Catalytic and stereoselective glycosylation with glycosyl N-trichloroacetylcarbamate

Article abstract of DOI:10.1016/j.tetlet.2005.11.027

Catalytic and stereoselective glycosylation efficiently proceeded by activating a glycosyl N-trichloroacetylcarbamate with a catalytic amount of Lewis acids in the presence of a glycosyl acceptor and molecular sieves 5 ?. Catalytic and one-pot dehydrative

Full text of DOI:10.1016/j.tetlet.2005.11.027

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 267–271
Catalytic and stereoselective glycosylation with glycosyl
N-trichloroacetylcarbamate
ꢀ
Jun-ichi Matsuo, Tatsuya Shirahata and Satoshi Omura*
Center for Basic Research, The Kitasato Institute, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8642, Japan
Received 9 August 2005; revised 3 November 2005; accepted 7 November 2005
Available online 22 November 2005
Abstract—Catalytic and stereoselective glycosylation efficiently proceeded by activating a glycosyl N-trichloroacetylcarbamate with
˚
a catalytic amount of Lewis acids in the presence of a glycosyl acceptor and molecular sieves 5 A. Catalytic and one-pot dehydrative
glycosylation of a 1-hydroxy carbohydrate was also performed stereoselectively by the reaction with trichloroacetyl isocyanate fol-
lowed by activation with a catalytic amount of activators.
Ó 2005 Elsevier Ltd. All rights reserved.
For an efficient O-glycosyl bond formation,1 it is desir-
able that glycosyl donors should be prepared conve-
niently, and thus-prepared glycosyl donors should be
activated under mild conditions to realize stereoselective
glycosylation. From these viewpoints, we were inter-
ested in the high reactivity of trichloroacetyl isocyanate,
which usually reacts with alcohols under neutral condi-
tions to give the corresponding N-trichloroacetyl carba-
mates, and we were also interested in the possibility that
the N-trichloroacetyl carbamate group would work as a
good leaving group. Although some glycosylation reac-
tions of glycosyl carbamates have been reported to date,
glycosyl carbamates were activated with a stoichiometric
amount of activators in these cases. For example, Kunz
and Zimmer reported a glycosylation of glycosyl N-allyl-
carbamates by activation of the allylic double bond
with soft electrophiles,2 and Lacombe and co-workers
reported a glycosylation by activating glycosyl N-phen-
ylcarbamates with 1.5 equiv of BF3–Et2O.3 Various
combinations of glycosyl carbamates and a stoichio-
metric amount of Lewis acids were investigated by
Redlich and co-workers.4 The only exception was that
glycosyl N-alkyl-N-p-toluenesulfonylcarbamates were
activated with a catalytic amount of Me3SiOTf,5 but,
in that case, N-unalkylated sulfonylcarbamates were
not activated with a catalytic amount of Me3SiOTf,
and N-methylation or N-cyanomethylation was needed
for the catalytic activation. In this letter, we describe
catalytic and stereoselective glycosylation with a glyco-
syl N-trichloroacetylcarbamate, and catalytic one-pot
dehydrative glycosylation of 1-hydroxy carbohydrate.
N-Trichloroacetylcarbamate donor 1 was prepared from
2,3,4,6-tetra-O-benzyl-D-glucopyranose 2 (a/b = 86/14,
1
determined by H NMR in C6D6) by the reaction of
1.1 equiv of trichloroacetyl isocyanate in dry CH2Cl2
at room temperature (Scheme 1).4 The reaction com-
pleted within 30 min, and evaporation of CH2Cl2 in
vacuo gave 1 quantitatively as a mixture of anomers
1
(a/b = 89/11, determined by H NMR). Thus-prepared
donor 1 could be employed in the next glycosylation
reaction without any further purification, and was
stored in a refrigerator. If necessary, 1 was purified by
column chromatography on silica gel, and the a-anomer
of 1 was isolated in 72% yield.6
Keywords: Glycosylation; Lewis acids; Solvent effects; Synthetic
methods.
*
Corresponding author. Tel.: +81 5791 6101; fax: +81 3 3444 8360;
e-mail: omura-s@kitasato.or.jp
Present address: Division of Pharmaceutical Sciences, Graduate
School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan.
Scheme 1. Preparation of a glycosyl donor 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.027

268
J. Matsuo et al. / Tetrahedron Letters 47 (2006) 267–271
Table 1. Effect of Lewis acids in glycosylation with the donor 1a
Entry
Activator (equiv)
Solvent
Reaction conditions
Isolated yield (%)
a/bb
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
15c
Zn(OTf)2 (1.2)
TfOH (1.2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
Et2O
MeCN
EtCN
rt, 2 days
rt, 2 h
rt, 1.5 h
rt, 2.5 h
0
40
49
73
84
95
92
61
84
98
99
97
98
93
93
—
71/29
40/60
73/27
74/26
61/39
70/30
47/53
44/56
87/13
93/7
Sc(OTf)3 (1.2)
Mg(ClO4)2 (1.2)
Cu(OTf)2 (1.2)
Me3SiOTf (1.2)
Me3SiOTf (0.2)
SnCl4 (1.2)
rt, 1.5 h
0 °C, 20 min
0 °C, 1 h
0 °C, 20 min
0 °C, 2 h then rt, 2 h
0 °C, 8 h
0 °C, 1 h
0 °C, 3 h
SnCl4 (0.2)
Me3SiOTf (1.2)
Me3SiClO4 (1.2)
Me3SiClO4 (0.2)
Me3SiClO4 (0.1)
Me3SiOTf (1.2)
Me3SiOTf (0.2)
94/6
93/7
6/94
7/93
0 °C, 18 h
À40 °C, 40 min
À40 °C, 40 min then À23 °C, 1 h
a The donor 1 (a/b = 89/11) was used unless otherwise noted.
b Determined by 1H NMR (500 MHz) and HPLC.
c The a-isomer of 1 was employed.
With the glycosyl donor 1 in hand, we next screened
suitable activation conditions in the glycosylation of 1
with methyl 2,3,4-tri-O-benzoyl-D-glucoside 3 in the
ation. Interestingly, the present catalytic glycosylation
had to be carried out in the presence of MS5A because
Me3SiClO4-catalyzed glycosylation did not proceed in
the presence of MS4A or MS3A. The reason for the out-
standing effects of MS5A was not clear, but the similar
effects of MS5A were observed in the catalytic glycosyl-
ation of glycosyl fluorides.9
˚
presence of molecular sieves 5 A in CH2Cl2 (Table 1,
entries 1–6, and 8). It was found that 1.2 equiv of
Me3SiOTf smoothly catalyzed the glycosylation at
0 °C to afford a disaccharide 4 in 95% yield as a mixture
of anomers (a/b = 61/39). The same reaction proceeded
slowly by using other Lewis acids such as Mg(ClO4)2
and Cu(OTf)2 even at room temperature, and Zn(OTf)2
did not activate the donor 1.
b-Selective glycosylation (a/b = 6/94) was performed by
using MeCN10 as a solvent and a stoichiometric amount
of Me3SiOTf11 (entry 14). In this case, the reaction pro-
ceeded at a lower temperature (À40 °C) than in the case
of the a-selective reaction in Et2O. Catalytic b-selective
glycosylation was also realized by using 20 mol % of
Me3SiOTf in EtCN12 to afford a disaccharide 4 in 93%
yield with a ratio of a/b = 7/93, and the a,b-selectivity
was not influenced by the a,b-ratio of the donor 1 (entry
15).
As in glycosylation with other glycosyl donors, such as
glycosyl fluorides,7 good a-selectivity (a/b = 87/13)
was observed in the Me3SiOTf-catalyzed glycosylation
in Et2O (entry 10). The a-selectivity was further
improved to a ratio of a/b = 93/7 by changing the acti-
vator Me3SiOTf to Me3SiClO4 (entry 11).8 The high
reactivity of 1 led us to consider that a catalytic amount
of Me3SiClO4 might catalyze the present glycosylation.
As expected, when a catalytic amount (20 mol %) of
Me3SiClO4 was employed, the reaction proceeded
smoothly to give 4 in 97% yield while maintaining the
high a-selectivity (entry 12). Even 10 mol % of Me3Si-
ClO4 catalyzed the glycosylation efficiently (entry 13).
In this case, purified a-isomer of 1 was used for the gly-
cosylation, and the a,b-selectivity did not change com-
pared to the case of using an a,b-mixture of 1, which
suggested that Me3SiClO4 effectively activated a carba-
mate carbonyl group of 1, and then an oxonium cation
intermediate was formed in the present glycosylation.
The catalytic glycosylation needed longer reaction time
compared to the stoichiometric glycosylation, and
nearly quantitative yields of disaccharides 4 were
obtained in both stoichiometric and catalytic glycosyl-
Next, the scope and limitations of the catalytic and
stereoselective glycosylation with 1 were investigated
by using various glycosyl acceptors under a- and b-
selective glycosylation conditions (Table 2). Glycosyl
acceptors having primary, secondary, and even tertiary
hydroxy groups readily reacted with the glycosyl donor
1 in Et2O to give a-glycosides in high yields and with
high a-selectivity by using 20 mol % of Me3SiClO4. On
the other hand, though high b-selectivity was observed
in Me3SiOTf-catalyzed glycosylation in EtCN with gly-
cosyl acceptors having a primary hydroxy group, mod-
erate b-selectivities were observed in the cases of
acceptors having secondary and tertiary hydroxy groups
because higher reaction temperature was required for
the reaction of secondary and tertiary hydroxy groups
than primary hydroxy groups. t-BuOH reacted with 1

J. Matsuo et al. / Tetrahedron Letters 47 (2006) 267–271
Table 2. Stereoselective and catalytic glycosylation of 1 with various acceptors
269
Acceptors (ROH)
a-Selective glycosylationa
0 °C, 4 h 99% a/b = 94/6
b-Selective glycosylationb
À40 °C, 0.5 h then À23 °C, 3 h 97% a/b = 7/93
0 °C, 5 h 93% a/b = 90/10
0 °C, 3 h 86% a/b = 96/4
À40 °C, 1.5 h then À23 °C, 16 h 83% a/b = 15/85
À20 °C, 1 h 74% a/b = 17/83
0 °C, 4 h 93% a/b = 94/6
0 °C, 2 h then rt, 1 h 88% a/b = 21/79
0 °C, 3 h 90% a/b = 92/8
0 °C, 19 h 89% a/b = 86/14
À40 °C, 0.5 h then À23 °C, 4.5 h 88% a/b = 20/80
rt, 4 daysc 38% a/b = 39/61
a Me3SiClO4 (20 mol %) in Et2O.
b Me3SiOTf (20 mol %) in EtCN.
c The glycosyl donor 1 (1.0 equiv) and t-BuOH (2.0 equiv) were employed.
very slowly in EtCN, and the corresponding t-butyl gly-
coside was obtained in low yield (38%). Moreover, a gly-
cosyl donor 12 which was prepared from 2,3,4,6-tetra-
O-benzyl-D-galactose 11 (quant., a/b = 66/34) was
smoothly activated with a catalytic amount of Me3Si-
ClO4 to give a disaccharide 13 in 90% yield (a/b = 87/
13, Scheme 2).
Most of the conventional glycosylation reactions have
been conducted by two steps: that is (1) isolation of a
glycosyl donor having a latent leaving group at the
anomeric position and (2) activation of the leaving
group in the presence of a glycosyl acceptor. When
glycosyl donors are unstable to be isolated, it is desirable
to perform the glycosylation by derivatizing a stable
1-hydroxy carbohydrate to a reactive glycosyl donor,
followed by the successive activation in a one-pot
manner. The one-pot glycosylation (i.e., dehydrative
glycosylation)13 was then investigated by the activation
of in situ-formed 1 as a model reaction, though 1 was
stable to be isolated (Table 3). In this dehydrative glyco-
sylation starting from 2, CH2Cl2 was used as co-solvent
in the preparation of the carbamate donor 1 because of
Scheme 2. Catalytic glycosylation with a donor 12.
the low solubility of 2 in Et2O and EtCN. Stoichiometric
one-pot glycosylation proceeded smoothly by using

270
J. Matsuo et al. / Tetrahedron Letters 47 (2006) 267–271
Table 3. One-pot dehydrative glycosylation
Entry
Activator (equiv)
Solventa
Reaction conditions
Isolated yield (%)
a/bb
1c
2
Me3SiClO4 (1.5)
Me3SiClO4 (0.2)
Me3SiOTf (1.5)
Me3SiOTf (0.2)
Et2O
Et2O
EtCN
EtCN
0 °C, 0.5 h
0 °C, 0.5 h
99
88
88
85
93/7
91/9
8/92
12/88
3c
4
À40 °C, 0.5 h then À23 °C, 0.5 h
À40 °C, 1 h then À23 °C, 1 h
a Solvent/CH2Cl2 = 5/1.
b Determined by 1H NMR (500 MHz).
c MS5A was not used.
3. Prata, C.; Mora, N.; Lacombe, J.-M.; Maurizis, J. C.;
1.5 equiv of Me3SiClO4 in Et2O or Me3SiOTf in EtCN
to afford a- or b-glycoside, respectively, in high yields
(entries 1 and 3). Also, catalytic one-pot dehydrative
glycosylation proceeded stereo- selectively in the pres-
ence of MS5A (entries 2 and 4). The one-pot stoichiom-
etric glycosylation proceeded smoothly in the absence of
MS5A, while the one-pot catalytic glycosylation needed
MS5A.
Pucci, B. Tetrahedron Lett. 1997, 38, 8859–8862.
4. Knoben, H.-P.; Schluter, U.; Redlich, H. Carbohydr. Res.
¨
2004, 339, 2821–2833.
5. Hinklin, R. J.; Kiessling, L. L. J. Am. Chem. Soc. 2001,
123, 3379–3380.
6. The preparation of 1: to the stirred solution of 2,3,4,6-
tetra-O-benzyl-D-glucopyranose 2 (1.00 g, 1.85 mmol) in
dry CH2Cl2 (freshly distilled from CaH2, 5 mL) was added
trichloroacetyl isocyanate (0.24 mL, 2.01 mmol) at 0 °C.
After the reaction mixture was stirred for 0.5 h at room
temperature (26 °C), the solvent was evaporated in vacuo
to give 1 as a colorless syrup (quant., a/b = 89/11,
determined by 1H NMR). If necessary, the a-isomer
(Rf = 0.40, hexane/AcOEt = 3/1) and the b-isomer
(Rf = 0.34, hexane/AcOEt = 3/1) were separated, and the
a-isomer was isolated in 72% yield by column chroma-
tography on silica gel (hexane/AcOEt = 7/1). a-Isomer:
1H NMR (500 MHz, CDCl3): 8.37 (s, 1H), 7.36–7.13 (m,
20H), 6.39 (d, J = 3.7 Hz, 1H), 4.95 (d, J = 11.0 Hz, 1H),
4.85 (d, J = 10.5 Hz, 1H), 4.84 (d, J = 11.0 Hz, 1H), 4.74
(d, J = 11.4 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.60 (d,
J = 12.4 Hz, 1H), 4.51 (d, J = 10.5 Hz, 1H), 4.48 (d,
J = 12.4 Hz, 1H), 3.97 (t, J = 9.6 Hz, 1H), 3.91 (m, 1H),
3.79–3.72 (m, 3H), 3.66 (dd, J = 10.5, 1.8 Hz, 1H); 13C
NMR (125 MHz, CDCl3): 157.4, 148.6, 138.3, 137.7,
137.5, 137.0, 128.4, 128.2, 128.0, 127.8, 127.6, 127.5, 93.7,
91.5, 81.2, 78.3, 76.5, 75.5, 75.1, 73.4, 73.4, 67.7. b-Isomer:
1H NMR (500 MHz, CDCl3): 8.20 (s, 1H), 7.33–7.12 (m,
20H), 5.62 (d, J = 8.2 Hz, 1H), 4.91–4.72 (m, 4H), 4.72 (d,
J = 11.5 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.52 (d,
J = 11.0 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.80–3.57 (m,
6H).
Thus, a- or b-selective glycosylation of using glycosyl N-
trichloroacetylcarbamate 1 as a glycosyl donor pro-
ceeded efficiently by activating the donor with a catalytic
amount of Me3SiClO4 in Et2O or Me3SiOTf in EtCN,
respectively, in the presence of MS5A.14 Preparation
of 1 from a 1-hydroxy carbohydrate 2 and successive
stereoselective and catalytic glycosylation were also real-
ized in a one-pot manner, and the desired a- or b-glyco-
side was obtained directly from 2. The easy operation of
the present glycosylation, especially one-pot dehydrative
glycosylation, would be useful in the synthesis of oligo-
saccharides or bioactive compounds having carbo-
hydrate parts.
Acknowledgements
The authors thank for the financial support from Nov-
artis Foundation, Japan, for the Promotion of Science,
and this work was partially supported by Grants-
in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan.
7. Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett.
1984, 25, 1379–1382.
8. Nakarahra, Y.; Ogawa, T. Carbohydr. Res. 1990, 200,
363–375.
9. (a) Jona, H.; Mandai, H.; Chavasiri, W.; Takeuchi, K.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 2002, 75, 291–309;
(b) Toshima, K.; Kasumi, K.; Matsumura, S. Synlett 1998,
643–645.
10. Kreuzer, M.; Thiem, J. Carbohydr. Res. 1986, 149, 347–
361.
11. Me3SiClO4 was not employed for b-selective glycosylation
because it was reported that ClO4À was a suitable counter
anion for a-selective glycosylation and less effective for b-
selective glycosylation.15
References and notes
1. (a) Boons, G. J. Tetrahedron 1996, 52, 1095–1121; (b)
Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
1996, 35, 1380–1419; (c) Schmidt, R. R.; Kinzy, W. Adv.
Carbohydr. Chem. Biochem. 1994, 50, 21–123; (d)
Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–
1531; (e) Sina¨y, P. Pure Appl. Chem. 1991, 63, 519–528.
2. Kunz, H.; Zimmer, J. Tetrahedron Lett. 1993, 34, 2907–
2910.

J. Matsuo et al. / Tetrahedron Letters 47 (2006) 267–271
271
12. EtCN gave better results for b-selective catalytic glycosyl-
ation with 1 than MeCN.
13. Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122,
4269–4279, and references cited therein.
14. Typical experimental procedure for the catalytic glycosyl-
ation is as follows (Table 1, entry 12): to a stirred
suspension of MS5A (120 mg), the acceptor 3 (20.0 mg,
0.040 mmol), and the donor 1 (34.6 mg, 0.047 mmol) in
dry Et2O (3 mL) was added a solution of Me3SiClO4 in
Et2O (0.1 N, 0.08 mL, prepared from Me3SiCl and
AgClO4) at 0 °C. After the reaction mixture was stirred
at 0 °C for 3 h, the reaction was quenched by adding
saturated NaHCO3 solution and the mixture was filtered
through Celite pad, extracted with AcOEt. The combined
organic extracts were washed with H2O and brine, dried
over anhydrous Na2SO4, filtered, and concentrated. A
crude product was purified by preparative TLC (silica gel,
benzene/AcOEt = 10:1) to afford
4 (a colorless oil,
39.5 mg, 0.038 mmol, 97%) as a mixture of anomers (a/
b) = 94/6, determined by 1H NMR (500 MHz) and by
HPLC (Pegasil 60-5, hexane/AcOEt = 4:1, 1 mL/min,
254 nm).
15. Jona, H.; Mandai, H.; Mukaiyama, T. Chem. Lett. 2001,
426–427.