Trimethylsilyl trifluoromethanesulfonate-promoted reductive 2'-o-arylmethylation of ribonucleoside derivatives

Article abstract of DOI:10.1080/15257770.2011.592171

Arylmethyl groups such as benzyl, p-methoxybenzyl, and 1-pyrenylmethyl groups were introduced to the 2'-O-position of nucleosides by reductive etherification. Combining corresponding aromatic aldehydes with 2'-O-trimethylsilylnucleoside derivatives in the

Full text of DOI:10.1080/15257770.2011.592171

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Trimethylsilyl
Trifluoromethanesulfonate-promoted
Reductive 2′-O-arylmethylation of
Ribonucleoside Derivatives
Naoki Uchiyama a , Toshihiko Ogata a , Natsuhisa Oka a & Takeshi
Wada a
a Department of Medical Genome Sciences, Graduate School of
Frontier Sciences, The University of Tokyo, Chiba, Japan
Published online: 22 Jul 2011.
To cite this article: Naoki Uchiyama , Toshihiko Ogata , Natsuhisa Oka & Takeshi Wada
(2011) Trimethylsilyl Trifluoromethanesulfonate-promoted Reductive 2′-O-arylmethylation of
Ribonucleoside Derivatives, Nucleosides, Nucleotides and Nucleic Acids, 30:6, 446-456, DOI:
10.1080/15257770.2011.592171
To link to this article: http://dx.doi.org/10.1080/15257770.2011.592171
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Nucleosides, Nucleotides and Nucleic Acids, 30:446–456, 2011
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2011.592171
TRIMETHYLSILYL TRIFLUOROMETHANESULFONATE-PROMOTED
REDUCTIVE 2ꢀ-O-ARYLMETHYLATION OF RIBONUCLEOSIDE
DERIVATIVES
Naoki Uchiyama, Toshihiko Ogata, Natsuhisa Oka, and Takeshi Wada
Department of Medical Genome Sciences, Graduate School of Frontier Sciences,
The University of Tokyo, Chiba, Japan
Arylmethyl groups such as benzyl, p-methoxybenzyl, and 1-pyrenylmethyl groups were introduced
2
to the 2 ꢁ-O-position of nucleosides by reductive etherification. Combining corresponding aromatic
aldehydes with 2 ꢁ-O-trimethylsilylnucleoside derivatives in the presence of trimethylsilyl trifluo-
romethanesulfonate (TMSOTf) resulted in moderate to good yields of the 2 ꢁ-O-arylmethyluridine
derivatives, whereas the corresponding cytidine and adenosine derivatives were obtained in low
yields. The reaction of ribonucleosides with aliphatic aldehydes did not proceed smoothly. Anomer-
ization of the uridine derivatives by TMSOTf was observed in CH2Cl2, toluene, and CH3CN, but
was completely suppressed when the reactions were conducted in 1,4-dioxane.
Keywords 2ꢁ-O-modified ribonucleoside; reductive etherification; arylmethylation
INTRODUCTION
Chemically modified oligonucleotides have a wide range of appli-
cations such as target gene therapy[1,2] and diagnosis.[3,4] 2ꢁ-O-Alkyl-
oligoribonucleotide analogues are especially attractive for these appli-
cations because of their resistance to nuclease degradation and high
hybridization affinity for complementary mRNA.[5,6] For these reasons,
2ꢁ-O-alkylribonucleosides are attractive synthetic targets. Various methods
for 2ꢁ-O-modification of ribonucleosides have been developed,[7] including
the reaction of partially protected ribonucleosides with alkylating agents,[8,9]
ring-opening reaction of 2,2ꢁ-anhydrouridine derivatives,[10] and glycosyla-
tion.[11] Although some of these reactions generate high yields of the desired
Received 27 April 2011; accepted 25 May 2011.
The authors thank Professor Kazuhiko Saigo (Kochi University of Technology) for helpful sugges-
tions. This work was financially supported by the Ministry of Education, Culture, Sports, Science, and
Technology (MEXT) Japan.
Address correspondence to Takeshi Wada, Department of Medical Genome Sciences, Graduate
School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwa, Chiba 277-8562, Japan. E-mail:
wada@k.u-tokyo.ac.jp
446

Synthesis of 2 ꢁ-O-arylmethylnucleosides
447
compounds, further optimization of the process is needed because of persis-
tent difficulties such as undesired base alkylation, low regioselectivity, depen-
dence of hazardous reagents, and limited product ranges. Thus, we sought
to develop a new method for the synthesis of 2ꢁ-O-alkylribonucleosides.
Reductive etherification of aldehydes and ketones with hydrosilanes,
silylated alcohols, and Lewis acids is useful for the synthesis of a wide range
of asymmetric ethers (Scheme 1).[12] This reaction is promoted by a cat-
alytic amount of a Lewis acid and is compatible with a variety of functional
groups, including esters, amides, nitriles, and acetals. Therefore, we ex-
pected that this methodology could be employed in the synthesis of 2ꢁ-O-
alkylribonucleosides. To the best of our knowledge, this reaction has not
been previously applied to the synthesis of O-alkylnucleoside derivatives. In
this paper, we describe the results of our study on the 2ꢁ-O-alkylation of
3ꢁ,5ꢁ-O-protected ribonucleoside derivatives by reductive etherification.
R
R'
R
R'
R
R'
H
Lewis acid
Et3SiH
+ R"OTMS
R"O
OTMS
R"O
O
SCHEME 1 Synthesis of asymmetric ethers from aldehydes and ketones by reductive etherification.
RESULTS AND DISCUSSION
To examine the applicability of reductive etherification for the
synthesis of 2ꢁ-O-modified nucleosides, we carried out 2ꢁ-O-benzylation
of three types of 3ꢁ,5ꢁ-O-protected 2ꢁ-O-TMS-uridine derivatives: 1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl (TIPDS) (1a), benzoyl (1b), and di-tert-
butylsilanediyl (DTBS) (1c) substituted uridine compounds. The derivatives
were allowed to react with benzaldehyde and triethylsilane in the presence
of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf)
at 0◦C (Scheme 2). However, 1a and 1b produced only trace amounts of the
desired 2ꢁ-O-benzyluridine derivatives 2a,b. The major side reaction was 2ꢁ-
desilylation, and the results were not improved even when the reactions were
carried out under strictly anhydrous conditions. In contrast, 2ꢁ-O-benzylation
proceeded smoothly when 1c was used as the starting materials, resulting in
moderate to high yield of the desired product 2c, in a mixture of α- and
β-isomers.[16] The significant difference in reactivity remains unexplained,
although low reactivity of 1b may be related to the Lewis basicity of the ben-
zoyl groups, which can coordinate with TMSOTf. The difference in reactivity
between 1a and 1c can be attributed to the difference in the steric hindrance
around their 2ꢁ-OH; however, there is no conclusive evidence for this because
it has been reported that the 2ꢁ-OH of a DTBS-protected guanosine deriva-
tive is less reactive to sulfonylation than to the TIPDS-protected counterpart,

448
N. Uchiyama et al.
PhCHO (1.1 equiv)
Et3SiH (1.1 equiv)
TMSOTf (0.1 equiv)
i-Pr2Si
O
i-Pr2Si
O
U
O
O
1a
O
U
O
O
CH2Cl2, 0 °C then rt, 1 d
i-Pr2Si
O
OBn
i-Pr2Si
O
OTMS
2a
trace
PhCHO (1.1 equiv)
Et3SiH (1.1 equiv)
TMSOTf (0.1 equiv)
BzO
U
BzO
U
O
CH2Cl2, 0 °C then rt, 1 d
BzO
OTMS
BzO
OBn
2b
1b
trace
O
PhCHO (1.1 equiv)
Et3SiH (1.1 equiv)
TMSOTf (0.1 equiv)
O
O
U
O
U
t-Bu
Si
t-Bu
t-Bu
Si
CH2Cl2, 0 °C then rt, 2 h
t-Bu
O
OBn
O
OTMS
2c
1c
50%
α:β = 34:66
SCHEME 2 2ꢁ-O-Benzylation of 3ꢁ,5ꢁ-O-protected uridine derivatives 1a–c by reductive etherification.
and the difference in reactivity was attributed to the steric hindrance on
the basis of a conformational search.8a Although the difference in reactivity
of 1a–c remains unexplained, our results showed that the DTBS was the
most effective choice for the reductive 2ꢁ-O-benzylation of ribonucleoside
derivatives.
Next, we attempted to optimize the reaction conditions, aiming to min-
imize anomerization and increase the yield of the desired product. The
2ꢁ-O-benzylation of 1c was carried out in various solvents listed in Table 1
(entries 1–8). CH2Cl2, toluene, and CH3CN did not suppress anomerization
(Table 1, entries 1–3). In contrast, ether-type solvents such as 1,2-
dimethoxyethane (DME) and 1,4-dioxane successfully suppressed the
anomerization (Table 1, entries 4 and 5). The reaction in dioxane was
particularly effective, giving moderate yield of the desired 2ꢁ-O-benzyl-β-
uridine derivative 2c (β) without any observable anomerization (Table 1,
entry 5). Anomerization was also suppressed in other ether-type solvents,
such as THF, Et2O and t-BuOMe, although the reaction was slowed down
probably because of the deactivation of TMSOTf by the stronger Lewis
basic solvents (entries 6–8).[15] These results indicate that the moderate

Synthesis of 2 ꢁ-O-arylmethylnucleosides
449
TABLE 1 Optimization of reaction conditions for 2ꢁ-O-benzylation of uridine derivative 1c and
reactions of N 3-benzoyluridine, cytidine and adenosine derivatives 1d–g in 1,4-dioxane
PhCHO (1.1 equiv)
Et3SiH (1.1 equiv)
TMSOTf
O
B
O
O
O
t-Bu
t-Bu
B
Si
t-Bu
t-Bu
Si
O
OTMS
O
OBn
1c−g
2c−g
Equiv of Temp Reaction
Yield of 2c–g Yield of 2c–g
Entry
Ba
Solvent
TMSOTf (◦C)
time
Product
(β) (%)
(α) (%)
1
2
3
4
5
6
7
8
U (1c)
U (1c)
U (1c)
U (1c)
CH2Cl2
toluene
CH3CN
DME
0.1
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0
0
0
0
rt
0
0
0
2 h
4 h
4 h
8 h
6 h
20 h
24 h
10 h
2c
2c
2c
2c
2c
2c
2c
2c
33
19
29
40
54
8
17
ca. 20b
11
trace
0
trace
trace
trace
U (1c) 1,4-dioxane
U (1c)
U (1c)
U (1c)
THF
ether
t-BuOMe
7
trace
9
10
11
Ubz (1d) 1,4-dioxane
0.1
0.5
1.0
rt
rt
rt
2 h
1 h
20 min
2d
2d
2d
61
70
75
0
0
0
U
bz (1d) 1,4-dioxane
Ubz (1d) 1,4-dioxane
12
13
14
C (1e) 1,4-dioxane
Cbz (1f) 1,4-dioxane
Abz2 (1g) 1,4-dioxane
10
2
1
rt
rt
rt
4 h
19 h
27 h
2e
2f
2g
11
16
21
0
0
0
a Ubz = N 3-benzoyluracil-1-yl, Cbz = N 4-benzoylcytosin-1-yl, Abz2 = N 6,N 6-dibenzoyladenin-9-yl.
b Not isolated.
Lewis basicity of dioxane may be appropriate for the suppression of anomer-
ization without deactivating TMSOTf.
The reaction was further improved by protecting of the N 3-position of
uracil (entry 9), and increasing the amount of TMSOTf. The addition of
TMSOTf accelerated the reaction and improved the yield of 2d (entries 10
and 11). Remarkably, epimerization of the product was not observed fol-
lowing the additional stoichiometric amounts of TMSOTf in dioxane (entry
11). Although the synthesis of substituted uridine was successful, attempts
to synthesize 2ꢁ-O-benzylcytidine and adenosine derivatives 1e–g gave low
yields of the products despite complete suppression of epimerization (en-
tries 12–14). 2ꢁ-Desilylation was the major side reaction, although there were
other unidentified byproducts. The low yields might also be due to the Lewis
basicity of cytosine and adenine base.
Finally, 2ꢁ-O-alkylation of the uridine derivative 1d was attempted using
various aldehydes listed in Table 2. As in the case of 2ꢁ-O-benzylation, 2ꢁ-O-
arylmethyl groups, such as p-methoxybenzyl and 1-pyrenylmethyl groups
were introduced into the 2ꢁ-O-position of 1d to give the desired 2ꢁ-O-
arylmethyluridine derivatives 3 and 4 with moderate yields (entries 2 and 3).
In contrast, aliphatic aldehydes did not produce the desired 2ꢁ-O-alkyluridine
derivatives efficiently, probably because of the low reactivity of the

450
N. Uchiyama et al.
TABLE 2 2ꢁ-O-Alkylation of uridine derivative 1d with various aldehydes
aldehyde (1.1 equiv)
Ubz
Et3SiH (1.1 equiv)
TMSOTf
O
Ubz
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
Si
Si
O
OTMS
O
OR
1d
2d, 3−8
Entry
Aldehyde
PhCHO
Equiv of TMSOTf
R
Reaction time Yield (%)
1
2
1.0
0.5
Bn (2d)
20 min
10 min
75
48
3
0.5
5 min
53
4a
5b
6
CH2 = CHCHO
CH3CHO
CH3CH2CHO
HCHO
1.0
1.0
1.0
1.0
Allyl (5)
Et (6)
Pr (7)
70 min
2 h
12 h
14c
0c
0c
0
7b
Me (8)
15 min
a Additional 1.1 equiv of acrolein and Et3SiH were added after 60 minutes.
b Excess aldehydes were used.
c Decomposition of starting material 1d was observed.
corresponding aldehydes (entries 4–7); only α,β-unsaturated aldehyde gave
the product 5 in low yield (entry 4).
CONCLUSION
We demonstrated successful use of reductive etherification in the synthe-
sis of 2ꢁ-O-arylmethyluridine derivatives. Using moderate Lewis basic dioxane
as a solvent, anomerization of uridine derivatives was suppressed, despite the
presence of stoichiometric amounts of TMSOTf. Anomerization of cytidine
and adenosine derivatives was also completely suppressed by dioxane, al-
though the desired 2ꢁ-O-arylmethylnucleoside derivatives were obtained in
low yields.
EXPERIMENTAL
General
1H NMR (300 MHz) spectra were recorded on a Varian MERCURY
1
300 spectrometer. H NMR spectra were obtained with tetramethylsilane

Synthesis of 2 ꢁ-O-arylmethylnucleosides
451
(TMS) as an internal standard in CDCl3. Analytical thin-layer chromatogra-
phy (TLC) was performed on Merck TLC plates (No. 5715) precoated with
silica gel 60 F254. Silica gel column chromatography was carried out using
Kanto silica gel 60N (spherical, neutral). Dry organic solvents were purified
and dried by appropriate procedures. Other organic solvents were reagent
grade and used as received. TMSOTf was purified by distillation prior to use.
Synthesis of 2 ꢀ-O-trimethylsilyl-3 ꢀ,5 ꢀ-O-(di-tert-butylsilanediyl)uridine (1c)
Typical procedure for 2 ꢁ-O-trimethylsilylation of 3 ꢁ,5 ꢁ-O-protected uridine
derivatives. 3ꢁ,5ꢁ-O-(Di-tert-butylsilanediyl)uridine was synthesized according
to the procedure described in the literature.[13] The obtained 3ꢁ,5ꢁ-O-(di-
tert-butylsilanediyl)uridine (1.15 g, 3.00 mmol) was dried by repeated co-
evaporations with dry pyridine and dissolved in dry pyridine (10 mL).
Chlorotrimethylsilane (0.53 mL, 4.2 mmol) was added dropwise to the solu-
tion at 0◦C under argon. The reaction mixture was stirred until completion
and evaporated under reduced pressure. The residue was then dissolved in
CH2Cl2 (50 mL). The solution was washed with saturated NaHCO3 aqueous
solution (3 × 40 mL), dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column chromatog-
raphy [hexane-ethyl acetate (2/1, v/v)] to afford 1c (1.36 g, 2.98 mmol,
99%) as a colorless foam. 1H NMR (CDCl3) δ 8.91 (1H, br, NH), 7.31 (1H,
d, J = 8.4 Hz, 6-H), 5.74 (1H, d, J = 8.4 Hz, 5-H), 5.62 (1H, s, 1ꢁ-H), 4.52-4.48
(1H, m, 4ꢁ-H), 4.24-4.18 (2H, m, 3ꢁ-H, 5ꢁ-H), 3.98 (1H, t, J = 9.9 Hz, 5ꢁ-H),
3.77 (1H, dd, J = 9.6, 4.2 Hz, 2ꢁ-H), 1.04 (9H, s, t-Bu-H), 1.02 (9H, s, t-Bu-H),
0.20 (9H, s, TMS-H).
2 ꢁ-O-Trimethylsilyl-3 ꢁ,5 ꢁ-O-(1,1,3,3-tetraisopropyldisiloxanediyl)uridine (1a).
Compound 1a was obtained from 3ꢁ,5ꢁ-O-(tetraisopropyldisiloxanediyl)
uridine (4.88 g, 10.0 mmol) as a colorless solid (5.61 g, 10.0 mmol, quant).
1H NMR (CDCl3) δ 8.27 (1H, br, NH), 7.95 (1H, d, J = 7.8 Hz, 6-H), 5.64
(1H, dd, J = 8.4, 2.4 Hz, 5-H), 5.57 (1H, s, 1ꢁ-H), 4.27-3.98 (5H, m, 2ꢁ-H,
3ꢁ-H, 4ꢁ-H, 5ꢁ-H, 5ꢁꢁ-H), 1.09-0.94 (27H, m, CH(CH3)2), 0.19 (9H, s, TMS-H).
2 ꢁ-O-Trimethylsilyl-3 ꢁ,5 ꢁ-O-dibenzolyluridine (1b). 3ꢁ,5ꢁ-O-Dibenzoyluridine
was synthesized according to the procedure described in the litera-
ture.[14] Compound 1b was obtained from 3ꢁ,5ꢁ-O-dibenzoyluridine (0.65 g,
1.4 mmol) as a colorless foam (0.75 g, 1.4 mmol, quant). 1H NMR (CDCl3)
δ 8.88 (1H, br, NH), 8.09-7.45 (11H, m, Ar-H, 6-H), 5.91 (1H, d, J = 3.0 Hz,
1ꢁ-H), 5.52 (1H, d, J = 7.8 Hz, 5-H), 5.31 (1H, t, J = 5.7 Hz, 3ꢁ-H), 4.85-4.57
(4H, m, 2ꢁ-H, 4ꢁ-H, 5ꢁ-H, 5ꢁꢁ-H), 0.05 (9H, s, TMS-H).
N3-Benzoyl-2 ꢁ-O-trimethylsilyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)uridine
(1d).
Uridine (1.22 g, 5.0 mmol) was dried by repeated coevaporations
with dry pyridine and dissolved in dry DMF (25 mL). Di-tert-butylsilyl
bis(trifluoromethanesulfonate) (2.0 mL, 5.5 mmol) was added dropwise
to the solution at 0◦C under argon. After being stirred for 10 minutes,
imidazole (1.70 g, 25 mmol) and chlorotrimethylsilane (0.89 mL, 7.0 mmol)

452
N. Uchiyama et al.
were added to the mixture and stirring was continued for another 10
minutes. Then the mixture was diluted with ethyl acetate (100 mL), washed
with water (7 × 100 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was dissolved dry pyridine (20 mL)
and cooled to 0◦C under argon. Diisopropylethylamine (4.3 mL, 25 mmol)
and benzoyl chloride (0.85 mL, 7.5 mmol) were added to the solution and
the mixture was stirred for 12 hours. After completion, the reaction was
quenched with EtOH (3 mL), and the mixture evaporated under reduced
pressure and then diluted with CH2Cl2 (50 mL). The solution was washed
with saturated NaHCO3 aqueous solution (3 × 30 mL), dried over Na2SO4,
filtered, evaporated under reduced pressure and coevaporated with toluene
(3 × 5 mL). The residue was purified by silica gel column chromatography
[hexane-ethyl acetate (4/1, v/v)] to afford 1d (2.68 g, 4.78 mmol, 96%
1
from uridine). Colorless foam. H NMR (CDCl3) δ 8.64 (1H, s, 8-H), 8.12
(1H, s, 2-H), 7.87-7.34 (10H, m, Ar-H), 5.99 (1H, s, 1ꢁ-H), 4.58-4.50 (2H, m,
3ꢁ-H, 4ꢁ-H), 4.34-4.26 (2H, m, 2ꢁ-H, 5ꢁ-H), 4.02 (1H, t, J = 9.4 Hz, 5ꢁꢁ-H),
1.04 (9H, s, t-Bu-H), 1.04 (9H, s, t-Bu-H), 0.23 (9H, s, TMS-H).
2 ꢁ-O-Trimethylsilyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)cytidine (1e). Cytidine
(0.972 g, 4.0 mmol) was dried by repeated coevaporations with
dry pyridine and dissolved in dry DMF (20 mL). Di-tert-butylsilyl
bis(trifluoromethanesulfonate) (1.6 mL, 4.4 mmol) was added drop-
wise to the solution at 0◦C under argon. After being stirred for 10 minutes,
imidazole (1.36 g, 20 mmol) and chlorotrimethylsilane (0.56 mL, 4.4 mmol)
were added to the mixture and stirring was continued for another
10 minutes. Then the mixture was diluted with ethyl acetate (100 mL),
washed with water (7 × 100 mL), dried over Na2SO4, filtered and con-
centrated. The residue was purified by silica gel column chromatography
[ethyl acetate-acetone-triethylamine (9/1/0.2, v/v/v)] to afford 1e (1.08 g,
1
2.37 mmol, 60% from cytidine). Colorless foam. H NMR (CDCl3) δ 7.35
(1H, d, J = 7.8 Hz, 6-H), 5.81 (1H, d, J = 7.8 Hz, 5-H), 5.66 (1H, s, 1ꢁ-H),
4.51 (1H, dd, J = 8.6, 4.8 Hz, 4ꢁ-H), 4.27-4.22 (2H, m, 3ꢁ-H, 5ꢁ-H), 3.98 (1H, t,
J = 9.9 Hz, 5ꢁꢁ-H), 3.75 (1H, dd, J = 9.6, 4.2 Hz, 2ꢁ-H), 1.07 (9H, s, t-Bu-H),
1.02 (9H, s, t-Bu-H), 0.19 (9H, m, TMS-H).
N4-Benzoyl-2 ꢁ-O-trimethylsilyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)cytidine (1f). 2ꢁ-
O-Trimethylsilyl-3ꢁ,5ꢁ-O-(di-tert-butylsilanediyl)cytidine 1e (456 mg, 1.0
mmol) was dried by repeated coevaporations with dry pyridine and dissolved
in dry pyridine (5 ml). Benzoyl chloride (0.13 mL, 1.1 mmol) was added to
the solution at 0◦C under argon. The mixture was then stirred for 10 min-
utes. The reaction was then quenched with EtOH (1 mL), and the mixture
was evaporated under reduced pressure and diluted with CH2Cl2 (25 mL).
The solution was washed with saturated NaHCO3 aqueous solution (3 ×
20 mL), dried over Na2SO4, filtered, evaporated under reduced pressure
and coevaporated with toluene (4 × 5 mL). The residue was purified by sil-
ica gel column chromatography [hexane–ethyl acetate (1/1, v/v)] to afford

Synthesis of 2 ꢁ-O-arylmethylnucleosides
453
1f (363 mg, 0.65 mmol, 65%). Colorless foam.1H NMR (CDCl3) δ 8.65 (1H,
br, NH), 7.90-7.27 (7H, m, Ar-H, 6-H, 5-H), 5.74 (1H, s, 1ꢁ-H), 4.57 (1H, m,
3ꢁ-H), 4.37-3.70 (4H, m, 2ꢁ-H, 4ꢁ-H, 5ꢁ-H, 5ꢁꢁ-H), 1.04 (9H, s, t-Bu-H), 1.04
(9H, s, t-Bu-H), 0.25 (9H, s, TMS-H).
N6,N6-Dibenzoyl-2 ꢁ-O-trimethylsilyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)adenosine
(1g). Adenosine (1.07 g, 4.0 mmol) was dried by repeated coevaporations
with dry pyridine and dissolved in dry DMF (20 mL). Di-tert-butylsilyl
bis(trifluoromethanesulfonate) (1.6 mL, 4.4 mmol) was added dropwise
to the solution at 0◦C under argon. After being stirred for 10 minutes,
imidazole (1.36 g, 20 mmol) and chlorotrimethylsilane (0.56 mL, 4.4 mmol)
were added to the mixture and stirring was continued for another
10 minutes. Then the mixture was diluted with ethyl acetate (100 mL),
washed with water (7 × 100 mL), dried over Na2SO4, filtered and con-
centrated under reduced pressure. The residue was coevaporated with dry
pyridine (3 × 7 mL), dissolved dry pyridine (20 mL) and cooled to 0◦C
under argon. Benzoyl chloride (1.21 mL, 10.5 mmol) was added to the
solution and the mixture was stirred for 7 hours. After completion, the
reaction was quenched with EtOH (3 mL), and the mixture was evaporated
under reduced pressure and diluted with CH2Cl2 (50 mL). The organic
solution was washed with saturated NaHCO3 aqueous solution (3 × 30 mL),
dried over Na2SO4, filtered, evaporated under reduced pressure and
coevaporated with toluene (3 × 5 mL). The residue was purified by silica
gel column chromatography [hexane–ethyl acetate (5/1 to 4/1, v/v)] to
1
afford 1g (2.00 g, 2.91 mmol, 73% from adenosine). Colorless foam. H
NMR (CDCl3) δ 8.64 (1H, s, 8-H), 8.12 (1H, s, 2-H), 7.87-7.34 (10H, m,
Ar-H), 5.99 (1H, s, 1ꢁ-H), 4.58-4.50 (2H, m, 3ꢁ-H, 4ꢁ-H), 4.34-4.26 (2H, m,
2ꢁ-H, 5ꢁ-H), 4.02 (1H, t, J = 9.4 Hz, 5ꢁꢁ-H), 1.04 (9H, s, t-Bu-H), 1.04 (9H, s,
t-Bu-H), 0.23 (9H, s, TMS-H).
N3-Benzoyl-2 ꢀ-O-benzyl-3 ꢀ,5 ꢀ-O-(di-tert-butylsilanediyl)uridine (2d)
General procedure for synthesis of 2 ꢁ-O-alkylribonucleoside derivatives 2a-g,
3-8. N 3-Benzoyl-2ꢁ-O-trimethylsilyl-3ꢁ,5ꢁ-O-(di-tert-butylsilyanediyl)uridine 1d
(56 mg, 0.10 mmol) was dried by coevaporations with dry pyridine (3 ×
1 mL) and dry toluene (3 × 1 mL), and dissolved in dry 1,4-dioxane (0.40
mL) under argon. A 0.28 M solution of benzaldehyde and triethylsilane in
dry 1,4-dioxane (0.40 mL) was added to the solution. The 0.5 M solution
of TMSOTf in dry 1,4-dioxane (0.20 mL) was added dropwise and the mix-
ture was stirred at room temperature. After completion, the reaction was
quenched with saturated NaHCO3 aqueous solution (1.0 mL) and the mix-
ture was diluted with CHCl3 (20 mL). The organic layer was separated and
washed with saturated NaHCO3 aqueous solution (3 × 20 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography [hexane-ethyl acetate (4/1,
1
v/v)] to afford 2d (43.6 mg, 0.075 mmol, 75%). Colorless foam. H NMR

454
N. Uchiyama et al.
(CDCl3) δ 7.96-7.26 (11H, m, ArH, 6-H), 5.86 (1H, d, J = 8.4 Hz, 5-H), 5.81
(1H, s, 1ꢁ-H), 4.87 (2H, dd, J = 36.2, 12.0 Hz, 2ꢁ-O-CH2Ph), 4.53 (1H, dd, J
= 37.9, 4.8 Hz, 4ꢁ-H), 4.27-4.20 (1H, m, 3ꢁ-H), 4.15 (1H, d, J = 4.8 Hz, 5ꢁ-H),
4.05-3.96 (2H, m, 2ꢁ-H, 5ꢁꢁ-H), 1.08 (9H, s, t-Bu-H), 1.05 (9H, s, t-Bu-H).
1
2 ꢁ-O-Benzyl-3 ꢁ,5 ꢁ-O-dibenzoyluridine (2b). Colorless oil. H NMR (CDCl3)
δ 8.11-7.19 (17H, m, Ar-H, 6-H), 6.08 (1H, d, J = 3.9 Hz, 1ꢁ-H), 5.45 (1H, t,
J = 5.1 Hz, 3ꢁ-H), 5.36 (1H, d, J = 8.1 Hz, 5-H), 4.78-4.59 (6H, m, 4ꢁ-H, 5ꢁ-H,
5ꢁꢁ-H, 2ꢁ-O-CH2Ph), 4.28 (1H, t, J = 5.1 Hz, 2ꢁ-H).
2 ꢁ-O-Benzyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)uridine (2c(α)). Colorless oil. 1H
NMR (CDCl3) δ 8.92 (1H, br, NH), 8.05 (1H, d, J = 8.1 Hz, 6-H), 7.38-7.28
(5H, m, Ar-H), 5.89 (1H, s, 1ꢁ-H), 5.24 (1H, d, J = 8.1 Hz, 5-H), 4.69-3.80
(7H, m, 2ꢁ-H, 3ꢁ-H, 4ꢁ-H, 5ꢁ-H, 5ꢁꢁ-H, 2ꢁ-O-CH2Ph), 1.05 (18H, s, t-Bu-H).
2 ꢁ-O-Benzyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)uridine (2c(β)). Colorless oil. 1H
NMR (CDCl3) δ 9.20 (1H, br, NH), 7.43-7.25 (6H, m, Ar-H, 6-H), 5.78 (1H,
s, 1ꢁ-H), 5.75 (1H, d, J = 8.9 Hz, 5-H), 4.91 (2H, dd, J = 41.3, 12.0 Hz,
2ꢁ-O-CH2Ph), 4.51 (1H, dd, J = 9.0, 4.8 Hz, 4ꢁ-H), 4.27-4.18 (1H, m, 3ꢁ-H),
4.13 (1H, d, J = 4.8 Hz, 5ꢁ-H), 4.03-3.96 (2H, m, 2ꢁ-H, 5ꢁꢁ-H), 1.07 (9H, s,
t-Bu-H), 1.05 (9H, s, t-Bu-H).
2 ꢁ-O-Benzyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)cytidine (2e). Colorless oil. 1H
NMR (CDCl3) δ 7.48-7.26 (6H, m, Ar-H, 6-H), 5.88 (1H, s, 1ꢁ-H), 5.68 (1H,
d, J = 7.5 Hz, 5-H), 4.99 (2H, s, 2ꢁ-O-CH2Ph), 4.52 (1H, dd, J = 8.5, 5.1 Hz,
4ꢁ-H), 4.30-4.25 (1H, m, 3ꢁ-H), 4.12 (1H, d, J = 4.2 Hz, 5ꢁ-H), 4.00 (1H, t, J =
9.9 Hz, 5ꢁꢁ-H), 3.92-3.86 (1H, m, 2ꢁ-H), 1.05 (18H, s, t-Bu-H).
N4-Benzoyl-2 ꢁ-O-benzyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)cytidine (2f). Colorless
1
oil. H NMR (CDCl3) δ 8.70 (1H, br, NH), 7.91-7.24 (12H, m, Ar-H, 6-H,
5-H), 5.94 (1H, s, 1ꢁ-H), 5.02 (2H, s, 2ꢁ-O-CH2Ph), 4.48 (1H, dd, J = 9.2,
4.8 Hz, 4ꢁ-H), 4.38-4.33 (1H, m, 3ꢁ-H), 4.15 (1H, d, J = 4.2 Hz, 5ꢁ-H), 4.05
(1H, t, J = 10.5 Hz, 5ꢁꢁ-H), 3.88 (1H, dd, J = 9.6, 4.2 Hz, 2ꢁ-H), 1.06 (18H,
s, t-Bu-H).
N6,N6-Dibenzoyl-2 ꢁ-O-benzyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)adenosine (2g).
1
Colorless oil. H NMR (CDCl3) δ 8.63 (1H, s, 8-H), 8.06 (1H, s, 2-H),
7.86-7.25 (15H, m, Ar-H), 6.07 (1H, s, 1ꢁ-H), 4.95 (2H, dd, J = 97.5, 12.0
Hz), 4.67 (1H, dd, J = 9.6, 4.8 Hz, 4ꢁ-H), 4.52-4.48 (2H, m, 3ꢁ-H, 5ꢁ-H),
4.33-4.25 (1H, m, 2ꢁ-H), 4.04 (1H, t, J = 9.9 Hz, 5ꢁꢁ-H), 1.10 (9H, s, t-Bu-H),
1.07 (9H, s, t-Bu-H).
N3-Benzoyl-2 ꢁ-O-(p-methoxybenzyl)-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)urdine (3).
1
Colorless oil. H NMR (CDCl3) δ 7.96-6.79 (10H, m, Ar-H, 6-H), 5.84 (1H,
d, J = 8.4 Hz, 5-H), 5.77 (1H, s, 1ꢁ-H), 4.70 (2H, dd, J = 45.0, 11.4 Hz,
2ꢁ-O-CH2Ar), 4.54-4.49 (1H, dd, J = 11.6, 4.6 Hz, 4ꢁ-H), 4.26-4.18 (1H, m,
3ꢁ-H), 4.13 (1H, d, J = 4.5 Hz, 5ꢁ-H), 4.04-3.95 (2H, m, 2ꢁ-H, 5ꢁꢁ-H), 3.79 (3H,
s, Ar-OCH3), 1.07 (9H, s, t-Bu-H), 1.06 (9H, s, t-Bu-H).
N3-Benzoyl-2 ꢁ-O-(1-pyrenylmethyl)-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)uridine (4).
Colorless form. 1H NMR (CDCl3) δ 8.41-7.25 (15H, m, Ar-H, 6-H), 5.87 (1H,
s, 1ꢁ-H), 5.74 (1H, d, J = 8.4 Hz, 5-H), 5.58 (2H, dd, J = 12.3, 5.4 Hz,

Synthesis of 2 ꢁ-O-arylmethylnucleosides
455
2ꢁ-O-CH2Ar), 4.52 (1H, dd, J = 9.3, 4.8 Hz, 4ꢁ-H), 4.31-4.25 (2H, m, 3ꢁ-H,
5ꢁ-H), 4.05-3.99 (2H, m, 27-H, 5ꢁꢁ-H), 1.07 (18H, s, t-Bu-H).
N3-Benzoyl-2 ꢁ-O-allyl-3 ꢁ,5 ꢁ-O-(di-tert-butylsilanediyl)uridine (5). Colorless
1
oil. H NMR (CDCl3) δ 7.96-7.37 (6H, m, Ar-H, 6-H), 5.91-5.82 (2H, m,
5-H, 2ꢁ-O-CH2CH = CH2), 5.72 (1H, s, 1ꢁ-H), 5.23 (2H, dd, J = 45.0, 13.2
Hz, 2ꢁ-O-CH2CH = CH2), 4.54-4.51 (1H, m, 4ꢁ-H), 4.38-3.98 (6H, m, 2ꢁ-H,
3ꢁ-H, 5ꢁ-H, 5ꢁꢁ-H, 2ꢁ-O-CH2CH = CH2), 1.05 (18H, m, t-Bu-H).
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