Synthesis of selenium- and tellurium-containing nucleosides derived from uridine

Article abstract of DOI:10.1016/j.tetlet.2009.03.164

The synthesis of selenium- and tellurium-containing nucleosides, derived from uridine is described herein. These compounds were prepared in a concise and short synthetic route in good yields, by nucleophilic substitution of a tosylate group by organoselen

Full text of DOI:10.1016/j.tetlet.2009.03.164

Tetrahedron Letters 50 (2009) 3005–3007
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of selenium- and tellurium-containing nucleosides derived
from uridine
Antonio L. Braga a, , Wolmar A. Severo Filho a,b, Ricardo S. Schwab a, Oscar E. D. Rodrigues a,
*
Luciano Dornelles b, Hugo C. Braga c, Diogo S. Lüdtke c,
*
a Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
b Departamento de Química e Física, Universidade de Santa Cruz do Sul, 96815-900 Santa Cruz do Sul, RS, Brazil
c Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, 05508-900 São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of selenium- and tellurium-containing nucleosides, derived from uridine is described
herein. These compounds were prepared in a concise and short synthetic route in good yields, by nucle-
ophilic substitution of a tosylate group by organoselenium nucleophiles.
Received 28 February 2009
Revised 21 March 2009
Accepted 24 March 2009
Available online 28 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nucleosides
Uridine
Selenium
Tellurium
Diselenide
Telluride
Organochalcogen
The synthesis of selenium derivatives of biologically important
molecules has gained increasing attention over the past years,
since the discovery that selenium is a nutritionally essential trace
element for humans.1 It is found in a number of selenoproteins
and selenopeptides, particularly in the form of the amino acid sele-
nocysteine.2 It is also known that the selenium atom plays a key
role in the mode of action of such proteins, which cannot be played
by its closest relative, sulfur.3 Moreover, organoselenium com-
pounds have been found to function as antioxidants, chemoprotec-
tors, apoptosis inducers, and chemopreventors in several organs
such as brain, liver, skin, colon, lung, and prostate.4 In this context,
the synthesis of selenium-modified nucleosides has attracted
attention5 and selenoanhydronucleosides,6 deoxynucleosides sel-
enocyanates,7 phosporoselenoate nucleosides,8 and 4’-selenonu-
cleosides9 have been described. Moreover, selenium-containing
nucleosides with interesting biological activities were also
reported. For example, 6-(phenylselenenyl)pyrimidine nucleosides
display in vitro activity against HIV-1 (human immunodeficiency
virus type-1) and HIV-2 (human immunodeficiency virus type-1)
in primary human lymphocytes,10 while oxaselenolane nucleo-
sides were also described to have potent HIV-1 and HBV (hepatitis
B virus) activities.11 In addition, selenium-containing nucleosides
have been used as a synthetic handle for the synthesis of deoxynu-
cleosides12 and the replacement of an oxygen atom in nucleotides
by selenium is largely used in the determination of 3-D structures
of DNA and RNA, by X-ray crystallography using MAD (multiwave-
length anomalous dispersion).13 In MAD experiments, selenium
serves as an effective anomalous scattering center and greatly
facilitates phase determination of crystals, thus allowing a high-
resolution determination of the structure of the nucleic acids.14
On the other hand, the tellurium derivatives of nucleosides have
been largely overlooked and only scarce reports have appeared in
the literature,6 despite the fact that, in many cases they were
shown to be more effective antioxidants and chemoprotectors than
their corresponding selenium and sulfur analogs.15
Stimulated by our recent work on the synthesis of chiral
selenium-containing non-natural amino acids and peptides,16
including selenocysteine17 and more recently, on chiral telluroami-
no acids that possess strong glutathione peroxidase-like (GPx-like)
activity,18 we decided to expand our interest to the introduction of
an organochalcogen moiety in the nucleoside framework. To
accomplish this task, we sought to functionalize the 50-position
of uridine with an organochalcogen group. This would be
* Corresponding authors. Tel./fax: 55 55 3220 8669 (A.L.B.); tel.: +55 11 3091
3687; fax: + 55 11 3815 4418 (D.S.L.).
E-mail addresses: albraga@quimica.ufsm.br (A.L. Braga), dsludtke@usp.br (D.S.
Lüdtke).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.164

3006
A. L. Braga et al. / Tetrahedron Letters 50 (2009) 3005–3007
HO
TsO
Se + LiEt3BH
HO
U
U
TsCl, Et3N,
DMAP
CH2Cl2, r.t.
U
O
O
O
N
HC(OMe)3
PPTS
THF
O
O
O
NH
NH
NH
O
O
O
2
O
HO
OH
uridine
95 % (2 steps)
AcS
TsO
Se
N
O
O
N
O
O
O
1
AcSH, KOH
Li2Se2
OMe
OMe
O
O
O
THF
EtOH
r.t., 24 h
r.t., 24 h
O
O
O
O
Scheme 1. Synthesis of tosylate 2 (U = uracil).
52 %
85 %
OMe
3
OMe
2
OMe
5
2
accomplished by nucleophilic substitution of an appropriate leav-
ing group, obtained by activation of the 50-hydroxyl at a protected
uridine derivative.
Scheme 2. Syntheses of 3 and 5.
As delineated in our synthesis plan, the success of our strategy
was closely linked to an efficient activation of the 50-hydroxyl
group in uridine. Thus, based on our previous experience on the
nucleophilic substitution of a tosylate group by chalcogen nucleo-
philes,19 we decided to transform the 50-hydroxyl group in their
corresponding p-toluenesulfonate ester, as already described by
Poulter et al.20 First, appropriate protection of the secondary hy-
droxyl groups of uridine was needed and this was accomplished
by reaction with trimethylorthoformate, in the presence of PPTS,
to afford the corresponding 2’,3’-methoxymethylidene derivative
1. The protected uridine 1 was treated, without purification, with
p-toluenesulfonyl chloride, in the presence of DMAP and Et3N, to
smoothly provide the required 5’-OTs uridine in an excellent 95
% yield, for the two steps (Scheme 1).20
With the required tosylate 2 in hand, we turned our attention to
the introduction of the organochalcogen moiety by nucleophilic
displacement. Pleasingly, we found that treatment of 2 with phe-
nylselenide anion, generated by reduction of diphenyl diselenide
with sodium borohydride, afforded the desired 5’-phenylseleno
nucleoside 3a in good yield, using a mixture of THF and ethanol
as solvent (Table 1, entry 1). Extension of these conditions to a
broader range of selenium nucleophiles proved to be viable, and
the reaction with the nucleophile derived from (4-ClPhSe)2 affor-
ded the corresponding selenium-containing uridine derivative 3b
in 72% yield (entry 2). Aliphatic diselenides, where R groups were
Bn, n-Bu, and Et, were also evaluated as the nucleophilic source
and products 3c–e were obtained in good yields (entries 3–5). In
order to expand the scope of the methodology to other chalcogens,
we decided to prepare tellurium derivatives of uridine. This was
accomplished in the same way as for the selenium derivatives,
and cleavage of diorganoditellurides with NaBH4, followed by reac-
tion with tosylate 2 smoothly provides the corresponding telluro-
nucleosides 3f–i in good yields (entries 6–9). Again, the reaction
is applicable to both aromatic and aliphatic tellurium nucleophiles.
Also, the reduction of (PhS)2 with NaBH4, followed by reaction with
2, under our standard conditions, furnished the sulfur derivative in
77 % yield (entry 10).21
Finally, treatment of tosylate 2 with thioacetic acid, under basic
conditions, afforded the corresponding thioacetate in 85 % yield
(Scheme 2). In addition, reaction of 2 with lithium diselenide,
generated in situ by the reaction of elemental selenium with
super-hydride,22,23 smoothly afforded the desired diselenide in a
moderate 52 % yield (Scheme 2).24
In summary, we have described herein the synthesis of sele-
nium- and tellurium-containing nucleosides, derived from uridine
in a concise and short synthetic route in good yields. Additionally,
the organochalcogen moiety might serve as a synthetic handle for
the synthesis of deoxynucleosides and, more importantly, we
believe that it might display GPx-like activity.
Acknowledgments
The authors would like to thank CNPq, CAPES, NANOBIOSIMES,
INCT-Catálise, and FAPESP for financial support.
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.164.
References and notes
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2. For
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Biol. Chem. 2007, 388, 997.
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W.; Sies, H. Chem. Rev. 2001, 101, 2125; (c) Nogueira, C. W.; Zeni, G.; Rocha, J. B.
T. Chem. Rev. 2004, 104, 6255.
Table 1
Synthesis of selenium- and tellurium-containing nucleosides
5. For a review, see: Wnuk, S. F. Tetrahedron 1993, 49, 9877.
O
O
N
6. Adiwidjaja, G.; Schulze, O.; Voss, J.; Wirsching, J. Carbohydr. Res. 2000, 325, 107.
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C.; Schinazi, R. F. J. Med. Chem. 2000, 43, 3906.
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Laghdach, A.; Matheu, M. I.; Castillón, S. J. Org. Chem. 1997, 62, 1501; (c) Diaz,
Y.; El-Laghdach, A.; Castillón, S. Tetrahedron 1997, 53, 10921.
NH
NH
TsO
RY
N
O
O
O
RYYR/NaBH4
O
O
THF/EtOH (3:1)
r.t., 10 h
3a-j
2
O
O
O
OMe
OMe
Entry
RYYR
RY
Yield (%)
13. (a) Du, Q.; Carrasco, N.; Teplova, M.; Wilds, C. J.; Egli, M.; Huang, Z. J. Am. Chem.
Soc. 2002, 124, 24; (b) Höbartner, C.; Micura, R. J. Am. Chem. Soc. 2004, 126,
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Chen, G.; Portilla, Y.; Germann, M. W.; Huang, Z. Org. Lett. 2005, 7, 5645.
14. For a review on selenium derivatization of nucleic acids for crystallography,
see: Jiang, J.; Sheng, J.; Carrasco, N.; Huang, Z. Nucleic Acid Res. 2007, 35, 477.
15. (a) Sies, H.; Arteel, G. E. Free Radical Biol. Med. 2000, 28, 1451; (b) Detty, M. R.;
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Hammarström, L.; Sjödin, M.; Engman, L. J. Am. Chem. Soc. 2001, 123, 3434.
1
2
3
4
5
6
7
8
9
(PhSe)2
PhSe
75
72
70
70
67
78
65
60
76
77
(4-ClPhSe)2
(PhCH2Se)2
(n-BuSe)2
(EtSe)2
4-ClPhSe
PhCH2Se
n-BuSe
EtSe
PhTe
4-ClPhTe
4-MeOPhTe
n-BuTe
PhS
(PhTe)2
(4-ClPhTe)2
(4-MeOPhTe)2
(n-BuTe)2
(PhS)2
10

A. L. Braga et al. / Tetrahedron Letters 50 (2009) 3005–3007
3007
16. (a) Braga, A. L.; Lüdtke, D. S.; Paixão, M. W.; Alberto, E. E.; Stefani, H. A.; Juliano,
L. Eur. J. Org. Chem. 2005, 4260; (b) Schwab, R. S.; Galetto, F. Z.; Azeredo, J. B.;
Braga, A. L.; Lüdtke, D. S.; Paixão, M. W. Tetrahedron Lett. 2008, 49, 5094.
17. (a) Schneider, A.; Rodrigues, O. E. D.; Paixão, M. W.; Appelt, H. R.; Braga, A. L.;
Wessjohann, L. A. Tetrahedron Lett. 2006, 47, 1019; (b) Braga, A. L.; Schneider, P.
H.; Paixão, M. W.; Deobald, A. M.; Peppe, C.; Bottega, D. P. J. Org. Chem. 2006, 71,
4305.
J = 2.5 Hz 1H), 5.12–4.96 (m, 2H), 4.32–4.24 (m, 1H), 3.29–3.22 (m, 5H); RMN
13C (CDCl3, 50 MHz, ppm) d 163.9; 149.9; 142.8; 132.8; 128.9; 127.1; 119,0;
118.0; 102.3; 95.8; 94.1; 86.6; 84.3; 83.4; 52.3; 51,2; 29,6; IV (cmꢀ1) 3170,
3057, 2939, 2832, 1685, 1577, 1454, 1378, 1270, 1121, 1075. HRMS-ESI: m/z
calcd for C17H18N2O6Se + Na+: 449.0227; found: 449.0222.
22. Braga, A. L.; Paixão, M. W.; Lüdtke, D. S.; Silveira, C. C.; Rodrigues, O. E. D. Org.
Lett. 2003, 5, 2635.
18. Braga, A. L.; Alberto, E. E.; Soares, L. C.; Rocha, J. B. T.; Sudati, J. H.; Roos, D. H.
Org. Biomol. Chem. 2009, 7, 43.
19. (a) Braga, A. L.; Lüdtke, D. S.; Sehnem, J. A.; Alberto, E. E. Tetrahedron 2005, 61,
11664; (b) Braga, A. L.; Lüdtke, D. S.; Alberto, E. E. J. Braz. Chem. Soc. 2006, 17,
11.
20. Davisson, V. J.; Davis, D. R.; Dixit, V. M.; Poulter, C. D. J. Org. Chem. 1987, 52,
1794.
21. General procedure for the preparation of 3a–j: Under an argon atmosphere,
23. Under an argon atmosphere, lithium diselenide was generated by reaction of
gray elemental selenium (0.0948 g, 1.2 mmol) with lithium triethylborohydride
(1.2 mL, 1.2 mmol) in dry THF (5 mL). The suspension was allowed to stir for at
least 20 min, and a THF (10 mL) solution of tosylate 2 (0.440 g, 1.0 mmol) was
added dropwise within 20 min. The resulting solution was stirred for 24 h at
room temperature. The mixture was quenched with a saturated NH4Cl solution
(20 mL), extracted with CH2Cl2, and the combined organic fractions were
collected, dried over MgSO4, and filtered, the solvent was removed in vacuo. The
crude product was purified by flash chromatography (hexane:ethyl acetate
80:20). Drying in vacuo afforded the diselenide 5. Analytical data for 5: Yield:
52%; RMN 1H (CDCl3, 200 MHz, ppm) for diastereomers A and B (ratio 91:9) d
10.29 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 5.99 and 5.91 (s, 1H), 5.76 (d, J = 7.6 Hz,
1H), 5.68 (s, 1H), 5.16 (d, J = 7.0 Hz, 1H), 4.93–4.88 (m, 1H), 4.54 (d, J = 3.6 Hz,
1H), 3.39–3.30 (m, 5H); 13C (CDCl3, 50 MHz, ppm) 163.8; 150.1; 143.4; 119.0;
102.6; 96.8; 87.9; 84.4; 83.6; 52.7; 51.2; 32.1; IV (cmꢀ1) 3175, 3057, 2939,
2832, 1695, 1459, 1372, 1270, 1127, 1081, 983, 819. HRMS-ESI: m/z calcd for
C22H26N4O12Se2 + Na+: 720.9775; found: 720.9769.
sodium borohydride was added to
a solution of the dichalcogenide
(0.55 mmol) in THF (4 mL). Ethanol (2 mL) was then added dropwise and the
clear solution formed was stirred at room temperature for 10 min. After this
time
a solution of tosylate (0.440 g, 1 mmol) in THF (1 mL) was added
dropwise. The resulting solution was stirred for 24 h at room temperature. The
mixture was quenched with a saturated NH4Cl solution (10 mL), extracted with
CH2Cl2, and the combined organic fractions were collected, dried over MgSO4,
and filtered, the solvent was removed in vacuo. The crude product was purified
by flash chromatography first eluting with hexanes and then with a mixture of
hexanes/ethyl acetate (80:20). Representative analytical data for 3a: Yield: 75%;
RMN 1H (CDCl3, 200 MHz, ppm) for diastereomers A and B (ratio 91:9) d 10.42
(s, 1H), 7.55–7.19 (m, 6H), 6.00 and 5.95 (s, 1H), 5.70 (d, J = 7.9 Hz 1H), 5.56 (d,
24. While this work was in progress, a synthesis of a diselenide derived from
uridine appeared in the literature: Sivapriya, K.; Suguna, P.; Shubasree, S.;
Sridhar, P. R.; Chandrasekaran, S. Carbohydr. Res. 2007, 342, 1151.