Synthesis of new acyclonucleosides comprising unexpected regioisomers in the case of purines

Article abstract of DOI:10.1016/j.tet.2003.09.093

Acyclonucleosides 4 have been obtained by a short way starting from ethyl 2-hydroxymethyl acrylate 5. The key intermediate was acetate 9. Its reaction with free or protected nucleic bases gave either the expected compounds or unusual regioisomers.

Full text of DOI:10.1016/j.tet.2003.09.093

Tetrahedron 59 (2003) 9635–9639
Synthesis of new acyclonucleosides comprising unexpected
regioisomers in the case of purines
a
Stephane Guillarme, Stephanie Legoupy, Nathalie Bourgougnon, Anne-Marie Aubertin
a
b
c
´
´
and Franc¸ois Hueta
,
*
a
` ´ ´
Laboratoire de Synthese Organique, UMR CNRS 6011, Faculte des Sciences et Techniques, Universite du Maine,
Avenue Olivier Messiaen, F-72085 Le Mans Cedex 9, France
b
´
Laboratoire de Biologie et Chimie Moleculaire, Centre de recherche et d’enseignement Yves Coppens, Campus de Tohannic,
BP 573, F-56017 Vannes, France
c
´ ´ ´ ´
Faculte de Medecine, Institut de Virologie, INSERM U544, Universite Louis Pasteur, 3 rue Koeberle, F-67000 Strasbourg, France
Received 30 May 2003; revised 2 September 2003; accepted 29 September 2003
Abstract—Acyclonucleosides 4 have been obtained by a short way starting from ethyl 2-hydroxymethyl acrylate 5. The key intermediate
was acetate 9. Its reaction with free or protected nucleic bases gave either the expected compounds or unusual regioisomers.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Ongoing our interest in the synthesis of acyclic nucleosides4
we considered the synthesis of new class of unsaturated
acyclonucleosides 4, which can be viewed as regioisomers
of the 10,20-seconucleoside of d4T 3, used in the treatment of
AIDS5 (Scheme 1).
Nucleoside analogues are currently used as antiviral agents,
for instance against human immunodeficiency virus (HIV),
or hepatitis B (HBV) and herpes viruses. In several cases,
acyclic nucleosides appeared as an useful class of
compounds for antiviral chemotherapy.1 Indeed, the
remarkable activity of acyclonucleosides such as acyclovir
12 and ganciclovir 23 which are potent antiherpetic agents
shows the interest of this class of compounds. In these cases,
the biological activity is remarkable despite important
modifications of the sugar moiety with respect to the natural
products (Fig. 1).
2. Results and discussion
Starting from ethyl 2-hydroxymethyl acrylate 5, adduct of
Baylis–Hillman,6 a two step synthesis led to alcohol 7 in
67% overall yield. However, first attempts to obtain directly
the acetate 9 by reaction of alcohol 7 with methyl
chloroacetate7 in basic conditions gave no result. Therefore,
we first prepared compound 8 following the method of Gras
et al.8 and it was obtained in 88% yield. Its treatment with
acetic anhydride in the presence of sulfuric acid provided
the required acetate 9 in 58% yield (Scheme 1).9
When 9 was subjected to the one-pot substitution by
thymine and N-4-benzoylcytosine in Vorbru¨ggen et al.10
Figure 1.
Scheme 1. (a) tBuPh2SiCl, pyridine; (b) DIBAL–H, toluene, 2708C; (c) CH2(OMe)2, LiBr, APTS; (d) H2SO4, Ac2O.
Keywords: nucleosides; purines; pyrimidines; regiochemistry.
*
Corresponding author. Tel.: þ33-2-43-83-33-38; fax: þ33-2-43-83-39-02; e-mail: fhuet@univ-lemans.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.093

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S. Guillarme et al. / Tetrahedron 59 (2003) 9635–9639
Scheme 2. (a) (1) BSA, CH3CN; (2) TMSOTf, 9; (b) TBAF, THF; (c) (1) NH3/MeOH, (2) TBAF, THF.
conditions modified by Dudycz et al.,11 the expected
products 10 and 11 were obtained in good yields (Scheme 2).
assign N-9 and N-1 regiochemistries for isomers 12 and 13,
respectively, HMBC experiments have been carried out
(Fig. 2). In purine derivatives, C-5 is the only quaternary C
of the base moiety close to only one N. Therefore, its signal
is always at higher field. The long-range couplings (3J)
between C-5 and H-8, but not with H-2, in the HMBC
spectrum, easily led to assignment of these two protons.
Afterwards the 1J 1H/13C correlation led to the assignments
of the corresponding carbons, C-2 and C-8. As C-6 was
correlated only with H-2, and C-4 with H-2 and H-8, they
also could be assessed. Finally, for 12, correlation (3J)
between H-10 and C-8 and C-4 proved the N-9 regio-
chemistry. For 13, correlation (3J) between H-10 and C-6
and C-2 proved the N-1 regiochemistry. Obtaining the
kinetic isomer N-1 13, which is quite unusual, could be
explained by the mechanism proposed by Vorbru¨gen et al.10b
Regioselectivity was surprising also for the protected
guanine, which exclusively led, at 208C, to the N-7 isomer
14 (Scheme 2) (Fig. 2). When alkylation reaction was
performed at 858C, the same result was obtained, and all
attempts to isomerize12 14 to the corresponding N-9 isomer
have been unsuccessful. This result was not expected,
however, such a regioselectivity has already been observed
by Goodnow et al.13 Removal of the protecting groups
afforded the acyclonucleosides 4a, 4b and 4c in 81, 53 and
53% yield, respectively.
Regiochemistry for the nucleoside 10 was confirmed by
HMBC experiments (Fig. 2). Condensation also worked
with the protected purine bases but in lower yield. On the
other hand unexpected isomers were isolated. With
protected adenine, at 208C, we were surprised to obtain a
mixture of N-9 12 and N-1 13 alkylated products, in a 1:1
ratio, which could be separated by chromatography
(Scheme 2). The reaction run at 858C afforded the
thermodynamically more stable regioisomer N-9 12. To
In conclusion, three new acyclonucleosides were isolated in
Figure 2. Relevant HMBC correlations.

S. Guillarme et al. / Tetrahedron 59 (2003) 9635–9639
9637
6 steps. To the best of our knowledge, obtaining of a N-1
isomer, from reaction with adenine has never been reported.
Biological tests showed that the compound 4a did no have
antitumor, anti-HIV and anti-herpes properties.
J¼5.6 Hz), 1.06 (s, 9H, CH3); 13C NMR (CDCl3) d: 147.1
(quat C), 135.5 (quat C), 132.2 (CH), 129.7 (CH), 127.7
(CH), 110.3 (CH2), 65.5 (CH2–O), 64.4 (CH2–O), 26.8
(CH3), 19.2 (quat C).
3.1.3. tert-Butyldiphenylsilyl 2-(methoxymethoxy-
methyl)-prop-2-enyl ether 8. A solution of 7 (4.0 g,
12.26 mmol), lithium bromide (266 mg, 3.06 mmol) and
p-toluenesulfonic acid (234 mg, 1.23 mmol) in dimethoxy-
methane (35 mL) was stirred at room temperature for 18 h.
Saturated aqueous NaCl was added (10 mL) and the
aqueous phase was extracted with Et2O (3£5 mL). The
organic extracts were dried (MgSO4) and evaporated under
reduced pressure. The residue was purified by column
chromatography (silica gel, cyclohexane/EtOAc 95:5) to
afford 8 (3.99 g, 10.79 mmol, 88%) as a colorless oil: IR
(neat, cm21) 3072, 3048, 2931, 2856, 1247, 1112; 1H NMR
(CDCl3) d: 7.62–7.47 (m, 10H, H arom), 5.31 (td, 1H,
vCH, J¼1.7, 2.0 Hz), 5.16 (m, 1H, vCH, J¼2.0 Hz), 4.55
(s, 2H, CH2–O), 4.22 (t, 2H, CH2–O, J¼1.7 Hz), 4.06 (s,
2H, CH2–O), 3.34 (s, 3H, CH3), 1.08 (s, 9H, CH3); 13C
NMR (CDCl3) d: 144.9 (quat C), 135.9 (quat C), 133.9
(CH), 130.9 (CH), 128.1 (CH), 122.4 (CH2), 95.2 (CH2–O),
68.3 (CH2–O), 65.0 (CH2–O), 55.1 (CH3), 27.2 (CH3), 19.7
(quat C); HRMS (EI) calcd for C17H19O2Si [M2C5H11O]þ:
283.1154. Found: 283.1158.
3. Experimental
3.1. General
All reagents were of commercial quality or purified if
necessary and all solvents were distilled and dried by
literature procedures.14 All moisture-sensitive reactions
were performed in oven-dried glassware and under inert
atmosphere. All melting points were uncorrected. Infrared
spectra were measured with a FT infrared spectrometer
1
Genesis, Matteson Instruments. H and 13C NMR spectra
were recorded on a Bruker AC400 spectrometer at 400 and
100.6 MHz, respectively. Chemical shifts are reported in
ppm downfield from TMS which was used as an internal
reference. Elemental analyses were carried out at the
Service de Microanalyse, CNRS ICSN, Gif-sur-Yvette.
High-resolution mass spectra were recorded on Varian
MAT 311 and ZabSpec TOF Micromass spectrometers at
the CRMPO, Rennes.
3.1.1. Ethyl 2-(tert-butyldiphenylsilyloxymethyl)-acryl-
ate 6. A solution of ethyl 2-hydroxymethyl-acrylate 56
(3.04 g, 23.38 mmol) and tert-butyldiphenylsilyl chloride
(6.75 g, 25.54 mmol) in pyridine (30 mL) was stirred at
room temperature for 18 h. The solvent was removed under
reduced pressure and then the residue was dissolved in
CH2Cl2 (30 mL) and washed twice with water (15 mL). The
organic layer was dried (MgSO4) and evaporated under
reduced pressure. Column chromatography (silica gel,
cyclohexane/EtOAc: 95:5) of the crude product afforded 6
(7.21 g, 19.64 mmol, 85%) as a pale yellow oil: IR (neat,
cm21) 3072, 3048, 1714, 1643, 1463, 1428, 1270; 1H NMR
(CDCl3) d: 7.62–7.40 (m, 10H, H arom), 6.32 (dt, 1H,
vCH, J¼2.0, 2.0 Hz), 6.10 (dt, 1H, vCH, J¼2.0, 2.2 Hz),
4.42 (dd, 2H, CH2–O, J¼2.0, 2.2 Hz), 4.16 (q, 2H, CH2–O,
J¼7.1 Hz), 1.25 (t, 3H, CH3, J¼7.1 Hz), 1.07 (s, 9H, CH3);
13C NMR (CDCl3) d: 166.0 (CvO), 139.6 (quat C), 135.4
(quat C), 133.2 (CH), 129.7 (CH), 127.7 (CH), 123.7 (CH2),
62.2 (CH2–O), 60.5 (CH2–O), 26.8 (CH3), 19.3 (quat C),
14.1 (CH3).
3.1.4. 2-(tert-Butyldiphenylsilyloxymethyl)-prop-2-enyl
acetate 9. To a solution of 8 (3.9 g, 10.52 mmol) in Ac2O
(14 mL) at 08C was added concentrated H2SO4 (233 mL,
4.5 mmol). The solution was stirred at 58C for 18 h and
poured at 08C in saturated aqueous solution of NaHCO3
(70 mL). Stirring continued at room temperature for 18 h.
The solution was then extracted with CH2Cl2 (5£15 mL)
and the organic phases were washed with water (30 mL),
dried (MgSO4) and evaporated under reduced pressure. The
crude product was purified by column chromatography
(silica gel, cyclohexane/EtOAc 95:5) to lead to 9 (2.45 g,
6.14 mmol, 58%) as a colorless oil: IR (neat, cm21) 3072,
1
3048, 2931, 2857, 1747, 1228, 1114; H NMR (CDCl3) d:
7.68–7.47 (m, 10H, H arom), 5.32 (td, 1H, vCH, J¼1.2,
1.5 Hz), 5.21 (s, 2H, CH2–O), 5.16 (td, 1H, vCH, J¼1.2,
1.5 Hz), 4.20 (t, 2H, CH2–O, J¼1.2 Hz), 4.16 (s, 2H,
CH2–O), 2.04 (s, 3H, CH3), 1.07 (s, 9H, CH3); 13C NMR
(CDCl3) d: 170.5 (CvO), 143.7 (quat C), 133.5 (quat C),
133.4 (CH), 129.6 (CH), 127.7 (CH), 112.7 (CH2), 88.1
(CH2–O), 70.5 (CH2–O), 64.3 (CH2–O), 26.5 (CH3), 20.9
(CH3), 19.2 (quat C); HRMS (EI) calcd for C18H19O3Si
[M2C5H11O]þ: 311.1103. Found: 311.1116.
3.1.2. 2-(tert-Butyldiphenylsilyloxymethyl)-prop-2-en-1-
ol 7.15 To a solution of 6 (6.0 g, 16.3 mmol) in anhydrous
toluene (90 mL) under inert atmosphere at 2708C was
added dropwise a solution 1 M of DiBAl–H in toluene
(70 mL, 70 mmol). The solution was stirred 3 h and
quenched with a solution 10% (300 mL) of citric acid.
The solution was then allowed to warm to room temperature
and the aqueous layer was extracted with EtOAc
(4£75 mL). The organic layer was dried (MgSO4) and
evaporated under reduced pressure. The residual oil was
purified by column chromatography (silica gel, cyclohex-
ane/EtOAc 90:10!85:15) to give 7 (4.22 g, 12.88 mmol,
79%) as a colorless oil. IR (neat, cm21) 3361, 3072, 3048,
3.1.5. 1-[20-(tert-Butyldiphenylsilyloxymethyl)-allyloxy-
methyl]-thymine 10. To a stirred suspension of thymine
(73.7 mg, 0.584 mmol) in anhydrous CH3CN (1.5 mL)
under inert atmosphere was added BSA (297 mg,
1.46 mmol). The solution was stirred at room temperature
until a clear solution was obtained. Then the mixture was
cooled to 08C and compound 9 (194 mg, 0.487 mmol) in
solution in anhydrous CH3CN (2 mL) and TMSOTf
(113.6 mg, 0.511 mmol) were added. The reaction mixture
was stirred at room temperature for 4 h. CH2Cl2 (2 mL) was
added and then a saturated aqueous solution of NaHCO3
until pH became basic. The organic solvents were removed
under reduced pressure and aqueous phase was extracted
1
1112; H NMR (CDCl3) d: 7.71–7.40 (m, 10H, H arom),
5.25 (m, 1H, vCH), 5.10 (m, 1H, vCH), 4.25 (s, 2H,
CH2–O), 4.16 (d, 2H, CH2–O, J¼5.6 Hz), 1.95 (t, 1H, OH,

9638
S. Guillarme et al. / Tetrahedron 59 (2003) 9635–9639
with EtOAc (3£3 mL). The organic layer was washed with
water (2 mL) and dried (MgSO4). The solvent was removed
under reduced pressure and the residue was purified by
column chromatography (silica gel, CH2Cl2/EtOAc 8:2) to
afford 10 (164 mg, 0.353 mmol, 73%) as a colorless oil: IR
(neat, cm21) 3206, 3070, 3048, 1681, 1112; 1H NMR
(CDCl3) d: 8.92 (broad s, 1H, NH), 7.68–7.63 (m, 4H, H
arom), 7.45–7.32 (m, 6H, H arom), 7.03 (q, 1H, CH,
J¼1.2 Hz), 5.24 (td, 1H, vCH, J¼1.5, 1.5 Hz), 5.18 (td,
1H, vCH, J¼1.5, 1.5 Hz), 5.05 (s, 2H, CH2–N), 4.18 (t,
2H, CH2–O, J¼ 1.5 Hz), 4.07 (s, 2H, CH2–O), 1.88 (d, 3H,
CH3, J¼1.2 Hz), 1.05 (s, 9H, CH3); 13C NMR (CDCl3) d:
163.9 (CvO), 151.0 (CvO), 143.4 (quat C), 138.9 (CH),
135.5 (quat C), 133.3 (CH), 129.7 (CH), 127.7 (CH), 113.2
(quat C), 111.6 (CH2), 75.7 (CH2–N), 69.9 (CH2–O), 64.2
(CH2–O), 26.7 (CH3), 19.2 (quat C) 12.3 (CH3); Anal calcd
for C26H32N2O4Si: C, 67.21; H, 6.94; N, 6.03. Found: C,
67.57; H, 7.23; N, 5.77.
148.6 (quat C), 142.1 (quat C), 142.0 (CH), 134.5 (CH),
132.6 (quat C), 131.7 (quat C), 128.7 (CH), 127.8 (CH),
126.9 (CH), 126.7 (CH), 126.6 (CH), 121.7 (quat C), 112.5
(CH2), 70.7 (CH2–N), 69.2 (CH2–O), 63.2 (CH2–O), 25.7
(CH3), 18.2 (quat C); HRMS (EI) calcd for C29H26N5O3Si
[M2C4H9]þ: 520.1804. Found: 520.1830.
Compound 13. IR (neat, cm21) 3224, 3069, 1634, 1595; 1H
NMR (CDCl3) d: 12.76 (broad s, 1H, NH), 8.34 (s, 1H, CH),
8.30–8.28 (m, 2H, H arom), 8.15 (s, 1H, CH), 7.66–7.62
(m, 4H, H arom), 7.54–7.50 (tt, 1H, H arom, J¼1.2,
7.4 Hz), 7.45–7.33 (m, 8H, H arom), 5.84 (s, 2H, CH2–N),
5.34 (dt, 1H, vCH, J¼1.2, 1.5 Hz), 5.17 (m, 1H, vCH,
J¼1.2 Hz), 4.21 (s, 2H, CH2–O), 4.19 (t, 2H, CH2–O,
J¼1.2 Hz), 1.02 (s, 9H, CH3); 13C NMR (CDCl3) d: 175.6
(CvO), 157.4 (quat C), 149.6 (quat C), 146.1 (CH), 143.3
(quat C), 141.7 (CH), 137.3 (quat C), 135.4 (CH), 133.2
(quat C), 132.2 (CH), 129.8 (CH), 129.7 (CH), 128.1 (CH),
127.6 (CH), 114.9 (quat C), 113.6 (CH2), 76.6 (CH2–N),
70.4 (CH2–O), 64.2 (CH2–O), 26.7 (CH3), 19.1 (quat C);
HRMS (EI) calcd for C29H26N5O3Si [M2C4H9]þ:
520.1804. Found: 520.1780.
3.1.6. 1-[20-(tert-Butyldiphenylsilyloxymethyl)-allyloxy-
methyl]-cytosine 11. N-4-Benzoylcytosine (215 mg,
1.0 mmol) and compound 9 (332 mg, 0.833 mmol) in
anhydrous CH3CN (7 mL) were stirred at room temperature
for 20 h in the same experimental conditions as for 10,
to give 11 (296 mg, 0.535 mmol, 64%) as a colorless oil
after column chromatography (silica gel, CH2Cl2/EtOAc
7:3!6:4): IR (neat, cm21) 3252, 3072, 1676, 1617, 1109;
1H NMR (CDCl3) d: 8.91 (broad s, 1H, NH), 7.93 (d, 2H, H
arom, J¼7.1 Hz), 7.69–7.63 (m, 5H, H arom and CH), 7.58
(tt, 1H, H arom, J¼1.2, 7.1 Hz), 7.51–7.46 (m, 2H,
H arom), 7.42–7.35 (m, 7H, H arom and CH), 5.35 (td,
1H, vCH, J¼1.2, 1.5 Hz), 5.22 (s, 2H, CH2–N), 5.19 (td,
1H, vCH, J¼1.2, 1.5 Hz), 4.19 (t, 2H, CH2–O, J¼1.2 Hz),
4.12 (s, 2H, CH2–O), 1.06 (s, 9H, CH3); 13C NMR (CDCl3)
d: 162.9 (CvO, 2 signals overlap), 156.0 (quat C), 147.3
(CH), 143.4 (quat C), 135.5 (CH), 133.4 (CH), 133.2 (quat
C, 2 signals overlap), 129.8 (CH), 129.0 (CH), 127.8 (CH),
127.7 (CH), 113.4 (CH2), 96.5 (CH), 77.5 (CH2–N), 70.7
(CH2–O), 64.5 (CH2–O), 27.0 (CH3), 19.3 (quat C); Anal
calcd for C32H35N3O4Si: C, 69.42; H, 6.37; N, 7.59. Found:
C, 69.65; H, 6.17; N, 7.79.
3.1.8. 7-[20-(tert-Butyldiphenylsilyloxymethyl)-allyloxy-
methyl]-N-acetyl-O-(diphenylcarbamoyl)-guanine 14.
N-2-Acetyl-O-6-(diphenylcarbamoyl)guanine16 (87.0 mg,
0.223 mmol) and compound 9 (74.0 mg, 0.186 mmol) in
anhydrous CH3CN (1.8 mL) were stirred at room tempera-
ture for 12 h in the same experimental conditions as for 10,
to afford 14 (39.8 mg, 0.054 mmol, 24%) as a white solid
after column chromatography (silica gel, CH2Cl2/EtOAc
1:1!2:3): mp 61–638C; IR (KBr, cm21) 3246, 3069, 1745,
1
1634, 1568, 1493, 1450, 1116; H NMR (CDCl3) d: 8.03
(broad s, 1H, NH), 7.98 (s, 1H, CH), 7.67–7.63 (m, 4H, H
arom), 7.46–7.29 (m, 14H, H arom), 7.25–7.20 (m, 2H, H
arom), 5.36 (m, 1H, vCH, J¼1.2 Hz), 5.24 (s, 2H, CH2–
N), 5.05 (m, 1H, vCH, J¼1.2 Hz), 4.13 (s, 2H, CH2–O),
3.78 (s, 2H, CH2–O), 2.64 (s, 3H, CH3), 1.05 (s, 9H, CH3);
13C NMR (CDCl3) d: 165.0 (CvO), 151.2 (quat C), 151.2
(quat C), 149.1 (CvO), 147.9 (CH), 142.3 (quat C), 140.9
(quat C), 135.1 (CH), 132.8 (quat C), 129.5 (CH), 128.9
(CH, several signals overlap), 127.4 (CH), 113.7 (CH2),
111.1 (quat C), 74.5(CH2–N), 68.7(CH2–O), 63.7(CH2–O),
26.4 (CH3), 24.8 (CH3), 18.8 (quat C); HRMS (FAB)
calcd for C41H43N6O5Si (MþH)þ: 727.3064. Found:
727.3062.
3.1.7. 9-[20-(tert-Butyldiphenylsilyloxymethyl)-allyloxy-
methyl]-N-benzoyl-adenine 12 and 1-[20-(tert-butyl-
diphenylsilyloxymethyl)-allyloxymethyl]-N-benzoyl-
adenine 13. N-6-Benzoyladenine (72.1 mg, 0.301 mmol)
and compound 9 (100 mg, 0.251 mmol) in anhydrous
CH3CN (2.5 mL) were stirred at room temperature for
2 h 45 in the same experimental conditions as for 10, to
lead to a mixture of 12 (35.3 mg, 0.062 mmol, 24.5%) as a
colorless oil and 13 (35.5 mg, 0.062 mmol, 24.5%) after
column chromatography (silica gel, CH2Cl2/EtOAc
3:2!1:1).
Compound 12. IR (neat, cm21) 3263, 3070, 1703, 1610,
1583; 1H NMR (CDCl3) d: 9.21 (broad s, 1H, NH), 8.77 (s,
1H, CH), 8.05 (s, 1H, CH), 8.01 (d, 2H, H arom, J¼7.4 Hz),
7.67–7.62 (m, 4H, H arom), 7.57 (tt, 1H, H arom, J¼1.2,
7.4 Hz), 7.51–7.44 (m, 2H, H arom), 7.42–7.32 (m, 6H, H
arom), 5.56 (s, 2H, CH2–N), 5.34 (m, 1H, vCH, J¼
1.2 Hz), 5.16 (m, 1H, vCH, J¼1.2 Hz), 4.17 (m, 2H,
CH2–O), 4.08 (s, 2H, CH2–O), 1.04 (s, 9H, CH3); 13C
NMR (CDCl3) d: 163.7 (CvO), 152.1 (CH), 151.4 (quat C),
3.1.9. 1-(20-(Hydroxymethyl-allyloxymethyl)thymine 4a.
To a solution of 10 (205 mg, 0.442 mmol) in THF (3 mL)
was added a 1M a solution of TBAF (0.885 mL,
0.885 mmol) in THF. The reaction mixture was stirred at
room temperature for 2 h and solvent was removed under
reduced pressure. The crude product was purified by column
chromatography (silica gel, CH2Cl2/MeOH 99:1!96:4) to
give 4a (81.0 mg, 0.358 mmol, 81%) as a white powder: mp
94–958C; IR (KBr, cm21) 3440, 3170, 3045, 1704, 1673,
1469, 1268; 1H NMR (CD3OD) d: 7.49 (q, 1H, CH,
J¼1.2 Hz), 5.19 (m, 1H, vCH), 5.14 (m, 3H, vCH and
CH2–N), 4.11 (s, 2H, CH2–O), 4.06 (s, 2H, CH2–O), 1.87
(d, 3H, CH3, J¼1.2 Hz); 13C NMR (CD3OD) d: 168.5
(CvO), 154.9 (CvO), 148.3 (quat C), 143.7 (quat C),
114.9 (CH2), 113.6 (quat C), 79.3 (CH2–N), 72.6 (CH2–O),
65.4 (CH2–O), 14.0 (CH3); Anal calcd for C10H14N2O4,

S. Guillarme et al. / Tetrahedron 59 (2003) 9635–9639
9639
0.2H2O: C, 52.26; H, 6.31; N, 12.19. Found: C, 52.26; H,
6.31; N, 12.08.
References
1. Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and
L-Nucleosides. Kluwer Academic: Dordrecht, 1998; pp
18–173.
3.1.10. 1-(20-(Hydroxymethyl-allyloxymethyl)-cytosine
4b. To a solution of 11 (253 mg, 0.457 mmol) in MeOH
(5 mL) was added, at 08C, a saturated solution of NH3 in
MeOH (4 mL). The mixture was stirred at room temperature
overnight and solvent was then removed under reduced
pressure. The residue was dissolved in THF (3 mL) and a
1M solution of TBAF (0.761 mL, 0.761 mmol) in THF was
added. The reaction mixture was stirred at room temperature
for 2 h and the solvent was removed under reduced pressure.
Purification of the crude product by column chroma-
tography (silica gel, CH2Cl2/MeOH 9:1) led to 4b
(51.5 mg, 0.244 mmol, 53%) as a white powder: mp 139–
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1
1418C; IR (KBr, cm21) 3331, 3134, 1659, 1630, 1484; H
NMR (CD3OD) d: 7.62 (d, 1H, CH, J¼7.4 Hz), 5.88 (d, 1H,
CH, J¼7.4 Hz), 5.18 (s, 2H, CH2–N), 5.17 (m, 1H, vCH),
5.13 (m, 1H, vCH), 4.12 (s, 2H, CH2–O), 4.05 (s, 2H,
CH2–O); 13C NMR (CD3OD) d: 169.6 (CvO), 160.5 (quat
C), 148.0 (CH and quat C), 114.4 (CH2), 97.8 (CH), 80.2
(CH2–N), 72.2 (CH2–O), 65.0 (CH2–O); Anal calcd for
C9H13N3O3, 0.6H2O: C, 48.69; H, 6.44; N, 18.92. Found: C,
48.41; H, 5.86; N, 18.69.
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3.1.11. 9-(20-(Hydroxymethyl-allyloxymethyl)-adenine
4c. Following the same procedure as for 4b, 12 (99.7 mg,
0.173 mmol) afforded, after column chromatography (silica
gel, CH2Cl2/MeOH 95:5), 4c (21.6 mg, 0.092 mmol, 53%)
as a white powder: mp 167–1698C; IR (KBr, cm21) 3302,
3086, 1680, 1607, 1107; 1H NMR (CD3OD) d: 8.24 (s, 1H,
CH), 8.23 (s, 1H, CH), 5.64 (s, 2H, CH2–N), 5.14 (m, 1H,
vCH), 5.10 (m, 1H, vCH), 4.12 (s, 2H, CH2–O), 4.01 (s,
2H, CH2–O); 13C NMR (CD3OD) d: 158.7 (quat C), 155.5
(CH), 155.4 (quat C), 147.5 (quat C), 144.2 (CH), 121.2
(quat C), 114.5 (CH2), 74.8 (CH2–N), 72.3 (CH2–O), 64.8
(CH2–O); HRMS (EI) calcd for C10H13N5O2: 235.1069.
Found: 235.1071.
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Acknowledgements
We thank the local section of Sarthe of the Ligue Nationale
contre le Cancer for a fellowship to S. G. and the NCI for the
evaluation of the antitumor properties.
15. Weigand, S.; Brueckner, R. Synthesis 1996, 475–482.
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