 was obtained as
a white solid (328 mg, 70%). Mp: 988C (Et2O). 1H NMR (400 MHz, CDCl3):
d ¼ 0.08 (s, 6H), 0.91 (s, 9H), 1.64 (m, 1H), 1.99 (d, J ¼ 1.0 Hz, 3H), 2.13
(m, 1H), 2.62 (m, 1H), 2.72 (m, 1H), 3.23 (m, 1H), 3.74 (m, 2H), 4.30 (dd,

Nucleoside Analogues with Methylenecyclobutane
3233
J ¼ 14.5, 7.3 Hz, 1H), 4.49 (dd, J ¼ 14.5, 7.3 Hz, 1H), 5.26 (m, 1H), 7.22
(q, J ¼ 1.0 Hz, 1H), 7.49 (m, 2H), 7.63 (m, 1H), 7.93 (m, 2H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 25.4, 12.4, 18.4, 19.3, 28.5, 25.9, 45.1, 45.8, 65.7,
110.3, 115.6, 129.0, 130.4, 131.7, 134.8, 139.7, 149.2, 149.9, 163.2,
169.2 ppm. IR (n cm21): 1744, 1687, 1645, 1086, 831. Anal. calcd. for
C25H34N2O4Si: C, 66.05; H, 7.54; N, 6.16. Found: C, 65.93; H, 7.65; N, 6.11.
(E)-3-Benzoyl-1-f2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethylg-5-methyl-1H-pyrimidine-2,4-dione (22)
With the same procedure as before from the protected alcohol 18 (250 mg,
1.03 mmol) and N3-benzoylthymine (502 mg, 2.18 mmol), 22 was obtained as
1
a white solid (282 mg, 60%). Mp: 97–988C (Et2O). H NMR (400 MHz,
CDCl3): d ¼ 0.05 (2, 6H), 0.90 (s, 9H), 1.80 (m, 1H), 1.95 (d, J ¼ 1.5 Hz,
3H), 2.11 (m, 1H), 2.68 (m, 2H), 3.13 (m, 1H), 3.65 (dd, J ¼ 12.8, 6.4 Hz,
1H), 3.67 (dd, J ¼ 12.8. 6.4 Hz, 1H), 4.21 (d, J ¼ 6.9 Hz, 2H), 5.34 (m, 1H),
7.08 (q, J ¼ 1.5 Hz, 1H), 7.48 (m, 2H), 7.63 (m, 1H), 7.92 (m, 2H) ppm.13C
NMR (100.6 MHz, CDCl3) d ¼ 25.4, 12.4, 18.2, 19.9, 26.7, 25.8, 45.4, 65.1,
45.4, 110.6, 113.6, 129.0, 130.3, 131.6, 134.8, 139.4, 149.8, 150.0, 163.1,
169.1 ppm. IR (n cm21): 1744, 1690, 1641, 1087, 835. Anal. calcd. for
C25H34N2O4Si: C, 66.05, H, 7.54; N, 6.16. Found: C, 65.66; H, 7.39; N, 6.08.
(Z)-1-f2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethylg-5-methyl-1H-pyrimidine-2,4-dione (23)
A solution of 21 (289 mg, 0.64 mmol) in methanol saturated with ammonia
(9.5 mL) was stirred for 14 h at rt. After removal of the volatile substances,
the residue was purified by column chromatography on silica gel to give 25
1
(209 mg, 93%) as a white powder. Mp: 130–1318C. H NMR (400 MHz,
CDCl3): d ¼ 0.07 (2s, 6H), 0.90 (s, 9H), 1.63 (m, 1H), 1.92 (d, J ¼ 1.0 Hz,
3H), 2.12 (m, 1H), 2.60 (m, 1H), 2.71 (m, 1H), 3.23 (m, 1H), 3.71 (dd,
J ¼ 10.3, 8.4 Hz, 1H), 3.76 (dd, J ¼ 10.3, 5.9 Hz, 1H), 4.27 (dd, J ¼ 14.3,
6.9 Hz, 1H), 4.44 (dd, J ¼ 14.3, 7.9 Hz, 1H), 5.23 (m, 1H), 7.11
(q, J ¼ 1.0 Hz, 1H), 8.46 (br s, 1H) ppm. 13C NMR (100.6 MHz, CDCl3)
d ¼ 25.4, 12.3, 18.3, 19.3, 28.4, 25.9, 45.0, 45.5, 65.7, 110.3, 116.0, 139.9,
148.5, 151.1, 164.5 ppm. IR (n cm21): 1675, 1639, 1079, 832. Anal. calcd.
for C18H30N2O3Si: C, 61.68; H, 8.63. Found: C, 61.37; H, 8.61.
(E)-1-f2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethylg-5-methyl-1H-pyrimidine-2,4-dione (24)
With the same procedure as before from the protected alcohol 22 (269 mg,
0.59 mmol), 24 was obtained as a white solid (188 mg, 91%). Mp:

3234
S. Danappe et al.
152.8–153.48C. 1H NMR (400 MHz, CDCl3): d ¼ 0.03 (s, 3H), 0.04 (s, 3H),
0.88 (s, 9H), 1.80 (m, 1H), 1.92 (d, J ¼ 1.0 Hz, 3H), 2.10 (m, 1H), 2.68
(m, 2H), 3.12 (m, 1H), 3.65 (m, 2H), 4.20 (d, J ¼ 6.9 Hz, 2H), 5.31
(m, 1H), 6.96 (q, J ¼ 1.0 Hz, 1H), 8.41 (br s, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 25.4, 12.3, 18.2, 19.9, 26.7, 25.8, 45.1, 65.2,
45.4, 110.6, 114.0, 139.6, 142.3, 151.0, 164.3 ppm. IR (n cm21): 1679,
1651, 1361, 834. Anal. calcd. for C18H30N2O3Si: C, 61.68; H, 8.63; N,
7.99. Found: C, 61.61; H, 8.53; N, 7.81.
(Z)-1-[2-(2-Hydroxymethyl-cyclobutylidene)-ethyl]-5-methyl-1H-
pyrimidine-2,4-dione (5)
With the same procedure as for 4, from the protected alcohol 23 (200 mg,
0.57 mmol), 5 was obtained as a white solid (113 mg, 84%). Mp: 103–
1
1058C. H NMR (400 MHz, CDCl3): d ¼ 1.72 (m, 1H), 1.86 (d, J ¼ 1.0 Hz,
3H), 2.12 (m, 1H), 2.57 (m, 1H), 2.72 (m, 1H), 3.28 (m, 1H), 3.69 (dd,
J ¼ 10.8, 7.4 Hz, 1H), 3.74 (dd, J ¼ 10.8, 6.4 Hz, 1H), 4.25 (dd, J ¼ 14.3,
6.9 Hz, 1H), 4.37 (dd, J ¼ 14.3, 7.4 Hz, 1H), 5.23 (7.47 (1H, q, J ¼ 1.0 Hz,
1H) ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 12.2, 20.6, 29.3, 46.2, 47.0,
65.3, 111.1, 117.2, 142.7, 148.9, 152.9, 166.8 ppm. IR (n cm21): 3448,
3153, 1668, 1635, 1033. Anal. calcd. for C12H16N2O3, 0.2 H2O: C, 60.09;
H, 6.89; N, 11.68. Found: C, 60.11; H, 6.86; N, 11.66.
(E)-1-[2-(2-Hydroxymethyl-cyclobutylidene)-ethyl]-5-methyl-1H-
pyrimidine-2,4-dione (7)
With the same procedure as before from the protected alcohol 24 (175 mg,
0.50 mmol), 7 was obtained as a white solid (106 mg, 90%). Mp: 118.7–
119.18C. 1H NMR (400 MHz, CDCl3): d ¼ 1.86 (m, 1H), 1.92
(d, J ¼ 1.0 Hz, 3H), 2.15 (m, 1H), 2.23 (br s, 1H), 2.70 (m, 2H), 3.19
(m, 1H), 3.70 (m, 2H), 4.16 (dd, J ¼ 14.8, 6.9 Hz, 1H), 4.25 (dd, J ¼ 14.8.
7.4 Hz, 1H), 5.35 (m, 1H), 6.99 (q, J ¼ 1.0 Hz, 1H), 9.53 (br s, 1H) ppm.
13C NMR (100.6 MHz, CDCl3) d ¼ 12.2, 19.9, 26.7, 45.4, 64.3, 110.6,
114.3, 139.9, 148.4, 151.1, 164.5 ppm. IR (n cm21): 3399, 3137, 1679,
1012. Anal. calcd. for C12H16N2O3, 0.1 H2O: C, 60.54; H, 6.86; N, 11.77.
Found: C, 60.44; H, 6.73; N, 11.75.
Acetic Acid (Z)-2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethyl Ester (25)
Acetic anhydride (1.75 mL, 18.4 mmol) was added slowly to a solution of
alcohol 17 (1 g, 4.125 mmol) in pyridine (58 mL) at 08C. After 10 min at this

Nucleoside Analogues with Methylenecyclobutane
3235
temperature, the mixture was stirred for 1 night at rt. Dichloromethane (60 mL)
was added, the organic layer was washed with water, the aqueous layer was
extracted with dichloromethane (2 ꢀ 30 mL), and the combinated organic
layers were dried (MgSO4) and then evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel to afford 25
1
(1.085 g, 92%) as a colorless oil. H NMR (400 MHz, CDCl3): d ¼ 0.06
(s, 6H), 0.90 (s, 9H), 1.69 (m, 1H), 2.05 (s, 3H), 2.09 (m, 1H), 2.56 (m, 1H),
2.68 (m, 1H), 3.19 (m, 1H), 3.69 (d, J ¼ 6.9 Hz, 2H), 4.46 (dd, J ¼ 12.3,
6.4 Hz, 1H), 4.59 (dd, J ¼ 12.3, 8.2 Hz, 1H), 5.34 (m, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 25.4. 18.3, 19.8, 28.6, 21.0, 25.9, 45.0, 61.7, 65.4,
116.3, 148.3, 170.9 ppm. IR (n cm21): 1743, 1234, 1094, 838. Anal. calcd. for
C15H28O3Si: C, 63.33; H, 9.92. Found: C, 63.19; H, 10.01.
Acetic Acid (E)-2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-
cyclobutylidene]-ethyl Ester (26)
With the same procedure as before from the protected alcohol 18 (1 g,
1
4.125 mmol), 26 was obtained as a colorless oil (1.113 g, 95%). H NMR
(400 MHz, CDCl3): d ¼ 0.05 (s, 6H), 0.89 (s, 9H), 1.75 (m, 1H), 2.05 (s, 3H),
2.08 (m, 1H), 2.65 (m, 2H), 3.11 (m, 1H), 3.64 (dd, J ¼ 12.3, 6.4 Hz, 1H),
3.67 (dd, J ¼ 12.3, 6.9 Hz, 1H), 4.45 (d, J ¼ 7.4 Hz, 2H), 5.39 (m, 1H) ppm.
13C NMR (100.6 MHz, CDCl3) d ¼ 25.4, 18.3, 20.3, 26.6, 20.9, 25.9, 45.5,
61.1, 65.4, 114.7, 149.0, 170.9 ppm. IR (n cm21): 1745, 1231, 1092, 841.
Anal. calcd. for C15H28O3Si: C, 63.33; H, 9.92. Found: C, 63.18; H, 9.95.
Acetic Acid (Z)-2-(2-hydroxymethyl-cyclobutylidene)-ethyl
Ester (27)
With the same procedure as for 4, from the protected alcohol 25 (1.053 mg,
3.7 mmol), 27 was obtained as a colorless oil (612 mg, 97%). 1H NMR
(400 MHz, CDCl3): d ¼ 1.77 (m, 1H), 2.06 (s, 3H), 2.11 (m, 1H), 2.59
(m, 1H), 2.70 (m, 1H), 3.27 (m, 1H), 3.71 (dd, J ¼ 11.3, 6.9 Hz, 1H), 3.80
(dd, J ¼ 11.3, 5.9 Hz, 1H), 4.51 (dd, J ¼ 11.8, 6.9 Hz, 1H), 4.58 (dd,
J ¼ 11.8, 8.4 Hz, 1H), 5.36 (m, 1H) ppm. 13C NMR (100.6 MHz, CDCl3)
d ¼ 19.5, 28.5, 21.0, 45.1, 61.7, 64.6, 116.6, 148.1, 171.2 ppm. IR (n
cm21): 3438, 1738, 1241. Anal. calcd. for C9H14O3, 0.1 H2O: C, 62.84; H,
8.32. Found: C, 62.52; H, 8.26.
Acetic Acid (E)-2-(2-hydroxymethyl-cyclobutylidene)-ethyl
Ester (28)
With the same procedure as before from the protected alcohol 26 (1.113 g,
1
3.9 mmol), 28 was obtained as a colorless oil (664 mg, 100%). H NMR

3236
S. Danappe et al.
(400 MHz, CDCl3): d ¼ 1.53 (t, J ¼ 5.9 Hz, 1H), 1.84 (m, 1H), 2.06 (s, 3H),
2.13 (m, 1H), 2.70 (m, 2H), 3.18 (m, 1H), 3.70 (m, 2H), 4.47 (d, J ¼ 7.4 Hz,
2H), 5.41 (m, 1H) ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 20.0, 26.7, 20.8,
45.3, 61.0, 64.4, 114.8, 148.3, 171.1 ppm. IR (n cm21): 3428, 1739, 1238.
Anal. calcd. for C9H14O3, 0.1 H2O: C, 62.84; H, 8.32. Found: C, 62.68; H,
8.29.
Acetic Acid (Z)-2-[2-(6-Amino-purin-9-ylmethyl)-cyclobutylidene]-
ethyl Ester (29)
With the same procedure as for 19, from acetate 27 (250 mg, 1.47 mmol), 29
1
was obtained as a white solid (215 mg, 51%). Mp: 142–143 8C. H NMR
(400 MHz, CDCl3): d ¼ 1.78 (m, 1H), 2.04 (s, 3H), 2.15 (m, 1H), 2.66
(m, 2H), 3.67 (m, 1H), 4.24 (d, J ¼ 7.4 Hz, 2H), 4.38 (dd, J ¼ 14.3, 7.9 Hz,
1H), 4.45 (dd, J ¼ 14.3, 6.9 Hz, 1H), 5.42 (m, 1H), 5.81 (br s, 2H), 7.84
(s, 1H), 8.38 (s, 1H) ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 20.9, 20.8,
28.3, 42.4, 46.4, 60.6, 118.0, 119.3, 140.4, 153.0, 145.8, 150.1, 155.7,
170.7 ppm. IR (n cm21): 3105, 1736, 1674, 1601, 1573, 1229. Anal. calcd.
for C14H17N5O2: C, 58.52; H, 5.96. Found: C, 58.44; H, 6.01.
Acetic acid (E)-2-[2-(6-Amino-purin-9-ylmethyl)-cyclobutylidene]-
ethyl Ester (30)
With the same procedure as before from acetate 28 (251 mg, 1.47 mmol), 30
was obtained as a colorless oil (249 mg, 59%). 1H NMR (400 MHz, CDCl3):
d ¼ 0.82 (m, 1H), 2.05 (s, 3H), 2.17 (m, 1H), 2.72 (m, 2H), 3.58 (m, 1H), 4.28
(dd, J ¼ 13.8, 7.9 Hz, 1H), 4.37 (dd, J ¼ 13.8, 6.9 Hz, 1H), 4.44
(d, J ¼ 7.3 Hz, 2H), 5.22 (m, 1H), 5.90 (br s, 2H), 7.81 (s, 1H), 8.37 (s, 1H)
ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 20.8, 21.4, 26.5, 42.6, 46.5, 60.6,
116.4, 119.4, 140.3, 152.9, 146.7, 150.0, 155.8, 170.8 ppm. IR (n cm21):
3139, 1738, 1650, 1598, 1574, 1217, 1033. Anal. calcd. for C14H17N5O2: C,
58.52; H, 5.96. Found: C, 58.52; H, 6.03.
(Z)-2-[2-(6-Amino-purin-9-ylmethyl)-cyclobutylidene]-ethanol (8)
With the same procedure as before from acetate 29 (210 mg, 0.73 mmol), 8
1
was obtained as a white solid (179 mg, 100%). Mp: 173–1758C. H NMR
(400 MHz, DMSO-d6) d ¼ 1.70 (m, 1H), 1.98 (m, 1H), 2.47 (m, 1H), 2.64
(m, 1H), 3.54 (m, 3H), 4.26 (dd, J ¼ 13.8, 8.4 Hz, 1H), 4.34 (dd, J ¼ 13.8,
6.4 Hz, 1H), 4.56 (t, J ¼ 5.4 Hz, 1H), 5.28 (m, 1H), 7.23 (br s, 2H), 8.13
(s, 1H), 8.14 (s, 1H) ppm. 13C NMR (100.6 MHz, DMSO-d6) d ¼ 20.4,
27.6, 42.1, 46.0, 57.2, 118.6, 123.9, 140.3, 140.9, 149.6, 152.4, 155.9 ppm.

Nucleoside Analogues with Methylenecyclobutane
3237
IR (n cm21): 3108, 1672, 1604, 1574, 1304, 1009. Anal. calcd. for
C12H15N5O: C, 58.76; H, 6.16; N, 28.55. Found: C, 58.61; H, 6.16; N, 28.31
(E)-2-[2-(6-Amino-purin-9-ylmethyl)-cyclobutylidene]-ethanol (10)
With the same procedure as before from acetate 30 (251 mg, 1.47 mmol), 10
1
was obtained as a colorless oil (249 mg, 59%). H NMR (400 MHz, DMSO-
d6) d ¼ 1.74 (m, 1H), 1.96 (m, 1H), 2.57 (m, 2H), 3.48 (m, 1H), 3.79 (m, 2H),
4.18 (dd, J ¼ 13.8, 8.4 Hz, 1H), 4.31 (dd, J ¼ 13.8, 6.4 Hz, 1H), 4.49
(t, J ¼ 5.4 Hz, 1H), 5.14 (m, 1H), 7.19 (br s, 2H), 8.127 (s, 1H), 8.132
(s, 1H) ppm. 13C NMR (100.6 MHz, DMSO-d6) d ¼ 21.3, 26.1, 42.3, 46.0,
57.4, 118.7, 121.9, 140.9, 141.3, 149.6, 152.4, 155.9 ppm. IR (n cm21):
3270, 3081, 1678, 1598, 1570, 1304, 1017. Anal. calcd. for C12H15N5O: C,
58.76; H, 6.16; N, 28.55. Found: C, 58.98, H, 6.18; N, 28.29.
Acetic Acid (Z)-2-[2-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-1-ylmethyl)-cyclobutylidene]-ethyl Ester (31)
With the same procedure as for 21, from alcohol 27 (152 mg, 0.89 mmol) and
N3-benzoylthymine (411 mg, 1.78 mmol), 31 was obtained as an oil (306 mg,
1
90%). H NMR (400 MHz, CDCl3): d ¼ 1.77 (m, 1H), 1.96 (d, J ¼ 1.0 Hz,
3H), 2.05 (s, 3H), 2.20 (m, 1H), 2.64 (m, 1H), 2.82 (m, 1H), 3.49 (m, 1H),
3.93 (dd, J ¼ 13.8, 6.9 Hz, 1H), 3.99 (dd, J ¼ 13.8, 8.9 Hz, 1H), 4.39 (dd,
J ¼ 12.3, 7.4 Hz, 1H), 4.48 (dd, J ¼ 12.3, 7.4 Hz, 1H), 5.42 (m, 1H), 7.14
(q, J ¼ 1.0 Hz, 1H), 7.49 (t, J ¼ 7.9 Hz, 2H), 7.64 (tt, J ¼ 1.5, 7.4 Hz, 1H),
7.93 (dd, J ¼ 1.5, 7.9 Hz, 2H) ppm. 13C NMR (100.6 MHz, CDCl3)
d ¼ 12.3, 20.9, 20.7, 28.6, 41.6, 51.1, 60.8, 110.5, 117.8, 129.1, 130.4,
131.6, 134.9, 140.2, 145.6, 150.0, 163.0, 168.9, 170.7 ppm. IR (n cm21):
1739, 1695, 1645, 1598, 1435, 1225. HRMS: calcd. for C21H22N2O5 [M]þ:
382.15287. Found: 382.1534.
Acetic Acid (E)-2-[2-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-1-ylmethyl)-cyclobutylidene]-ethyl Ester (32)
With the same procedure as before from alcohol 28 (239 mg, 1.4 mmol), 32
was obtained as an oil (532 mg, 99%). 1H NMR (400 MHz, CDCl3):
d ¼ 1.81 (m, 1H), 1.96 (d, J ¼ 1.0 Hz, 3H), 2.05 (s, 3H), 2.22 (m, 1H), 2.75
(m, 2H), 3.39 (m, 1H), 3.85 (dd, J ¼ 13.8, 6.9 Hz, 1H), 3.90 (dd, J ¼ 13.8,
7.9 Hz, 1H), 4.46 (d, J ¼ 6.9 Hz, 2H), 5.33 (m, 1H), 7.10 (q, J ¼ 1.0 Hz,
1H), 7.50 (t, J ¼ 7.9 Hz, 2H), 7.65 (tt, J ¼ 1.5, 7.9 Hz, 1H), 7.91
(dd, J ¼ 1.5, 8.4 Hz, 2H) ppm. 13C NMR (100.6 MHz, CDCl3) d ¼ 12.3,
20.9, 21.4, 26.7, 42.0, 51.2, 60.7, 110.2, 116.5, 129.1, 30.3, 131.6, 135.9,

3238
S. Danappe et al.
140.4, 146.6, 149.9, 163.0, 168.9, 70.8 ppm. IR (n cm21): 1738, 1695, 1645,
1598, 1224. HRMS: calcd. for C21H22N2O5 [M]þ: 382.15287.
Found: 382.1532.
(Z)-1-[2-(2-Hydroxy-ethylidene)-cyclobutylmethyl]-5-methyl-1H-
pyrimidine-2,4-dione (9)
With the same procedure as for 23, from acetate 31 (300 mg, 0.78 mmol), 9
1
was obtained as a white solid (56 mg, 83%). Mp: 74.5–75.58C. H NMR
(400 MHz, CDCl3): d ¼ 1.72 (m, 1H), 1.91 (d, J ¼ 1.0 Hz, 3H), 2.19
(m, 1H), 2.48 (m, 1H), 2.60 (m, 1H), 2.78 (m, 1H), 3.44 (m, 1H), 3.85 (dd,
J ¼ 6.9, 13.8 Hz, 1H), 3.96 (m, 2H), 3.99 (dd, J ¼ 7.9, 13.8 Hz, 1H), 5.44
(m, 1H), 7.07 (q, J ¼ 1.0 Hz, 1H), 9.66 (br s, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 12.1, 20.9, 28.4, 41.6, 51.4, 59.0, 110.4, 122.6,
140.9, 142.3, 151.5, 164.6 ppm. IR (n cm21): 3465, 3018, 1668. HRMS:
calcd. for C21H22N2O5 [M-H2O]þ: 218.10553. Found: 218.1044.
(E)-1-[2-(2-Hydroxy-ethylidene)-cyclobutylmethyl]-5-methyl-1H-
pyrimidine-2,4-dione (11)
With the same procedure as before, from acetate 32 (516 mg, 1.35 mmol), 11
was obtained as a white solid (246 mg, 77%). Mp: 65–678C. 1H NMR
(400 MHz, CDCl3): d ¼ 1.81 (m, 1H), 1.86 (d, J ¼ 1.0 Hz, 3H), 2.13
(m, 1H), 2.72 (m, 2H), 3.36 (m, 1H), 3.86 (dd, J ¼ 7.9, 0.98 Hz, 2H), 3.95
(d, J ¼ 6.9 Hz, 2H), 5.31 (m, 1H), 7.46 (q, J ¼ 1.0 Hz, 1H) ppm. 13C NMR
(100.6 MHz, CDCl3) d ¼ 12.2, 22.4, 27.2, 43.3, 52.2, 59.2, 110.7, 122.2,
143.6, 144.8, 153.1, 166.8 ppm. IR (n cm21): 1667. Anal. calcd. for
C12H16N2O3, 0.1 H2O: C, 60.54; H,. 6.86; N, 11.77. Found: C, 60.19; H,
6.61; N, 11.68.
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