LETTER
Selective 5¢-O-Trityl Protection of Inosine Derivatives
1735
Table 3 Microwave-Assisted Tritylation of N1-Substituted Inosines
reaction vessel was sealed, stirred, and subsequently irradiated for
15 min at 100 °C in a single-mode microwave reactor (EmrysTM
Synthesizer, Biotage AB). After cooling to ambient temperature,
the mixture was loaded onto a silica gel column and purified by
flash chromatography eluting with mixtures CH2Cl2–MeOH (100:0
to 100:10).
O
O
R1
R1
N
N
N
N
N
N
R2
R2
N
N
TrCl (1.7 equiv)
DMAP (0.5 equiv)
pyridine
TrO
HO
O
O
Acknowledgment
OH OH
MW, 100 °C
OH OH
E.C. acknowledges the Consejería de Educación de la Comunidad
de Madrid and the Fondo Social Europeo (F.S.E.) for a predoctoral
fellowship. This work has been supported by grants from the
Spanish MEC (SAF2006-12713-C02) and from the Christian
Doppler Research Society (CDG).
6 R1 = Allyl R2 = H
7 R1 = Bn R2 = H
3 R1 = Allyl R2 = H
4 R1 = Bn R2 = H
8 R1 = H
R2 = Br
5 R1 = H
R2 = Br
Entry
Substrate
Time (min) Product
Yield (%)a
References and Notes
1
2
3
4
5
6
3
3
4
4
5
5
15
30
15
30
15
30
6
6
7
7
8
8
52
69
49
68
40
71
(1) Muramatsu, N.; Takenishi, T. J. Org. Chem. 1965, 30, 3211.
(2) Hampton, A.; Nichol, A. W. Biochemistry 1966, 5, 2076.
(3) Green, R.; Szostak, J. W.; Benner, S. A.; Rich, A.; Usman,
N. Nucleic Acids Res. 1991, 19, 4161.
(4) Matulic-Adamic, J.; Beigelman, L. Synth. Commun. 2000,
30, 3963.
(5) Liekens, S.; Hernández, A. I.; Ribatti, D.; De Clercq, E.;
Camarasa, M. J.; Pérez-Pérez, M. J.; Balzarini, J. J. Biol.
Chem. 2004, 279, 29598.
(6) Pankiewicz, K. W.; Krzeminski, J.; Ciszewski, L. A.; Ren,
W. Y.; Watanabe, K. A. J. Org. Chem. 1992, 57, 553.
(7) Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose, N.;
Izawa, K. Tetrahedron Lett. 2001, 42, 2321.
a Isolated yields of pure product after column chromatography.
sugar and, as a consequence, the 5¢-OH of the ribose is
sterically hindered. Indeed, when the reaction between
8-bromoinosine15 and trityl chloride was performed under
standard thermal conditions (TrCl, pyridine, DMAP,
100 °C) a very poor 14% yield of 5¢-O-trityl derivative
was isolated. However, when the optimized microwave
conditions were applied, the desired 8-bromo-5¢-O-trityl-
inosine (8)16 was isolated in 40% yield after 15 minutes. If
the reaction time was increased to 30 minutes, the yield
was significantly improved up to 71%.
(8) Casanova, E.; Hernández, A. I.; Priego, E. M.; Liekens, S.;
Camarasa, M. J.; Balzarini, J.; Pérez-Pérez, M. J. J. Med.
Chem. 2006, 49, 5562.
(9) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(10) This paper mostly reports on the tritylation reaction in the
presence of DABCO in molten TBAB. Attempted
microwave irradiation produces low yields and the
nucleobase is lost. See: Khalafi-Nezhad, A.; Moktari, B.
Tetrahedron Lett. 2004, 45, 6737.
(11) Hyde, R. M.; Broom, A. D.; Buckheit, R. W. Jr. J. Med.
Chem. 2003, 46, 1878.
(12) Watanabe, K. A.; Pankiewicz, K. W.; Krzeminski, J.;
Nawrot, B. WO 9211276, 1992; Chem. Abstr. 1993, 118,
7325.
In conclusion, we have developed an efficient protocol for
the selective 5¢-O-trityl protection of inosine and structur-
ally related analogues, using single mode microwave irra-
diation under controlled conditions. Our protocol allows
higher conversions and considerable shorter reaction
times compared to the previously published thermal con-
ditions. The results contained in this letter will therefore
be useful to other researchers in the field of inosine chem-
istry and nucleoside protection in general. In addition, the
reported high-speed O-tritylation can be useful for other
protective strategies involving the selective protection of
primary versus secondary hydroxyl groups.
(13) Spectroscopic data for N1-benzylinosine (4): 1H NMR (360
MHz, DMSO-d6): d = 3.60 (m, 2 H, H-5¢), 3.93 (m, 1 H, H-
4¢), 4.11 (m, 1 H, H-3¢), 4.48 (m, 1 H, H-2¢), 5.05 (t, J = 5.7
Hz, 1 H, OH), 5.21–5.23 (m, 3 H, CH2, OH), 5.49 (m, 1 H,
OH), 5.85 (d, J = 5.8 Hz, 1 H, H-1¢), 7.24–7.36 (m, 5 H, Ph),
8.36, 8.62 (s, 2 H, H-2, H-8). MS (ES, positive mode): m/z =
358 [M + 1]+.
(14) Fukuoka, M.; Shuto, S.; Minakawa, N.; Ueno, Y.; Matsuda,
A. J. Org. Chem. 2000, 65, 5238.
(15) Holmes, R. E.; Robins, R. K. J. Am. Chem. Soc. 1964, 86,
1242.
(16) Spectroscopic data for 8-bromo-5¢-O-tritylinosine (8): white
solid, mp 175–178 °C (MeOH). 1H NMR (300 MHz,
DMSO-d6): d = 3.16 (m, 2 H, H-5¢), 4.05 (m, 1 H, H-4¢), 4.42
(m, 1 H, H-3¢), 5.06 (m, 1 H, H-2¢), 5.22 (d, J = 4.8 Hz, 1 H,
OH), 5.56 (d, J = 5.7 Hz, 1 H, OH), 5.83 (d, J = 4.2 Hz, 1 H,
H-1¢), 7.19–7.30 (m, 15 H, Ph), 7.88 (s, 0.66 H, H-2), 7.93
(s, 0.33 H, H-2), 12.56 (br s, 1 H, NH). MS (ES, positive
mode): m/z = 589 [M + 1]+.
Typical Procedure for the Microwave-Assisted 5¢-O-Trityl
Protection of Inosine and Inosine Derivatives
In a 0.5–2.5 mL Pyrex microwave process vial, the appropriate
inosine derivative (0.15 mmol), trityl chloride (0.25 mmol), DMAP
(0.07 mmol), and anhyd pyridine (1.0 mL) were placed. The
Synlett 2007, No. 11, 1733–1735 © Thieme Stuttgart · New York