One-pot preparation and activation of glycosyl trichloroacetimidates: Operationally simple glycosylation induced by combined use of solid-supported, reactivity-opposing reagents

Article abstract of DOI:10.1016/j.tetlet.2004.03.170

By the combined use of solid-supported reactivity-opposing reagents, that is, basic PTBD and acidic Nafion-SAC resins, sequential reactions consisting of glycosyl trichloroacetimidate formation and glycosylation can be effected in a one-pot ope

Full text of DOI:10.1016/j.tetlet.2004.03.170

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4039–4042
One-pot preparation and activation of glycosyl
trichloroacetimidates: operationally simple glycosylation induced by
combined use of solid-supported, reactivity-opposing reagents
a,b,
b
Tatsushi Tanaka, Naohiro Fukuda and Shoichi Kusumoto
b
b
*
Masato Oikawa,
a
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Tsutsumidori-Amamiya, Aoba-ku,
Sendai 981-8555, Japan
b
Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama-cho 1-1, Toyonaka 560-0043, Japan
Received 5 March 2004; revised 22 March 2004; accepted 26 March 2004
â
Abstract—By the combined use of solid-supported reactivity-opposing reagents, that is, basic PTBD and acidic Nafion -SAC resins,
sequential reactions consisting of glycosyl trichloroacetimidate formation and glycosylation can be effected in a one-pot operation
starting from 1-O-unprotected sugars. The solid-supported reagents can be introduced into the reaction vessel either sequentially or,
more conveniently, in a ‘one-shot’ manner in comparable yields.
Ó 2004 Elsevier Ltd. All rights reserved.
â
â
Efficient methodology for the construction of glycosidic
linkage plays an important role in the synthesis of bio-
logically important carbohydrates. For this transfor-
mation, solid-supported reagents (SSRs) have recently
received growing attention over soluble reagents since
they allow operational simplicity and reduction of
waste, as well as the safe handling of toxic, odorous, or
Nafion -SAC (a nanocomposite of Nafion resin with
11
12
porous silica) with glycosyl trichloroacetimidates. In
combination with a solid-supported basic reagent that
catalyzes the formation of imidates from 1-O-unpro-
tected hexopyranoses, the one-pot reaction consisting of
imidation and glycosylation became possible. The
simultaneous presence of both cationic and anionic
SSRs was proved not to interfere with the functions of
each other as follows.
1
explosive reagents. Glycosylations with glycosyl sulf-
4
2
3
oxides, glycosyl fluorides, and glycosyl phosphite, and
5
also Fischer glycosylation are representative of the
methods promoted by SSRs so far reported. On the
other hand, we have found, during the course of our
synthetic studies of a bacterial lipopolysaccharide, that
glucosaminidyl trichloroacetimidate can be prepared by
The glucose derivative 2 was used as a glycosyl acceptor.
Glycosylation of 2 with glucosyl imidate 1 was at first
examined by the action of three Nafion reagents in
6
â
2 2 2 3 2 2 6
CH Cl , Et O, CH CN, and CH Cl /C F14 (3:1) (Table
ꢀ
using basic Dowex 1-X8 resin (OH form) and can be
1). All reactions were carried out in the presence of
molecular sieves 4 A at room temperature. After several
experiments to explore the conditions that gave the
disaccharide 3 in >50% yield using CH Cl as a solvent,
â
7
activated with acidic Nafion -TMS resin (perfluori-
nated solid-supported sulfonic acid trimethylsilyl ester)
to construct a glucosamine disaccharide, which is the
essential structure for biological functions of the glyco-
conjugate. Inspired by this finding we undertook inves-
tigation of versatile SSRs that would allow efficient
glycosylation mediated by glycosyl trichloroacetimi-
dates, which is one of the most popular glycosyl
2
2
the required stoichiometry was determined to be
â
0.40 equiv for Nafion -H (15 h, run 1), 0.13 equiv for
â
Nafion -TMS (15 h, run 5), and 0.036 equiv for
â
10
Nafion -SAC (1 h, run 9). From these results, the
â
â
reactivities are in the order of Nafion -SAC ꢁ Nafion -
8
;9
â
donors. In the present paper, we report our pre-
liminary results regarding an efficient protocol for gly-
TMS > Nafion -H. With the corresponding soluble
acidic catalyst, TMSOTf, the same reaction proceeds
â
10
â
9
cosylation catalyzed by Nafion -H, Nafion -TMS, or
rapidly at a temperature even below )20 °C, indicating
that activation by the perfluorinated alkylsulfonic acid
functionality on a solid support is apparently milder
than that by soluble TMSOTf. We have also confirmed
the reaction medium was neutral (pH 6–7) for all runs in
*
Corresponding author. Tel.: +81-22-717-8827; fax: +81-22-717-8897;
e-mail: mao@bios.tohoku.ac.jp
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.170

4040
M. Oikawa et al. / Tetrahedron Letters 45 (2004) 4039–4042
â
a
Table 1. Glycosylation of 2 by Trichloroacetimidate donor 1 with Nafion resins
BnO
BnO
O
HO
BnO
BnO
BnO
Nafion® resins
BnO
O
O
NH
CCl3
BnO
BnO
O
BnO
BnO
O
BnO
MS4A
rt
BnO
O
OMe
2 (0.67 eq)
BnO
BnO
1
(1 eq)
3
OMe
Selectivity ða=bÞ
â
b
c
Run
Nafion resins/equiv
Solvent
CH Cl
Et
Time (h)
Yield (%)
â
1
2
3
4
Nafion -H/0.40
2
2
15
15
1.5
15
61
77
89
79
1.5:1.0
1.4:1.0
1.0:2.8
1.2:1.0
2
O
CH
CH
3
2
CN
Cl
2
2
/C
6
6
6
F14 (3:1)
F14 (3:1)
F14 (3:1)
â
5
6
7
8
Nafion -TMS/0.13
CH
2
Cl
15
15
72
15
54
94
88
82
1.4:1.0
1.9:1.0
1.0:2.6
1.2:1.0
2
Et O
CH
CH
3
2
CN
Cl
2
/C
â
9
Nafion -SAC/0.036
CH
Et
2
Cl
2
1
84
90
75
86
1.2:1.0
1.3:1.0
1.0:3.5
1.2:1.0
10
11
12
2
O
1
CH
CH
3
2
CN
Cl /C
4
1.5
2
a
b
c
All reactions were carried out with 70 mg (0.10 mmol) of 1.
Isolated yields based on the acceptor 2.
1
Determined from H NMR spectra (270 MHz).
Table 1 as judged from pH indication paper, showing
that the glycosylation is certainly promoted by the acidic
functionality on the solid support.
ration of the glucosyl imidate 1 from 4 by using solid-
supported bases. Among several reagents (Dowex
14
ꢀ
1-X8 OH form, N,N-(diisopropyl)aminomethylpoly-
styrene, and so on) examined, 2.3 equiv of polymer-
15
Our attention next turned to the solvent effect on the
glycosylation yield. Low yields were recorded when Naf-
supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PTBD)
was found to be the most powerful to convert 4 into 1 in
â
â
10
ion -H or Nafion -TMS was used in CH
5
2
Cl
2
(runs 1 and
) or toluene (<57% yield, data not shown), because resins
a quantitative yield (Scheme 1). Though Dowex 1-X8
ꢀ
(OH form) is a good basic catalyst for imidation of a
6
1
1
are poorly swollen in these nonpolar solvents. The yields
were improved by using coordinative solvents, Et O or
CH CN (runs 2, 3, 6, and 7). The most reactive Nafion -
glucosamine derivative, this is not the case for the 2-O-
benzyl glucose 4.
2
â
3
SAC showed different tendencies; the disaccharide 3 was
produced in good yield (84%) even in CH Cl (run 9) and
With this efficient imidation method in hand, the con-
ditions for one-pot sequential reactions consisting of
imidation and glycosylation by the action of basic
2
2
3
in moderate yield (75%) in CH CN (run 11). The lower
â
â
yield is due to the inherent hygroscopicity of Nafion -
SAC, which rapidly hydrolyzes the imidate 1. The
PTBD and acidic Nafion resins were explored. For
â
â
Nafion resins, the most reactive Nafion -SAC was
used. Because imidation does not smoothly proceed in
hydrolysis competes seriously in CH
3
CN wherein the rate
for the glycosylation is slow. It should also be noted here
â
Et
glycosylation as shown in Table 1, Et O was added to
2
O, which is an efficient solvent for Nafion -mediated
13
that a positive effect of fluorophobicity was observed for
â
2
all Nafion reagents; yields in a mixed solvent system of
the reaction mixture at the subsequent glycosylation
stage. A typical procedure is as follows. The hexopyr-
anosyl donor precursor (4–7, 0.056 mmol, Fig. 1) was
2 2 6
CH Cl –C F14 were generally higher than the reactions in
CH Cl alone (runs 1 vs 4, 5 vs 8, and 9 vs 12).
2
2
mixed with 5 equiv of CCl CN and basic PTBD in
3
As for the stereoselectivity, glycosylation in CH
(
3
CN
2 2
CH Cl (0.6 mL) at room temperature for 2 h. After this
imidation period, Nafion -SAC, powdered molecular
sieves 4 A (300 mg), and a solution of the glycosyl
acceptor 2 (0.67 equiv) in Et O (0.9 mL) were introduced
2
to the reaction mixture for glycosylation. After 15 h, all
insoluble materials were filtered off, and the filtrate was
â
runs 3, 7, and 11) was b-predominant (a:b ¼ 1.0:2.6–
3
.5) as usual, whereas only detectable a-selectivity was
Cl , Et O,
/perfluorohexane. When the reaction with
Nafion -SAC was carried out in CH CN at )20 ° C for
observed in other solvent systems such as CH
and CH Cl
2
2
2
2
2
â
3
4
h, the b-selectivity increased to 1.0:13.3 in 66% yield
(
data not shown). This selectivity enhancement is com-
BnO
parable to the case where a soluble catalyst is used,
suggesting the reaction proceeds via a kinetically
favored a-nitrilium-nitrile-conjugate intermediate.
CCl3CN
2O
BnO
BnO
1 (100%)
9
BnO
OH
PTBD (2.3 equiv)
rt
4
Encouraged by these successful glycosylations with
polymer-supported acids, we next attempted the prepa-
Scheme 1.

M. Oikawa et al. / Tetrahedron Letters 45 (2004) 4039–4042
4041
1
6;17
Ph
glycosylation agrees well with precedent reports.
As
O
2O
for the stereoselectivity, all reactions were completely b-
selective (runs 2–4) for donor precursors 5–7 bearing
participating groups at the neighboring C2-position.
O
O
BnO
2O
O
BzO
OH
TrocO
5
7
3
NH OH
Troc
6
BnO
BnO
The one-pot procedure was extended to the glycosyla-
tion by ‘one-shot mixing’ of all reactants and reagents to
achieve higher operational simplicity (Table 3). The
reactions were effected by the concurrent introduction of
2O
MPMO
3
NH OH
Troc
â
PTBD and Nafion -SAC to the mixture of the donor
precursor (4–7), the glycosyl acceptor 2, CCl
molecular sieves 4 A in CH Cl without Et O. At first,
3
CN, and
Figure 1. Donor precursors used in the one-pot glycosylations.
2
2
2
glycosylation was attempted with the donor precursor 4
concentrated and the residue was purified by silica-gel
chromatography.
(
(
run 1). In this case, the stereoselectivity decreased
a:b ¼ 1.2:1.0) as compared to that observed in the
above sequential mixing procedure (run 1, Table 2)
Optimized results for one-pot reactions by sequential
â
2
because of the absence of Et O. The yield for the
mixing of PTBD and Nafion -SAC are summarized in
Table 2. By the procedure, the disaccharide 3 was pro-
disaccharide (56%) was also lower because of the
undesired imidation of the acceptor 2. This competitive
imidation became a serious side process owing to the
low reactivity of the 1-hydroxy group of 4 toward imi-
dation. By contrast, with the more reactive 2-O-benzoyl
donor precursor 5, undesirable imidation of 2 was sup-
pressed relatively and the disaccharide was obtained in
2 3
vided in good yield (86%, run 1). With Cs CO instead
of PTBD, the yield was poor (<70%, data not shown),
â
probably because of the deactivation of Nafion -SAC
by the cesium cation. The glycosylation with the donor
precursor 4 in run 1 was apparently a-selective, as
observed in the stepwise reaction of 1 and 2 (Table 1).
83% yield (run 2). The glycosylation yield with the dis-
armed glucosamine donor derived from 6 (run 3) was
16
This one-pot procedure was further applied to other
donor precursors 5–7. As can be seen from run 2 in
Table 2, the 2-O-benzoyl donor precursor 5 gave a
disaccharide in an excellent yield (93%). In contrast to
the glucose derivatives 4 and 5, for which excess amount
of PTBD was practically required for complete imida-
tion (data not shown), a lesser amount (0.67 equiv) of
PTBD was found to be sufficient for imidation of glu-
cosamine derivatives 6 and 7 (runs 3 and 4). The gly-
cosylation of the imidate in situ formed from 6 provided
a disaccharide in a moderate yield (70%, run 3). It is
comparable to that by the sequential mixing procedure
(run 3, Table 2). Coupling of the glucosamine derivative
7
with 2 in the ‘one-shot mixing’ procedure also pro-
ceeded satisfactorily in a high yield of 89% (run 4),
which was even higher than that of the same coupling
with the sequential mixing procedure (run 4, Table 2).
This is the most successful demonstration for ‘one-shot
mixing’ glycosylation where the formation and the
activation of the trichloroacetimidate proceed smoothly
without suffering interference by undesirable side reac-
tions.
â
worthy of mention that the efficiency of Nafion -SAC
was shown again by the observation that the imidate
5
Fischer direct glycosylation of 2 with 4 was sluggish
â
â
derived from 6 was not activated by Nafion -TMS at
even with a large amount of Nafion -SAC (0.21 equiv),
and less than 50% of disaccharide 3 was formed after
all. When the electron-withdrawing 3-O-Troc group of 6
was replaced with an electron-donating MPM group,
glycosylation proceeded smoothly to give a disaccharide
in 79% yield (run 4). The effect of protecting groups on
15 h in various solvents (data not shown). This fact
indicates that the one-pot reaction by the ‘one-shot-
mixing’ procedure proceeds via the in situ-formed
Table 3. Trichloroacetimidation followed by glycosylation in one-pot
â
Table 2. Trichloroacetimidation followed by glycosylation in one-pot
â
a
a
by ‘one-shot’ addition of PTBD and Nafion -SAC
by sequential addition of PTBD and Nafion -SAC
2
(0.67 equiv)
1
2
)
)
CCl3CN (5 equiv), PTBD
CH2Cl2, rt, 2 h
CCl3CN (5 equiv), PTBD
glycosyl donor precursor
-7 (1.0 equiv)
glycosyl donor precursor
disaccharides
disaccharides
4
4
-7 (1.0 equiv)
®
®
2 (0.67 equiv), Nafion -SAC
Nafion -SAC, MS4A
CH2Cl2, rt, 15 h
MS4A, Et2O, rt, 15 h
â
â
Run
Donor
precursor
PTBD
(equiv)
Nafion -
SAC
Yield
b
(%)
Selectivity
c
Run
Donor
precursor
PTBD
(equiv)
Nafion -
SAC
(equiv)
Yield
b
(%)
Selectivity
c
ða=bÞ
ða=bÞ
(
equiv)
1
2
3
4
4
5
6
7
1.4
1.5
0.036
0.021
0.039
0.054
86
93
70
79
2.1:1.0
0:1.0
0:1.0
0:1.0
1
2
3
4
4
5
6
7
1.3
1.1
0.036
0.018
0.054
0.023
56
83
71
89
1.2:1.0
0:1.0
0:1.0
0:1.0
0.67
0.67
0.67
0.87
a
b
c
a
b
c
For experimental procedures, see text.
Isolated yields based on the acceptor 2.
All reactions were carried out with 0.056 mmol of a glycosyl donor.
Isolated yields based on the acceptor 2.
1
1
Determined from H NMR spectra (270 MHz).
Determined from H NMR spectra (270 MHz).

4042
M. Oikawa et al. / Tetrahedron Letters 45 (2004) 4039–4042
glycosyl imidate intermediates as expected. In all runs,
trehalose-type dimeric products, which are often
observed as undesirable side products in Fischer and
other dehydrative glycosylations, were not detected at
all. This is another merit of the present glycosylation
procedure starting from 1-O-unprotected sugars.
2. Nagai, H.; Kawahara, K.; Matsumura, S.; Toshima, K.
Tetrahedron Lett. 2001, 42, 4159–4162.
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4
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. Toshima, K.; Kasumi, K.; Matsumura, S. Synlett 1999,
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. Nagai, H.; Matsumura, S.; Toshima, K. Tetrahedron Lett.
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002, 43, 847–850.
. Toshima, K.; Nagai, H.; Matsumura, S. Synlett 1999,
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1
This work provides a new simple one-pot procedure for
imidate-mediated glycosylation starting from reducing
sugars as sources of glycosyl donors. The procedure is
based on the characteristic of SSRs, which do not
. Yoshizaki, H.; Fukuda, N.; Sato, K.; Oikawa, M.; Fukase,
K.; Suda, Y.; Kusumoto, S. Angew. Chem., Int. Ed. 2001,
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7. Murata, S.; Noyori, R. Tetrahedron Lett. 1980, 21, 677–
â
19
770; Nafion is a registered trademark of E.I. DuPont de
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interact or interfere with each other’s functions. Thus,
in the stepwise protocol the basic reagent, PTBD, which
catalyzes the formation of the imidates, does not need to
be removed prior to glycosylation. PTBD did not inhibit
8
9
. Schmidt, R. R. Angew. Chem. 1986, 98, 213–236; Roussel,
F.; Knerr, L.; Grathwohl, M.; Schmidt, R. R. Org. Lett.
2
000, 2, 3043–3046.
â
the function of the acidic Nafion -SAC added to the
mixture and the desired glycosides were formed in sat-
isfactory yields.
. Schmidt, R. R.; Kinzy, W. In Advances in Carbohydrate
Chemistry and Biochemistry; Horton, D., Ed.; Academic
Press: San Diego, 1994; Vol. 50, pp 21–123.
â
1
0. Nafion -H (0.8 mmol/g) was purchased from Wako Co.,
â
â
The same glycosylation was effected by a more conve-
nient, complete one-pot procedure where all the reaction
partners were mixed in ‘one-shot’: the same series of
reactions occurred as in the stepwise protocol and the
desired glycosides were formed in fair to good yields. In
some cases, the yields were not satisfactory because of
undesired imidation of the acceptor and/or decomposi-
tion of the imidates in the presence of acidic and hygro-
whereas Nafion -SAC (0.12 mmol/g), Nafion -TMS
(0.5 mmol/g), and PTBD (2.7 mol/g) were from Aldrich
Co.
11. Harmer, M. A.; Farneth, W. E.; Sun, Q. J. Am. Chem.
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3. Percec, V.; Johansson, G.; Ungar, G.; Zhou, J. P. J. Am.
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scopic Nafion -SAC. But in other cases, an even higher
yield was obtained than that with the corresponding
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Lett. 2004, 6, 719–722.
20
1
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1
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1
skillful measurement of H NMR spectra.
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20. Oikawa, M.; Tanaka, T.; Kusumoto, S., in prepa-
ration.