New α-selective thermal glycosylation of acetyl-protected 2-acetamido-2-deoxy-β-D-glucopyranosyl diphenylphosphinate

Article abstract of DOI:10.1016/S0008-6215(00)00069-0

This paper describes new α-selective thermal glycosylation using acetyl-protected 2-acetamido-2-deoxy-β-D-glucopyranosyl diphenylphosphinate (4) as a glycosyl donor. When the glycosylation of 4 with 1-hexanol was carried out under various conditions, the conditions using trimethylsilyl trifluoromethanesulfonate as a promoter in nitromethane at reflux temperature were most suitable for the formation of the α anomer. The glycosylation of 4 with the other common alcohols gave corresponding α-glycosides in relatively high yields under the conditions. When cholesterol, a very steric hindered alcohol, was used as a glycosyl acceptor, α-glycoside was also produced predominantly. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(00)00069-0

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Carbohydrate Research 327 (2000) 341–344
Note
New a-selective thermal glycosylation of acetyl-protected
2-acetamido-2-deoxy-b-
D
-glucopyranosyl
diphenylphosphinate
Jun-ichi Kadokawa *, Takeshi Nagaoka, Jun Ebana, Hideyuki Tagaya, Koji Chiba
Department of Materials Science and Engineering, Faculty of Engineering, Yamagata Uni6ersity,
Yonezawa 992-8510, Japan
Received 9 September 1999; accepted 24 February 2000
Abstract
This paper describes new a-selective thermal glycosylation using acetyl-protected 2-acetamido-2-deoxy-b-
D
-glu-
copyranosyl diphenylphosphinate (4) as a glycosyl donor. When the glycosylation of 4 with 1-hexanol was carried out
under various conditions, the conditions using trimethylsilyl trifluoromethanesulfonate as a promoter in ni-
tromethane at reflux temperature were most suitable for the formation of the a anomer. The glycosylation of 4 with
the other common alcohols gave corresponding a-glycosides in relatively high yields under the conditions. When
cholesterol, a very steric hindered alcohol, was used as a glycosyl acceptor, a-glycoside was also produced
predominantly. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Glycosylation; N-Acetyl- -glucosamine; Diphenylphosphinate; a-Glycoside; Anomerization
D
bioorganic chemistry. Among a variety of pre-
viously reported glycosylation procedures of
Glycosides of 2-acetamido-2-deoxy-
D
-glu-
copyranose (N-acetyl-
D
-glucosamine) deriva-
N-acetyl-
D
-glucosamine
derivatives,
the
tives play an important role in organic and
stereoselectivity has been controlled mainly by
the acetamido group at C-2, in which the
reaction has proceeded through oxazoline-ring
formation and b-glycosides were obtained al-
most exclusively [1]. Although a anomers have
been formed by the anomerization of b
anomers, which were initially formed by the
glycosylation of acetylated 2-acetamido-2-de-
oxy-a- -glucopyranosyl chloride with alco-
D
hols, as long a reaction time as 1.5–2 days is
necessary for anomerization [2]. The other
way to obtain a anomers is by the thermal
glycosylation of the above glycosyl chloride in
the presence of an acid scavenger [3]. To
produce a anomers predominantly in the ther-
Scheme 1.
* Corresponding author. Tel.: +81-238-263116; fax: +81-
238-263413.
E-mail address: kadokawa@chem.yz.yamagata-u.ac.jp (J.-i.
Kadokawa).
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00069-0

342
J.-i. Kadokawa et al. / Carbohydrate Research 327 (2000) 341–344
using acetyl-protected 2-acetamido-2-deoxy-b-
-glucopyranosyl diphenylphosphinate (2-
-glu-
D
acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-
D
copyranosyl diphenylphosphinate (4)), as a
glycosyl donor (Scheme 2), which yields a-gly-
cosides predominantly.
Scheme 2.
First, we examined the glycosylation reac-
tion using 4 with 1-hexanol under various
conditions ([4]:[1-hexanol]:[promoter]=1:2:1)
to establish appropriate conditions for the
formation of the a anomer. Table 1 shows the
results of the glycosylation in the presence of
TMSOTf in nitromethane solvent; TMSOTf
and nitromethane were more effective for the
production of the a anomer than the other
promoters and solvents such as SnCl4 and
acetonitrile, respectively. The yields of a and b
anomers were directly determined by 1H
NMR spectra of the reaction mixtures. The
reaction proceeded smoothly for 2 h at the
reflux temperature in nitromethane solvent to
give the a anomer predominantly (entry 4,
Table 1), whereas only the b anomer was
obtained at lower temperature, e.g., 40 °C (en-
try 1). When the reaction mixture of entry 1
was heated at reflux temperature, initially
formed b anomer was gradually anomerized
to the a anomer (entries 2 and 3). Thus, there
are two possibilities for the reaction route to
form a anomer in the glycosylation of 4; one
is the direct route via the free oxonium
cationic intermediate, and the other one is the
anomerization of the b anomer initially
formed.
The thermal glycosylation of 4 with various
alcohols as glycosyl acceptors was carried out
under the conditions of entry 4 in Table 1
(Table 2). In the reaction of 4 with common
alcohols, a glycosides were obtained predomi-
nantly (entries 1–4). Furthermore, cholesterol,
a very steric hindered alcohol, also gave a
corresponding a-glycoside as a predominant
product, although the yield was lower than
that using other alcohols (entry 5).
In conclusion, we examined the thermal gly-
cosylation of 4 having diphenylphosphinate as
a leaving group in the presence of TMSOTf in
nitromethane. The reaction of 4 with various
alcohols proceeded at reflux temperature to
give the a-glycosides predominantly.
Table 1
Glycosylation of 4 with 1-hexanol under various conditions a
Entry Reaction temperature and time
Yield (%) b
a/b anomers
1
2
3
4
40 °C, 2 h
1.4/30.7
40 °C, 2 h“reflux, 5 min
40 °C, 2 h“reflux, 2 h
reflux, 2 h
12.1/23.6
33.9/trace
57.8/trace
a Promoter; Me3SiOTf, solvent; nitromethane, [4]:[glycosyl
acceptor]:[Me3SiOTf]=1.0:2.0:1.0.
b Determined by 1H NMR spectra using trimethylhy-
droquinone as an internal standard.
mal glycosylation, a high reaction tempera-
ture, such as 160 °C, was required and the
acetylation of glycosyl acceptors proceeded as
a side-reaction at that temperature.
The leaving group of glycosyl donors is one
of the most fundamental parameters responsi-
ble for the selectivity and yield of glycosyla-
tion reactions. One of the current
developments in the variation of leaving
groups is glycosylation using glycosyl donors
with phosphorus-containing leaving groups,
such as phosphates [4], phosphinimidates [5,6],
phosphoramidates [7–9], and phosphites [10–
19]. Recently, we have reported the glycosyla-
tion
of
acetylated
b- -glucopyranosyl
D
diphenylphosphinate (1) in the presence of
trimethylsilyl trifluoromethanesulfonate (TM-
SOTf) in nitromethane (Scheme 1) [20]. The
reaction proceeded through an orthoester in-
termediate to produce the corresponding glu-
cosides 2 and the glucosides 3, which were
deacetylated at C-2. In the reaction,
diphenylphosphinate was employed as a new
leaving group of the glycosyl donor.
When this leaving group was applied to
glycosylation using a N-acetyl- -glucosamine
derivative, we found the predominant forma-
tion of the corresponding a-glycosides under
the selected conditions. We now report this
new stereoselective thermal glycosylation
D

J.-i. Kadokawa et al. / Carbohydrate Research 327 (2000) 341–344
343
1. Experimental
powder (9.18 g, 16.8 mmol, 42.5% yield); mp
158–160 °C; [h]D +59.7° (c 0.66, chloro-
1
form); H NMR (CDCl3): l 1.97–2.10 (4 s, 12
General.—TMSOTf, nitromethane, and liq-
uid alcohols as glycosyl acceptors were
purified by distillation under reduced pressure
prior to use. The other reagents were used
without further purification. NMR spectra
were recorded on a Varian Mercury 200 spec-
trometer. Melting points were determined on
a Yanako micro melting point apparatus. Op-
tical rotations were measured with a Jasco
DIP-370 digital polarimeter.
H, CH3CꢀO), 3.96–4.23 (m, 3 H, H-5, 6), 4.40
(m, 1 H, H-2), 5.21 (t, 1 H, J 9.2 Hz, H-4),
5.33 (t, 1 H, J 9.2 Hz, H-3), 5.60 (q, 1 H,
JHCCH 7.6, JHCOP 3.2 Hz, H-1), 6.41 (d, 1 H, J
8.8 Hz, NH), 7.58 (m, 10 H, C6H5). Anal.
Calcd for C26H30NO10P: C, 57.04; H, 5.52; N,
2.56. Found: C, 56.91; H, 5.50; N, 2.51.
General procedure for the glycosylation reac-
tions.—Under argon, 4 (0.100 g, 0.180 mmol)
and alcohol (0.360 mmol) were mixed in ni-
tromethane (2.00 mL) at rt. Then, Me3SiOTf
(0.180 mmol, 0.0353 mL) was added to the
solution and the mixture was heated under
reflux temperature for 2 h. The mixture was
diluted with CHCl3, washed with satd aq
NaHCO3, dried over Na2SO4, filtered, and
evaporated. The yields of respective isomers
were determined by the integrated ratio of the
anomeric peaks with an aromatic peak of
trimethyl hydroquinone as an internal stan-
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-i-
-glucopyranosyl
D
diphenylphosphinate
(4)
[12].—Diphenyl N,N-diethylphosphoramidite
[21–23] (25.7 g, 99.8 mmol) in CH2Cl2 (100
mL) was added to a solution of 2-acetamido-
3,4,6-tri-O-acetyl-2-deoxy- -glucopyranose
D
[12] (13.7 g, 39.4 mmol) and 1,2,4-triazole
(10.9 g, 157 mmol) in CH2Cl2 (500 mL), and
stirred for 12 h at room temperature (rt). The
solution was evaporated, diluted with diethyl
ether, washed with ice-cold satd aq NaHCO3,
and water, dried over Na2SO4, filtered, and
dried in vacuo. Then the residue was dissolved
in CH2Cl2 (100 mL) and H2O2 (30 wt%, 50
mL) was added to the solution. After the
mixture was stirred for 1 h at rt, the solution
was washed with satd aq NaHCO3, dried over
Na2SO4, filtered, and dried in vacuo. The
crude product was purified by silica gel
column chromatography (1:3 hexane–
EtOAc), and the resulting material was
washed with diethyl ether to give 4 as a white
1
dard in the H NMR spectra of the reaction
mixtures (CDCl3). The obtained crude prod-
ucts were isolated by silica gel column chro-
matography. The analytical data of the
isolated a-glycosides are shown as follows.
Hexyl 2-acetamido-3,4,6-tri-O-acetyl-2-de-
oxy-h- -glucopyranoside.—[h]D +81.9° (c
D
1
1.5, chloroform); H NMR (CDCl3): l 0.88–
0.94 (t, 3 H, J 6.4 Hz, CH2CH3), 1.25–1.42
(m, 6 H, (CH2)3CH3), 1.58–1.71 (m, 2 H,
OCH2CH2), 1.96–2.10 (4 s, 12 H, CH3CꢀO),
3.56 (m, 2 H, OCH2CH2), 3.94 (m, 1 H, H-5),
4.17 (m, 2 H, H-6), 4.34 (m, 1 H, H-2), 4.83
(d, 1 H, J 3.8 Hz, H-1), 5.11 (t, 1 H, J 9.0 Hz,
H-4), 5.21 (t, 1 H, J 9.0 Hz, H-3), 5.67 (d, 1
H, J 9.6 Hz, NH). Anal. Calcd for
C20H33NO9: C, 55.67; H, 7.71; N, 3.25. Found:
C, 56.19; H, 8.23; N, 3.28.
Table 2
Glycosylation of 4 with various alcohols a
Entry
Glycosyl acceptor
Yield (%) b
a/b anomers
Cyclohexyl 2-acetamido-3,4,6-tri-O-acetyl-
1
2
3
4
5
1-Hexanol
Methanol
Cyclohexanol
Allyl alcohol
Cholesterol
57.8 (54.4)/trace
35.2/7.9
77.6 (63.6)/14.0
40.0 (22.3)/6.8
(28.0)/nd
2-deoxy-h- -glucopyranoside.—[h]D +89.8°
D
1
(c 0.76, chloroform); H NMR (CDCl3): l
0.83–1.86 (m, 10 H, ꢁ(CH2)5ꢁ), 2.09–1.95 (4 s,
12 H, CH3), 3.54 (m, 1 H, OCH(CH2)CH2),
4.00–4.21 (m, 3 H, H-5, 6), 4.31 (m, 1 H,
H-2), 4.98 (d, 1 H, J 3.8 Hz, H-1), 5.10 (t, 1
H, J 9.6 Hz, H-4), 5.22 (t, 1 H, J 9.6 Hz, H-3),
5.65 (d, 1 H, J 9.4 Hz, NH). Anal. Calcd for
C20H31NO9: C, 55.93; H, 7.28; N, 3.26. Found:
C, 55.90; H, 7.59; N, 3.31.
a Promoter; Me3SiOTf, solvent; nitromethane, temperature;
reflux, reaction time; 2 h, [4]:[glycosyl acceptor]:[Me3SiOTf]=
1.0:2.0:1.0.
b Determined by 1H NMR spectra using trimethylhy-
droquinone as an internal standard. Values in parentheses are
isolated yields by silica gel column chromatography.

344
J.-i. Kadokawa et al. / Carbohydrate Research 327 (2000) 341–344
2-Propenyl 2-acetamido-3,4,6-tri-O-acetyl-
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2-deoxy-h- -glucopyranoside.—[h]D +79.8°
D
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The authors are indebted to Ms Masa
Karasu of our research group for the technical
assistance. The authors also thank Mr
Takeyoshi Takahashi of Yamagata University
for performing the elemental analyses.
.
.