Synthesis of mono- and polyhydroxylated cyclobutane nucleoside analogs

Article abstract of DOI:10.1016/j.tet.2005.05.096

Enantiomerically enriched cyclobutene compounds 13 and 24 are good precursors of several cyclobutane nucleoside analogs. The synthetic ways involve, in the key step, either hydroboration or dihydroxylation.

Full text of DOI:10.1016/j.tet.2005.05.096

Tetrahedron 61 (2005) 7607–7612
Synthesis of mono- and polyhydroxylated cyclobutane
nucleoside analogs
a
Yoann Marsac, Arnaud Nourry, Stephanie Legoupy, Muriel Pipelier, Didier Dubreuil,
a
a,
b
b
*
´
Anne-Marie Aubertin,c Nathalie Bourgougnon,d Rachid Benhidae and Franc¸ois Hueta,
*
a
` ´ ´
Laboratoire de Synthese Organique, UCO2M, UMR CNRS 6011, Faculte des Sciences et Techniques, Universite du Maine,
Avenue Olivier Messiaen, F-72085 Le Mans cedex 9, France
´
b
d
`
`
Laboratoire de Synthese Organique, UMR CNRS 6513, FR CNRS 2465, Faculte des Sciences et Techniques, 2 rue de la Houssiniere,
BP 92208, F-44322 Nantes cedex 03, France
´ ´ ´ ´
Faculte de Medecine, Institut de Virologie, INSERM U 544, Universite Louis Pasteur, 3 rue Koeberle, F-67000 Strasbourg, France
c
´
Laboratoire de Biologie et Chimie Moleculaire, Centre de recherche et d’enseignement Yves Coppens, Campus de Tohannic, BP 573,
F-56017 Vannes, France
Laboratoire de Chimie Bioorganique, UMR CNRS 6001, Universite de Nice-Sophia Antipolis, Parc Valrose,
e
´
F-06108 Nice cedex 2, France
Received 26 April 2005; revised 27 May 2005; accepted 31 May 2005
Available online 17 June 2005
Abstract—Enantiomerically enriched cyclobutene compounds 13 and 24 are good precursors of several cyclobutane nucleoside analogs.
The synthetic ways involve, in the key step, either hydroboration or dihydroxylation.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Several nucleoside analogs have interesting biological
activities and may act as antiviral or anticancer agents.
Among them, oxetanocin 1,1 and its carbocyclic analogs 2
cyclobut-A and cyclobut-G,2 are important examples of
dihydroxylated four membered ring compounds of this
family. Another carbocyclic analog, carbovir 3,3 and its
prodrug abacavir 4,4 showed antiviral properties. In
previous works, we prepared cyclobutene analogs of
carbovir 5,5 then compounds 66 with a methylene spacer
between the carbocycle and the base. We then envisioned,
using the carbon–carbon double bond of an intermediate of
synthesis of compounds 6, or a related product, to prepare
dihydroxylated nucleoside analogs A and B, via an
hydroboration step. On the other hand, a dihydroxylation
Figure 1.
step would lead to trihydroxylated products C and D
(Fig. 1).
2. Results and discussion
In a first approach in racemic series,7 we carried out a
Mitsunobu reaction with the benzylated compounds 8a or
8b and N-3-benzoylthymine (Scheme 1). However, an
Keywords: Nucleoside analogs; Mitsunobu reaction; Hydroboration;
unexpected migration of the benzyloxy groups occurred and
Dihydroxylation.
a mixture of the two regioisomers 9a and 9b was obtained.
Fortunately, the migration did not occur starting from a
*
Corresponding authors. Tel.: C33 2 43 83 33 38; fax: C33 2 43 83 39 02;
e-mail addresses: slegoupy@univ-lemans.fr; fhuet@univ-lemans.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.096

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Y. Marsac et al. / Tetrahedron 61 (2005) 7607–7612
Isomer 20 was assigned thanks to the NOESY spectrum in
the phase mode showing correlations between H near of
1
1
OH and H of the vicinal CH2. Desilylation of 20 and 21
gave the two trihydroxylated nucleosides, 22 and 23,
respectively.
Scheme 1.
silylated compound 10, which only led to the product of
direct substitution 11.
Scheme 4. (a) OsO4, NMO, THF/H2O; (b) HF–pyridine.
We then used this protecting group for the synthesis of the
enantiomerically enriched compounds (Scheme 2). The
starting material was the monoacetate 12, which is available
in high enantiomeric excess by an enzymatic acylation.8 In
this approach, the base coupling was envisioned before the
addition step.
Hydroboration of compound 246 provided a mixture of 25,
26, 27a and 27b (Scheme 5). The trans-isomers 25 and 26
were separated and equally identified thanks to NMR
experiments, whereas the cis-isomers 27a and 27b could not
be separated. Finally, desilylation of 25 and 26 provided
nucleosides 28 and 29, respectively.
Scheme 2.
Compound 13, previously described,6 was subjected to
hydroboration, which provided a mixture of the four
expected products 14–17 (Scheme 3). These compounds
were identified by NMR experiments including HMBC
spectra to assign position of secondary OH groups.7
Deprotection of 14 and 15 by a treatment with HF–pyridine
provided the target molecules 18 and 19, respectively.
Compound 18 is a cyclobutane analog of carbocyclic
thymidine, (C)-Carba-T,9 which proved to be effective
against HSV-1 and HSV-2, whereas the (K)-isomer was
inactive.
Scheme 5. (a) tBuPh2SiCl/imidazole/DMF; (b) NH3/MeOH; (c) PPh3/
DEAD/adenine/THF; (d) BH3$THF; (e) H2O2/NaOH; (f) HF–pyridine.
Dihydroxylation of 24 yielded a mixture of 30 and 31
(Scheme 6). Compound 31 was desilylated to lead to
another trihydroxylated nucleoside 32. In contrast, the same
reaction failed from 30 probably due to its insolubility in
CH2Cl2.
Scheme 6. (a) OsO4, NMO, THF/H2O; (b) HF–pyridine.
Scheme 3. (a) tBuPh2SiCl/imidazole/DMF; (b) NH3/MeOH; (c) PPh3/
DEAD/N-3-benzoylthymine; (d) NaOH10; (e) BH3$THF; (f) H2O2/NaOH;
(g) HF–pyridine.
Several of these new products were subjected to biological
evaluation. Compounds 19, 22, 23, 28–30 and 32 did not
show significant activity against HSV-1 and HIV-1.
Compounds 19 and 22 showed neither cytotoxicity (KB
cells) nor significant inhibition of acetylcholine esterase.
Dihydroxylation of cyclobutene compound 13 by reaction
with N-methylmorpholine N-oxide in the presence of
osmium tetroxide as catalyst11 yielded a mixture of
compounds 20 and 21, which were separated (Scheme 4).

Y. Marsac et al. / Tetrahedron 61 (2005) 7607–7612
7609
3. Conclusion
3048, 2930–2856, 1677, 1469–1426, 1363, 1255, 1109, 1059,
822, 739–703. Anal. Calcd for C27H34N2O4Si$0.4H2O: C,
66.75; H, 7.22; N, 5.77. Found: C, 66.56; H, 7.06; N, 5.64.
Data for 15: white solid, mp 62.1–64.3 8C; [a]2D0 K54 (c
In conclusion, we prepared four dihydroxylated (18, 19, 28,
29), and three trihydroxylated (22, 23, 32) new cyclobutane
nucleosides as well as eight monohydroxylated (14–17, 25,
26, 27a C 27b) and four dihydroxylated (20, 21, 30, 31)
monosilylated precursors. We think that, it should be worth
incorporating several of them in oligonucleotidic short
sequences to test the biological properties. This following
part of our research program is in progress.
1
1.895, CHCl3); H NMR (CDCl3) d 10.1 (br s, 1H), 7.67–
7.64 (m, 4H), 7.46–7.37 (m, 6H), 6.97 (m, 1H), 4.37 (ddd,
1H, JZ7.9, 7.9, 7.9 Hz), 4.15 (dd, 1H, JZ14.3, 9.8 Hz),
3.80 (dd, 1H, JZ14.3, 4.4 Hz), 3.78 (dd, 1H, JZ10.8,
7.4 Hz), 3.71 (dd, 1H, JZ10.8, 4.4 Hz), 3.66–3.62 (m, 1H),
2.67–2.59 (m, 1H), 2.47–2.37 (m, 1H), 2.05–1.91 (m, 2H),
1.81 (d, 3H, JZ1.2 Hz), 1.08 (s, 9H); 13C NMR (CDCl3) d
163.8, 150.9, 140.1, 134.6 (4C), 132.1 (2C), 128.8 (2C),
126.8 (4C), 109.8, 69.1, 63.3, 48.3, 45.9, 30.8, 30.1, 25.9
(3C), 18.2, 11.2; IR (n cmK1) 3404 (br), 3208 (br), 3049,
2932–2857, 1682, 1361, 1259–1224, 1111, 1075, 823, 740–
702; HRMS calcd for C27H34N2O4SiNa [MCNa]C:
501.2186. Found: 501.2194. Data for 16: colorless oil;
[a]2D0 C362 (c 2.105, CHCl3); 1H NMR (CDCl3) d 9.09 (br
s, 1H, N–H); 7.71–7.66 (m, 4H), 7.49–7.39 (m, 6H), 6.68 (d,
1H, JZ1.2 Hz), 4.36–4.29 (m, 1H), 4.12 (dd, 1H, JZ11.3,
5.9 Hz), 4.05 (dd, 1H, JZ11.3, 5.4 Hz), 3.82 (dd, 1H, JZ
13.8, 5.9 Hz), 3.70 (dd, 1H, JZ13.8, 9.3 Hz), 2.94 (d, 1H,
JZ7.4 Hz), 2.77–2.69 (m, 1H), 2.52–2.44 (m, 1H), 2.43–
2.33 (m, 1H), 2.05–1.98 (m, 1H), 1.81 (d, 3H, JZ1.2 Hz),
1.11 (s, 9H); 13C NMR (CDCl3) d 164.2, 150.8, 140.3, 135.6
(4C), 132.4 (2C), 130.1 (2C), 127.8 (4C), 110.3, 65.5, 61.1,
4. Experimental
4.1. General
NMR spectra were recorded on a Bruker AC 400
spectrometer at 400 and 100.6 MHz, for 1H and 13C,
respectively. All melting points are uncorrected. Elemental
analyses were performed by the service of microanalyses,
CNRS, ICSN, Gif sur Yvette. High resolution mass spectra
were recorded on a ZabSpec TOF Micromass spectrometer
at the CRMPO, Rennes. Infrared spectra were measured
with a FT infrared spectrometer Genesis Matteson
instrument.
49.7, 44.5, 36.9, 28.3, 27.0, (3C), 19.1, 12.3; IR (n cmK1
)
4.1.1.
(C)-N1-[(1S,2R,3S)-2-(tert-Butyl-diphenyl-
3428, 3068–3048, 2929–2856, 1681, 1363, 1252–1223,
1109, 1074, 741–704; HRMS calcd for C27H34N2O4NaSi
[MCNa]C: 501.2186. Found: 501.2186. Data for 17:
colorless oil; [a]D20 C179 (c 1.390, CHCl3); 1H NMR
(CDCl3) d 9.08 (br s, 1H), 7.66 (dd, 4H, JZ7.8, 1.5 Hz),
7.48–7.38 (m, 6H), 7.13 (d, 1H, JZ1.2 Hz), 4.25–4.20 (m,
1H), 4.19 (dd, 1H, JZ14.3, 11.3 Hz), 4.08 (m, 1H), 3.89
(dd, 1H, JZ14.3, 3.0 Hz), 3.85 (dd, JZ11.3, 6.9 Hz), 3.75
(dd, 1H, JZ11.3, 3.9 Hz), 2.87–2.78 (m, 1H), 2.55–2.46 (m,
1H), 2.44–2.37 (m, 1H), 1.91 (d, 3H, JZ1.2 Hz), 1.72 (ddd,
1H, JZ12.8, 5.4, 4.2 Hz), 1.11 (s, 9H); 13C NMR (CDCl3) d
164.2, 151.5, 141.2, 135.5 (4C), 132.8 (2C), 130.0 (2C),
127.8 (4C), 111.0, 66.7, 64.2, 44.5, 42.4, 34.9, 31.6, 26.9
(3C), 19.2, 12.3; IR (n cmK1) 3427, 3060, 2957–2857, 1673,
1368, 1243–1219, 1112, 1079, 737–702.
silyloxymethyl)-3-hydroxy-cyclobutyl]methyl-5-methyl-
1H,3H-pyrimidine-2,4-dione, 14; (K)-N1-[(1S,2R,4R)-2-
(tert-butyl-diphenyl-silyloxymethyl)-4-hydroxy-cyclo-
butyl]methyl-5-methyl-1H,3H-pyrimidine-2,4-dione, 15;
(C)-N1-[(1S,2R,3R)-2-(tert-butyl-diphenyl-silyloxy-
methyl)-3-hydroxy-cyclobutyl]methyl-5-methyl-1H,3H-
pyrimidine-2,4-dione, 16; (C)-N1-[(1S,2R,4S)-2-(tert-
butyl-diphenyl-silyloxymethyl)-4-hydroxy-cyclobutyl]-
methyl-5-methyl-1H,3H-pyrimidine-2,4-dione, 17. A
1 M solution of BH3$THF (2.3 mL, 2.3 mmol) in dry THF
(4.5 mL) was added dropwise at 0 8C under argon and with
stirring to a solution of 136 (0.800 g, 1.74 mmol), obtained
from a sample of 128 of O96.8% ee, in dry THF (3.5 mL).
The reaction mixture was stirred for 3 h at room temperature
then 3 M NaOH (770 mL, 2.3 mmol) and then 30–35% H2O2
(250 mL, w2.3 mmol) were added at 0 8C. The reaction
mixture was stirred for 1 h at room temperature. Evapora-
tion, extraction of the resulting aqueous phase with Et2O
(4!15 mL), washing of the combined organic phases with
brine (20 mL), drying (MgSO4), evaporation then column
chromatography on silica gel (cyclohexane/EtOAc: 3:1/
3:2) successively led to 17 (23 mg, 0.048 mmol, 4%), 16
(32 mg, 0.067 mmol, 6%), 14 (218 mg, 0.877 mmol), 14C
15 (99 mg, 0.207 mmol) then 15 (184 mg, 0.384 mmol),
yields of 14 and 15 w30 and 27%, respectively. Data for 14:
white solid, mp 101.5–102.7 8C; [a]2D0 C116 (c 2.100,
CHCl3); 1H NMR (CDCl3) d 9.57 (br s, 1H), 7.68–7.63 (m,
4H), 7.45–7.37 (m, 6H), 6.91 (d, 1H, JZ1.2 Hz), 4.32 (ddd,
1H, JZ7.4, 7.4, 7.4 Hz), 4.02 (dd, 1H, JZ13.8, 11.3 Hz),
3.84 (dd, 1H, JZ11.3, 4.9 Hz), 3.78 (dd, 1H, JZ11.3,
6.9 Hz), 3.75 (dd, 1H, JZ13.8, 4.9 Hz), 3.65–3.61 (m, 1H),
2.68–2.58 (m, 1H), 2.57–2.50 (m, 1H), 2.13 (ddd, 1H, JZ
11.3, 7.4, 2.9 Hz), 1.92–1.82 (m, 4H), 1.07 (s, 9H); 13C
NMR (CDCl3) d 164.4, 151.3, 140.2, 135.5 (4C), 133.2 (2C),
129.9 (2C), 127.8 (4C), 110.7, 66.7, 61.8, 49.0, 48.7, 32.7,
28.9, 27.0 (3C), 19.2, 12.3; IR (n cmK1) 3412 (br), 3195 (br),
4.1.2. (C)-N1-[(1S,2R,3S)-2-Hydroxymethyl-3-hydroxy-
cyclobutyl]methyl-5-methyl-1H,3H-pyrimidine-2,4-
dione, 18. A solution of 65–70% HF–pyridine (9 mL) was
added to a cooled solution (0 8C) of 14 (40 mg, 0.084 mmol)
in CH2Cl2 (0.6 mL). The reaction mixture was stirred for
one night at room temperature then a small amount of
NaHCO3 was added. After 30 min more of stirring,
evaporation then column chromatography on silica gel
(CH2Cl2/MeOH: 95:5) provided 18 (11 mg, 0.046 mmol,
55%) as a white solid, mp%25 8C; [a]2D0 C529 (c 1.295,
MeOH); 1H NMR (CD3OD) d 7.45 (d, 1H, JZ0.8 Hz), 4.16
(ddd, 1H, JZ7.4, 7.4, 7.4 Hz), 3.93 (dd, 1H, JZ13.6,
10.6 Hz), 3.88 (dd, 1H, JZ13.6, 6.0 Hz), 3.72 (dd, 1H, JZ
11.0, 6.0 Hz), 3.67 (dd, 1H, JZ11.0, 8.0 Hz), 2.70–2.60 (m,
1H), 2.53–2.45 (m, 1H), 2.11 (ddd, 1H, JZ11.2, 7.4,
2.4 Hz), 1.86 (m, 4H); 13C NMR (CD3OD) d 168.5, 154.9,
144.7, 112.7, 69.4, 62.4, 51.8, 51.1, 34.7, 31.2, 13.8; IR
(n cmK1) 3402, 2935, 2500, 1681, 1375, 1257, 1084, 772;
HRMS calcd for C11H16N2O4Na [MCNa]C: 263.1008.
Found: 263.1002.

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Y. Marsac et al. / Tetrahedron 61 (2005) 7607–7612
4.1.3. (C)-N1-[(1S,2R,4R)-2-Hydroxy-4-hydroxymethyl-
cyclobutyl]methyl-5-methyl-1H,3H-pyrimidine-2,4-
dione, 19. Desilylation of 15 (40 mg, 0.084 mmol) (see
preparation of 18) followed by column chromatography on
silica gel (CH2Cl2/MeOH: 95:5) provided 19 (8 mg,
0.033 mmol, 40%) as a white solid, mp 186.3–187.0 8C;
[a]2D0 C106 (c 0.960, MeOH); 1H NMR (DMSO-d6) d 7.53
(d, 1H, JZ1.0 Hz), 4.92 (d, 1H, JZ7.4 Hz), 4.61 (dd,
1H, JZ5.3, 4.7 Hz), 3.99 (ddd, 1H, JZ7.6, 7.6, 7.6 Hz),
3.78–3.71 (m, 2H), 3.57–3.41 (m, 2H), 2.47–2.39 (m, 1H),
2.20–2.12 (m, 1H), 1.88 (ddd, 1H, JZ10.3, 7.6, 2.0 Hz),
1.74–1.66 (m, 4H); 13C NMR (DMSO-d6) d 168.4, 155.0,
141.7, 112.7, 68.2, 61.4, 46.7, 45.9, 32.5, 30.5, 12.2; IR
(n cmK1) 3488, 3044–2940, 1670, 1464–1422, 1338, 1220,
1080, 756; HRMS calcd for C11H16N2O4Na [MCNa]C:
263.1008. Found: 263.1006.
4.1.5. (C)-N1-[((1S,2S,3R,4R)-2,3-Dihydroxy-4-hydroxy-
methyl)cyclobutyl]methyl-5-methyl-1H,3H-pyrimidine-
2,4-dione, 22. Desilylation of 20 (11 mg, 0.063 mmol) (see
preparation of 18) followed by column chromatography on
silica gel (EtOAc/EtOAc/MeOH: 8:2) provided 22
(11 mg, 0.043 mmol, 68%) as a white solid, mp 197.2–
198.9 8C; [a]2D0 C266 (c 1.450, DMSO); 1H NMR (DMSO-
d6) d 11.15 (br s, 1H), 7.52 (d, 1H, JZ1.0 Hz), 4.71 (d, 1H,
JZ4.0 Hz), 4.67 (d, 1H, JZ5.9 Hz), 4.59–4.56 (m, 1H),
3.90–3.83 (m, 2H), 3.74 (d, 2H, JZ8.4 Hz), 3.51–3.44 (m,
2H), 2.55–2.48 (m, 1H), 2.17–2.10 (m, 1H), 1.72 (d, 3H, JZ
1.0 Hz); 13C NMR (DMSO-d6) d 164.3, 151.0, 141.7, 108.1,
69.5, 68.9, 59.2, 46.5, 43.3, 42.2, 12.0; IR (n cmK1) 3324,
3186, 2950, 1669, 1478, 1417, 1365, 1217, 1156, 1021, 874;
HRMS calcd for C11H16N2O5Na [MCNa]C: 279.0957.
Found: 279.0961.
4.1.6. (C)-N1-[((1S,2R,3S,4R)-2,3-Dihydroxy-4-hydroxy-
methyl)cyclobutyl]methyl-5-methyl-1H,3H-pyrimidine-
2,4-dione, 23. Desilylation of 21 (56 mg, 0113 mmol) (see
preparation of 18) followed by column chromatography on
silica gel (CH2Cl2/MeOH: 95:5/9:1) provided 23 (16 mg,
0.033 mmol, 40%) as a white solid, mp 53.7–54.1 8C; [a]D20
C824 (c 2.850, MeOH);1H NMR(CD3OD) d7.53(d, 1H, JZ
1.0 Hz), 4.31–4.27 (m, 1H), 4.25–4.22 (m, 1H), 4.10–3.95 (m,
2H), 3.91–3.88 (m, 2H), 2.67–2.59 (m, 2H), 1.85 (d, 3H, JZ
1.0 Hz); 13C NMR (CD3OD) d 167.1, 153.4, 144.2, 110.9,
71.1, 68.8, 59.6, 45.6, 44.3, 38.5, 12.4; IR (n cmK1) 3381,
3226, 2938, 1671, 1423, 1335, 1222, 1149; HRMS calcd for
C11H16N2O5Na [MCNa]C: 279.0957. Found: 279.0957.
4.1.4. (K)-N1-[(1S,2S,3R,4R)-2,3-Dihydroxy-4-(tert-
butyl-diphenyl-silyloxymethyl)-cyclobutyl]methyl-5-
methyl-1H,3H-pyrimidine-2,4-dione, 20; (C)-N1-
[(1S,2R,3S,4R)-2,3-dihydroxy-4-(tert-butyl-diphenyl-
silyloxymethyl)-cyclobutyl]methyl-5-methyl-1H,3H-
pyrimidine-2,4-dione, 21. 4-Methylmorpholine N-oxide
(390 mg, 3.320 mmol) and a 4% aqueous solution of OsO4
(140 mL, 5.6 mg, 0.022 mmol) were added to a solution of
13 (500 mg, 1.085 mmol) in a THF/H2O (10:1) mixture
(5 mL). The reaction mixture was stirred for 2 h at 30 8C.
Cooling, treatment with a 20% aqueous solution of NaHSO3
(3 mL), evaporation, dilution with brine (5 mL), extraction
with EtOAc (5!15 mL), drying of the organic phases
(Na2SO4), evaporation then column chromatography on
silica gel (cyclohexane/EtOAc: 2:1/1:5) successively led
to 21 (168 mg, 0.340 mmol, 31%), then to 20 (336 mg,
0.680 mmol, 63%). Data for 20: white solid, mp 155.8–
4.1.7. (C)-N9-[(1S,2R,3S)-2-(tert-Butyl-diphenyl-silyl-
oxymethyl)-3-hydroxy-cyclobutyl]methyl-9H-purin-6-
amine, 25; (K)-N9-[(1S,2R,4R)-2-(tert-butyl-diphenyl-
silyloxymethyl)-4-hydroxy-cyclobutyl]methyl-9H-purin-
6-amine, 26 and cis-isomers, 27a and 27b. Hydroboration
of 24 (750.9 mg, 1.6 mmol) (see preparation of 14–17)
followed by column chromatography on silica gel (EtOAc)
successively provided a mixture of 27a and 27b (65.5 mg,
0.134 mmol), a mixture of 27a, 27b and 25 (72.1 mg,
0.148 mmol), 25 (176.8 mg, 0.362 mg), a mixture of 25 and
26 (21.9 mg, 0.045 mmol) then 26 (201.6 mg, 0.413 mmol),
yields of 27aC27b, 25, 26 w14, 24 and 31%, respectively.
Data for 25: white solid, mp 93.5–95.3 8C; [a]2D0 C218 (c
156.6 8C; [a]2D0 K8 (c 1.707, CHCl3); H NMR (CDCl3) d
1
9.96 (br s), 7.66–7.63 (m, 4H), 7.46–7.37 (m, 6H), 6.89 (d,
1H, JZ1.4 Hz), 4.39 (dd, 1H, JZ6.4, 6.4 Hz), 4.31–4.29
(m, 1H), 4.20 (dd, 1H, JZ14.3, 10.3 Hz), 4.19–4.18 (m,
1H), 3.81 (dd, 1H, JZ10.8, 6.4 Hz), 3.73 (dd, 1H, JZ10.8,
4.2 Hz), 3.71 (dd, 1H, JZ14.3, 4.7 Hz), 3.28 (d, 1H, JZ
3.9 Hz), 2.87–2.79 (m, 1H), 2.40–2.35 (m, 1H), 1.81 (d, 3H,
JZ1.4 Hz), 1.08 (s, 9H); 13C NMR (CDCl3) d 164.6, 151.8,
140.9, 135.6 (4C), 132.9, 132.7, 129.9 (2C), 127.9 (4C),
111.0, 70.2, 70.1, 61.9, 48.9, 44.5, 42.6, 26.9 (3C), 19.1,
12.3; IR (n cmK1) 3395, 3069, 2930, 2858, 1682, 1427,
1386, 1361, 1220, 1143, 1111, 1005, 908, 822, 735–702;
HRMS calcd for C27H34N2O5NaSi [MCNa]C: 517.2134.
Found: 517.2135. Data for 21: white solid, mp 66.8 8C;
[a]2D0 C415 (c 1.625, CHCl3); 1H NMR (CDCl3) d 8.92 (br
s), 7.69–7.65 (m, 4H), 7.48–7.38 (m, 6H), 7.11 (d, 1H, JZ
1.5 Hz), 4.39 (d, 1H, JZ4.4 Hz), 4.34–4.29 (m, 1H), 4.26
(m, 1H), 4.07–3.99 (m, 3H), 3.83 (dd, 1H, JZ14.3, 3.4 Hz),
3.05 (d, 1H, JZ6.4 Hz), 2.84–2.75 (m, 1H), 2.51–2.44 (m,
1H), 1.91 (d, 3H, JZ1.5 Hz), 1.09 (s, 9H); 13C NMR
(CDCl3) d 163.8, 151.3, 140.9, 135.5 (4C), 132.6, 132.5,
130.0 (2C), 127.9 (4C), 111.2, 69.6, 66.4, 61.6, 44.1, 43.5,
36.9, 26.9 (3C), 19.1, 12.3; IR (n cmK1) 3403, 3192, 3070–
3048, 2930, 2893–2857, 1678, 1427, 1385, 1365, 1247,
1217, 1158, 1111, 1008, 909, 823, 734–703; HRMS calcd
for C27H34N2O5NaSi [MCNa]C: 517.2134. Found:
517.2130. Anal. Calcd for C27H34N2O5Si$0.6H2O: C,
64.16; H, 7.02; N, 5.54. Found: C, 64.07; H, 6.81; N, 5.46.
1
2.025, CH2Cl2); H NMR (CDCl3) d 8.34 (s, 1H), 7.75 (s,
1H), 7.68–7.65 (m, 4H), 7.47–7.38 (m, 6H), 5.63 (br s, 2H),
4.45–4.39 (m, 2H), 4.29 (dd, 1H, JZ13.8, 10.8 Hz), 3.88
(dd, 1H, JZ11.2, 5.2 Hz), 3.83 (dd, 1H, JZ11.2, 6.4 Hz),
2.94–2.84 (m, 1H), 2.58–2.51 (m, 1H), 2.13 (ddd, 1H, JZ
11.7, 8.4, 2.9 Hz), 1.90 (ddd, 1H, JZ11.7, 8.7, 7.4 Hz), 1.08
(s, 9H); 13C NMR (CDCl3) d 155.4, 152.8, 150.1, 140.1,
135.6 (2C), 135.5 (2C), 133.4, 133.2, 129.9 (2C), 127.8
(4C), 119.4, 66.8, 61.8, 60.4, 48.8, 45.3, 33.3, 26.9 (3C),
19.2; IR (n cmK1) 3330–3185, 2930–2857, 1709–1597,
1472–1415, 1361, 1220, 1106, 1059, 823, 740–698; HRMS
calcd for C27H34N5O2Si [MCH]C: 488.2482. Found:
488.2453. Data for 26: white solid, mp 75.5–76.7 8C;
[a]2D0 K19 (c 1.705, CH2Cl2); H NMR (CDCl3) d 8.28 (s,
1
1H), 7.70–7.67 (m, 4H), 7.65 (s, 1H), 7.48–7.38 (m, 6H),
5.85 (br s, 2H), 4.51 (ddd, 1H, JZ8.0, 8.0, 8.0 Hz), 4.47 (dd,
1H, JZ14.3, 4.4 Hz), 4.37 (dd, 1H, JZ14.3, 9.5 Hz),
3.86 (dd, 1H, JZ10.8, 6.9 Hz), 3.81 (dd, 1H, JZ10.8,
4.9 Hz), 2.83–2.75 (m, 1H), 2.55–2.47 (m, 1H), 2.15 (ddd,

Y. Marsac et al. / Tetrahedron 61 (2005) 7607–7612
7611
1H, JZ11.3, 8.0, 2.5 Hz), 1.90 (ddd, 1H, JZ11.3, 9.8,
8.0 Hz), 1.11 (s, 9H); 13C NMR (CDCl3) d 155.4, 152.6,
149.7, 140.3, 135.7–135.6 (4C), 133.3–133.2 (2C), 129.9
(2C), 127.8 (4C), 119.3, 69.7, 64.2, 47.5, 44.7, 31.5, 31.2,
27.0 (3C) 19.2; IR (n cmK1) 3329, 2932–2858, 1709–1599,
1473–1417, 1361, 1221, 1105, 1074, 823, 741–701; HRMS
calcd for C27H34N5O2Si [MCH]C: 488.2482. Found:
488.2470.
1600, 1361, 1258, 1150, 1088, 1042, 880, 739–701. Anal.
Calcd for C27H33N5O3Si$0.6H2O: C, 63.03; H, 6.70; N,
13.61. Found: C, 63.01; H, 6.63; N, 13.56. Data for 31:
white solid, mp 74.1–75.3 8C; [a]2D0 C200 (c 1.160, CHCl3);
1H NMR (CDCl3) d 8.27 (s, 1H), 7.74 (s, 1H), 7.70–7.66 (m,
4H), 7.45–7.35 (m, 6H), 6.40 (br s, 2H), 4.60 (dd, 1H, JZ
14.5, 11.5 Hz), 4.31 (dd, 1H, JZ14.5, 3.2 Hz), 4.32–4.27
(m, 2H), 4.23–4.20 (m, 1H), 4.10 (dd, 1H, JZ10.8, 5.1 Hz),
2.91–2.83 (m, 1H), 2.49–2.42 (m, 1H), 1.08 (s, 9H); 13C
NMR (CDCl3) d 155.8, 152.3, 149.2, 141.0, 135.5 (4C),
132.2 (2C), 129.8 (2C), 127.8 (4C), 119.5, 69.7, 66.0, 61.9,
44.4, 40.0, 38.5, 26.9 (3C), 19.1; IR (n cmK1) 3453, 2956–
2864, 1650–1621, 1338–1328, 1256, 1169, 1095, 827, 744–
707; HRMS calcd for C27H33N5O3NaSi [MCNa]C:
526.2250. Found: 526.2250.
4.1.8. (C)-N9-[(1S,2R,3S)-2-Hydroxymethyl-3-hydroxy-
cyclobutyl]methyl-9H-purin-6-amine, 28. Desilylation of
25 (36.8 mg, 0.076 mmol) (see preparation of 18) followed
by column chromatography on silica gel (EtOAc/MeOH:
5:1) provided 28 (13.3 mg, 0.053 mmol; 71%) as a white
solid, mp 97.5–98.7 8C; [a]2D0 C461 (c 0.750, MeOH); H
1
NMR (DMSO-d6) d 8.14 (s, 1H), 8.12 (s, 1H), 7.17 (br s,
2H), 5.04 (d, 1H, JZ5.9 Hz), 4.59 (br s, 1H), 4.33 (dd, 1H,
JZ13.8, 5.4 Hz), 4.19 (dd, 1H, JZ13.8, 11.3 Hz), 4.12–
4.05 (m, 1H), 3.57–3.52 (m, 2H), 2.74–2.64 (m, 1H), 2.38–
2.31 (m, 1H), 1.91 (ddd, 1H, JZ10.8, 7.4, 2.5 Hz), 1.63
(ddd, 1H, JZ10.8, 9.2, 8.2 Hz); 13C NMR (DMSO-d6) d
155.4, 152.5, 150.1, 141.1, 119.5, 65.8, 52.2, 49.2, 44.4,
32.9, 29.1; IR (n cmK1) 3274, 2938, 1643, 1483–1420,
1365, 1217, 1081, 1007; HRMS calcd for C11H16N5O2
[MCH]C: 250.1304. Found: 250.1304.
4.1.11. (C)-N9-[(1S,2R,3S,4R)-2,3-Dihydroxy-4-hydroxy-
methylcyclobutyl]methyl-9H-purin-6-amine, 32. Desilyl-
ation of 31 (59.3 mg, 0.117 mmol) (see preparation of 18)
followed by column chromatography on silica gel (EtOAc/
MeOH: 6:1) provided 32 (20.7 mg, 0.078 mmol, 66%) as a
white solid, mp 188.6–191.3 8C; [a]2D0 C438 (c 1.415,
1
DMSO); H NMR (CD3OD) d 8.19 (s, 1H), 8.16 (s, 1H),
4.61 (dd, 1H, JZ14.3, 10.8 Hz), 4.45 (dd, 1H, JZ14.3,
4.7 Hz), 4.34–4.31 (m, 1H), 4.24–4.20 (m, 1H), 4.02–3.89 (m,
2H), 2.82–2.75 (m, 1H) 2.71–2.65 (m, 1H); 13C NMR
(CD3OD) d 159.0, 155.2, 152.2, 145.1, 121.7, 72.4, 70.5,
61.2, 45.7, 42.7, 41.2; IR (n cmK1) 3152, 2936, 1737, 1642–
1601, 1478, 1365, 1230–1217, 1155, 1019; HRMS calcd for
C11H15N5O3Na [MCNa]C: 288.1073. Found: 288.1071.
4.1.9. (K)-N9-[(1S,2R,4R)-2-Hydroxymethyl-3-hydroxy-
cyclobutyl]methyl-9H-purin-6-amine, 29. Desilylation of
26 (51.8 mg, 0.106 mmol) (see preparation of 18) followed
by column chromatography on silica gel (EtOAc/MeOH:
9:1) provided 29 (17.9 mg, 0.072 mmol, 68%) as a white
solid, mp 233.8–235.7 8C; [a]2D0 K122 (c 0.900, DMSO);
1H NMR (DMSO-d6) d 8.36 (s, 1H), 8.09 (s, 1H), 7.26 (br s,
2H), 5.11 (br s, 1H), 4.87 (br s, 1H), 4.37 (dd, 1H, JZ14.0,
7.8 Hz), 4.19 (dd, 1H, 14.0, 7.4 Hz), 4.04 (ddd, 1H, JZ7.4,
7.4, 7.4 Hz), 3.55 (dd, 1H, JZ10.8, 7.9 Hz), 3.45 (dd, 1H,
JZ10.8, 5.9 Hz), 2.64–2.57 (m, 1H), 2.17–2.09 (m, 1H),
1.86 (ddd, 1H, JZ9.8, 7.4, 1.4 Hz), 1.63 (m, 1H); 13C NMR
(DMSO-d6) d 155.9, 152.2, 149.5, 140.9, 118.7, 68.3, 61.3,
46.7, 42.5, 32.4, 30.5; IR (n cmK1) 3114, 2942, 1703, 1615,
1481–1422, 1371–1300, 1215, 1075, 1038; HRMS calcd for
C11H16N5O2 [MCH]C: 250.1304. Found: 250.1303.
Acknowledgements
We thank the local section of Sarthe of the Ligue Nationale
contre le cancer for a fellowship to Y. M. and French
´
Government and Region des Pays de la Loire for financial
support (CER chimie fine).
References and notes
4.1.10. (C)-N9-[(1S,2S,3R,4R)-2,3-Dihydroxy-4-(tert-
butyl-diphenyl-silyloxymethyl)cyclobutyl]methyl-9H-
purin-6-amine, 30; (C)-N9-[(1S,2R,3S,4R)-2,3-di-
hydroxy-4-(tert-butyl-diphenyl-silyloxymethyl)cyclo-
butyl]methyl-9H-purin-6-amine, 31. Dihydroxylation of
24 (512 mg, 1.090 mmol) (see preparation of 20C21)
followed by column chromatography on silica gel
(EtOAc/MeOH, 99:1/90:10) successively led to 31
(263 mg, 0.522 mmol, 48%) then to 30 (231 mg,
0.459 mg, 42%). Data for 30: white solid, mp 203.2–
1. Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii,
A.; Takita, T. J. Antibiot. 1986, 39, 1623–1625. Nakamura, H.;
Hasegawa, S.; Shimada, N.; Fujii, A.; Takita, T.; Iitaka, Y.
J. Antibiot. 1986, 39, 1626–1629. Hoshino, H.; Shimizu, N.;
Shimada, N.; Takita, T.; Takeuchi, T. J. Antibiot. 1987, 40,
1077–1078.
2. Hayashi, S.; Norbeck, D. W.; Rosenbrook, W.; Fine, R. L.;
Matsukura, M.; Plattner, J. J.; Broder, S. B.; Mitsuya, H.
Antimicrob. Agents Chemother. 1990, 34, 287–294.
3. Coates, J. A. V.; Inggall, H. J.; Pearson, B. A.; Penn, C. R.;
Storer, R.; Williamson, C.; Cameron, J. M. Antiviral Res.
1991, 15, 161–168.
204.7 8C; [a]2D0 C62 (c 1.520, DMSO); H NMR (DMSO-
1
d6) d 8.14 (s, 1H), 8.08 (s, 1H), 7.62 (dd, 4H, JZ7.4,
1.5 Hz), 7.48–7.40 (m, 6H), 7.20 (br s, 2H), 4.88 (d, 1H, JZ
5.4 Hz), 4.81 (d, 1H, JZ6.4 Hz), 4.37 (dd, JZ13.8, 6.7 Hz),
4.31 (dd, 1H, JZ13.8, 9.4 Hz), 4.07–3.98 (m, 2H), 3.84 (dd,
1H, JZ10.8, 6.9 Hz), 3.79 (dd, 1H, JZ10.8, 5.1 Hz), 2.87–
2.80 (m, 1H), 2.40–2.33 (m, 1H), 1.00 (s, 9H); 13C NMR
(DMSO-d6) d 156.0, 152.4, 149.7, 140.6, 135.2 (4C), 133.0
(2C), 129.9 (2C), 128.0 (4C), 118.9, 69.9, 68.7, 62.1, 43.5,
42.9, 42.6, 26.8, (3C) 18.9; IR (n cmK1) 3319, 2853, 1650–
4. Hugues, W.; McDowell, J. A.; Shenep, J.; Flynn, P.; Kline,
M. W.; Yogev, R.; Symonds, W.; Lou, H.; Hetherington, S.
Antimicrob. Agents Chemother. 1999, 43, 609–615.
5. Gourdel, M.-E.; Huet, F. J. Org. Chem. 1997, 62, 2166–2172.
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7612
Y. Marsac et al. / Tetrahedron 61 (2005) 7607–7612
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Tetrahedron 2002, 58, 3775–3778.
10. We observed, in the course of this work, that using 25%
NH4OH (25 mL for 5.16 mmol of benzoyl derivative in MeOH
solution (65 mL)) led to an increase of the yield with respect to
reaction with NaOH. Compound 13 was thus, obtained in 93%
(in 48 h at room temperature) instead of 85% (in 72 h at room
temperature).
7. Marsac, Y.; Nourry, A.; Legoupy, S.; Pipelier, M.; Dubreuil,
D.; Huet, F. Tetrahedron Lett. 2004, 45, 6461–6463.
8. Pichon, C.; Hubert, C.; Alexandre, C.; Huet, F. Tetrahedron:
Asymmetry 2000, 11, 2429–2434.
´ ´
9. Beres, J.; Sagi, G.; Tomoskozi, L.; Gruber, L.; Baitz-Gacs, E.;
´
¨
¨
11. Wengel, J.; Svendsen, M. L.; Jørgensen, P. N.; Nielson, C.
Nucleosides Nucleotides 1995, 14, 1465–1479.
¨
Otvos, L.; De Clercq, E. J. Med. Chem. 1990, 33, 1353–1360.
¨