Intramolecular glycosylation as a regio- and stereocontrolled approach for the synthesis of 8-oxo-purine nucleosides

Article abstract of DOI:10.1016/j.tetlet.2012.06.055

Intramolecular glycosylation of purine derivatives that are temporarily connected to the 5 position of ribofuranosyl donors at their 8 position through an ethereal linkage leads to 8-oxo-purine β-nucleosides in a stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2012.06.055

Tetrahedron Letters 53 (2012) 4460–4463
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular glycosylation as a regio- and stereocontrolled approach for the
synthesis of 8-oxo-purine nucleosides
⇑
Hideyuki Sugimura , Daisuke Nitta
Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1, Fuchinobe, Chuo-ku, Sagamihara-shi 252-5258, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular glycosylation of purine derivatives that are temporarily connected to the 5 position of
ribofuranosyl donors at their 8 position through an ethereal linkage leads to 8-oxo-purine b-nucleosides
in a stereoselective manner.
Received 10 May 2012
Revised 6 June 2012
Accepted 13 June 2012
Available online 18 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
8-Oxo-purine nucleosides
Intramolecular reaction
Glycosylation
Stereocontrolled reaction
Synthetic procedures for the construction of purine nucleosides
and their analogs are important for the preparation of potential
therapeutic agents with a broad spectrum of biological activities.1
One strategy for nucleoside construction involves glycosylation of
purine bases with an appropriate ribosyl donor. However, such
synthetic approaches usually result in the formation of regioiso-
glycosides during the step involving modification of the carbohy-
drate moieties as well as during the introduction of the pyrimidine
base, whereas the 1-thioglycosides can act as powerful glycosylat-
ing agents when they are treated with an appropriate thiophilic
reagent. A suitable activator was found to be Me2S(SMe)BF4. The
synthetic applicability of this method is demonstrated by the syn-
theses of several pharmaceutically important deoxynucleosides:
ddC, AZT, FLT,6 some base-modified nucleosides,7 isonucleosides,8
50-modified nucleosides,9 and nucleoside antibiotics.10 We envision
that this intramolecular glycosylation strategy could be expanded
to purine bases in which the N7 position would be blocked by a
pre-installed protecting group, leading to a both regio- and diaste-
reocontrolled b-N9 glycosylation product. Here, we describe intra-
molecular glycosylation of purine derivatives that are temporarily
connected to the 5 position of ribofuranosyl donors at their 8 posi-
tion through an ethereal linkage, which leads to b-8-oxo-purine
nucleosides in a stereoselective fashion.
Initially, the intramolecular glycosylation was investigated
using readily available N-benzyl-2-chlorobenzimidazole as a mod-
el compound to optimize the reaction conditions (Scheme 1). The
model substrate 3 was prepared in 90% yield by reacting the so-
dium salt of thioglycoside 15 with N-benzyl-2-chloroimidazole
(2) in DMF at room temperature for 3 h. The intramolecular glyco-
sylation was performed by treating 3 with 1.5 equiv of a thiophilic
reagent in the presence of powdered MS 4A under high dilution
conditions. After the disappearance of 3 (monitored by thin layer
chromatography), 1 M NaOH aq was added to the reaction mixture
at 0 °C, and stirring was continued at rt for 1 h. The results are
summarized in Table 1. To our delight, Me2S(SMe)BF4 smoothly
promoted the intramolecular glycosylation in CH2Cl2 solvent at rt
meric mixtures of N7- and N9-glycosylpurines, and
a/b-anomeric
mixtures can also be encountered when the neighboring participa-
tion group is absent at the C2 of the ribosyl donor. Therefore,
improvement in the regioselectivity for N9 isomers as well as
enhancement of b anomeric selectivity is the primary focus in their
syntheses. For instance, the purine sodium salt glycosylation meth-
od, which is most commonly used in the preparation of purine
nucleosides, usually gives good b/a anomeric stereoselectivity
but variable selectivity for the N9 versus N7 purine regioisomers.2
Robins et al. recently solved this problem by using purines bearing
a 2-alkylimidazole or triazole at the 6-position to achieve highly
regio- and stereoselective glycosylation employing the sodium salt
method.3 More recently, based on this protocol, McLaughlin et al.
found that tetramethylsuccinimide at the 6-position is a more con-
venient directing/protecting group for the synthesis of b-N9
nucleosides with high regio- and stereoselectivity.4
On the other hand, we previously reported the development of a
convenient method for the stereocontrolled synthesis of pyrimidine
nucleosides that utilizes an intramolecular aglycon delivery
system.5 An important feature of this method is that it uses 1-thio-
glycosides as glycosyl donors, which can be considered stable
⇑
Corresponding author. Tel./fax: +81 42 759 6227.
E-mail address: sugimura@chem.aoyama.ac.jp (H. Sugimura).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.055

H. Sugimura, D. Nitta / Tetrahedron Letters 53 (2012) 4460–4463
4461
Scheme 1. Model reaction of intramolecular glycosylation using 2-chlorobenzimidazole derivative 2.
requisite 8-bromo-purine derivative (Scheme 2). Treatment of
commercially available 6-chloropurine (5) with NaOMe furnished
6-methoxypurine derivative 6, which was benzylated with NaH/
BnBr to produce N7-benzyl-6-methoxypurine (7) in 33% yield along
with a 47% yield of the N9-benzylated isomer. After separation of
N7-benzylpurine derivative 7, bromination with NBS furnished
the desired 8-bromo-6-methoxypurine derivative 8. Recently, Dvo-
rák et al. reported a facile pathway for the selective preparation of
N7-alkylated purines via 7,8-dihydropurines.14 According to this
protocol, N7-benzyl-6-chloropurine was obtained from 5 as a single
regioisomeric product and was treated with NaOMe to produce 7N-
benzyl-6-methoxypurine (7) in 56% total yield from 5.
Table 1
Intramolecular glycosylation using substrate 3
Entry Activator (equiv)
Concentration (M) Time (h) Yielda (%)
1
2
3
4
5
6
7
8
Me2S(SMe)BF4 (1.5)
Me2S(SMe)BF4 (1.5)
Me2S(SMe)BF4 (1.5)
NBS (1.5)
0.005
0.01
0.05
1
>99
96
75
0
0.5
0.5
3
0.005
NBS (1.5)—AgOTf (0.1) 0.005
3
3
3
3
58
42
87
77
NIS (1.5)
NIS (1.5)—AgOTf (0.1)
NIS (1.5)—AgOTf (0.1)
0.005
0.005
0.05
a
Isolated yield.
By introducing the purine bases to thiofuranoside 1 using 8-bro-
mo-purine derivative 8 in a similar manner to that described above,
glycosylation substrate 9 could be obtained. To our delight,
the following intramolecular glycosylation proceeded well under
the optimized conditions to afford b-8-oxopurine nucleoside 1015
in excellent yield (Scheme 3).
Next, our attention was turned to the synthesis of the
unnatural, regioisomeric N7-20-deoxyribofuranosyl 8-oxo-purine
nucleoside utilizing this glycosylation protocol. N9-Benzyl-6-
methoxypurine, the side product obtained from benzylation of 6-
methoxypurine (6) (Scheme 2), was similarly brominated to give
N9-benzyl-8-bromo-6-methoxypurine (80) (70%), which was used
for the intramolecular glycosylation and produced N7-glycosylated
8-oxo-purine 1216 in a regiospecific and stereoselective manner
(Scheme 4).
To further expand the synthetic utility of the reaction, structural
variation in the ribosyl donor was also examined. 2,3-O-Isopropyl-
idene-1-thioribofuranoside 13 was prepared as a ribosyl donor
without neighboring group participation (Scheme 5). The introduc-
tion of a purine base at the 5 position of the ribosyl donor using 8-
bromopurine derivative 8 was then followed by the intramolecular
glycosylation under similar reaction conditions to those described
above. In this case, however, since the reaction was rather sluggish
and the corresponding b-8-oxopurine nucleoside 1517 was ob-
tained in low yield (19%), the solvent was switched from CH2Cl2
and, after hydrolysis of the cyclic intermediate, the desired b-N-
glycoside 411 was obtained in a quantitative yield (Table 1, entry
1). The b-configuration at the newly formed anomeric center was
unequivocally established by analysis of NOE spectra. To avoid
intermolecular glycosylation, the reaction needs to be conducted
under high-dilution conditions. In this reaction, a 0.01 M concen-
tration provided a similarly high yield of the product (entry 2),
whereas a 0.05 M concentration led to a decrease in product yield
(entry 3). Changing the activator to a halonium system—NBS, NBS-
AgOTf, NIS, or NIS-AgOTf—did not improve the yields (entries 4–8).
However, a combination of NIS (1.5 equiv) and AgOTf (0.1 equiva-
lents) was also found to be effective (entry 7).
Encouraged by these results, we next adapted these optimized
glycosylation conditions to the stereoselective synthesis of
8-oxo-purine nucleosides. 8-Oxo-7,8-dihydro-20-deoxyguanosine
(8-oxodG) and 8-oxo-7,8-dihydro-20-deoxyadenosine (8-oxodA)
are well-known oxidized bases in DNA and may play key roles in
oxidative mutagenesis and carcinogenesis in humans.12,13 Conse-
quently, the development of a synthetic route to structurally mod-
ified 8-oxo-purine nucleosides will contribute to the elucidation of
the biological mechanisms of DNA damage and repair processes.
Toward our goal to develop a novel approach for the synthesis of
8-oxo-20-deoxypurine nucleosides, we first set out to prepare the
Scheme 2. Preparation of 8-bromopurine derivative 8.

4462
H. Sugimura, D. Nitta / Tetrahedron Letters 53 (2012) 4460–4463
Scheme 3. Synthesis of 6-methoxy-8-oxo-purine nucleoside 10 via intramolecular glycosylation.
Scheme 4. Synthesis of N7-ribosyl purine nucleoside 12 via intramolecular glycosylation.
Scheme 5. Synthesis of 6-methoxy-8-oxo-purine nucleoside 15 via intramolecular glycosylation.
7. Sugimura, H.; Motegi, M.; Sujino, K. Nucleosides Nucleotides 1995, 14, 413–416.
8. Sujino, K.; Sugimura, H. J. Chem. Soc., Chem. Commun. 1994, 2541–2542.
9. Sugimura, H.; Katoh, Y. Chem. Lett. 1999, 28, 361–362.
10. Sugimura, H.; Sujino, K. Nucleosides Nucleotides 1998, 17, 53–63; Sugimura, H.;
Watanabe, R. Chem. Lett. 2008, 37, 1038–1039.
to CH3CN, which led to a remarkable improvement in the yield of
15 (74%) presumably due to the stabilization of the resulting cyclic
intermediate by the polar solvent.
In conclusion, we have developed an intramolecular glycosyla-
tion reaction for the regio- and stereocontrolled synthesis of
b-8-oxo-purine nucleosides. By employing this strategy, b-N9-20-
deoxyribofuranosyl- and b-N9-ribofuranosyl-8-oxo-purine nucleo-
sides 10 and 15 could be obtained in high yield with complete
stereoselectivity. These nucleoside products can be converted into
8-oxo-adenosine, 8-oxo-inosine, and further structural variants of
the purine base. In addition, starting from an N9-protected purine
derivative, unnatural N7-ribosyl-purine nucleoside 12 was formed
in a regiospecific and stereoselective manner. We are currently
exploring an extension of this methodology to guanine-base equiv-
alents, which are expected to be building blocks of DNA-lesion-
containing oligonucleotides for DNA-repair studies.
11. Spectral data for compound 4: 1H NMR (500 MHz, CDCl3) d: 2.35 (1H, dd,
J = 13.0, 5.5 Hz, H-20), 3.14 (1H, ddd, J = 13.0, 9.0, 6.0 Hz, H-20), 3.73 (1H, t,
J = 10.0 Hz, H-50), 3.98 (1H, d, J = 12.0 Hz, H-50), 4.30 (1H, s, H-40), 4.49 (1H, d,
J = 5.5 Hz, H-30), 4.60 (3H, s, –O–CH2–Ph, –OH), 4.97 (1H, d, J = 15.0 Hz, –N–
CH2–Ph), 5.05 (1H, d, J = 15.0 Hz, –N–CH2–Ph), 6.26 (1H, dd, J = 9.0, 6.0 Hz, H-1),
6.89 (1H, d, J = 7.5 Hz, Ar), 7.23 (1H, t, J = 8.0 Hz, Ar), 7.08 (1H, t, J = 7.0 Hz), 7.14
(1H, d, J = 7.0 Hz), 7.24–7.36 (6H, m, Ar), 7.39 (4H, d, J = 4.5 Hz, Ar); 13C NMR
(125 MHz, CDCl3) d: 33.5, 42.9, 62.2, 69.8, 78.7, 82.9, 84.1, 106.5, 107.0, 112.0,
120.2, 125.8, 126.1, 126.2, 126.9, 127.1, 134.1, 136.1, 151.9.
12. For recent studies towards the biological effects, see: (a) Damsma, G.; Cramer,
P. J. Biol. Chem. 2009, 284, 31658–31663; (b) Markus, T. Z.; Daube, S. S.;
Naaman, R.; Fleming, A. M.; Muller, J. G.; Burrows, C. J. J. Am. Chem. Soc. 2009,
131, 89–95; (c) Li, Z.; Nakagawa, O.; Koga, Y.; Taniguchi, Y.; Sasaki, S. Bioorg.
Med. Chem. 2010, 18, 3992–3998; (d) Furman, J. L.; Mok, P.-W.; Badran, A. H.;
Ghosh, I. J. Am. Chem. Soc. 2011, 133, 12518–12527.
13. For recent synthetic studies, see: (a) Cadena-Amaro, C.; Delepierre, M.; Pochet,
S. Bioorg. Med. Chem. Lett. 2005, 15, 1069–1073; (b) Chatgilialoglu, C.;
Navacchia, M. L.; Postigo, A. Tetrahedron Lett. 2006, 47, 711–714; (c) Kannan,
A.; Burrows, C. J. J. Org. Chem. 2011, 76, 720–723.
References and notes
14. Kotek, V.; Chudíková, N.; Tobrman, T.; Dvorák, D. Org. Lett. 2010, 12, 5724–5727.
15. Spectral data for compound 10: 1H NMR (500 MHz, CDCl3) d: 2.38 (1H, dd,
J = 13.3, 5.5 Hz, H-20), 2.85 (1H, ddd, J = 13.3, 9.9, 5.5 Hz, H-20), 3.69 (1H, td,
J = 12.4, 1.4 Hz, H-50), 3.93 (1H, d, J = 12.4 Hz, H-50), 4.08 (3H, s, –O–Me), 4.30
(1H, s, H-40), 4.44 (1H, d, J = 5.5 Hz, H-30), 4.53 (1H, d, J = 11.5 Hz, –CH2-Ph),
4.60 (1H, d, J = 11.5 Hz, –CH2-Ph), 5.15 (1H, d, J = 14.9 Hz, –CH2-Ph), 5.16 (1H, d,
J = 14.9 Hz, –CH2-Ph), 5.74 (1H, d, J = 10.5 Hz, –OH), 6.49 (1H, dd, J = 10.1,
5.50 Hz, H-10), 7.25–7.41 (10H, m, Ar), 8.28 (1H, s, H-2); 13C NMR (125 MHz,
CDCl3) d: 35.8, 46.4, 54.2, 64.1, 71.2, 80.6, 84.3, 86.5, 108.4, 127.7, 127.9, 128.1,
128.3, 128.6, 128.8, 136.8, 137.8, 147.8, 149.8, 151.8, 153.0.
1. For instance, see: Bambuch, V.; Pohl, R.; Hocek, M. Eur. J. Org. Chem. 2008,
2783–2788. and references cited therein.
2. For a representative study, see: Hildebrand, C.; Wright, G. E. J. Org. Chem. 1992,
57, 1808–1813.
3. (a) Zhong, M.; Nowak, I.; Robins, M. J. Org. Lett. 2005, 7, 4601–4603; (b) Zhong,
M.; Nowak, I.; Robins, M. J. J. Org. Chem. 2006, 71, 7773–7779.
4. (a) Arico, J. W.; Calhoun, A. K.; Salandria, K. J.; McLaughlin, L. W. Org. Lett. 2010,
12, 120–122; (b) Arico, J. W.; Calhoun, A. K.; McLaughlin, L. W. J. Org. Chem.
2010, 75, 1360–1365.
16. Spectral data for compound 12: 1H NMR (500 MHz, CDCl3) d: 2.34 (1H, dd,
J = 13.5, 6.0 Hz, H-20), 3.03 (1H, ddd, J = 13.5, 8.9, 6.4 Hz, H-20), 3.69 (1H, t,
5. Sujino, K.; Sugimura, H. Chem. Lett. 1993, 22, 1187–1190.
6. Sujino, K.; Sugimura, H. Tetrahedron Lett. 1994, 35, 1883–1886.

H. Sugimura, D. Nitta / Tetrahedron Letters 53 (2012) 4460–4463
4463
J = 12.1 Hz, H-50), 3.92 (1H, d, J = 12.1 Hz, H-50), 4.06 (3H, s, –O-Me), 4.28 (1H, s,
H-40), 4.45 (1H, d, J = 6.4 Hz, H-30), 4.58 (2H, s, –CH2-Ph), 5.07 (2H, s, –CH2-Ph),
6.53 (1H, dd, J = 9.2, 6.0 Hz, H-10), 7.24–7.34 (4H, m, Ar), 7.35–7.40 (4H, m, Ar),
7.48 (2H, d, J = 7.8 Hz, Ar), 8.35 (1H, s, H-2); 13C NMR (125 MHz, CDCl3) d: 35.9,
43.9, 54.3, 63.8, 71.6, 80.0, 86.1, 86.2, 107.0, 127.8, 128.0, 128.1, 128.6, 128.8,
135.8, 137.9, 149.1, 151.0, 152.2, 152.5.
4.07 (3H, s, –O-Me), 4.42 (1H, s, H-40), 5.04 (1H, dd, J = 6.0, 1.4 Hz, H-30), 5.14
(1H, d, J = 15.1 Hz, –CH2-Ph), 5.15 (1H, d, J = 15.1 Hz, –CH2-Ph), 5.18 (1H, d,
J = 11.0 Hz, OH), 5.24 (1H, t, J = 5.0 Hz, H-20), 6.13 (1H, d, J = 5.0 Hz, H-10), 7.24–
7.33 (3H, m, Ar), 7.36–7.40 (2H, d, J = 6.9 Hz, Ar), 8.28 (1H, s, H-2); 13C NMR
(125 MHz, CDCl3) d: 25.5, 27.7, 46.5, 54.3, 63.6, 81.5, 81.8, 85.3, 89.3, 108.2,
114.1, 128.1, 128.3, 128.8, 136.7, 147.7, 150.1, 151.8, 153.0.
17. Spectral data for compound 15: 1H NMR (500 MHz, CDCl3) d: 1.36 (3H, s, CH3),
1.64 (3H, s, CH3), 3.74 (1H, t, J = 12.4 Hz, H-50), 3.89 (1H, d, J = 12.4 Hz, H-50),