Synthesis of disaccharide nucleosides by the O-glycosylation of natural nucleosides with thioglycoside donors

Article abstract of DOI:10.1002/asia.201403319

Disaccharide nucleosides constitute an important group of naturally-occurring sugar derivatives. In this study, we report on the synthesis of disaccharide nucleosides by the direct O-glycosylation of nucleoside acceptors, such as adenosine, guanosine, thy

Full text of DOI:10.1002/asia.201403319

DOI: 10.1002/asia.201403319
Full Paper
Glycosylation
Synthesis of Disaccharide Nucleosides by the O-Glycosylation of
Natural Nucleosides with Thioglycoside Donors
Shin Aoki,*[a, b] Taketo Fukumoto,[a] Taiki Itoh,[a] Masayuki Kurihara,[a] Shigeto Saito,[a] and
Shin-ya Komabiki[a]
Abstract: Disaccharide nucleosides constitute an important
group of naturally-occurring sugar derivatives. In this study,
we report on the synthesis of disaccharide nucleosides by
the direct O-glycosylation of nucleoside acceptors, such as
adenosine, guanosine, thymidine, and cytidine, with glycosyl
donors. Among the glycosyl donors tested, thioglycosides
were found to give the corresponding disaccharide nucleo-
sides in moderate to high chemical yields with the above
nucleoside acceptors using p-toluenesulfenyl chloride
(TolSCl) and silver triflate (AgOTf) as promoters. The interac-
tion of these promoters with nucleoside acceptors was ex-
1
amined by H NMR spectroscopic experiments.
Introduction
Disaccharide nucleosides consti-
tute an important class of natu-
ral compounds that are found in
tRNA, poly(ADP-ribose), antibiot-
ics, and other biologically active
compounds.[1] These compounds
contain an external sugar moiety
linked to one of the hydroxy
groups of the nucleoside via an
O-glycoside bond.[1,2] Typical ex-
amples include adenophostins
1,[3] HF-7 2,[4] cytosaminomycins
3
and ezomycin derivatives,[6]
and some candidates for inhibi-
tors of chitin synthetase 4,[7]
which contain adenine, guanine,
cytosine, and uracil moieties as
the nucleobase moiety, respec-
tively (Scheme 1). The efficient
Scheme 1. Typical examples of disaccharide nucleosides having adenine, guanine, cytosine, and uracil moieties.
synthesis of these compounds and analogues continues to be
a challenging task in synthetic organic chemistry.
Reports on the synthesis of disaccharide nucleosides, al-
though limited, can be classified into the following three cate-
gories. The first is chemical N-glycosylation, in which glycosyl
donors 5 (X=acyl or halide) are reacted with activated nucleo-
bases to give the precursor of the disaccharide nucleoside 6
(Scheme 2a).[8] The drawbacks of this method include rather
lower chemical yields (less than 50%), the necessity of prepar-
ing the rather unstable glycosyl halides 5, and the use of toxic
Hg salts for the activation of 5 (Koenigs–Knorr-type glycosyla-
tion).
[a] Prof. S. Aoki, T. Fukumoto, T. Itoh, M. Kurihara, S. Saito, S.-y. Komabiki
Faculty of Pharmaceutical Sciences
Tokyo University of Science
2641 Yamazaki, Noda 278-8510 (Japan)
Fax: (+81)4-7121-3670
E-mail: shinaoki@rs.noda.tus.ac.jp
[b] Prof. S. Aoki
Center for Technologies against Cancer
Tokyo University of Science
2641 Yamazaki, Noda 278-8510 (Japan)
The second method involves the O-glycosylation of nucleo-
sides via the use of enzymes, specifically, glycosylases
(Scheme 2b).[9] Typically, a reactive glycosyl donor such as p-ni-
trophenyl-b-d-galactoside is hydrolyzed by b-galactosidase in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403319.
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and stereochemistry, one possi-
ble drawback would be the neu-
tralization (inactivation) of pro-
moters, which are generally
Lewis acids or Brønsted acids, by
the nucleobase units of nucleo-
sides. In addition, side reactions
such as the cleavage of the
anomeric CÀN bond of nucleo-
sides and anomerization reac-
tions under glycosylation condi-
tions have also been reported.[13]
These findings prompted us
to explore the general reaction
conditions for the synthesis of
disaccharide nucleosides 6’ via
the O-glycosylation of nucleo-
Scheme 2. Reported methodologies for the synthesis of disaccharide nucleosides (PG: protecting group).
aqueous solution and then instantly reacts with nucleosides
having adenine, uracil, thymine, and other nucleobase analogs.
However, the application of this method is not widespread,
due to the limited availability of specific glycosidases for the
given glycosyl donors.
The third strategy is chemical O-glycosylation,[3c,10,11] as
shown in Scheme 2c. This method has been applied to the
synthesis of adenophostin A 1,[12] which has a 10- to 100-fold
more potent activity than inositol 1,4,5-trisphosphate
(Ins(1,4,5)P3) in releasing Ca2+ in living cells. Although this
method would be expected to have widespread applications
with respect to variations in substrates (donors and acceptors)
sides; glycosyl donors (7), nucleoside acceptors (8), promoters,
solvent, and temperature (Scheme 3). In this manuscript, we
report on the synthesis of disaccharide nucleosides by the
direct O-glycosylation of Ade-, Gua-, Thy-, and Cyt-nucleo-
sides[14] by the combined use of p-toluenesulfenyl chloride
(TolSCl) and silver triflate (AgOTf).
Abstract in Japanese:
Scheme 3. Synthesis of disaccharide nucleosides by the chemical O-glycosy-
lation of nucleoside acceptors with glycosides.
Results and Discussion
O-Glycosylation of nucleosides with thioglycosides and
other glycosyl donors
We first attempted the glycosylation of 3’-O-TBDMS-deoxyade-
nosine 10a[15] with thioglycosides 9a[16] and 9b,[17] because it is
well known that thioglycosides are glycosyl donors that are
stable, readily available, and can be easily modified. In addi-
tion, a variety of promoters for the activation of thioglycosides
have been reported.[10,18]
As listed in entries 1–4 in Table 1, the findings showed that
promoters such as NIS-TMSOTf,[19] DMTST,[20] NIS-AgOTf,[21] and
NMPTC-Tf2O[22] were insufficient in terms of producing the de-
sired glycosides 11 a (NMPTC=N-(p-methylphenylthio)-e-capro-
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lactam). When a mixture of TolSCl and AgOTf[23]
was used for the glycosylation with 9b, the de-
sired disaccharide 11 a was obtained in 9% yield
(entry 5). The reaction of N-protected adenosine
acceptor 10b[24] and 9b in the presence of the
same promoters gave negligible product (entry 6).
We assume that the low chemical yield in Table 1
is due to acyl-transfer from 9b to 10a or 10b (5’-
O-acetyl nucleosides were isolated in some cases)
and/or the cleavage of TBDMS group of 10a,b
and/or 11a,b.
Table 1. The O-Glycosylation of nucleosides with thioglycosides and other glycosyl
donors.
Next, the O-glycosylation of the 3’-O-TBDPS-pro-
tected deoxyadenosine 10c[25] was examined by
using the thioglycoside 12, the glycosyl bromide
13,[26] the trichloroimidate 14,[27] and the glycosyl
phosphite 15,[28] in which the hydroxy groups are
protected with benzoyl groups to prevent trans-
acylation. As listed in Table 2, glycosylation with
12 by using TolSCl and AgOTf gave a higher yield
than the other glycosyl donors using their repre-
sentative activators, when CH2Cl2, CH2Cl2/1,4-diox-
ane (3:1), and CH2Cl2/Et2O (3:1) were used as the
solvent (entries 1–3 vs. entries 5~9). We assume
that low yields in entries 6–9 are possibly due to
the cleavage of the N-glycosidic
Entry[a] Donor Acceptor Promoters
(eq against donor)
T
Product Yield
[%]
1
2
3
4
5
6
9a
9a
9a
9b
9b
9b
10a
10a
10a
10a
10a
10b
NIS (1.5 eq)/TMSOTf (cat.)
NIS (1.5 eq)/AgOTf (0.1 eq)
DMTST (10 eq)
NMPTC (1.2 eq)/Tf2O (1.3 eq) À408C to r.t.
TolSCl (1.2 eq)/AgOTf (3.0 eq) À408C
TolSCl (1.2 eq)/AgOTf (3.0 eq) À408C
À608C to r.t.
08C to r.t.
08C to r.t.
–
–
–
–
trace
trace
trace
trace
9
b-11 a
–
trace
[a] All reactions were carried out in the presence of 1.2 equivalents of acceptors against
glycosyl donors (9a–9b).
linkage under these conditions.
Because the reaction conditions
for the glycosylation of 10c with
Table 2. Comparison of the reactivities of 12 and other glycosyl donors in the O-Glycosylation of 10c.
13, 14, and 15 have not been
optimized in this work, we do
not exclude the possibility that
these glycosyl donors may afford
11 a under different reaction
conditions. The reaction of 12
and 10c using p-nitrobenzene-
sulfenyl chloride (p-NO2PhSCl)
and AgOTf[29] gave almost the
identical result as that using
Entry[a]
Donor
Promoters
Conditions
Product
Yield [%]
(eq. against donor)
(solvents, temperature)
TolSCl/AgOTf
entry 3).
(entry 4
vs.
1
2
12
12
TolSCl (1.3 eq)
AgOTf (3.0 eq)
TolSCl (1.3 eq)
AgOTf (3.0 eq)
CH2Cl2
b-16
b-16
61
52
À408C
The O-glycosylations of some
other nucleosides with 12 were
performed, and the results are
summarized in Table 3. In en-
tries 1 and 2, the reactions of thi-
oglycoside 12 with unprotected
10c and 10b, in which the
amino group is protected, gave
the desired glycosides in 61%
and 34% yields, respectively.
Note that the reaction of adeno-
sine using 10c (entry 1), in
which the adenosine moiety is
not protected, gave a higher
yield than that for the protected
10b (entry 2) (this point is dis-
cussed below). In entry 3, the re-
CH2Cl2/1,4-Dioxane
(3/1)
À40 to308C
CH2Cl2/Et2O
(3/1)
3
12
TolSCl (1.3 eq)
AgOTf (3.0 eq)
b-16
67
74
À408C
4
5
6
7
8
9
12
13
14
14
p-NO2PhSCl (1.3 eq)
AgOTf (3.0 eq)
AgClO4 (1.5 eq)
(exclusively a)
TMSOTf (1.5 eq)
(exclusively a)
CH2Cl2
b-16
b-16
b-16
b-16
–
À408C to r.t.
CH2Cl2
À408C to r.t.
CH2Cl2
complex mixture
(<40)
complex mixture
(<10)
À408C
BF3·Et2O (2.5 eq)
CH2Cl2
33
À408C
15
ZnCl2 (2.0 eq)
AgOTf (4.0 eq)
TMSOTf (2.5 eq)
CH2Cl2
trace
trace
(a:b=1.8:1)
15
À408C
CH2Cl2
–
À408C
[a] All reactions were carried out in the presence of 1.2 equivalents of 10c against glycosyl donors (12–15).
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Reactions of the glucosaminyl donor 24[32] with
10c, 17, 18b, and 19b gave the corresponding
products (25–28) in acceptable yields, as listed in
Table 4.
Table 3. O-Glycosylation of other nucleosides with thioglycosides.
The glycosylation of the 3’-OH-free adenosine
derivatives 29[33] with 12 gave b-30 exclusively in
52% yield (Scheme 4a). In addition, the reactions
of 31[34] and 33[35] with 10c afforded 32 and 34 in
46% (a/b=3:1) and 57% (a/b=2.5:1) yields, re-
spectively (Scheme 4b and 4c). For comparison,
the reaction of 10a, which contains TBDMS at the
3’-OH group (see Table 1), with 33 resulted in a neg-
ligible yield of the desired product.
The deprotection of the representative glycosyla-
tion products, 16 and 21, by treatment with
TBAF[36] and then MeNH2,[37] gave the deprotected
compounds, 35 and 36, respectively (Scheme 5a).
The deprotection of a-34 gave a-37, as shown in
Scheme 5b.
Interaction of adenosyl acceptors with TolSCl and
1
AgOTf studied by H NMR spectroscopy
The results in entries 1 and 2 in Table 3 suggest
that the adenosine derivative 10c, in which the 6-
NH2 group is not protected, gives a better yield
than that of N-protected adenosine derivative 10b.
To determine the reason for this, we collected
1H NMR spectra of 38a,[38] in which the 6-NH2
group is not protected and the 3’- and 5’-OH
groups are protected with TBDPS (to increase the
solubility of the compound in an organic solvent),
and 6-N-benzoyl-3’,5’-O-bis-TBDPS-2’-deoxyadeno-
sine 38b[39] in the absence and presence of TolSCl
and AgOTf (in CDCl3 at À408C).
Entry
Donor
Acceptor[a]
Solvent
Product
Yield [%]
1[b]
2
3
4
5
6
7
8
12
12
12
12
12
12
12
12
12
12
10c (Ade)
10b (AdeBz)
17 (Thy)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtCN
b-16
b-20
b-21
b-22a
b-22b
b-23a
b-23b
b-21
61
34
88
49
76
14
46
62
26
43
18a (Cyt)
18b (CytBz)
19a (Gua)
1
19b (GuaiBu
17 (Thy)
)
As shown in Figure 1a–b, the H NMR spectrum
of 38a remained essentially unchanged upon the
addition of TolSCl+AgOTf, while 38b was decom-
posed under identical conditions, as indicated in
Figure 1c–e. The products produced from 38b
with AgOTf and TolSCl were isolated and identified
as N-benzoyladenine 39 (as 1:1 and 2:1 complexes
with Ag+, as suggested by the FAB-mass spectrum
9
10
18b (CytBz)
19b (GuaiBu
EtCN
EtCN
b-22b
b-23b
)
[a] All reactions were carried out in the presence of 1.2 equivalents of acceptors, 1.2–
1.8 equivalents of TolSCl, and 3.0–3.5 equivalents of AgOTf against 12. [b] Taken from
entry 1 of Table 2.
action of the thioglycoside 12 with 17[30] proceeded in CH2Cl2
to afford b-21 in 88% yield.
in Figure S1 in the Supporting Information) and 40 (Scheme 6).
This strongly suggests that the lower chemical yield in entry 2
of Table 3 compared to entry 1 is due to the depurination of
10b and/or 20.[40,41]
In entries 4 and 5, the reactions of 12 with the unprotected
and the protected Cyt-nucleoside acceptors, 18a[25] and
18b,[30] afforded the desired products in 49% and 76% yields,
respectively. In entries 6 and 7, glycosylations with the unpro-
tected and protected Gua-nucleoside acceptors, 19a and
19b,[30] afforded the desired glycosides in 14% and 46%
yields, respectively. Therefore, the use of the protected Cyt- or
Gua-nucleosides (18b and 19b) rather than the unprotected
ones (18a and 19a) (entries 4 and 6 vs. entries 5 and 7) is an
advantage in this type of synthesis. The chemical yields for the
O-glycosylation in EtCN[31] (entries 8–10) were lower than those
for reactions conducted in CH2Cl2 (entries 3, 5, and 7).
Conclusions
Herein, we report on the synthesis of disaccharide nucleosides
by the direct O-glycosylation of nucleosides. The glycosylation
of deoxyadenosine 10a and 10c with thioglycosides such as
9b and 12 using a combination of TolSCl/AgOTf as glycosyla-
tion promoters gave the desired products in reasonable chemi-
cal yields. We synthesized disaccharide nucleosides by the
direct O-glycosylation of Ade-, Gua-, Thy-, and Cyt-nucleosides
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sylation yields, while Thy- and
Cyt-nucleoside acceptors have
Table 4. O-Glycosylation of nucleosides with thioglycosides and other glycosyl donors.
negligible
interactions
These
with
TolSCl/AgOTf.
results
afford important information re-
garding the glycosylation of nu-
cleosides or other nucleobase-
containing glycosyl acceptors for
the synthesis of a variety of bio-
logically relevant nucleoside
disaccharide derivatives.
Entry[a]
Donor
Acceptor
Product
Yield [%]
1
2
3
4
24
24
24
24
10c (Ade)
17 (Thy)
b-25
b-26
b-27
b-28
63
74
65
37
18b (CytBz)
19b (GuaiBu
)
Experimental Section
[a] All reactions were carried out in the presence of 1.2 equivalents of acceptors, 1.2–1.8 equivalents of TolSCl,
and 3.0–3.5 equivalents of AgOTf against 24.
General Information
Reagents and solvents were pur-
chased at the highest commercial
quality and were used without fur-
ther purification. Anhydrous CH2Cl2
and CDCl3 were prepared by distil-
lation from calcium hydride, and
propionitrile (EtCN) was prepared
by distillation from calcium hy-
dride and the successive distilla-
tion from phosphorus(V) oxide. All
aqueous solutions were prepared
using deionized water.
1H (300 and 400 MHz) and 13C (75
and 100 MHz) NMR spectra were
recorded on a JEOL Always 300
and a JEOL Lambda 400 spectrom-
eter, respectively. Tetramethylsilane
(TMS) was used as an internal ref-
erence for 1H and 13C NMR meas-
urements in CDCl3, [D6]DMSO and
CD3OD. 3-(Trimethylsilyl)propionic-
2,2,3,3-d4 acid sodium (TSP) was
used an internal reference for
1H NMR measurements in D2O. IR
spectra were recorded on a Perki-
nElmer FTIR Spectrum 100 instru-
ment at room temperature. MS
measurements were performed on
a JEOL JMS-SX102A and a Varian
TQ-FT spectrometer. Thin-layer
(TLC) and silica gel column chro-
matography was performed using
Merck Silica gel 60 F254 plates and
Fuji Silica Chemical FL-100D, re-
Scheme 4. Synthesis of 30, 32, and 34.
spectively. GPC experiments were
carried out using a system consist-
with 12 and the thioglucosaminide 24 and found that this
method gives the desired products in moderate to good
yields. The a-glycosylation of the thioglycoside 31 and depro-
tection of representative compounds 16, 21, and 34 were also
ing of a POMP P-50 (Japan Analytical Industry Co., Ltd.), a UV/VIS
DETECTOR S-3740 (Soma, Japan), a Manual Sample Injector 7725i
(Rheodyne, USA) and a MDL-101 1 PEN RECORDER (Japan Analyti-
cal Industry Co., Ltd.), equipped with two GPC columns, JAIGEL-1H
and JAIGEL-2 (Japan Analytical Industry Co., Ltd.) (20f x 600 mm,
No. A605201 and A605204).
1
demonstrated. H NMR measurements of the adenosine deriva-
tives 38a and 38b in the presence of TolSCl/AgOTf suggest
that the 6-NH2 protected adenosine derivatives 10b and 38b
undergo CÀN cleavage (depurination), resulting in lower glyco-
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Scheme 5. Deprotection reactions of 16, 21, and 34.
Preparation of p-toluenesulfenyl chloride (TolSCl)[23]
Sulfuryl chloride (1.0 mL, 12 mmol) was added to a solution of tol-
uenethiol (1.242 g, 10.00 mmol) in anhydrous hexane (5.0 mL) at
08C over a period of 5 min, followed by stirring at room tempera-
ture for 1 h. The reaction mixture was concentrated under reduced
pressure and then distilled (548C, 1 mmHg) to give the TolSCl as
a red liquid (1.374 g, 87%). This product was stored in the dark at
À208C prior to use for periods of 1–3 months.
4-Bromophenyl 2,3,4,6-tetra-O-acetyl-1-thio-b-d-galactopyra-
noside (9a)[16]
A mixture of 1,2,3,4,6-penta-O-acetyl-d-galactopyranose (500 mg,
1.3 mmol), p-bromothiophenol (290 mg, 1.5 mmol) and MS3A in
anhydrous CH2Cl2 (8.0 mL) was stirred for 1 h at room temperature
and then cooled to 08C, to which BF3·OEt2 (1.7 mL, 6.4 mmol) was
added at the same temperature. The reaction mixture was stirred
for 30 min at 08C and allowed to warm to room temperature. After
stirring overnight at room temperature, the reaction mixture was
quenched by saturated aqueous NaHCO3 and the resulting solution
was diluted with CHCl3. The suspension was filtered through Celite,
and the filtrate was washed with saturated aqueous NaHCO3 and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (CHCl3) to give 9a as a colorless amorphous solid
(668 mg, quant.): 1H NMR (300 MHz, CDCl3, TMS): d=1.98 (s, 3H),
2.05 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 3.91 (t, J=6.6 Hz, 1H), 4.07–
4.21 (m, 2H), 4.65 (d, J=9.6 Hz, 1H), 5.02 (dd, J=3.3, 9.9 Hz, 1H),
5.17 (t, J=9.9 Hz, 1H), 5.41 (d, J=3.0 Hz, 1H), 7.38 (dd, J=1.8,
7.2 Hz, 2H), 7.43 ppm (dd, J=1.8, 8.4 Hz, 2H); 13C NMR (75 MHz,
CDCl3, TMS): d=20.1, 20.1, 20.2, 20.3, 61.3, 66.7, 66.8, 71.4, 74.0,
85.2, 122.1, 130.8, 131.4, 133.9, 168.8, 169.4, 169.6, 169.7 ppm;
Figure 1. 1H NMR spectra of 38a and 38b (14 mm) in CDCl3 in the absence
and presence of TolSCl (30 mm) and AgOTf (44 mm). (a) 38a at À408C,
(b) 38a+TolSCl/AgOTf at À408C, (c) 38b at À408C, (d) 38b+TolSCl/AgOTf
at À408C (10 min), (e) 38b at À408C+TolSCl/AgOTf at À408C (4 h).
HRMS (FAB+): calcd for [M+Na]+, C20H2379BrO9SNa, 541.0144;
found, 541.0145.
3’-O-tert-Butyldimethylsilyl-2’-
deoxyadenosine (10a)[15a]
2’-Deoxyadenosine
(462 mg,
1.8 mmol) was dried by co-evapo-
ration with dry pyridine (three
times), dissolved in dry pyridine
(10 mL) and then cooled to 08C, to
which 4,4’-dimethoxytrityl chloride
Scheme 6. Reaction of 38b with TolSCl and AgOTf.
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1
(751 mg, 2.2 mmol) was added.[15b] The reaction mixture was stirred
for 30 min at 08C and was allowed to warm to room temperature.
After stirring overnight, the reaction mixture was poured into
water, extracted with CHCl3, and the organic layer was washed
with brine, dried over Na2SO4, filtered and concentrated under re-
duced pressure. The resulting residue was purified by silica gel
column chromatography (CHCl3/AcOEt/MeOH=100:2:1) to give
the 5’-O-DMTritylated derivative[15b] as a pale yellow amorphous
phous solid (6 mg, 9% yield): H NMR (300 MHz, CDCl3, TMS): d=
0.01 (s, 6H), 0.91 (s, 9H), 2.00 (s, 3H), 2.02 (s, 3H), 2.04 (s, 3H), 2.20
(s, 3H), 2.36–2.43 (m, 1H), 2.62–2.71 (m, 1H), 3.68 (dd, J=3.6,
10.2 Hz, 1H), 3.91 (t, J=6.3 Hz, 1H), 4.10–4.21 (m, 4H), 4.53–4.56
(m, 2H), 5.03 (dd, J=3.3, 10.2 Hz, 1H), 5.25 (dd, J=7.8, 10.5 Hz,
1H), 5.40 (d, J=3.3 Hz, 1H), 5.72 (s, 2H), 6.48 (t, J=6.6 Hz, 1H),
8.22 (s, 1H), 8.35 ppm (s, 1H); 13C NMR (75 MHz, CDCl3, TMS): d=
À5.0, À4.9, 17.8, 20.4, 20.5, 20.5, 20.6, 25.6, 40.9, 61.1, 66.8, 66.8,
68.4, 68.8, 70.6, 70.7, 72.2, 84.1, 85.9, 100.7, 119.7, 139.2, 149.4,
152,4, 155.5, 169.3, 170.0, 170.2, 170.2 ppm; IR (ATR): n˜ =3013,
1666, 1541, 1465, 1347, 1221, 1154, 1076, 1020, 921, 851, 748,
1
solid (694 mg, 68% yield): H NMR (300 MHz, CDCl3, TMS): d=2.01
(d, J=3.6 Hz, 1H), 2.49–2.57 (m, 1H), 2.80–2.87 (m, 1H), 3.39 (t, J=
5.4 Hz, 1H), 3.78 (s, 6H), 4.10 (q, J=4.5 Hz, 1H), 4.67–4.69 (m, 1H),
5.48 (brs, 2H), 6.41 (t, J=6.6 Hz, 1H), 6.78 (td, J=3.3, 9.0 Hz, 4H),
7.21–7.32 (m, 11H), 7.38–7.41 (m, 2H), 7.95 (s, 1H), 8.29 ppm (s,
1H).
579 cmÀ1
696.2912; found, 696.2914.
;
HRMS (FAB+): calcd for [M+H]+, C30H46N5O12Si,
The 5’-O-DMTritylated compound synthesized above (300 mg,
0.54 mmol) and imidazole (111 mg, 1.6 mmol) were dissolved in an-
hydrous DMF, to which tert-butyldimethyl chloride (123 mg,
0.81 mmol) was added.[15c] The reaction mixture was stirred at
room temperature for 1 d, poured into water and extracted with
CHCl3. The organic layer was washed with saturated aqueous
NaHCO3, water and brine, dried over Na2SO4, filtered and concen-
trated under reduced pressure. The resulting residue was purified
by silica gel column chromatography (CHCl3/MeOH=100:1) to give
3’-O-tert-Butyldiphenylsilyl-5’-O-(2“,3”,4“,6”-tetra-O-benzoyl-
b-d-galactopyranosyl)-2’-deoxyadenosine (b-16) (Entry 1 in
Table 2)
Reaction conditions for the synthesis of b-16 were the same as
those for b-11 a. The resulting residue was purified by silica gel
column chromatography (hexanes/AcOEt=1:3 to 0:1) to give b-16
as a colorless amorphous solid (30.3 mg, 61% yield): 1H NMR
(300 MHz, CDCl3, TMS): d=1.00 (s, 9H), 2.40–2.52 (m, 2H), 2.75 (dd,
J=2.7, 10.5 Hz 1H), 3.91 (dd, J=2.4, 10.2 Hz, 1H), 3.98–4.02 (m,
1H), 4.21 (t, J=7.8 Hz, 1H), 4.31 (d, J=4.8 Hz, 1H), 4.39 (dd, J=7.2,
11.1 Hz, 1H), 4.43 (d, J=8.1 Hz, 1H), 4.63 (dd, J=6.3, 8.1 Hz, 1H),
5.58 (dd, J=3.4, 10.3 Hz, 1H), 5.70 (s, 2H), 5.70 (t, J=7.3 Hz 1H),
5.96 (d, J=3.0 Hz, 1H), 5.62 (dd, J=6.6, 8.4 Hz, 1H), 7.20–7.66 (m,
22H), 7.74–7.7.79 (m, 4H), 7.98 (d, J=6.9 Hz, 2H), 8.12 (d, J=
7.5 Hz, 2H), 8.37 (s, 1H), 8.39 ppm (s, 1H); 13C NMR (75 MHz, CDCl3,
TMS): d=19.0, 26.8, 41.6, 61.8, 67.8, 69.6, 69.8, 71.1, 71.3, 74.3, 84.2,
86.9, 101.4, 119.8, 127.8, 128.3, 128.4, 128.5, 128.7, 128.9, 128.9,
129.3, 129.5, 129.7, 129.8, 129.8, 130.1, 130.2, 133.1, 133.3, 133.3,
133.4, 133.6, 135.6, 135.7, 139.4, 149.8, 152.7, 155.4, 165.2, 165.5,
165.5, 166.0 ppm; HRMS (FAB+): calcd for [M+H]+, C60H58N5O12Si,
1068.3851; found, 1068.3854.
the 3’-O-TBDMS-5’-O-DMTr-2’-deoxyadenosine[15c] as
a colorless
amorphous solid (332 mg, 92% yield): 1H NMR (300 MHz, CDCl3,
TMS): d=0.01 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 2.38–2.45 (m, 1H),
2.69–2.78 (m, 1H), 3.25 (dd, J=4.2, 10.5 Hz, 1H), 3.36 (dd, J=4.5,
10.5 Hz, 1H), 3.79 (s, 6H), 4.08 (dd, J=4.3, 7.8 Hz, 1H), 4.57 (td, J=
3.7, 5.7 Hz, 1H), 5.53 (brs, 2H), 6.40 (t, J=6.4 Hz, 1H), 6.77 (td, J=
2.0, 8.7 Hz, 4H), 7.17–7.42 (m, 10H), 8.31 ppm (s, 1H).
TFA (90 mL, 1.2 mmol) was added to a solution of 3’-O-TBDMS-5’-O-
DMTr-2’-deoxyadenosine (200 mg, 0.30 mmol) in CH2Cl2 at room
temperature. The reaction mixture was stirred for 45 min at room
temperature, quenched by the addition of aqueous 1N NaOH
(1.0 mL), and then extracted with CHCl3. The organic layer was
washed with water and brine, dried over Na2SO4, filtered and con-
centrated under reduced pressure. The resulting residue was puri-
fied by silica gel column chromatography (AcOEt) to give 10a as
a white powder (87 mg, 80% yield): 1H NMR (300 MHz, CDCl3,
TMS): d=0.12 (s, 6H), 0.93 (s, 9H), 2.16 (dd, J=5.5, 13.0 Hz, 1H),
3.00–3.09 (m, 1H), 3.71 (t, J=11.7 Hz, 1H), 3.94 (d, J=12.8 Hz, 1H),
4.15 (s, 1H), 4.70 (d, J=5.0 Hz, 1H), 5.68 (brs, 2H), 6.26 (dd, J=5.1,
5.5 Hz, 1H), 6.52 (d, J=11.2 Hz, 1H), 7.86 (s, 1H), 8.32 ppm (s, 1H);
13C NMR (75 MHz, CDCl3, TMS): d=À4.8, 17.9, 25.9, 41.2, 63.1, 73.9,
87.5, 90.2, 121.0, 140.0, 148.5, 152.3, 156.2 ppm; HRMS (FAB+):
calcd for [M+H]+, C16H28N5O3Si, 366.1961; found, 366.1963.
3’-O-tert-Butyldiphenylsilyl-2’-deoxyguanosine (19a)
Ethylenediamine (8.0 mL, 12 mmol) was added to a solution of
19b[30] (173 mg, 0.30 mmol) in EtOH at room temperature. The re-
action mixture was stirred for 3 h and then concentrated under re-
duced pressure. The resulting residue was purified by silica gel
column chromatography (CHCl3/MeOH=97:3) to give 19a as
a white powder (140 mg, 92% yield): 1H NMR (300 MHz, CDCl3,
TMS): d=1.11 (s, 9H), 2.18 (dd, J=4.8, 12.4 Hz, 1H), 3.04 (t, J=
12.1 Hz, 1H), 3.66 (d, J=12.8 Hz, 1H), 4.09 (s, 1H), 4.64 (d, J=
4.8 Hz, 1H), 6.03–6.31 (m, 3H), 7.36–7.51 (m, 7H), 7.62–7.68 ppm
(m, 4H); 13C NMR (75 MHz, CDCl3, TMS): d=19.0, 26.8, 40.7, 62.9,
74.9, 87.5, 89.7, 118.3, 127.9, 130.0, 133.2, 133.3, 135.5, 135.7, 149.8,
153.4, 158.9 ppm; HRMS (FAB+): calcd for [M+H]+, C26H32N5O4Si,
506.2224; found, 506.2228.
3’-O-tert-Butyldimethylsilyl-5’-O-(2“,3”,4“,6”-tetra-O-acetyl-b-
d-galactopyranosyl)-2’-deoxyadenosine (b-11a) (Entry 5 in
Table 1)
A mixture of 9b (45 mg, 0.10 mmol), 10a (43 mg, 0.12 mmol) and
MS4A in anhydrous CH2Cl2 (2.8 mL) was stirred for 1 h at room
temperature and then cooled to À408C, to which AgOTf (64 mg,
0.25 mmol) and TolSCl (23 mL, 0.16 mmol) were added at the same
temperature. The reaction mixture was stirred for 2 h at À408C
and quenched by adding saturated aqueous NaHCO3 (600 mL) and
the resulting solution was diluted with CH2Cl2. The suspension was
filtered through Celite, and the organic layer was washed with sa-
turated NaHCO3 aq. and brine, dried over Na2SO4, filtered and con-
centrated under reduced pressure. The resulting residue was puri-
fied by silica gel column chromatography (CHCl3/MeOH=1:0 to
50:1) followed by GPC (CHCl3) to give b-11 a as a colorless amor-
6-N-Benzoyl-3’-O-tert-butyldiphenylsilyl-5’-O-(2“,3”,4“,6”-
tetra-O-benzoyl-b-d-galactopyranosyl)-2’-deoxyadenosine
(b-20) (Entry 2 in Table 3)
Reaction conditions for the synthesis of b-20 were the same as
those for b-11a. The resulting residue was purified by silica gel
column chromatography (hexanes/CHCl3 =1:4 to 0:1, then hex-
anes/AcOEt=2/1) to give b-20 as a colorless amorphous solid
(34.4 mg, 34% yield): 1H NMR (300 MHz, CDCl3, TMS): d=1.08 (s,
9H), 2.40–2.54 (m, 2H), 3.10 (dd, J=3.6, 10.8 Hz 1H), 3.40 (dd, J=
3.3, 10.2 Hz, 1H), 4.11–4.15 (m, 1H), 4.33 (dd, J=5.7, 10.8 Hz, 1H),
Chem. Asian J. 2015, 10, 740 – 751
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Full Paper
4.42 (dt, J=2.1, 6.3 Hz, 1H), 4.45–4.51 (m, 1H), 4.53–4.59 (m, 2H),
5.39 (dd, J=4.5, 6.3 Hz, 1H), 5.74 (dd, J=2.7, 4.2 Hz, 1H), 5.94 (d,
J=4.8 Hz, 1H), 6.62 (t, J=6.9 Hz 1H), 7.28–7.63 (m, 27H), 7.89–8.02
(m, 8H), 8.19 (s, 1H), 8.75 (s, 1H), 9.05 ppm (brs, 1H); 13C NMR
(75 MHz, CDCl3, TMS): d=19.0, 26.9, 41.0, 62.3, 63.5, 66.4, 68.9,
69.5, 69.9, 73.3, 74.3, 84.7, 86.5, 98.2, 120.1, 123.2, 125.8, 127.9,
127.9, 128.4, 128.4, 128.5, 128.8, 128.9, 129.1, 129.4, 129.7, 129.8,
129.8, 129.9, 130.1132.7, 133.0, 133.0, 133.2, 133.4, 133.6, 133.7,
135.7, 135.7, 136.0, 141.6, 149.4, 151.6, 152.6, 164.6, 165.2, 165.2,
165.9 ppm; HRMS (FAB+): calcd for [M+H]+, C67H62N5O13Si,
1172.4113; found, 1172.4110.
(300 MHz, CDCl3, TMS): d=0.97 (s, 9H), 1.85–1.95 (m, 1H), 2.54–
2.60 (m, 2H), 3.92–3.96 (m, 2H), 4.16 (d, J=5.9 Hz, 1H), 4.21 (t, J=
6.8 Hz, 1H), 4.29 (d, J=7.3 Hz, 1H), 4.42 (dd, J=6.8, 11.2 Hz, 1H),
4.69 (dd, J=6.6, 11.4 Hz, 1H), 5.54–5.67 (m, 2H), 5.97 (d, J=2.2 Hz,
1H), 6.54 (dd, J=5.9, 8.1 Hz, 1H), 7.18–7.35 (m, 6H), 7.38–7.62 (m,
20H), 7.72–7.77 (m, 4H), 7.81–7.85 (m, 2H), 8.01–8.04 (m, 4H), 8.25
(d, J=7.5 Hz, 1H), 8.60 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3,
TMS): d=18.9, 26.8, 42.2, 61.8, 67.9, 69.1, 69.6, 71.0, 71.5, 74.0, 87.2,
97.1, 101.5, 127.6, 127.9, 128.3, 128.5, 128.6, 128.7, 128.8, 128.9,
129.4, 129.4, 129.7, 129.8, 129.9, 130.0, 130.1, 132.9, 133.0, 133.4,
133.4, 133.5, 133.6, 135.6, 135.7, 145.0, 154.7, 162.0, 165.0, 165.5,
165.6, 166.0 ppm; HRMS (FAB+): calcd for [M+H]+, C66H62N3O14Si,
1148.4001; found, 1148.4001.
3’-O-tert-Butyldiphenylsilyl-5’-O-(2“,3”,4“,6”-tetra-O-benzoyl-
b-d-galactopyranosyl)-thymidine (b-21) (Entry 3 in Table 3)
Reaction conditions for the synthesis of b-21 were the same as
those for b-11 a. The resulting residue was purified by silica gel
column chromatography (hexanes/AcOEt=2:1) to give b-21 as
3’-O-tert-Butyldiphenylsilyl-5’-O-(2“,3”,4“,6”-tetra-O-benzoyl-
b-d-galactopyranosyl)-2’-deoxyguanosine (b-23a) (Entry 6 in
Table 3)
a
colorless amorphous solid (133 mg, 88% yield): 1H NMR
(300 MHz, CDCl3, TMS): d=0.93 (s, 9H), 1.78–1.88 (m, 1H), 2.04–
2.14 (m, 4H), 2.43 (dd, J=1.5, 10.6 Hz 1H), 3.84–3.88 (m, 1H), 3.96
(dd, J=1.5, 10.5 Hz, 1H), 4.06 (d, J=5.4, 1H), 4.18–4.23 (m, 2H),
4.37 (d, J=6.9, 10.8 Hz, 1H), 4.62 (dd, J=6.6, 11.4 Hz, 1H), 5.56–
5.68 (m, 2H), 5.95 (d, J=2.4 Hz 1H), 6.50 (dd, J=5.4, 9.3 Hz, 1H),
7.22–7.50 (m, 20H), 7.55–7.81 (m, 3H), 7.72–7.80 (m, 4H), 7.98–
8.03 ppm (m, 5H); 13C NMR (75 MHz, CDCl3, TMS): d=12.7, 18.9,
26.7, 40.3, 61.6, 68.0, 69.5, 69.9, 70.9, 71.5, 74.0, 84.7, 86.5, 102.1,
111.3, 127.9, 128.3, 128.5, 128.5, 128.6, 128.7, 128.8, 129.2, 129.3,
129.7, 129.7, 129.9, 130.0, 132.9, 133.3, 133.4, 133.6, 133.8, 135.6,
135.7, 136.2, 150.5, 163.7, 165.2, 165.5, 165.5, 166.0 ppm; HRMS
(FAB+): calcd for [M+H]+, C60H59N2O14Si, 1059.3736; found,
1059.3735.
Reaction conditions for the synthesis of b-23a were the same as
those for b-11a. The resulting residue was purified by NH silica gel
column chromatography (CHCl3/MeOH=100:1 to 10:1) to give b-
23a as a colorless amorphous solid (7.0 mg, 14% yield): 1H NMR
(300 MHz, CDCl3, TMS): d=0.99 (s, 9H), 2.27–2.44 (m, 2H), 2.82 (d,
J=9.0 Hz, 1H), 3.91–4.01 (m, 2H), 4.20–4.45 (m, 4H), 4.60–4.69 (m,
1H), 5.56 (dd, J=3.3, 10.2 Hz, 1H), 5.71 (dd, J=7.9, 10.4 Hz, 1H),
5.95 (d, J=3.3 Hz, 1H), 6.31 (t, J=7.2 Hz, 1H), 7.20–7.64 (m, 22H),
7.74–7.82 (m, 4H), 7.96–8.00 (m, 3H), 8.09 ppm (d, J=6.9 Hz, 2H);
13C NMR (75 MHz, CDCl3, TMS): d=19.0, 26.9, 29.7, 41.0, 46.0, 50.8,
61.8, 67.8, 69.3, 69.7, 71.2, 74.2, 77.2, 83.8, 86.7, 101.3, 117.3, 127.8,
128.3, 128.4, 128.5, 128.7, 128.9, 129.0, 129.3, 129.5, 129.8, 130.0,
130.1, 130.1, 133.1, 133.3, 133.4, 133.8, 135.6, 135.7, 136.2, 151.8,
153.6, 159.2, 165.2, 165.5, 165.6, 166.1 ppm; HRMS (FAB+): calcd
for [M+H]+, C60H58N5O13Si, 1084.3801; found, 1084.3802.
3’-O-tert-Butyldiphenylsilyl-5’-O-(2“,3”,4“,6”-tetra-O-benzoyl-
b-d-galactopyranosyl)-2’-deoxycytidine (b-22a) (Entry 4 in
Table 3)
Reaction conditions for the synthesis of b-22a were the same as
those for b-11a. The resulting residue was purified by silica gel
column chromatography (CHCl3/MeOH=200:1 to 50:1) to give b-
1
22a as a colorless amorphous solid (24.7 mg, 49% yield): H NMR
2-N-Isobutyryl-3’-O-tert-butyldiphenylsilyl-5’-O-(2“,3”,4“,6”-
tetra-O-benzoyl-b-d-galactopyranosyl)-2’-deoxyguanosine
(b-23b) (Entry 6 in Table 3)
(300 MHz, CDCl3, TMS): d=0.96 (s, 9H), 1.73–1.79 (m, 3H), 2.43
(ddd, J=1.3, 5.9, 13.7 Hz, 1H), 2.59 (dd, J=1.5, 10.3 Hz, 1H), 3.86–
3.93 (m, 2H), 4.15 (d, J=6.2 Hz, 1H), 4.20 (t, J=7.0 Hz, 1H), 4.28 (d,
J=7.3 Hz, 1H), 4.39 (dd, J=6.6, 11.4 Hz, 1H), 4.59 (dd, J=6.6,
11.4 Hz, 1H), 5.53–5.66 (m, 3H), 5.95 (dd, J=0.9, 3.0 Hz, 1H), 6.55
(dd, J=5.9, 8.1 Hz, 1H), 7.20–7.34 (m, 7H), 7.38–7.65 (m, 15H), 7.75
(dd, J=1.2, 6.9 Hz, 4H), 7.89 (d, J=7.3 Hz, 1H), 7.98–8.06 ppm (m,
4H); 13C NMR (75 MHz, CDCl3, TMS): d=18.9, 26.8, 41.9, 46.1, 61.8,
68.1, 69.0, 69.6, 71.1, 71.3, 73.7, 86.1, 86.4, 94.4, 101.3, 127.8, 128.3,
128.5, 128.6, 128.7, 128.8, 129.0, 129.3, 129.4, 129.7, 129.8, 129.9,
130.0, 133.1, 133.4, 133.5, 133.8, 135.6, 135.7, 141.7, 155.9, 165.2,
165.4, 165.5, 165.5, 166.0 ppm; HRMS (FAB+): calcd for [M+H]+,
C59H58N3O13Si, 1044.3739; found, 1044.3742.
Reaction conditions for the synthesis of b-23b were the same as
those for b-11a. The resulting residue was purified by NH silica gel
column chromatography (CHCl3/MeOH=1:0 to 200:1) to give b-
1
23b as a colorless amorphous solid (22.9 mg, 46% yield): H NMR
(300 MHz, CDCl3, TMS): d=0.91 (d, J=6.7 Hz, 3H), 0.98 (s, 9H), 1.13
(d, J=6.7 Hz, 3H), 1.99 (dd, J=54.9, 12.9 Hz, 1H), 2.48 (tt, J=6.6,
6.9 Hz, 1H), 2.69 (dd, J=3.0, 11.4 Hz, 1H), 2.92 (ddd, J=5.7, 10.2,
13.0 Hz, 1H), 3.95–3.98 (m, 2H), 4.17–4.36 (m, 4H), 4.62 (dd, J=6.0,
11.1 Hz, 1H), 5.54 (dd, J=3.6, 7.8 Hz, 1H), 5.70 (dd, J=7.8, 10.5 Hz,
1H), 5.96 (d, J=2.7 Hz, 1H), 6.13 (dd, J=4.8, 10.2 Hz, 1H), 7.22–
7.28 (m, 4H), 7.33–7.70 (m, 18H), 7.71–7.81 (m, 4H), 7.95–8.01 (m,
3H), 8.07 (dd, J=1.5, 8.4 Hz, 2H), 9.33 (s, 1H), 12.08 ppm (s, 1H);
13C NMR (75 MHz, CDCl3, TMS): d=18.5, 18.9, 19.0, 26.8, 36.3, 39.0,
61.6, 67.7, 68.5, 70.0, 71.2, 71.3, 73.7, 85.3, 86.7, 101.2, 122.5, 127.9,
128.0, 128.3, 128.5, 128.6, 128.6, 128.8, 129.0, 129.3, 129.4, 129.6,
129.8, 129.9, 130.0, 130.2, 133.1, 133.3, 133.4, 133.5, 133.9, 134.1,
135.6, 135.8, 139.1, 147.4, 148.5, 155.6, 165.5, 165.5, 166.1, 166.1,
178.5 ppm; HRMS (FAB+): calcd for [M+H]+, C64H64N5O14Si,
1154.4219; found, 1154.4223.
4-N-Benzoyl-3’-O-tert-butyldiphenylsilyl-5’-O-(2“,3”,4“,6”-
tetra-O-benzoyl-b-d-galactopyranosyl)-2’-deoxycytidine
(b-22b) (Entry 5 in Table 3)
Reaction conditions for the synthesis of b-22b were the same as
those for b-11a. The resulting residue was purified by silica gel
column chromatography (hexanes/AcOEt=2:1 to 3:2) to give b-
22b as a colorless amorphous solid (76 mg, 76% yield): 1H NMR
Chem. Asian J. 2015, 10, 740 – 751
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3’-O-tert-Butyldiphenylsilyl-5’-O-(3“,4”,6“-tri-O-acetyl-2”-
deoxy-2“-phthalimido-b-d-glucopyranosyl)-2’-deoxyadeno-
sine (b-25) (Entry 1 in Table 4)
2-N-Isobutyryl-3’-O-tert-butyldiphenylsilyl-5’-O-(3“,4”,6“-tri-
O-acetyl-2”-deoxy-2“-phthalimido-b-d-glucopyranosyl)-2’-de-
oxyguanosine (b-28) (Entry 4 in Table 4)
Reaction conditions for the synthesis of b-25 were the same as
those for b-11a. The resulting residue was purified by silica gel
column chromatography (hexanes/AcOEt=1:1 to 1:3) followed by
GPC (CHCl3) to give b-25 as a colorless amorphous solid (31 mg,
Reaction conditions for the synthesis of b-28 were the same as
those for b-11a. The resulting residue was purified by NH silica gel
column chromatography (hexanes/CHCl3 =1:4, then CHCl3/MeOH=
100:1) to give b-28 as a colorless amorphous solid (18.4 mg, 37%
yield): 1H NMR (300 MHz, CDCl3, TMS): d=0.96 (s, 9H), 1.27–1.30
(m, 7H), 1.86 (s, 3H), 2.03 (s, 3H), 2.09 (s, 3H), 2.43–2.53 (m, 1H),
2.61–2.71 (m, 2H), 3.65–3.79 (m, 2H), 3.89 (s, 1H), 4.07–4.28 (m,
4H), 5.03 (d, J=8.4 Hz, 1H), 5.10 (t, J=9.6 Hz, 1H), 5.78 (dd, J=9.0,
10.2 Hz, 1H), 6.09 (dd, J=4.8, 9.6 Hz, 1H), 7.31–7.49 (m, 10H),
7.65–7.75 (m, 5H), 8.87 (s, 1H), 12.02 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3, TMS): d=19.0, 19.0, 19.1, 20.4, 20.6, 20.8, 26.8,
29.7, 36.5, 39.6, 54.4, 61.8, 68.8, 68.9, 70.4, 71.9, 73.7, 84.5, 86.5,
97.9, 122.0, 123.5, 127.9, 128.1, 130.0, 130.2, 130.9, 132.9, 133.0,
134.6, 135.4, 135.6, 138.0, 147.3, 148.1, 155.5, 167.6, 169.3, 170.0,
170.8, 178.4 ppm; HRMS (FAB+): calcd for [M+H]+, C50H57N6O14Si,
993.3702; found, 993.3702.
1
63% yield): H NMR (300 MHz, CDCl3, TMS): d=0.97 (s, 9H), 1.85 (s,
3H), 2.03 (s, 3H), 2.10 (s, 3H), 2.23–2.31 (m, 2H), 2.73 (dd, J=4.2,
10.8 Hz, 1H), 3.74–3.80 (m, 2H), 3.91–3.94 (m, 1H), 4.09–4.28 (m,
4H), 5.03 (d, J=8.4 Hz, 1H), 5.13 (t, J=9.3 Hz, 1H), 5.77–5.84 (m,
3H), 6.43 (t, J=7.2 Hz, 1H), 7.31–7.48 (m, 10H), 7.62–7.71 (m, 4H),
8.03 (s, 1H), 8.33 ppm (s, 1H); 13C NMR (75 MHz, CDCl3, TMS): d=
18.8, 20.3, 20.5, 20.7, 41.2, 54.3, 61.8, 68.9, 69.4, 70.1, 71.7, 73.9,
84.4, 86.8, 98.0, 120.0, 123.4, 127.8, 127.9, 129.9, 130.0, 130.9, 132.9,
134.3, 135.4, 135.5, 139.5, 149.2, 151.0, 154.6, 167.3, 169.4, 170.0,
170.7 ppm; IR (ATR): n˜ =2935, 1747, 1716, 1633, 1594, 1471, 1427,
1385, 1365, 1334, 1222, 1104, 1075, 1033, 948, 900, 823, 798, 743,
721, 702, 647, 504 cmÀ1
;
HRMS (FAB+): calcd for [M+H]+,
C46H51N6O12Si, 907.3334; found, 907.3334.
3’-O-(2“,3”,4“,6”-Tetra-O-benzoyl-b-d-galactopyranosyl)-5’-O-
tert-butyldiphenylsilyl-2’-deoxyadenosine (b-30) (Scheme
4a)
3’-O-tert-Butyldiphenylsilyl-5’-O-(3“,4”,6“-tri-O-acetyl-2”-
deoxy-2“-phthalimido-b-d-glucopyranosyl)-thymidine (b-26)
(Entry 2 in Table 4)
Reaction conditions for the synthesis of b-30 were the same as
those for b-11a. The resulting residue was purified by silica gel
column chromatography (CHCl3/MeOH=100:1 to 50:1) followed
by GPC (CHCl3) to give b-30 as a colorless amorphous solid (52 mg,
Reaction conditions for the synthesis of b-26 were the same as
those for b-11a. The resulting residue was purified by silica gel
column chromatography (hexanes/AcOEt=2:1 to 1:1) to give b-26
1
52% yield): H NMR (300 MHz, CDCl3, TMS): d=1.03 (s, 9H), 2.73–
as
a
colorless amorphous solid (76 mg, 74% yield): 1H NMR
2.94 (m, 2H), 3.66 (dd, J=4.0, 11.0 Hz, 1H), 3.83 (dd, J=6.0,
11.0 Hz, 1H), 3.99–4.21 (m, 1H), 4.23 (t, J=6.8 Hz, 1H), 4.41 (dd, J=
6.3, 11.5 Hz, 1H), 4.62–4.68 (m, 2H), 4.82 (d, J=8.1 Hz, 1H), 5.54–
5.60 (m, 3H), 5.79 (dd, J=8.1, 10.3 Hz, 1H), 5.98 (d, J=3.3 Hz, 1H),
6.27 (t, J=7.0 Hz, 1H), 7.23–7.68 (m, 22H), 7.78–7.97 (m, 7H), 8.11
(dd, J=1.3, 8.2 Hz, 2H), 8.23 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3, TMS): d=19.2, 26.9, 38.0, 62.0, 63.1, 68.0, 69.6, 71.5, 80.3,
84.6, 85.1, 101.4, 120.2, 127.9, 127.9, 128.3, 128.4, 128.5, 128.7,
128.7, 129.0, 129.1, 129.3, 129.6, 129.8, 130.0, 130.1, 130.1, 132.9,
133.3, 133.4, 133.7, 135.5, 135.5, 139.3, 149.5, 152.5, 155.3, 165.2,
165.6, 165.6, 165.9 ppm; HRMS (FAB+): calcd for [M+H]+,
C60H58N5O12Si, 1068.3851; found, 1068.3846.
(300 MHz, CDCl3, TMS): d=0.92 (s, 9H), 1.55 (ddd, J=5.0, 8.5,
14.2 Hz, 1H), 1.86 (s, 3H), 2.02–2.11 (m, 10H), 2.25 (dd, J=1.8,
10.1 Hz, 1H), 3.74–3.82 (m, 3H), 3.88 (d, J=5.5 Hz, 1H), 4.07 (dd,
J=2.2, 12.5 Hz, 1H), 4.13 (dd, J=8.4, 10.8 Hz, 1H), 4.35 (dd, J=4.4,
12.5 Hz, 1H), 4.90 (d, J=8.4 Hz, 1H), 5.10 (dd, J=9.1, 10.8 Hz, 1H),
5.83 (dd, J=9.2, 10.8 Hz, 1H), 6.40 (dd, J=5.4, 9.2 Hz, 1H), 7.32–
7.49 (m, 11H), 7.61–7.79 (m, 4H), 8.21 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3, TMS): d=12.5, 18.8, 20.4, 20.5, 20.6, 26.7, 40.5,
54.4, 61.6, 68.8, 69.5, 70.0, 72.0, 74.0, 84.9, 86.5, 98.2, 111.3, 123.4,
127.9, 127.9, 129.9, 130.1, 130.8, 132.8, 133.0, 134.5, 135.4, 135.5,
135.5, 150.4, 163.7, 167.3, 169.3, 170.0, 170.5 ppm; HRMS (FAB+):
calcd for [M+H]+, C46H52N3O14Si, 898.3219; found, 898.3218.
3’-O-tert-Butyldiphenylsilyl-5’-O-(2“,3”,4“-tri-O-benzyl-6”-O-
trityl-d-glucopyranosyl)-2’-deoxyadenosine (32) (Scheme 4b)
4-N-Benzoyl-3’-O-tert-butyldiphenylsilyl-5’-O-(3“,4”,6“-tri-O-
acetyl-2”-deoxy-2“-phthalimido-b-d-glucopyranosyl)-2’-
deoxycytidine (b-27) (Entry 3 in Table 4)
Reaction conditions for the synthesis of 32 were the same as those
for b-11a. The resulting residue was purified by silica gel column
chromatography (CHCl3/MeOH=200:1 to 50:1) to give 32 as a col-
orless amorphous solid (22.8 mg, 46% yield, a/b=3:1): 1H NMR
(400 MHz, CDCl3, TMS): d=1.06 (s, 6.7H), 1.11 (s, 2.3H), 2.33–2.38
(m, 1.5H), 2.48–2.52 (m, 0.5H), 3.03 (dd, J=2.6, 10.1 Hz, 0.75H),
3.13–3.38 (m, 3.75H), 3.42–3.68 (m, 2.5H), 3.76 (t, J=9.2 Hz, 0.75H),
3.87 (t, J=9.4 Hz, 0.25H), 4.22–4.30 (m, 2H), 4.36–4.41 (m, 1H),
4.55–4.60 (m, 1H, H-1“ of b-anomer and other proton of a and b-
anomers), 4.62–4.81 (m, 3.5H, H-1” of a-anomer and other protons
of a and b-anomers), 4.88–4.96 (m, 1.25H), 5.28 (s, 0.5H), 5.55 (s,
1.5H), 6.61 (t, J=7.0 Hz, 0.25H, H-1’ of b-anomer), 6.68 (t, J=
7.2 Hz, 0.75H, H-1’ of a-anomer) 6.82–6.88 (m, 2H), 7.08–7.48 (m,
35.75H), 7.53–7.58 (m, 3H), 7.62–7.68 (m, 1.25H), 8.20 (s, 0.25H),
8.27 (s, 0.25H), 8.35 (s, 0.75H), 8.57 ppm (s, 0.75H); 13C NMR
(100 MHz, CDCl3, TMS): d=18.9, 19.0, 26.9, 29.6, 41.7, 41.9, 61.7,
62.4, 67.6, 69.2, 72.1, 73.2, 74.7, 74.8, 74.9, 75.0, 75.8, 75.8, 77.4,
77.7, 79.3, 81.9, 82.4, 83.8, 84.6, 84.8, 86.2, 86.3, 86.4, 86.9, 97.5,
Reaction conditions for the synthesis of b-27 were the same as
those for b-11a. The resulting residue was purified by silica gel
column chromatography (hexanes/CHCl3 =1:3 to 0:1) to give b-27
as a colorless amorphous solid (32.5 mg, 65% yield): 1H NMR
(300 MHz, CDCl3, TMS): d=0.94 (s, 9H), 1.49–1.58 (m, 1H), 1.85 (s,
3H), 2.04 (s, 3H), 2.16 (s, 3H), 2.38–2.50 (m, 2H), 3.74–3.85 (m, 3H),
3.95 (d, J=6.0 Hz, 1H), 4.09–4.19 (m, 2H), 4.39 (dd, J=4.2, 12.6 Hz,
1H), 4.96 (d, J=8.7 Hz, 1H), 5.16 (t, J=9.3 Hz 1H), 5.82 (dd, J=9.0,
10.8 Hz, 1H), 6.39 (dd, J=5.4, 8.1 Hz, 1H), 7.30–7.75 (m, 18H), 7.93
(d, J=6.9 Hz, 2H), 8.01 (d, J=7.5 Hz, 1H), 8.69 ppm (brs, 1H);
13C NMR (75 MHz, CDCl3, TMS): d=18.9, 20.4, 20.6, 20.8, 26.8, 42.2,
54.4, 61.7, 68.8, 69.3, 70.1, 72.1, 74.0, 87.2, 87.3, 97.0, 98.1, 123.5,
127.6, 127.9, 128.0, 129.0, 129.9, 130.1, 130.9, 132.8, 133.1, 133.1,
133.3, 134.6, 135.5, 135.6, 144.5, 162.0, 167.3, 169.4, 170.1,
170.8 ppm; HRMS (FAB+): calcd for [M+H]+, C52H55N4O14Si,
987.3484; found, 987.3484.
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103.1, 119.6, 119.9, 126.8, 126.9, 127.5, 127.6, 127.7, 127.7, 127.8,
127.9, 127.9, 128.0, 128.1, 128.2, 128.2, 128.3, 128.3, 128.4, 128.7,
129.9, 130.0, 130.1, 132.8, 133.0, 133.2, 135.5, 135.6, 135.6, 135.7,
138.0, 138.3, 138.4, 139.9, 143.8, 149.5, 149.9, 152.5, 152.7, 155.2,
155.3 ppm; HRMS (FAB+): calcd for [M+H]+, C72H74N5O8Si,
1164.5307; found, 1164.5308.
129.3, 129.7, 129.8, 129.8, 130.1, 133.4, 133.5, 133.6, 139.3, 149.6,
152.8, 155.5, 165.5, 165.6, 166.1 ppm; HRMS (FAB+): calcd for
[M+H]+, C44H40N5O12Si, 830.2674; found, 830.2672.
The desilylated compound (31.4 mg, 37.8 mmol) was treated with
2.0 mL of methylamine in MeOH (10m) for 6 h under an argon at-
mosphere at room temperature. After evaporation of the solvent,
the oily residue was dissolved in water and the N-methylbenz-
amide was removed by successive washing of the aqueous phase
with CH2Cl2. The aqueous layer was concentrated under reduced
pressure, and resulting yellow suspension was centrifuged and
washed with ethanol to give b-35 as a colorless amorphous solid
(11.9 mg, 76% from b-16): 1H NMR (400 MHz, D2O, TSP): d=2.63
(ddd, J=4.1, 6.4, 14.2 Hz, 1H), 2.91 (dt, J=6.3, 13.5 Hz, 1H), 3.52
(dd, J=7.7, 9.9 Hz, 1H), 3.59–3.64 (m, 2H), 3.72–3.74 (m, 2H), 3.84
(dd, J=5.4, 11.5 Hz, 1H), 3.91 (d, J=3.4 Hz, 1H), 4.16 (dd, J=3.4,
11.5 Hz, 1H), 4.29–4.32 (m, 1H), 4.38 (d, J=7.8 Hz, 1H), 4.60–4.94
(m, 1H), 6.52 (t, J=6.6 Hz, 1H), 8.26 (s, 1H), 8.42 ppm (s, 1H);
13C NMR (100 MHz, D2O, 1,4-dioxane): d=38.7, 61.0, 68.7, 69.4, 70.8,
71.1, 72.8, 75.2, 83.9, 85.7, 103.1, 118.8, 140.0, 148.6, 152.5,
155.4 ppm; HRMS (FAB+): calcd for [M+H]+, C16H24N5O8Si,
414.1629; found, 414.1622.
3’-O-tert-Butyldiphenylsilyl-5’-O-(6“-O-acetyl-2”,3“,4”-tri-O-
benzyl-d-mannopyranosyl)-2’-deoxyadenosine (34) (Scheme
4c)
Reaction conditions for the synthesis of 34 were the same as those
for b-11a. The resulting residue was purified by silica gel column
chromatography (CHCl3/MeOH=1:0 to 100:1) to give 34 as a color-
less amorphous solid (31.9 mg, 57% yield, a/b=2.5:1): a-34;
1H NMR (300 MHz, CDCl3, TMS): d=1.09 (s, 9H), 2.00 (s, 3H), 2.24
(m, 1H), 2.39 (m, 1H), 3.56 (m, 2H), 3.84 (t, J=9.3 Hz, 1H), 4.06–
4.16 (m, 3H), 4.51–4.56 (m, 5H, H-1“ of a-anomer and other pro-
tons), 4.64–4.70 (m, 2H), 4.87 (d, J=10.8 Hz, 1H), 5.70 (s, 2H), 6.41
(t, J=6.0 Hz, 1H, H-1’ of a-anomer), 7.19–7.38 (m, 25H), 7.62–7.65
(m, 6H), 8.32 ppm (s, 1H); 13C NMR (75 MHz, CDCl3, TMS): d=19.0,
20.8, 19.0, 26.9, 40.9, 63.0, 67.0, 70.2, 71.8, 72.8, 73.6, 73.9, 74.8
75.1, 77.2, 79.4, 84.3 (C-1’ of a-anomer), 86.0, 98.2 (C-1” of a-
anomer), 120.0, 127.5, 127.6, 127.7, 127.8, 127.9, 128.1, 128.3, 128.3,
128.4, 130.2, 130.2, 132.8, 132.9, 134.8, 135.6, 135.7, 138.1, 138.2,
138.2, 138.5, 149.6, 153.0, 155.4, 170.8 ppm; b-34; 1H NMR
(300 MHz, CDCl3, TMS): d=1.07 (s, 9H), 2.00 (s, 3H), 2.30–2.44 (m,
1H), 2.45–2.55 (m, 1H), 3.26–3.59 (m, 2H), 3.41 (dd, J=2.8, 9.0 Hz,
1H), 3.77 (d, J=2.6 Hz, 1H), 3.85–3.92 (m, 2H), 4.20–4.26 (m, 3H,
H-1“ of b-anomer and other protons), 4.32 (dd, J=2.2, 12.1 Hz,
1H), 4.47 (d, J=3.9 Hz, 1H), 4.52–4.58 (m, 2H), 4.67 (s, 2H), 4.89 (d,
J=10.5 Hz, 1H), 5.88 (brs, 2H), 6.46 (t, J=7.2 Hz, 1H, H-1’ of b-
anomer), 7.14–7.46 (m, 20H), 7.65 (d, J=7.5 Hz, 5H), 8.10 (s, 1H),
8.29 ppm (s, 1H); 13C NMR (75 MHz, CDCl3, TMS): d=19.0, 20.9,
26.9, 40.7, 63.6, 69.5, 71.6, 73.7, 73.8, 74.1, 74.2, 74.4, 75.2, 76.6,
77.2, 82.1, 84.4 (C-1’ of b-anomer), 86.4, 101.2 (C-1” of b-anomer),
127.4, 127.5, 127.7, 127.8, 127.9, 128.0, 128.1, 128.1, 128.4, 128.4,
130.1, 133.1, 133.2, 135.7, 135.8, 137.9, 138.0, 138.3, 139.7, 152.7,
155.3, 171.0 ppm; HRMS (FAB+): calcd for [M+H]+, C55H62N5O9Si,
964.4317; found, 964.4318.
5’-O-b-d-Galactopyranosyl-2’-thymidine (b-36) (Scheme 5a)
1m Bu4NF in THF (38 mL, 38.0 mmol) was slowly added to a solution
of b-21 (40.2 mg, 38.0 mmol) in THF (1.0 mL) at 08C. The mixture
was stirred at 08C under an argon atmosphere for 4 h. After re-
moving solvent by evaporation, the residue was dissolved in
CH2Cl2, and the resulting solution was washed with H2O and brine,
dried over Na2SO4 and concentrated. The remaining residue was
purified by silica gel column chromatography (CHCl3/MeOH=200:1
to 50:1) to give the desilylated compound as a colorless amor-
phous solid (27.8 mg): 1H NMR (300 MHz, CDCl3, TMS): d=2.03–
2.09 (m, 5H), 2.18 (brs, 1H), 3.73 (dd, J=2.3, 10.5 Hz, 1H), 4.05 (d,
J=2.6 Hz, 1H), 4.21–4.26 (m, 1H), 4.25–4.49 (m, 3H), 4.72 (dd, J=
6.2, 11.0 Hz, 1H), 4.85 (d, J=7.7 Hz, 1H), 5.71 (dd, J=3.5, 10.5 Hz,
1H), 5.80 (dd, J=7.7, 10.5 Hz, 1H), 6.02 (dd, J=0.8 Hz, 3.5 Hz, 1H),
6.37 (t, J=7.1 Hz, 1H), 7.22–7.28 (m, 2H), 7.37–7.68 (m, 11H), 7.77
(dd, J=1.2, 8.3 Hz, 2H), 7.91–8.08 (m, 4H), 8.44 ppm (brs, 1H).
The desilylated compound (27.6 mg, 33.6 mmol) was treated with
2.0 mL of methylamine in MeOH (10m) for 6 h under an argon at-
mosphere at room temperature. After evaporation of the solvent,
the resulting oily residue was dissolved in water and the N-methyl-
benzamide was removed by successive washing of the aqueous
phase with CH2Cl2. The aqueous phase evaporated to dryness, and
the resulting yellow foam was centrifuged and washed with meth-
anol to give b-36 as a colorless amorphous solid (13.4 mg, 89%
5’-O-b-d-Galactopyranosyl-2’-deoxyadenosine (b-35)
(Scheme 5a)
1m Bu4NF in THF (44.5 mL, 44.5 mmol) was slowly added to an ice-
cooled solution of b-16 (47.5 mg, 44.5 mmol) in THF (1.3 mL). The
mixture was stirred on an ice bath under an argon atmosphere for
4 h. After removing the solvent by evaporation, the residue was
dissolved in CH2Cl2, the solution washed with H2O and brine, dried
over Na2SO4 and concentrated. The residue purified by silica gel
column chromatography (CHCl3/MeOH=100:2 to 100:3) to give
1
from b-21): H NMR (400 MHz, D2O, TSP): d=1.91 (s, 3H), 2.32–2.46
(m, 2H), 3.55–3.89 (m, 6H), 3.93 (d, J=3.2 Hz, 1H), 4.17–4.22 (m,
2H), 4.46 (d, J=7.8 Hz, 1H), 4.51–4.56 (m, 1H), 6.32 (t, J=5.1 Hz,
1H), 7.63 ppm (s, 1H); 13C NMR (100 MHz, D2O, 1,4-dioxane): d=
11.6, 38.3, 61.1, 68.6, 69.5, 70.9, 70.9, 72.8, 75.3, 85.2, 85.4, 103.2,
111.6, 137.5, 151.7, 166.6 ppm; HRMS (FAB+): calcd for [M+H]+,
C16H25N2O10, 405.1510, found, 405.1509.
the desilylated compound as
a colorless amorphous solid
(36.9 mg): 1H NMR (300 MHz, CDCl3, TMS): d=2.38–2.42 (m, 2H),
2.67–2.77 (m, 1H), 3.85 (dd, J=2.7, 7.8 Hz, 1H), 4.08–4.14 (m, 1H),
4.23 (dd, J=3.6, 10.8 Hz, 3H), 4.35 (t, J=4.8 Hz, 1H), 4.45 (dd, J=
4.8, 8.4 Hz, 1H), 4.53–4.58 (m, 1H), 4.71 (dd, J=1.8, 8.4 Hz, 1H),
4.88 (d, J=8.0 Hz, 1H), 5.55 (brs, 2H), 5.67 (dd, J=2.7, 8.1 Hz, 1H),
5.82 (dd, J=6.3, 10.8 Hz, 1H) 6.01 (d, J=1.8 Hz, 1H), 6.45 (t, J=
5.1 Hz, 1H) 7.22–7.27 (m, 2H), 7.35–7.46 (m, 5H), 7.49–7.54 (m, 4H),
7.64 (t, J=5.7 Hz, 1H), 7.78 (dd, J=0.9, 6.6 Hz, 2H), 7.93 (dd, J=
0.9, 6.3 Hz, 2H), 8.00 (dd, J=0.9, 6.3 Hz, 2H), 8.14 (dd, J=1.2,
6.6 Hz, 2H), 8.25 (s, 1H), 8.34 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3, TMS): d=40.7, 61.9, 68.0, 69.9, 69.9, 71.2, 71.6, 72.3, 84.0,
85.4, 101.6, 120.0, 128.3, 128.5, 128.5, 128.7, 128.7, 128.9, 129.0,
5’-O-a-d-Mannopyranosyl-2’-deoxyadenosine (a-37) (Scheme
5b)
1m Bu4NF in THF (21 mL, 21 mmol) was slowly added to a solution
of a-34 (20.0 mg, 20.7 mmol) in THF (0.7 mL) at 08C. The mixture
was stirred at 08C under an argon atmosphere for 2 h. After re-
moving solvent by evaporation, the residue was dissolved in
CH2Cl2, the solution washed with H2O and brine, dried over Na2SO4
Chem. Asian J. 2015, 10, 740 – 751
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and concentrated. The remaining residue was purified by silica gel
column chromatography (CHCl3/MeOH=100:1 to 98:2) to give the
desilylated compound as a colorless amorphous solid (13.9 mg):
1H NMR (300 MHz, CDCl3, TMS): d=2.04 (s, 3H), 2.45 (m, 1H), 2.64
(m, 1H), 3.01 (brs, 1H), 3.65 (dd, J=4.8, 11.1 Hz, 1H), 3.72–3.95 (m,
5H), 4.12 (d, J=4.0 Hz, 1H), 4.21 (dd, J=5.9, 11.7 Hz, 1H), 4.31 (dd,
J=1.8, 11.7 Hz, 1H), 4.55–4.78 (m, 6H), 4.85 (t, J=11.0 Hz, 2H), 5.67
(s, 2H), 6.36 (t, J=5.9 Hz, 1H), 7.27–7.40 (m, 15H), 7.97 (s, 1H),
8.34 ppm (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d=20.9, 40.4,
63.8, 67.0, 70.2, 71.3, 72.0, 73.0, 74.6, 74.8, 75.3, 77.2, 79.8, 84.6,
85.2, 98.5, 127.7, 127.7, 128.0, 128.3, 128.3, 128.4, 137.9, 138.1,
138.2, 138.9, 149.4, 152.9, 155.4, 171.1 ppm; HRMS (FAB+): calcd
for [M+H]+, C39H44N5O9, 726.3139; found, 726.3138.
135.8,141.2, 143.2, 149.39, 151.4, 152.0, 152.6, 164.6, 172.2 ppm;
HRMS (FAB+): calcd for [M+H]+, C49H54N5O4Si2 832.3714; found,
832.3719.
1H NMR measurements of nucleoside derivatives in the pres-
ence of glycosylation promoters
To a solution of the nucleoside derivative (0.010 mmol) in anhy-
drous CDCl3 (700 mL), AgOTf (7.9 mg, 0.030 mmol) and/or TolSCl
(3.2 mg, 2.7 mL, 0.020 mmol) were added at À408C. NMR spectra
were then recorded at À408C by using a NMR spectrometer (at
1
400 MHz for H NMR spectra).
Reaction of 38b with TolSCl+AgOTf that affords 1:1 or 2:1
complexes of N-benzoyladenine and Ag+ (39), methyl 3’,5’-O-
bis-tert-butyldiphenylsilyl-d-2’-deoxyriboside (40) (Scheme 6)
The desilylated compound (7.0 mg, 9.6 mmol) was dissolved in
0.1m a solution of sodium methoxide in MeOH (150 mL) and stirred
for 6 h under an argon atmosphere at room temperature. The solu-
tion was neutralized with 0.1 N HCl aq., extracted with CH2Cl2,
washed with brine, dried over Na2SO4, and evaporated in vacuo to
give the deacetylated compound as a colorless amorphous solid
To a solution of 38b (35 mg, 0.042 mmol) in CH2Cl2 (1.0 mL), TolSCl
(10 mg, 9.1 mL, 0.063 mmol) and AgOTf (32 mg, 0.13 mmol) were
added at À408C. The reaction mixture was stirred for 3 h at À408C
and quenched by adding MeOH (several drops). The mixture was
concentrated in vacuo. The residue was washed with Et2O to give
39 as a white solid (25 mg, mixture) (see Figure S5 in the Support-
1
(5.5 mg): H NMR (300 MHz, CD3OD, TMS): d=0.89 (brs, 1H), 1.28
(s, 1H), 2.48 (m, 2H), 3.48 (m, 1H), 3.59–3.94 (m, 8H), 4.12 (dd, J=
3.3, 6.6 Hz, 1H), 4.40 (d, J=11.7 Hz, 1H), 4.52–4.68 (m, 5H), 4.82 (d,
J=10.6 Hz, 1H), 6.37 (t, J=6.2 Hz, 1H), 7.11–7.39 (m, 17H), 8.21 (s,
1H), 8.25 ppm (s, 1H); 13C NMR (100 MHz, CD3OD, TMS): d=41.8,
54.8, 62.5, 68.1, 72.6, 72.6, 74.3, 74.4, 75.7, 76.0, 76.6, 80.7, 86.2,
87.4, 99.4, 120.6, 128.6, 128.7, 128.8, 129.0, 129.2, 129.3, 129.4,
139.6, 139.8, 140.5, 150.2, 153.9, 157.3 ppm; HRMS (FAB+): calcd
for [M+H]+, C37H42N5O8, 684.3033; found, 684.3036.
1
ing Information): H NMR (300 MHz, [D6]DMSO, TMS): d=7.21–7.79
(m, 7H), 8.12 (d, J=7.5 Hz, 2H), 8.75 (s, 1H), 8.88 (s, 1H),
11.91 ppm (brs, 1H); HRMS (FAB+): calcd for [M+Ag]+,
C12H9N5O107Ag: 345.9858, C12H9N5O109Ag: 347.9855; found,
345.9858, 347.9855. HRMS (FAB+): calcd for [M+Ag]+,
[C12H9N5O]2107Ag: 585.0665, [C12H9N5O]2109Ag: 587.0662; found,
585.0665, 587.0661.
A mixture of the deacetylated compound (21.9 mg, 0.032 mmol),
10% Pd/C (70 mg) and MeOH/H2O (10/1) (1.1 mL) was vigorously
stirred under a H2 atmosphere at room temperature for 2 days.
The mixture was filtered through Celite with MeOH/H2O (5:1 to
0:1), and the filtrate was concentrated under reduced pressure to
give a-37 as a colorless amorphous solid (12.2 mg, 72% from a-
The supernatant fraction was concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatogra-
phy (hexanes/CHCl3 =10:1 to 1:1) to give compound 40 as a color-
less amorphous solid (15 mg, 58%, a/b=1:1): 1H NMR (300 MHz,
CDCl3, TMS): d=0.95 (d, J=9.0 Hz, 9H), 1.03 (s, 9H), 1.86–1.87 (m,
1H), 1.91–1.92 (m, 1H), 3.25 (s, 1.5H), 3.31 (dd, J=4.4, 11.4 Hz,
0.5H), 3.41 (s, 1.5H), 3.45 (d, J=5.9 Hz, 1H), 3.56 (dd, J=2.6,
11.0 Hz, 0.5H), 4.06–4.10 (m, 0.5), 4.13–4.17 (m, 0.5H), 4.27–4.33 (m,
0.5H), 4.36–4.41 (m, 0.5H), 4.96 (dd, J=2.2, 5.9 Hz, 0.5H), 5.09 (dd,
J=3.3, 5.5 Hz, 0.5H), 7.25–7.43 (m, 12H), 7.53–7.65 ppm (m, 8H);
13C NMR (75 MHz, CDCl3, TMS): d=19.1, 19.2, 26.7, 26.9, 41.6, 41.9,
54.8, 55.2, 63.9, 65.0, 72.9, 73.7, 77.2, 85.6, 87.3, 105.0, 105.5, 127.5,
127.6, 127.6, 127.6, 127.7, 127.7, 129.5, 129.7, 129.7, 133.5, 133.5,
133.5, 133.5, 133.8, 133.8, 133.9, 135.6, 135.6, 135.6, 135.7, 135.7,
135.8, 135.9 ppm; HRMS (FAB+): calcd for [M+Na]+, C38H48O4Si2Na
647.2989; found, 647.2990.
1
34): H NMR (300 MHz, D2O, TSP): d=2.58–2.64 (m, 1H), 2.82–2.89
(m, 1H), 3.22 (m, 1H), 3.55–3.97 (m, 7H), 4.09 (dd, J=3.1, 11.5 Hz,
1H), 4.26 (m, 1H), 4.58–4.69 (m, 1H), 6.43 (t, J=6.6 Hz, 1H), 8.64 (s,
1H), 8.45 ppm (s, 1H); 13C NMR (75 MHz, D2O, 1,4-dioxane): d=
39.5, 58.8, 61.7, 70.0, 71.0, 72.0, 73.6, 77.0, 84.6, 86.5, 101.0, 119.4,
140.9, 149.4, 153.4, 156.3 ppm; HRMS (FAB+): calcd for [M+H]+,
C16H24N5O8, 414.1625, found, 414.1626.
6-N-Benzoyl-3’,5’-O-bis-tert-butyldiphenylsilyl-2’-deoxyade-
nosine (38b)[39]
Benzoyl chloride (60 mL, 1.03 mmol) was slowly added to a solution
of 38a (125 mg, 0.17 mmol) in dry pyridine (1.5 mL) at 08C. The
mixture was stirred at 08C under an argon atmosphere for 4 h, to
which H2O (0.35 mL) and conc. aqueous NH3 (0.70 mL) were added.
The mixture was stirred at room temperature under an argon at-
mosphere for 1.5 h. After removing solvent by evaporation, the res-
idue was dissolved in CHCl3, washed with H2O and brine, dried
over Na2SO4 and concentrated. The remaining residue was purified
by silica gel column chromatography (hexanes/CHCl3 =1:1 to 0:1)
to give compound 38b as a colorless amorphous solid (135 mg,
Acknowledgements
This work was supported by grants-in-aid from the Ministry of
Education, Culture, Sports, Science, and Technology (MEXT) of
Japan (Nos. 223900051, 226590051, and 24659011 for S.A) and
High-Tech Research Center Project for Private Universities
(matching fund subside from NEXT). We appreciate the assis-
tance of Mrs. Fukiko Hasegawa (Faculty of Pharmaceutical Sci-
ences, Tokyo University of Science) for collecting and interpret-
ing the mass spectral data and Mrs. Noriko Sawabe for the
1
96%): H NMR (300 MHz, CDCl3, TMS): d=0.93 (s, 9H), 1.11 (s, 9H),
2.46 (m, 2H), 3.37 (dd, J=3.6, 11.4 Hz, 1H), 3.67 (dd, J=3.6,
11.4 Hz, 1H), 4.14 (q, J=3.6 Hz, 1H), 4.14–4.18 (m, 1H), 6.58 (t, J=
7.2 Hz, 1H), 7.25–7.67 (m, 23H), 8.00 (d, J=8.7 Hz, 2H), 8.11 (s, 1H),
8.76 (s, 1H), 9.03 ppm (s, 1H); 13C NMR (75 MHz, CDCl3, TMS): d=
19.0, 19.1, 26.8, 26.9, 41.1, 63.7, 73.7, 77.12, 84.5, 88.2, 123.1, 127.7,
127.8, 127.9, 128.6, 128.8, 129.4, 129.8, 129.8, 130.0, 132.5, 132.6,
132.8, 132.9, 133.1, 133.1, 133.7, 134.0, 135.4, 135.5, 135.7,
1
measurement of H NMR at low temperature.
Keywords: chemical glycosylation · disaccharide nucleosides ·
nucleosides · O-glycosylation · thioglycoside
Chem. Asian J. 2015, 10, 740 – 751
www.chemasianj.org
750
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: November 17, 2014
Revised: December 21, 2014
Published online on July 18, 2014
Chem. Asian J. 2015, 10, 740 – 751
www.chemasianj.org
751
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim