TMSCl as a mild and effective source of acidic catalysis in Fischer glycosidation and use of propargyl glycoside for anomeric protection

Article abstract of DOI:10.1271/bbb.66.211

Practical Fischer glycosidation was effected at room temperature or 60°C by using 5 to 10 equiv. of TMSCl. The anomeric propargyl group formed by this method was found to be a versatile new protecting group, being stable in neat TFA but readily cleaved by treatment with Co₂(CO)₈ and TFA in CH₂Cl₂ via the formation of an alkyne-Co complex.

Full text of DOI:10.1271/bbb.66.211

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TMSCl as a Mild and Effective Source of Acidic
Catalysis in Fischer Glycosidation and Use of
Propargyl Glycoside for Anomeric Protection
Minoru IZUMIa, Koichi FUKASEa & Shoichi KUSUMOTOa
a Department of Chemistry, Graduate School of Science, Osaka University Toyonaka,
Osaka 560-0043, Japan
Published online: 22 May 2014.
To cite this article: Minoru IZUMI, Koichi FUKASE & Shoichi KUSUMOTO (2002) TMSCl as a Mild and Effective Source
of Acidic Catalysis in Fischer Glycosidation and Use of Propargyl Glycoside for Anomeric Protection, Bioscience,
Biotechnology, and Biochemistry, 66:1, 211-214, DOI: 10.1271/bbb.66.211
To link to this article: http://dx.doi.org/10.1271/bbb.66.211
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Biosci. Biotechnol. Biochem., 66 (1), 211–214, 2002
Note
TMSCl as a Mild and EŠective Source of Acidic Catalysis in Fischer
Glycosidation and Use of Propargyl Glycoside for Anomeric Protection
Minoru IZUMI, Koichi FUKASE,† and Shoichi KUSUMOTO
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
Received August 6, 2001; Accepted September 25, 2001
Practical Fischer glycosidation was eŠected at room
temperature or 60 C by using 5 to 10 equiv. of TMSCl.
9
The anomeric propargyl group formed by this method
was found to be a versatile new protecting group, being
stable in neat TFA but readily cleaved by treatment with
Co2(CO)8 and TFA in CH2Cl2 via the formation of an
alkyne–Co complex.
Fig. 1. Possible Mechanism for Fischer Glycosidation with
TMSCl.
Key words: Fischer glycosidation; protective group;
TMSCl; acid catalyst
Chlorotrimethylsilane (TMSCl) has been used as
an acid catalyst for esteriˆcation and ketal forma-
tion.1,2) In these reactions, TMSCl ˆrst reacts with al-
cohols or carboxylic acids to form HCl which is
probably the ultimate catalyst for these reaction sys-
tems. TMSCl can also trap water and thus eŠectively
promote dehydration reactions when more than a
stoichiometric amount of TMSCl is used.
Table 1. Fischer Glycosidation with TMSCl
Fischer glycosidation has been used for the ano-
meric protection of monosaccharides. Since the reac-
tion is carried out in the presence of an acid catalyst
in alcohols under re‰ux, certain amounts of by-
products are generally formed. In the present study,
we found that TMSCl eŠectively promoted Fischer
glycosidation under milder reaction conditions.
Glycosidation proceeded at room temperature by us-
ing 10 equiv. of TMSCl and alcohols as solvents
(Table 1, entries 1–8). At the early stage of the reac-
tion,
days were required for su‹cient anomerization from
-anomers to -anomers, although most of the start-
ing materials were glycosidated after 1 d. -Glyco-
b-anomers were preferentially formed. Three
b
a
a
sides were obtained with high selectivity after being
converted to the 4,6-benzylidene derivative with sub-
sequent crystallization. Since the anomerization rate
of the allyl glycoside of
slow, a mixture of - and
even after the reaction had proceeded for 3 d
(Table 1, entry 4). The glycosidation reaction
proceeded more rapidly at 60
of TMSCl was su‹cient for the reaction (Table 1, en-
tries 9–14). With the present glycosidation reaction, a
N
-acetylglucosamine was
-anomers was obtained
a
b
large excess of alcohols as solvents was required; the
reaction didn't proceed in THF, dioxane, or toluene
(TMSCl, 10 equiv.; alcohol, 3 equiv.).
We have recently reported a propargyloxycarbonyl
group for protecting amino and hydroxy functions.3)
This new protecting group is stable against neat TFA
9
C; in this case, 5 equiv.
†
To whom correspondence should be addressed. Tel: +81-6-6850-5391; Fax: +81-6-6850-5419; E-mail: koichi
＠
chem.sci.osaka-u.ac.jp
Abbreviations: Alloc, allyloxycarbonyl; Troc, 2,2,2-trichloroethoxycarbonyl

212
M. IZUMI et al.
Table 2. Cleavage of the 1-O-Propargly Group with Co2(CO)8
and TFA
but is readily cleaved at ambient temperature by
treatment with Co2(CO)8 and TFA in CH2Cl2 via for-
mation of the corresponding alkyne–Co complex.
We, therefore, expected propargyl glycosides to simi-
larly serve as a good protecting group for anomeric
hydroxy functions. Propargyl glycosides have been
prepared from glycosyl acetate with propargyl alco-
4)
・
hol in the presence of BF3 Et2O, since Fischer
glycosidation with propargyl alcohol under conven-
tional conditions aŠords complex mixtures owing to
polymerization of the propargyl group. We found
that propargyl glycosides could be obtained in good
yields under the present mild conditions by using
10 equiv. of TMSCl at room temperature (Table 1,
entries 5–8). Reaction at a higher temperature
9
(5 equiv. of TMSCl at 60 C) gave a complex mixture.
Propargyl glycosides are stable under various reac-
tion conditions, e.g., treatment with neat TFA, alka-
line hydrolysis, and benzylation with BnBr and NaH.
the reaction mixture gave a solid which was succes-
sively washed with water and Et2O-hexane (1:1) to
However, the 1-
O
-propargyl group could be readily
give pure product 2a in a yield of 1.97 g (64
z
).
removed by treating with Co2(CO)8, purifying the
alkyne–Co complex, and cleaving the complex with
TFA and H2O in CH2Cl2.5) Both the benzylidene and
propargyl groups were cleaved by a treatment with
2a: 1H-NMR (CDCl3)
d: 2.61 (1H, s, 3-OH),
3.59–3.60 (2H, m, H-2 and H-4), 3.62 (1H, d,
＝
J
5.2 Hz, H-6b), 3.86–3.88 (1H, m, H-5), 3.92–4.15
＝
＝
10.4,
(2H, m, OCH2–CH CH2), 4.26 (1H, dd,
5.2 Hz, H-6a), 4.51 (1H, t, 9.0 Hz, H-3),
3.0 Hz, H-1), 5.29–5.34 (2H, m,
OCH2–CH CH2), 5.54 (1H, s, PhCHO2), 5.89 (1H,
m, OCH2–C CH2), 7.35–7.48 (5H, m, PhCHO2).
2b: 1H-NMR (CDCl3)
: 2.61 (1H, s, 3-OH),
3.57 (1H, dd, 9.2, 9.1 Hz, H-4), 3.76 (1H, t,
J
50
z
TFA in CH2Cl2 (Table 2).
J
＝
＝
J
As described, TMSCl works as both an acid
5.05 (1H, d,
＝
catalyst and dehydrating agent in the presence of an
alcohol. Although excess TMSCl was required for
the foregoing reactions, TMSCl could be readily re-
moved by simple evaporation. Propargyl glycosides
were easily prepared by this Fischer glycosidation
method and readily cleaved by a treatment with
Co2(CO)8 and TFA.
H
＝
d
J
＝
＝
＝
10.1, 9.2,
J
10.1 Hz, H-6b), 3.85 (1H, ddd,
4.8 Hz, H-5), 3.92–4.04 (2H, m, H-2 and H-3),
4.04–4.15 (2H, m, OCH2–CH CH2), 4.28 (1H,
10.1, 4.8 Hz, H-6a), 4.79 (1H, d,
11.9 Hz, CCl3CH2OCO), 4.82 (1H, d,
J
＝
＝
J
dd,
＝
＝
J
J
Experimental
＝
3.2 Hz,
＝
11.9 Hz, CCl3CH2OCO), 4.93 (1H, d,
J
NMR spectra were taken with a Jeol Lambda-600
NMR spectrometer (600 MHz for protons). Unless
otherwise stated, the chemical shift in CDCl3 is given
H-1), 5.29–5.33 (3H, m, NH and OCH2–CH CH2),
5.56 (1H, s, PhCHO2), 5.90 (1H, m, OCH2–CH
CH2), 7.35–7.50 (5H, m, PhCHO2).
＝
in
d
values from tetramethylsilane (0 ppm) as an in-
2c: 1H-NMR (CDCl3)
d: 3.68–3.84 (3H, m, H-2, H-3
＝ ＝
and H-6b), 3.76–3.97 (2H, m, C( O)OCH2–CH
ternal standard. Elemental analyses were performed
by the staŠ of our department. Anhydrous solvents
were purchased from Kanto Chemicals Co., all other
commercially obtained materials being used as
received.
CH2), 3.99 (1H, m, H-4), 4.15 (1H, m, H-5),
4.25–4.27 (1H, m, H-6a), 4.62–4.84 (2H, m,
＝
OCH2–CH CH2), 4.84 (1H, s, N
H ), 4.93 (1H, d,
J
＝
3.2 Hz, H-1), 5.20–5.34 (4H, m, OCH2–CH
＝
×
CH2 2), 5.58 (1H, s, PhCHO2), 5.83–5.93 (2H, m,
The typical procedure for Fischer glycosidation at
room temperature used 10 equiv. of TMSCl. To a
suspension of glucose 1a (1.80 g, 10 mmol) in allyl
alcohol (29.1 ml, 500 mmol) was added chlo-
rotrimethylsilane (12.6 ml, 100 mmol). The mixture
was stirred at room temperature for 3 d and then con-
centrated under reduced pressure. Toluene was ad-
ded to the residue, and the solution evaporated. To a
solution of the residue in CH3CN (25 ml) were added
benzaldehyde dimethylacetal (2.25 ml, 15 mmol) and
＝
×
OCH2–C
2d: 1H-NMR (CDCl3)
2.99–3.63 (2H, m, H-4 and H-6b), 3.76–3.92 (3H, m,
H
CH2 2), 7.35–7.49 (5H, m, PhCHO2).
d
: 2.06 (3H, s, AcNH),
＝
H-2, H-3 and H-5), 4.27 (1H, m, OC
H
2–CH CH2),
＝
4.31–4.39 (2H, m, OCH2–CH CH2, H-6a), 4.89
＝
(1 2H, d,
J
8.1 Hz, H-1
b), 5.03 (1 2H, d,
W
W
J
＝
3.9 Hz, H-1a), 5.56 (1H, s, PhCHO2), 7.35–7.50
(5H, m, PhCHO2).
3a: 1H-NMR (CDCl3)
d
: 2.47 (1H, t,
J
＝
3.0 Hz,
p
-toluenesulfonic acid (0.19 g, 1 mmol). The mixture
OCH2–CCH), 3.59–3.60 (2H, m, H-2 and H-4), 3.62
＝
was stirred at room temperature for 5 h. The addition
of a saturated aqueous NaHCO3 solution (50 ml) to
(1H, d,
J
5.2 Hz, H-6b), 3.86–3.88 (1H, m, H-5),
10.4, 5.2 Hz, H-6a), 4.30 (2H, d,
4.26 (1H, dd,
J
＝

TMSCl-Promoted Fischer Glycosidation
213
＝
＝
J
3.0 Hz, OCH2–CCH), 4.51 (1H, t,
J
9.0 Hz,
3.0 Hz, H-1), 5.54 (1H, s,
PhCHO2), 7.35–7.48 (5H, m, PhCHO2). Anal.
fonic acid (0.19 g, 1 mmol). The mixture was stirred
at room temperature for 5 h. The solution was neu-
tralized with a saturated aqueous NaHCO3 solution
(50 ml) to give a solid which was successively washed
with water and Et2O-hexane (1:1) to give pure
＝
J
H-3), 5.05 (1H, d,
・
z. Calcd. for C16H18O6
Found: C, 61.24; H, 5.98
1 2H2O: C, 60.95; H, 6.07
z
.
W
3b: 1H-NMR (CDCl3)
d
: 2.43 (1H, t,
J
3.0 Hz,
product 2a in a yield of 2.16 g (70z).
＝
OCH2–CCH), 3.57 (1H, m, H-4), 3.76 (1H, m, H-
6b), 3.85–3.98 (3H, m, H-2, H-3 and H-5), 3.99–4.04
Acknowledgments
＝
＝
3.0 Hz,
(2H, m, OCH2–CH CH2), 4.16 (2H, d,
OC 2–CCH), 4.28 (1H, dd, 10.1, 4.8 Hz, H-6a),
4.79–4.82 (2H, m, CCl3CH2OCO), 4.93 (1H, d,
J
H
J
＝
The present work was ˆnancially supported in part
by ``Research for the Future'' program No.
97L00502 from the Japan Society for the Promotion
of Science, by special coordination funds from the
Science and Technology Agency of the Japanese
Government, and by grant-aid for scientiˆc research
Nos. 09044086 and 12640571 from the Ministry of
Education, Science and Culture, Japan.
＝
J
3.4 Hz, H-1), 5.56 (1H, s, PhCHO2), 7.35–7.50
(5H, m, PhCHO2). Anal. Found: C, 47.54; H, 4.08;
N, 2.95 . Calcd. for C19 H20O7NCl3: C, 47.47; H,
4.19; N, 2.91
3c: 1H-NMR (CDCl3)
OCH2–CCH), 3.52 (t, 1H,
3.68–3.78 (4H, m, H-4, H-5 and H-6), 3.81–3.84
z
z
.
＝
d
: 2.42 (1H, t,
J
3.0 Hz,
＝
J
10.9 Hz, H-3),
＝
＝
3.0 Hz,
(2H, m, OCH2–CH CH2), 4.25 (2H, d,
J
References & Notes
OCH2–CCH), 4.44–4.45 (1H, m, H-2), 4.48 (1H, s,
＝
3.7 Hz, H-1), 5.06–5.25 (2H,
N
H
), 4.98 (1H, d,
J
1) Brook, M. A. and Chan, T. H., A simple procedure
＝
m, OCH2–CH CH2), 5.55 (1H, s, PhCHO2),
for the esteriˆcation of carboxylic acids. Synthesis
201–203 (1983).
,
＝
5.86–5.92 (1H, m, OCH2–CH CH2), 7.34–7.50
2) Chan, T. H., Brook, M. A., and Chaly, T., A simple
procedure for the acetalization of carbonyl com-
pounds. Synthesis, 203–205 (1983). Esteriˆcation was
basically eŠected by using 2.2 equiv. of TMSCl and an
alcohol as the solvent at room temperature or under
re‰ux in THF. We found that the esteriˆcation of N-
‰uorenylmethyloxycarbonyl (Fmoc) amino acids also
proceeded smoothly in CH2Cl2 at room temperature by
using 2 equiv. of an alcohol and 5 equiv. of TMSCl
against a carboxylic acid to give the desired ester quan-
titatively.
(5H, m, PhCHO2). Anal. Found: C, 59.45; H, 5.89;
N, 3.48
z
. Calcd. for C20 H23O7N
・
2 3H2O: C, 59.84;
W
H, 6.11; N, 3.49
z
.
1
3d: H-NMR (CDCl3)
(1H, t, 3.0 Hz, OCH2–CCH), 3.48-3.63 (2H, m,
d
: 2.06 (3H, s, AcNH), 2.49
J
＝
H-4 and H-6b), 3.73–3.95 (3H, m, H-2, H-3 and
H-5), 4.17–4.39 (4H, m, OCH2–CCH, H-4 and H-
＝
6a), 4.89 (1 6H, d,
J
8.3 Hz, H-1
), 5.56 (1H, s, PhCHO2), 7.35–7.50
(5H, m, PhCHO2). Anal. Found: C, 60.54; H, 6.09;
b), 5.03 (5 6H, d,
W
W
＝
J
4.0 Hz, H-1a
・
z. Calcd. for C18 H21O6N 1 2H2O: C, 60.67;
3) Fukase, K., Fukase, Y., and Kusumoto, S., Propar-
gyloxycarbonyl and propargyl groups for novel protec-
tion of amino, hydroxy, and carboxy functions. Tetra-
hedron Lett., 40, 1169–1170 (1999).
N, 3.87
W
H, 6.22; N, 3.93
z
.
1
4a: H-NMR (CDCl3)
d
: 2.66 (1H, s, 3-OH), 3.30
3), 3.55–3.62 (3H, m, H-2, H-4 and H-
6b), 3.86–3.88 (1H, m, H-6a), 4.23 (1H, dd, 9.1,
9.1 Hz, H-53), 4.75
3.6 Hz, H-1), 5.54 (1H, s, PhC O2),
7.35–7.48 (5H, m, PhCHO2).
5a: 1H-NMR (CDCl3)
: 2.67 (1H, s, 3-OH),
3.59–3.60 (2H, m, H-2 and H-4), 3.62 (1H, d,
(3H, s, OC
H
4) Hydrogenation of propargyl glycosides by using a Lin-
dlar catalyst gave the corresponding allyl glycosides.
(See Mereyala, H. B., and Gurrala, S. R., A highly di-
astereoselective, practical synthesis of allyl, propargyl
J
＝
＝
J
5.2 Hz, H-3), 4.34 (1H, t,
(1H, d,
J
＝
H
2,3,4,6-tetra-
sides and allyl, propargyl heptaacetyl-
Carbohydr. Res., 307, 351–354 (1998).) Mereyla et al
O
-acetyl-
b
-
D
-gluco,
b
-
D
-galactopyrano-
d
b-D
-lactosides.
.
＝
J
5.2 Hz, H-6b), 3.86–4.10 (2H, m, H-3 and H-5),
have also reported the glycosidation reaction from
propargyl glycosides via oxymercuration, Baeyer-
Villiger oxidation, and then activation of the resulting
4.26 (1H, dd, 10.4, 5.2 Hz, H-6a), 4.46 (2H, d,
J
＝
＝
＝
4.0 Hz, H-1),
J
8.9 Hz, PhCH2–), 5.01 (1H, d,
J
・
acetoxymethyl glycosides by BF3 Et2O. (See Mereyala,
5.56 (1H, s, PhCHO2), 7.26–7.50 (10H, m, PhCH2–
and PhCHO2).
H. B. and Gurrala, S. R., Design, development and
utility of glycosyl donors bearing an acetoxymethoxy
leaving group. Chem. Lett., 863–864 (1998).) Inter-
molecular alkyne cyclotrimerization by using Grubbs'
catalyst has been reported and applied to the synthesis
of trivalent carbohydrate derivatives from propargyl
glycosides. (See Das, S. K. and Roy, R., Mild
ruthenium-catalyzed intermolecular alkyne cyclotr-
imerization. Tetrahedron Lett., 40, 4015–4018 (1999).)
5) A typical cleavage reaction of a propargyl glycoside
with Co2(CO)8 involved adding to a solution of
1-propargyl glycoside 3a (30.6 mg, 0.10 mmol) in
The typical procedure for Fischer glycosidation at
609C used 5 equiv. of TMSCl. To a suspension of
glucose 1a (1.80 g, 10 mmol) in allyl alcohol (29.1 ml,
500 mmol) was added chlorotrimethylsilane (6.3 ml,
9
50 mmol). The mixture was stirred at 60 C for 5 h,
concentrated under reduced pressure, and the resid-
ual volatile material was coevaporated with toluene.
The residue was dissolved in CH3CN (25 ml). To the
resulting mixture were added benzaldehyde
dimethylacetal (2.25 ml, 15 mmol) and p-toluenesul-

214
M. IZUMI et al.
CH2Cl2 (4 ml), TFA (0.5 ml), water (0.5 ml) and
ed with AcOEt, and the organic layer was washed with
Co2(CO)8 (34.1 mg, 0.10 mmol). The mixture was
stirred at r.t. for 5 h and then an aqueous saturated
NaHCO3 solution was added. The mixture was extract-
brine, dried over MgSO4, and concentrated in vacuo.
The residue was washed with ether to give 1a in a yield
of 18.1 mg (quant.).