Stereocontrolled approach for the syntheses of 3-isopurine nucleosides: 3-(2-deoxy-β-d-ribofuranosyl)xanthine and isoguanine by intramolecular glycosylation

Article abstract of DOI:10.1016/j.tetlet.2015.09.045

3-Isopurine nucleosides, namely 3-(ribofuranosyl)purine nucleosides, are interesting owing to their potential biological activity and as components of modified oligonucleotides. A regio- and stereocontrolled method was developed for the synthesis of β-2′-

Full text of DOI:10.1016/j.tetlet.2015.09.045

Tetrahedron Letters 56 (2015) 6019–6021
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereocontrolled approach for the syntheses of 3-isopurine
nucleosides: 3-(2-deoxy-b-D-ribofuranosyl)xanthine and isoguanine
by intramolecular glycosylation
⇑
Hideyuki Sugimura , Sho Endo, Ken Ishizuka
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:
3-Isopurine nucleosides, namely 3-(ribofuranosyl)purine nucleosides, are interesting owing to their
potential biological activity and as components of modified oligonucleotides. A regio- and stereocon-
trolled method was developed for the synthesis of b-20-deoxy-3-isopurine nucleosides using the
intramolecular glycosylation protocol. The availability of this method was shown by the first chemical
Received 3 August 2015
Revised 3 September 2015
Accepted 15 September 2015
Available online 15 September 2015
synthesis of 3-(2-deoxy-b-
D
-ribofuranosyl)xanthine and isoguanine.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
3-Isopurine nucleoside
Intramolecular glycosylation
20-Deoxy-3-isoxanthine
3-(2-Deoxyribosyl)isoguanine
Stereoselective reaction
Structurally modified nucleosides play a central role in the
development of genetic therapies such as triplex and antisense
strategies. In these approaches, 20-deoxyoligonucleotides can pre-
vent the expression of specific genes, thus inhibiting the produc-
tion of disease related proteins. Therefore, methods for the
synthesis of modified 20-deoxynucleosides are of general interest
and widespread importance.1
3-Isopurine nucleosides are structural isomers of regular purine
nucleosides in which the ribose moiety is attached to the purine
base at the N-3 position rather than the N-9 position. They attract
continuing interest in their potential activity in enzyme-catalyzed
reactions2 and as the components of artificial oligonucleotides.3
Modified nucleosides of this type have been synthesized by several
methods. A common approach is glycosylation of the purine
derivatives with an appropriately protected ribosyl donor. For
instance, 3-isoadenosine was synthesized using the glycosylation
procedure by several groups.2b,4–7 However, the instability to
undergo 1,3-migration in both basic and acidic conditions to
result in adenosine, made synthesis difficult and low yielding.
Another approach involves the modification of existing
pyrimidine nucleosides.8,9 Since 3-isoxanthosine and 3-(ribosyl)
isoguanine contain pyrimidine-base framework in their base moi-
eties, these 3-isopurine nucleoside derivatives have been synthe-
sized from pyrimidine nucleosides with the appropriate exocyclic
groups in a suitable position for forming the imidazole ring.
Although the N-3 glycosylation of 8-substituted xanthine deriva-
tives has successfully proceeded to afford the corresponding 3-
isoxanthosine derivatives,10 the stereoselective formation of the
b-glycosidic bond when using 2-deoxyribosyl donor remains a con-
siderable synthetic challenge. The present work describes a com-
pletely regio- and stereocontrolled synthesis of b-20-deoxy-3-
isopurine nucleosides: 3-(2-deoxy-b-D-ribofuranosyl)-xanthine 1
and isoguanine 2 via the intramolecular glycosylation protocol
developed by our laboratories.
Previously, we developed
a convenient method for the
stereocontrolled synthesis of pyrimidine nucleosides using
intramolecular aglycon delivery.11 The synthetic applicability of
this method has been demonstrated by the syntheses of several
⇑
Corresponding author. Tel./fax: +81 42 759 6227.
E-mail address: sugimura@chem.aoyama.ac.jp (H. Sugimura).
http://dx.doi.org/10.1016/j.tetlet.2015.09.045
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6020
H. Sugimura et al. / Tetrahedron Letters 56 (2015) 6019–6021
pharmaceutically important deoxynucleosides such as ddC, AZT,
FLT12 as well as base- and sugar-modified nucleosides,13,14 and
nucleoside antibiotics.15 Recently, we reported the successful
application of this approach for the stereocontrolled synthesis of
8-oxo-purine nucleosides.16 Herein, we report
a convenient
method for the stereocontrolled synthesis of b-20-deoxy-3-
isopurine nucleosides 1 and 2 using direct N-3 glycosylation by
intramolecular aglycon delivery as shown in Scheme 1.
Scheme 2. Reagents and conditions: (a) NaOMe (1.1 equiv)/MeOH, reflux, 2 days,
83%; (b) NaH, BnBr/DMF, rt, 18 h, 5 37%, 6 41%; (c) (i) TrCl, Et3N/CH2Cl2, rt, 1 h, 98%;
(ii) DIBAL-H/THF, ꢀ78 °C to rt, 0.5 h, 97%; (iii) NaH, BnBr/DMF, rt, 24 h; (iv) TFA/
CH2Cl2, ꢀ78 °C to rt, 1 h, 83% (two steps); (v) NaOMe/MeOH-CH2Cl2, rt, 2 h, 98%.
Toward our goal to develop a novel approach for the synthesis
of 20-deoxy-3-isopurine nucleosides, we first set out to prepare
the requisite 2-chloropurine derivatives (Scheme 2). The treatment
of commercially available 2,6-dichloropurine (3) with NaOMe fur-
nished 6-methoxypurine derivative 4, which was benzylated with
NaH/BnBr to afford 7-benzyl-6-methoxypurine (5) in 37% yield
along with N-9 benzylated isomer 6 in 41% yield. As described in
details later, a more selective route was required for the prepara-
tion of N-7 benzylated purine derivative 5 rather than N-9 pro-
tected 6. Dovorák et al reported
a facile pathway for the
regioselective preparation of N-7 alkylated purines via 7,8-dihy-
dropurines.17 Using this method, 7-benzyl-2,6-dichloropurine
was obtained from 3 as a single regioisomeric product; further
treatment with NaOMe afforded 7-benzyl-2-chloro-6-methoxy-
purine (5) in 77% overall yield.
For the initial study on the intramolecular N-3 glycosylation of a
purine base, N-9 benzyl protected purine derivative 6 was investi-
gated (Scheme 3). Intramolecular glycosylation substrate 8 was
prepared in 77% yield by reacting the sodium salt of 2-deoxy-1-
Scheme 3. Reagents and conditions: (a) NaH, 6/DMF, rt, 20 h, 77%; (b) (i) Me2S
(SMe)BF4, MS 4A/CH2Cl2 (0.01 M), ꢀ20 °C, 4 h, then 1 M aq NaOH, 0 °C to rt, 2 h.
thioribofuranoside 7a, obtained from 2-deoxy-D-ribose by a
reported method,11 with 9-benzyl-2-chloro-6-methoxypurine (6)
in DMF at room temperature for 20 h. The intramolecular glycosy-
lation was attempted by treating 8 with 1.5 equiv of Me2S(SMe)BF4
in the presence of powdered MS 4A under dilute conditions
(0.01 M) followed by hydrolysis with 1 M aq NaOH at 0 °C for
2 h; however, the expected N-3 glycosylated purine derivative 9
was not obtained, resulting in a complex mixture.
Figure 1. Steric effect of N-9 benzyl group on the intramolecular glycosylation.
We speculated this was due to a steric repulsion between the N-
9 benzyl group and the furanose moiety in an intermediate confor-
mation where the N-3 nitrogen of the purine base ought to
intramolecularly attack the anomeric carbon (Fig. 1). To avoid this
steric repulsion, next, N-7 protected purine derivative 5 was used
for this transformation (Scheme 4). The effect of aryl substituents
on the arylthio moiety was also investigated. The intramolecular
glycosylation substrates 10a and 10b were prepared from thiofura-
nosides 7a and 7b and 2-chloropurine 5 in a manner similar to 8.
To our delight, the subsequent intramolecular glycosylation
smoothly proceeded to afford b-3-isopurine nucleoside 11 in good
yields.18 Among the aryl substituents, the use of a less sterically
hindered phenyl group afforded the products in higher yields in
the both steps.
Scheme 4. Reagents and conditions: (a) NaH, 5/DMF, rt, 3 h, 73% for 10a, 78% for
10b; (b) (i) Me2S(SMe)BF4, MS 4A/CH2Cl2 (0.01 M), ꢀ20 °C, 4 h, then 1 M aq NaOH,
ꢀ5 °C, 1 h, 60% from 10a, 75% from 10b.
The relative regio- and stereochemistry of nucleoside 11 was
confirmed by NOESY and HMBC experiments. An NOE correlation
between H-10 and H-40 as well as HMBC correlations between
Scheme 1. Plan for the stereocontrolled synthesis of 20-deoxy-3-isopurine nucle-
osides by intramolecular glycosylation.
Figure 2. Observed correlations in NOESY and HMBC experiments.

H. Sugimura et al. / Tetrahedron Letters 56 (2015) 6019–6021
6021
3. Bhat, B.; Neelima; Leonard, N. J.; Robinson, H.; Wang, A. H.-J. J. Am. Chem. Soc.
1996, 118, 3065–3066.
4. Leonard, N. J.; Laursen, R. A. Biochemistry 1965, 4, 354–365.
5. Schmidt, C. L.; Townsend, L. B. J. Org. Chem. 1972, 37, 2300–2302.
6. Tindall, C. G., Jr.; Robins, R. K.; Tolman, R. L. J. Org. Chem. 1972, 37, 3985–3989.
7. Nair, V.; Buenger, G. S.; Leonard, N. J.; Balzarini, J.; De Clercq, E. J. Chem. Soc.,
Chem. Commun. 1991, 1650–1651.
8. Lipkin, D.; Cori, C. T.; Rabi, J. A. J. Heterocycl. Chem. 1969, 6, 995–996.
9. Rajeev, K. G.; Broom, A. D. Org. Lett. 2000, 2, 3595–3598.
10. (a) Schmidt, C. L.; Townsend, L. B. J. Heterecycl. Chem. 1973, 10, 687–688; (b)
Schmidt, C. L.; Townsend, L. B. J. Chem. Soc., Perkin Trans. 1975, 1, 1257–1260.
11. Sujino, K.; Sugimura, H. Chem. Lett. 1993, 22, 1187–1190.
12. Sujino, K.; Sugimura, H. Tetrahedron Lett. 1994, 35, 1883–1886.
13. Sugimura, H.; Motegi, M.; Sujino, K. Nucleos. Nucleot. 1995, 14, 413–416.
14. (a) Sujino, K.; Sugimura, H. J. Chem. Soc., Chem. Commun. 1994, 2541–2542; (b)
Sugimura, H.; Katoh, Y. Chem. Lett. 1999, 28, 361–362.
15. (a) Sugimura, H.; Sujino, K. Nucleos. Nucleot. 1998, 17, 53–63; (b) Sugimura, H.;
Watanabe, R. Chem. Lett. 2008, 37, 1038–1039.
16. Sugimura, H.; Nitta, D. Tetrahedron Lett. 2012, 53, 4460–4463.
17. Kotek, V.; Chudíková, N.; Tobrman, T.; Dvorák, D. Org. Lett. 2010, 12, 5724–
5727.
18. General procedure for intramolecular glycosylation: To a solution of glycosylation
substrates 10a or 10b (0.20 mmol) and powdered molecular sieves 4A in
CH2Cl2 (20 mL) was added dimethyl(methylthio)sulfonium tetrafluoroborate
(0.30 mmol) at ꢀ20 °C. After stirring for 4 h, the resulting mixture was
hydrolyzed with 1 M aq NaOH at ꢀ5 °C for 1 h. The mixture was filtered and
extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified by silica
gel column chromatography (3% MeOH/CHCl3), affording the desired
nucleoside 11. 1H NMR (500 MHz, CDCl3) d: 2.36 (dd, J = 5.7, 13.2 Hz, 1H, H-
20) 2.75 (ddd, J = 5.7, 9.7, 13.2 Hz, 1H, H-20), 3.66 (dd, J = 11.5, 12.6 Hz, 1H, H-
50), 3.91 (d, J = 12.6 Hz, 1H, H-50), 4.08 (s, 3H, OCH3), 4.27 (s, 1H, H-40), 4.44 (d,
J = 5.7 Hz, 1H, H-30), 4.50 (d, J = 11.5 Hz, 1H, OCH2-Ph), 4.59 (d, J = 11.5 Hz, 1H,
OCH2-Ph), 5.35 (s, 2H, N-CH2-Ph), 6.02 (d, J = 11.5 Hz, 1H, OH), 6.96 (dd, J = 5.7,
9.7 Hz, 1H, H-10), 7.20–7.41 (m, 10H, Ar), 7.55 (s, 1H, 8-H); 13C NMR (125 MHz,
CDCl3) d: 35.1, 51.1, 54.7, 63.5, 71.1, 80.1, 85.9, 86.2, 105.9, 127.5, 127.6, 127.7,
128.3, 128.9, 129.2, 134.1, 137.7, 141.0, 151.4, 155.3, 159.4.
Scheme 5. Reagents and conditions: (a) 1 M aq NaOH–dioxane (1:1) rt, 2 h, 83%; (b)
28% aq NH3–MeOH (1:1), 60 °C (sealed tube), 24 h, 91%; (c) H2 (1 atm), 10% Pd-C/
EtOH, rt, 22 h, 91% for 1, 77% for 2.
H-10 and the purine carbon atoms C-2 and C-4 confirmed the struc-
ture of nucleoside 11 as shown in Figure 2.
The conversions of nucleoside 11 to 3-(2-deoxy-b-
D-ribofura-
nosyl)xanthine 1219 and 3-(2-deoxy-b-
D
-ribofuranosyl)isoguanine
1320 were accomplished by treating with 1 M aq NaOH and 28%
aq NH3, respectively. Finally, the desired 3-isopurine nucleosides
were obtained by deprotection of the benzyl groups in nucleosides
12 and 13 using 10% Pd/C under H2, affording 121 and 222 in 91%
and 77% (unoptimized) yields, respectively (Scheme 5).
19. Spectral data for compound 12: 1H NMR (500 MHz, CDCl3) d: 2.31 (dd, J = 5.7,
13.2 Hz, 1H, H-20), 2.84 (ddd, J = 5.7, 9.7, 13.2 Hz, 1H, H-20), 3.69 (t, J = 12.0 Hz,
1H, H-50), 3.91 (d, J = 12.0 Hz, 1H, H-50), 4.29 (s, 1H, H-40), 4.45 (d, J = 5.7 Hz, 1H,
H-30), 4.54 (d, J = 11.4 Hz, 1H, O-CH2-Ph), 4.60 (d, J = 11.4 Hz, 1H, O-CH2-Ph),
5.45 (d, J = 14.3 Hz, 1H, N-CH2-Ph), 5.51 (d, J = 14.3 Hz, 1H, N-CH2-Ph), 5.91 (d,
J = 11.5 Hz, 1H, OH), 6.81 (dd, J = 5.7, 9.7 Hz, 1H, H-10), 7.30–7.45 (m, 10H, Ar),
7.61 (s, 1H, H-8), 8.48 (s, 1H, NH); 13C NMR(125 MHz, CDCl3) d: 41.0, 50.4, 71.9,
75.2, 81.7, 84.0, 86.2, 113.2, 127.7, 128.1, 128.4, 128.7, 128.9, 129.0, 135.8,
141.0, 145.6, 148.0, 154.8, 161.9.
In summary, we developed
a regio- and stereocontrolled
method for the synthesis of b-20-deoxy-3-isopurine nucleosides
using the intramolecular glycosylation protocol. The availability
of this approach is shown by the first chemical synthesis of 3-(2-
20. Spectral data for compound 13: 1H NMR (500 MHz, CDCl3) d: 2.29 (dd, J = 5.7,
13.2 Hz, 1H, H-20), 2.81 (ddd, J = 5.7, 9.1, 13.2 Hz, 1H, H-20), 3.67 (t, J = 10.3 Hz,
1H, H-50), 3.91 (d, J = 12.6 Hz, 1H, H-50), 4.25 (s, 1H, H-50), 4.43 (d, J = 5.7 Hz, 1H,
H-30), 4.50 (d, J = 12.0 Hz, 1H, O-CH2Ph), 4.58 (d, J = 12.0 Hz, 1H, O-CH2-Ph),
5.40 (s, 2H, N-CH2-Ph), 6.08 (br, 1H, OH), 6.89 (br, 1H, H-10), 7.16 (s, 1H, NH2),
7.18 (s, 2H, NH2), 7.24–7.43 (m, 10H, Ar), 7.54 (s, 1H, H-8); 13C NMR(125 MHz,
CDCl3) d: 29.7, 34.9, 50.8, 63.6, 71.1, 80.4, 85.4, 86.0, 127.0, 127.6, 127.7, 128.4,
129.3, 129.7, 138.0.
deoxy-b-D-ribofuranosyl)xanthine 1 and isoguanine 2.
References and notes
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2. (a) Forrest, H. S.; Hatfield, D.; Lagowski, J. M. J. Chem. Soc. 1961, 963–967; (b)
Leonard, N. J.; Laursen, R. A. J. Am. Chem. Soc. 1963, 85, 2026–2028; (c) Gerzon,
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21. Spectral data for compound 1: 1H NMR (500 MHz, ethanol-d6) d: 2.02 (dd,
J = 5.7, 12.6 Hz, 1H, H-20), 2.80 (ddd, J = 6.3, 9.2, 12.6 Hz, 1H, H-20), 3.63 (dd,
J = 2.3, 12.0 Hz, 1H, H-50), 3.76 (dd, J = 2.3, 12.0 Hz, 1H, H-50), 3.97 (dd, J = 1.7,
2.3 Hz, 1H, H-40), 4.50 (dd, J = 1.7, 6.3 Hz, 1H, H-30), 6.71 (dd, J = 5.7, 9.2 Hz, 1H,
H-10), 7.81 (s, 1H, H-8).
22. Spectral data for compound 2: 1H NMR (500 MHz, methanol-d4) d: 2.00–2.10
(m, 1H, H-20), 2.73 (m, 1H, H-20), 3.68 (d, J = 12.0 Hz, 1H, H-50), 3.80 (d,
J = 12.0 Hz, 1H, H-50), 3.98 (d, J = 2.3 Hz, 1H, H-40), 4.49 (d, J = 6.3 Hz, 1H, H-30),
6.80 (dd, J = 5.7, 9.2 Hz, 1H, H-10), 7.54 (s, 1H, H-8).