5220
A. Khalafi-Nezhad et al. / Tetrahedron Letters 48 (2007) 5219–5222
1
1
R O
HO
R O
HO
B
B
B
B
SSA , MeCN
O
N
O
O
SSA , MeCN
r.t
O
H O
2
r.t, 2-17 min
R2
R
3
R2
R3
R2
R3
R2
R3
1-Uracil, R1 = Tr, R2 = R = OH
3
1b
1b
1b
4b
5b
6b
7b
8b
9b
1
2
a
a
B =
B =
3a B =
4a B =
N
N
N
N
N
N
N
N
N
N
N
B =
1-Uracil,
= Tr, MMTr, DMTr
N
1-Thymine,
N
9-Adenine
1
2
3
1-Uracil, R = MMT, R = R = OH
1
1-Uracil, R1 = DMT, R = R = OH
2
3
R
2
3
1
2
3
R / R = H, OH, OTBDMS, OTIPS, PMB, O
-
CR
2
-
O, O
-
CAr
2
-O
1-Thymine, R = Tr, R = R = OH
1
2
3
5
6
7
8
9
1
1
a
a
a
a
a
B =
B =
B =
B =
B =
9-Adenine, R = Tr, R = OH, R = H
1-Uracil, R1 = Tr, R2 = OH, R = OPMB
3
Scheme 1.
1
2
3
1-Uracil, R = Tr, R = R = O-C(CH
2
)
5
-O
1-Uracil, R1 = Tr, R2 = R = O-C(
3
p
-MeOC
H
)
-O
6
4
2
1
2
3
2
1-Uracil, R = Tr, R = R = O-CMe -O
0a B =
1a B =
1-Uracil, R1 = Tr, R2 = H, R3 = OTBDMS
1-Uracil, R1 = Tr, R2 = OH, R3 = OTIPS
10b
11b
O
N
O
O
NH2
O
N
NH
NH
HN
N
HN
N
O
N
O
N
N
DMTO
O
HO
N
O
O
O
N
1-Thymine
N
9-Adenine
N
1-Uracil
SSA, Solvent
r.t
Scheme 3.
OH
OH
OH
OH
Scheme 2.
As expected, the more acid sensitive mono- (MMT) and
dimethoxytrityl (DMT) groups were removed more rap-
idly than trityl (Tr) with regard to the stability of their
in acetonitrile (10 mL) and water (0.36 g) as a model
reaction (Scheme 2).
+
+
+
carbocationic species (DMT > MMT > Tr ). Depro-
0
tection of 5 -O-Tr thymidine (4a) was also efficient
In the first experiment, the effect of different amounts of
SSA on the efficiency of the model reaction in MeCN
was studied. It was found that 2 mmol (20 mol %) of
SSA was an appropriate amount for catalyzing the reac-
tion. Using further amounts of SSA had no distinguish-
able effect on the efficiency of the model reaction. The
choice of solvent was also important. Different solvents
such as MeCN, CH Cl , CHCl , DMF, THF and CCl
4
(
93%). In order to study the efficiency of the described
catalyst for purine nucleosides, which are known to be
more susceptible to depurination, the reaction was
examined with 5 -O-Tr deoxyadenosine (5a). As shown
in Table 2, the corresponding nucleoside (5b) was affor-
ded in good yield (82%). To indicate the selectivity of
our method, we also examined the detritylation reac-
tions of a variety of nucleoside trityl ethers having other
acid sensitive protecting groups within their structures
0
2
2
3
were used in the reaction and among them, MeCN was
the most efficient and thus was the solvent of choice
(
6a–11a). Various protecting groups such as PMB, iso-
(
Table 1).
propylidene, cyclohexylidene, di-(p-anisyl)methylidne,
TIPS and TBDMS were chosen in order to study the
selectivity in the presence of the Tr group (Scheme 3).
The Tr group was chosen because it is the least reactive
protecting group in comparison with MMT and DMT.
Fascinatingly, excellent selectivity was observed for the
removal of trityl moieties rather than other acid sensitive
hydroxyl protecting groups. Reaction of 6a with SSA
afforded 2 -p-methoxybenzyloxy uridine (6b) in excellent
yield (95%). When the same reaction was performed on
7
and the 2 -OH and 3 -OH groups were protected by ace-
tal groups including cyclohexylidene, di(p-anisyl)methyl-
idene and isopropylidene, it was observed that the Tr
group was deprotected selectively, while the acetal moi-
eties were maintained. Similar results were obtained
To investigate the generality and versatility of this meth-
od, the reaction was extended to various structurally
diverse protected nucleosides. Using, the optimized
reaction conditions, the deprotection of, trityl ethers of
purine and pyrimidine nucleosides 1a–11a were exam-
ined (Scheme 3).
0
0
Firstly, we examined the deprotection of 5 -O-Tr
0
0
uridine, 5 -O-MMT uridine and 5 -O-DMT uridine
1a–3a). As shown in Table 2, the free nucleoside 1b
was obtained in excellent yields (88–91%).
0
a, 8a and 9a, in which the 5 -OH was protected with Tr
(
0
0
0
Table 1. Effect of solvent on the detritylation of 5 -dimethoxytrityl
uridine (10 mmol) with a catalytic amount of SSA (0.76 g, 2 mmol,
0
0
when 5 -trityloxy-2 -t-butyldimethylsilyloxy uridine
(
good yield (83%) of 2 -t-butyldimethylsilyloxy uridine
(10b). Furthermore, examination of the reaction of 11b
illustrated the selective deprotection of the Tr group in
the presence of the acid sensitive TIPS group.
20 mol %) at room temperature
10a) was exposed to detritylation, which afforded a
a
0
Entry
Solvent
MeCN
Time (min)
Yield (%)
1
2
3
4
5
6
2
4
8
5
12
140
91
70
51
60
72
26
2 2
CH Cl
CHCl
DMF
THF
3
In an experiment to compare the catalytic effect of SSA
with silica-supported sulfuric acid, we performed the
deprotection of 5 -O-Tr uridne with SiO –H SO
CCl
4
a
0
Isolated yield.
2
2
4