Microwave-assisted synthesis of 2'-O-aryluridine derivatives

Article abstract of DOI:10.1021/ol902142w

A new method for the synthesis of 2′-O-arylurldlnes was developed via the microwave-mediated reaction of 2,2′-anhydrourldlne with aromatic alcohols. Aminophenol and aminonaphthol derivatives underwent selective 2′-O-arylation with 2,2′-anhydrourldlne to p

Full text of DOI:10.1021/ol902142w

ORGANIC
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2009
Vol. 11, No. 24
5582-5585
Microwave-Assisted Synthesis of
2′-O-Aryluridine Derivatives
Yusuke Oeda, Yoshihiro Iijima, Haruhiko Taguchi, Akihiro Ohkubo, Khoji Seio,
and Mitsuo Sekine*
Department of Life Science, Tokyo Institute of Technology, J2-12, 4259 Nagatsuta,
Midoriku, Yokohama 226-8501, Japan
msekine@bio.titech.ac.jp
Received September 16, 2009
ABSTRACT
A new method for the synthesis of 2′-O-aryluridines was developed via the microwave-mediated reaction of 2,2′-anhydrouridine with aromatic
alcohols. Aminophenol and aminonaphthol derivatives underwent selective 2′-O-arylation with 2,2′-anhydrouridine to produce 2′-O-
(aminoaryl)uridine derivatives. These reactions proved to proceed without the need for any bases or solvents, but better results were obtained
by use of N,N-dimethylacetamide (DMA) as the solvent in some cases.
In connection with recent developments in gene therapies based
on antisense and RNAi strategies, a large number of 2′-O-
modified RNA oligomers have been synthesized as promising
nucleotide drugs.1-5 However, most of these modified RNA
oligomers are 2′-O-alkylated species. To the best of the
authors’ knowledge, only two examples have been reported
as 2′-O-arylated RNA modifiers in the antisense and RNAi
strategies.6,7 One is the simplest derivative (i.e., oligode-
oxynucleotides), incorporating 2′-O-phenyluridine, reported
by Altmann in his review.6 However, no details of the
synthesis of the key starting material of 2′-O-phenyluridine
were given in this review. The other example comprises
oligoribonucleotides incorporating 2′-O-(2,4-dinitrophenyl)-
(5) (a) Sasami, T.; Odawara, Y.; Ohkubo, A.; Seio, K.; Sekine, M.
Bioorg. Med. Chem. 2009, 17, 1398–1403. (b) Smicius, R.; Engels, J. W.
J. Org. Chem. 2008, 73, 4994–5002. (c) Bobkov, G. V.; Mikhailov, S. N.;
Van Aerschot, A.; Herdewijn, P. Tetrahedron 2008, 64, 6238–6251. (d)
Saneyoshi, H.; Tamaki, K.; Ohkubo, A.; Seio, K.; Sekine, M. Tetrahedron
2008, 64, 4370–4376. (e) Prakash, T. P.; Kawasaki, A. M.; Wancewicz,
E. V.; Shen, L. J.; Monia, B. P.; Ross, B. S.; Bhat, B.; Manoharan, M.
J. Med. Chem. 2008, 51, 2766–2776. (f) Odadzic, D.; Bramsen, J. B.;
Smicius, R.; Bus, C.; Jorgen, K.; Engels, J. W. Bioorg. Med. Chem. 2008,
16, 518–529. (g) Saneyoshi, H.; Okamoto, I.; Masaki, Y.; Ohkubo, A.; Seio,
K.; Sekine, M. Tetrahedron Lett. 2007, 63, 11195–11203. (h) Bobkov, G. V.;
Brilliantov, K. V.; Mikhailov, S. N.; Rozenski, J.; Van Aerschot, A.;
Herdewijn, P. Collect. Czech. Chem. Commun. 2006, 804–819. (i) Saneyosi,
H.; Seio, K.; Sekine, M. J. Org. Chem. 2005, 70, 10453. (j) Pattanayek,
R.; Sethaphong, L.; Pan, C. L.; Prhavc, M.; Prakash, T. P.; Manoharan,
M.; Egli, M. J. Am. Chem. Soc. 2004, 126, 15006–15007. (k) Prakash, T. P.;
Puschl, A.; Lesnik, E.; Mohan, V.; Tereshko, V.; Egli, M.; Manoharan, M.
Org. Lett. 2004, 6, 1971–1974. (l) Meldgaard, M.; Wengel, J. J. Chem.
Soc., Perkin Trans. 1 2000, 1, 3539–3554. (m) Grotli, M.; Douglas, M.;
Eritja, R.; Sproat, B. S. Tetrahedron 1998, 54, 5899–5914. (n) Griffey,
R. H.; Monia, B. P.; Cummins, L. L.; Freier, S.; Greig, M. J.; Guinosso,
C. J.; Lesnik, E.; Manalili, S. M.; Mohan, V.; Owens, S.; Ross, B. R.;
Sasmor, H.; Wancewicz, E.; Weiler, K.; Wheeler, P. D.; Cook, P. D. J. Med.
Chem. 1996, 39, 5100–5109. (o) Lesnik, E. A.; Guinosso, C. J.; Kawasaki,
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2008, 13, 842–855. (b) Corey, D. R. J. Clin. InVest. 2007, 117, 3615–
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10.1021/ol902142w CCC: $40.75
Published on Web 11/13/2009
 2009 American Chemical Society

ribonucleosides, reported by Wang.7 According to Wang’s
paper, these modified oligomers are directly obtained via the
reaction of oligoribonucleotides with 2,4-dinitrophenyl fluo-
ride. At the level of nucleosides, the synthesis of 2′-O-(2,4,6-
trinitrophenyl)uridine via the reaction of uridine with 2,4,6-
trinitrophenyl sulfonate was reported, but this compound was
obtained as a Meisenheimer complex having a 2′,3′-cyclic
spiro ring.8 Thus far, little has been reported about the general
and regioselective synthesis of 2′-O-arylribonucleosides.
To expand the limited use of 2′-O-alkylated ribonucleosides
as components of modified RNA oligomers, it is desirable to
find practical methods for the synthesis of 2′-O-arylribonucleo-
sides as new RNA backbone structures. In addition, it is
expected that two neighboring aryl groups could interact with
each other when introduced into 2′-O-arylated oligoribonucle-
otides to stabilize RNA duplexes. Oligoribonucleotides incor-
porating 2′-O-arylribonucleosides would be of great interest as
new siRNA molecules.
In this paper, we report a generally useful method for the
synthesis of 2′-O-aryluridine derivatives using microwave-
mediated ring-opening reactions of 2,2′-anhydrouridine with aryl
alcohols.
Since no information concerning the synthesis of 2′-O-
phenyluridine as the simplest 2′-O-aryluridine derivative is
available, we decided to establish a practical method to
synthesize this material. Since 2′-(S)-aryluridine derivatives were
synthesized via the ring-opening reaction of 2,2′-anhydrouridine
(1) with arylthiolates,9 a similar reaction of 1 with 3 equiv of
phenol was carried out in the presence of 3 equiv of triethy-
lamine in N,N-dimethylacetamide (DMA) at 120 °C for 24 h.
As a result, this reaction gave 2′-O-phenyluridine (2a) in 65%
yield (Scheme 1). In order to shorten the reaction time, this
of sodium phenoxide in DMA also gave the product 2a in 60%
yield using this microwave system (140 °C, 30 min). However,
more interestingly, it was found that this reaction did not require
any base or solvent. In conclusion, the neat reaction of 1 with
5 equiv of phenol gave the product 2a in the highest yield of
82%, as shown in Table 1.
As far as the solvent is concerned, the use of DMA as the
solvent gave better results when phenol derivatives have high
melting temperatures (entries 8 and 9) or low ignition points
(entry 7) and also tend to be easily air-oxidized (entries 16
and 17).
In the present microwave-assisted method, 1-naphthol and
2-naphthol underwent similar reactions with compound 1 to
give the desired products 2b and 2c (entries 2 and 3 of Table
1). The use of halogenated phenols, such as 4-fluorophenol,
2-fluorophenol, 4-bromophenol, 2-bromophenol, and 2-bro-
monaphthol, gave the corresponding 2′-O-modified products
3a, 3b, 4a, 4b, and 4c in 26-77% yields (entries 4-8). These
products might be used for Buchwald-Hartwig reactions for
further modification of the aromatic rings with various
functional groups. However, the reaction of compound 1 with
1-bromo-2-naphthol failed. This result might be due to the
steric hindrance of this phenol. In the case of 4-iodophenol
and 2-iodophenol, the reactions gave complex mixtures,
suggesting that the once-formed products 5a and 5b decom-
posed.
The reaction of compound 1 with 2-nitrophenol (pKa 7.15)
gave a 3:5 mixture of the product 6b and its 3′-O-arylated
regioisomer 6b′ in 23% yield. It is likely that the latter
product was obtained by isomerization of the once-formed
initial product 6a under the MW conditions via an intermedi-
ate like a well-known Meisenheimer spiro complex.10 On
the other hand, the desired product 6a could not be obtained
by the reaction of compound 1 with more acidic 4-nitrophe-
nol (pKa 7.08). In contrast to these results, phenol derivatives
substituted with a methoxy group as an elecron-donating
group gave the 2′-O-aryluridine derivatives 7a and 7b in
good yields (entries 14 and 15 of Table 1).
Scheme 1. Synthesis of 2′-O-Phenyluridine (2a)
Bifunctional compounds containing two hydroxyl groups
(i.e., 1,4-benzenediol and 1,5-naphthalenediol) gave the
monosubstituted products 8a and 8b (entries 16 and 17). The
remaining phenolic hydroxyl groups of these compounds
could be used as reaction sites for further introduction of
valuable functional groups into the uridine moiety.
When 4-aminophenol was used as a phenol derivative, the
chemoselective reaction occurred exclusively to give the sole
product 9a without formation of the 2′-N-(4-hydroxyphenyl)-
substituted product 10, as shown in Scheme 2. Highly
chemoselective reactions were also observed in the other
aminophenol and aminonaphthol derivatives, which gave the
products 9b-9f, as shown in Table 2 (entries 2-6). When
1,5-naphthalenediamine was used as a nucleophile, no
reaction was observed. On the basis of the above results, it
was concluded that compound 1 showed no reactivity toward
aromatic amines in the present microwave-assisted reaction.
It is noteworthy that the amino group on the aromatic ring
of products 9a-f would also be better reaction sites for
further modifications.
reaction was applied to a microwave-mediated reaction. This
microwave-assisted reaction of 1 with 3 equiv of phenol in
DMA at 150 °C gave the desired product 2a in 65% yield only
after 30 min. The use of other bases such as Hu¨nig’s base or
pyridine produced similar results. The reaction of 1 with 3 equiv
(6) Altmann, K. H.; Dean, N. M.; Fabbro, D.; Freier, S. M.; Geiger, T.;
Haner, R.; Husken, D.; Martin, P.; Monia, B. P.; Muller, M.; Natt, F.;
Nicklin, P.; Phillips, J.; Pieles, U.; Sasmor, H.; Moser, H. E. Chimia 1996,
50, 168–176.
(7) Chen, X. L.; Shen, L.; Wang, J. H. Oligonucleotides 2004, 14, 90–
99.
(8) Azegami, M.; Iwai, K. J. Biochem. 1964, 55, 346–348.
(9) (a) Robins, M. J.; Mullah, K. B.; Wnuk, S. F.; Dalley, N. K. J. Org.
Chem. 1992, 57, 2357–2364. (b) Matsuda, A.; Miyasaka, T. Heterocycles
1983, 20, 55–58. (c) Divakar, K. J.; Reese, C. B. J. Chem. Soc., Perkin
Trans. 1 1982, 1625–1628.
(10) Ah-Kow, G.; Terrier, F.; Pouet, M.-J.; Simonnin, M.-P. J. Org.
Chem. 1980, 45, 4399–4404.
Org. Lett., Vol. 11, No. 24, 2009
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Table 1. Microwave-Assisted Synthesis of 2′-O-Aryluridines
Scheme 2. Chemoselective Reaction of 1 with 4-Aminophenol
Table 2. 2′-O-Selective Arylation of 2,2′-Anhydrouridine with
Aminophenol and Aminonaphthol Derivatives
the reaction of 1 with 3 equiv of phenol using microwaves at
140 °C was carried out in the presence of amines, such as
triethylamine and diisopropylethylamine, compound 2a could
not be formed. This is in sharp contrast to the results obtained
via the reactions without the use of microwaves, as described
earlier. The addition of BF3 etherate to the original system gave
no ring-opening product at all. The best results obtained in all
cases were via the reactions with simple phenol derivatives
without using any solvent, base, or catalyst. On the other hand,
the reactions of 1 with aliphatic alcohols, such as propanol, allyl
alcohol, and benzyl alcohol, failed. All attempts to use acetic
acid, p-toluenesulfonic acid, or 10-camphorsulfonic acid as an
acid catalyst also failed in the reaction of 1 with methanol. These
results suggest that this reaction required protonation of the
4-oxygen or 3-nitrogen atom of 1 for activation through the
a Compound 6b′ is 3′-O-(2-nitrophenyl)uridine.
To understand the inherent properties of this microwave-
mediated reaction, several experiments were performed. When
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Org. Lett., Vol. 11, No. 24, 2009

use of more acidic phenols as reactants and the generation of
phenoxide ions with sufficient nucleophilicity.
nucleosides were arranged in a consecutive manner. Par-
ticularly, the use of the 2-naphthyl group showed higher
hybridization affinity than that of the phenyl and 1-naphthyl
groups when 2′-O-methylated RNA oligomers were used as
the complementary strands.
In this sense, we are now studying further applications
using these new 2′-O-aryluridine derivatives. These results
will be reported in the near future.
In particular, we showed that a variety of aromatic
substituents could be introduced into the 2′-hydroxyl group
of uridine. Therefore, there is increasing potential for these
new 2′-O-arylated uridine derivatives as modification sites
of RNA. 2′-O-Aryl-modified uridine derivatives containing
halogenated aryl groups such as compounds 4a-d could be
used for the introduction of various functional groups by
combination with the well-known Buchwald-Hartwig reac-
tion,11 which would enable the postmodification of RNA.
The amino group on the aromatic rings of compounds 9a-9f
would also be useful for the introduction of fluorescent
molecules using the amino group. Therefore, 2′-O-aryluridine
derivatives are promising key intermediates for a wide variety
of modifications. In our preliminary experiments, the intro-
duction of several 2′-O-naphthyluridine moieties into oli-
goribonucleotides led to marked recovery of the hybridization
ability of the mother RNA molecules, as long as the modified
Acknowledgment. This work was supported by a grant
from a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan, and in part by a grant from by Health Sciences
Research Grants for Research on Psychiatric and Neurologi-
cal Diseases and Mental Health from the Ministry of Health,
Labor and Welfare of Japan, and by the global COE project.
1
Supporting Information Available: Material on the H
and 13C data of all the new products reported here. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413–2415. (b)
Hartwig, J. F. Pure. Appl. Chem. 1999, 71, 1417–1423. (c) Paul, F.; Patt,
J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969–5970. (d) Guram,
A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901–7902.
OL902142W
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