6
088 J . Org. Chem., Vol. 64, No. 16, 1999
Notes
THF, dioxane, dichloromethane, and pyridine were not
useful as the solvent. These results indicated that the
use of imidazole is essential for the reaction, and thus it
is conceivable that dimethoxytritylimidazolide is inter-
mediately produced from dimethoxytrityl chloride and
imidazole to act as the true tritylating agent. How-
ever, H NMR analysis of the reaction of dimethoxytrityl
chloride (1 equiv) and imidazole (2 equiv) in the presence
of diisopropylethylammonium mesylate (2 equiv) in DMF-
42.8, 54.5. Anal. Calcd for C
9
H
23NO
3
S: C, 47.97; H, 10.29; N,
6
.22. Found: C, 47.83; H, 10.44; N, 6.19.
A Typ ica l P r oced u r e for 5′-O-Select ive Tr it yla t ion of
Deoxyr ibon u cleosid es. Meth od A. To a suspension of a
deoxyribonucleoside (40.0 mmol), imidazolium mesylate (13.1 g,
8
0.0 mmol), and diisopropylethylamine (10.3 g, 13.9 mL, 80.0
mmol) in dry DMF (200 mL) was added p,p′-dimethoxytrityl
chloride (13.6 g, 40.0 mmol) in three portions at room temper-
ature. The reaction mixture was stirred for 2 h. During this
period, the mixture became homogeneous. The resulting solution
was poured into water (3 L), and the resulting precipitate was
collected by filtration. The crude product was recrystallized or
subjected to silica gel column chromatography to give a 5′-O-
1
7
d showed no signals supporting the intervention of di-
methoxytritylimidazolide. This reaction formed a complex
mixture, and the addition of a nucleoside to this mix-
ture gave no desired tritylation product. These results
also suggest that the presence of equimolar amounts of
methanesulfonic acid and diisopropylethylamine is im-
portant to obtain good chemoselectivity. This mixture
might create a certain buffering effect favorable for
gaining the desirable chemoselectivity, but the effect has
not been fully elucidated. Thus, although the individual
roles of the additives have not yet been exactly defined,
we know that the use of 2 equiv each of imidazole,
methanesulfonic acid, and diisopropylethylamine toward
a nucleoside and dimethoxytrityl chloride in DMF is
crucial for obtaining good chemoselectivity and high
product yield.11
(p,p′-dimethoxytrityl)-2′-deoxyribonucleoside as crystals or an
amorphous solid.
Meth od B. To a suspension of a deoxyribonucleoside (40.0
mmol), imidazole (5.45 g, 80.0 mmol), and diisopropylethylam-
monium mesylate (18.0 g, 80.0 mmol) in dry DMF (200 mL) was
added p,p′-dimethoxytrityl chloride (13.6 g, 40.0 mmol) in three
portions at room temperature, and the resulting mixture was
stirred for 2 h. The reaction mixture was poured into water (3
L). The resulting precipitate was purified as described above to
give a 5′-O-(p,p′-dimethoxytrityl)-2′-deoxyribonucleoside as crys-
tals or an amorphous solid.
Meth od C. To a stirred solution of imidazole (5.45 g, 80.0
mmol), methanesulfonic acid (5.19 mL, 7.69 g, 80.0 mmol), and
diisopropylethylamine (13.9 mL, 10.3 g, 80.0 mmol) in dry
DMF (100 mL) were successively added a deoxyribonucleoside
(40.0 mmol) in three portions and p,p′-dimethoxytrityl chloride
In summary, we have developed a general, convenient
method for 5′-O-selective dimethoxytritylation of 2′-deoxy-
ribonucleosides to produce N-free 5′-O-protected deriva-
tives. This approach is particularly useful for the prepa-
ration of the deoxyguanosine derivative 7, whose pro-
duction currently requires expensive reagents and a
multistep process.
(13.6 g, 40.0 mmol) in three portions at room temperature.
Stirring was continued for 2 h. The resulting homogeneous
mixture was poured into water (3 L) to give a precipitate, which
was recrystallized or subjected to silica gel column chromatog-
raphy to give a 5′-O-(p,p′-dimethoxytrityl)-2′-deoxyribonucleo-
side.
The reaction on a 4.00 mmol scale was carried out in a similar
manner. Purification conditions and yield of the product are as
follows.
5
′-O-(p,p′-Dim eth oxytr ityl)-2′-d eoxya d en osin e (5). Silica
Exp er im en ta l Section
gel column chromatography of the crude product of a 40 mmol
synthesis with a 9:1 mixture of ethyl acetate and hexane as the
eluent afforded 5 (17.5 g, 79% yield) as a colorless amorphous
solid. This product showed IR, UV, and H and C NMR spectral
data identical to those of an authentic sample of 5.2 When the
reaction was carried out on 4 mmol scale, 5 was obtained in an
6% yield (1.90 g).
5′-O-(p,p′-Dim eth oxytr ityl)-2′-d eoxycytid in e (6). Column
chromatography of the crude product obtained in a 40 mmol
scale preparation on silica gel eluted with a 1:20 mixture of
methanol and dichloromethane gave 6 (16.1 g, 76% yield) as a
colorless powder. The IR, UV, and H and C NMR spectral data
of this compound were identical with those of an authentic
Ma ter ia ls. E. Merck Kieselgel 60 (70-230 mesh) deactivated
by adding 6% water was used for column chromatography. DMF
was distilled from CaH under reduced pressure. The solvents
2
for chromatography were used after simple distillation of the
commercially available solvents. Commercially supplied imida-
zole (Nacalai Tesque), methanesulfonic acid (Tokyo Chemical
Industry), diisopropylethylamine (Tokyo Chemical Industry), 2′-
deoxyribonucleosides (Yamasa), and p,p′-dimethoxytrityl chlo-
ride (Tokyo Chemical Industry) were used without further
purification.
Im id a zoliu m Mesyla te. To a solution of imidazole (34.0 g,
.499 mol) in dichloromethane (500 mL) was added dropwise
methanesulfonic acid (48.0 g, 32.4 mL, 0.499 mol) at 0 °C. The
resulting precipitate was collected by filtration and washed with
dichloromethane (100 mL) to give imidazolium mesylate as a
1
13
,4
8
1
13
0
2
sample of 6. The 4 mmol scale synthesis gave 6 in an 85% yield
(1.94 g).
5′-O-(p,p′-Dim eth oxytr ityl)-2′-d eoxygu a n osin e (7). Re-
crystallization of the crude precipitate from a mixture of ethyl
acetate and acetone gave 7 (17.8 g, 78% yield; 40 mmol synthesis)
as colorless needles, mp 190-191 °C, which indicated IR, UV,
and 1H and C NMR spectra superimposable on those of an
colorless powder (81.1 g, 99%), mp 184-186 °C. IR (KBr): 3140,
1
1
(
589, 1460, 1437, 1339, 1194 cm-1. H NMR (DMSO-d
6
): δ 2.49
1
3
s, 3H), 7.62 (s, 2H), 9.03 (s, 1H). C NMR 40.1, 119.7, 134.8.
13
Anal. Calcd for C S: C, 29.26; H, 4.91; N, 17.06. Found:
4
8 2 3
H N O
2
C, 29.06; H, 4.90; N, 17.15.
authentic sample of 7. The yield of 7 in the synthesis on a 4
Diisop r op ylet h yla m m on iu m Mesyla t e. To a solution of
diisopropylethylamine (64.4 g, 500 mmol) in dichloromethane
mmol scale was 74% (1.56 g).
5′-O-(p,p′-Dim eth oxytr ityl)th ym id in e (8). Silica gel col-
umn chromatography of the crude product of 40 mmol synthesis,
eluting with a 3:1 mixture of ethyl acetate and hexane, afforded
8 (17.9 g, 82% yield) as a colorless amorphous solid. This product
is identical in all respects with the commercially supplied
material. The product 8 was obtained in an 89% yield (1.94 g)
in the preparation on a 4.00 mmol scale.
(50 mL) was added methanesulfonic acid (48.1 g, 32.4 mL, 500
mmol) at room temperature. The mixture was concentrated and
dried under reduced pressure to afford diisopropylethylammo-
nium mesylate as a colorless solid (112.5 g, 100%). This material
was hygroscopic and the melting point could not be measured:
-
1 1
IR (KBr) 2668, 1649, 1427, 1395, 1318 cm . H NMR (DMSO-
d
3
8
6
) δ 1.34 (t, 3H, J ) 7.3 Hz), 1.37 (d, 12H, J ) 6.3 Hz), 2.46 (s,
H), 3.23 (q, 2H, J ) 7.3 Hz), 3.70 (seven lines, 2H, J ) 6.3 Hz),
Ack n ow led gm en t. This work was supported in part
by Grants-in-Aid for Scientific Research (Nos. 08454200,
1
3
6
.88 (br s, 1H). C NMR (DMSO-d ) δ 12.7, 16.9, 18.3, 40.0,
1
0169225, and 10554042) from the Ministry of Educa-
tion, Science, Sports and Culture, by a grant from the
Research for the Future” Program of the J apan Society
for the Promotion of Science (J SPS-RFTF97I00301), and
(
11) Preparation of N-free 5′-O-monomethoxytrityl- and 5′-O-trityl-
2
′-deoxyribonucleosides was similarly achieved via the direct, chemose-
lective reaction of the parent substances using p-methoxytrityl chloride
or trityl chloride, respectively.
“