Side products of glycosidation with selected 2-acetamido-2-deoxy-D-glucopyranosides

Article abstract of DOI:10.1016/S0008-6215(02)00207-0

Allyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-formyl-α-D-glucopyranoside, N-acetyl-2,3,4-tri-O-acetyl-L-fucopyranosylamine and products of O-acetyl group migration were found as side products during glycosidation of selected 2-acetamido-2-deoxy-D-glucopyranosides.

Full text of DOI:10.1016/S0008-6215(02)00207-0

Carbohydrate Research 337 (2002) 1495–1498
www.elsevier.com/locate/carres
Note
Side products of glycosidation with selected
2-acetamido-2-deoxy- -glucopyranosides
D
Janusz Madaj,* Anna Trynda, Magdalena Jankowska, Andrzej Wis´niewski
Sugar Chemistry Group, Department of Chemistry, Uni6ersity of Gdan´sk, ul. Sobieskiego 18, PL-80952 Gdan´sk, Poland
Received 11 June 2002; accepted 9 July 2002
Abstract
Allyl
2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-formyl-a-
D
-glucopyranoside,
N-acetyl-2,3,4-tri-O-acetyl-L-fucopyran-
osylamine and products of O-acetyl group migration were found as side products during glycosidation of selected 2-acetamido-2-
deoxy- -glucopyranosides. © 2002 Elsevier Science Ltd. All rights reserved.
D
Keywords: Acetyl migration; 2-Acetamido-2-deoxy-D-glucopyranosides; N-Acetyl-2,3,4-tri-O-acetyl-L
-fucopyranosylamine; 1H and 13C NMR
In our work on disaccharides containing 2-acetam-
ido-2-deoxy- -glucopyranose (N-acetylglucosamine)
(7) was formed in almost 50% yield as a product of
intermolecular O-acetyl group migration. Additional
O-acetyl group signals at l 2.06 (1H NMR) and l
171.430, 23.587 (13C NMR) confirmed its structure
(Scheme 1).
In the reaction between 2 and 5, we expected disac-
charide formation. In the literature, it is described that
in some reactions of glycopyranosyl bromides3 and
trichloroacetimidates4 with unreactive glycosyl accep-
tors, O-acetyl migration as the side reaction is known.
In some cases an O-allyl group on the anomeric
carbon atom can cause lower activity of the glycosyl
acceptor.10 To find what is the influence of the double
bond in the O-allyl group on this reaction, propyl
D
units, we do not develop new synthetic methodology
but rather apply known chemistry in as efficient man-
ner as possible to the solution of synthetic problems. In
many laboratories, side reactions have been found to
occur during glycosidation reactions, such as aglycon
transfer,1,2 acyl transfer3,4 or formylation.5,6 So we de-
cided to share problems which have occurred in our
lab.
Allyl
glucopyranoside (2), prepared from allyl 2-acetamido-2-
deoxy-a-
-glucopyranoside7 (1), was used as a glycosyl
acceptor in the reaction with methyl 2,3,4-tri-O-acetyl-
a-
-glucopyranosyluronate bromide8 (3). Silver triflate
2-acetamido-4,6-O-benzylidene-2-deoxy-a-
D-
D
2-acetamido-4,6-O-benzylidene-2-deoxy-a-D-glucopy-
D
ranoside (4) was prepared and used in a similar reac-
tion. In the reaction of 3 with 5 in the presence of silver
triflate (Reaction 2), a small amount of the desired
disaccharide (about 5%) and almost 20% propyl 2-
was used as the promoter in the reactions studied.
Unchanged substrates were found in the post-reaction
mixtures, which indicated low reactivity of both com-
pounds under these conditions. In the next reaction
(Reaction 1, see Section 1) the more reactive methyl
acetamido-3-O-acetyl-4,6-O-benzylidene-2-deoxy-a-D-
glucopyranoside (6) were formed. The results indicate
that the influence of a double bond on the reactivity of
compound 2 could be of no great importance. On the
other hand, the lower reactivity of uronic acid deriva-
tives is well known.11,12 To answer the question whether
too low activities of compounds 3 and 5 as glycosyl
donors can cause unsatisfactory results in the synthesis
2,3,4-tri-O-acetyl-a-D-glucopyranosyluronate
trichloroacetimidate9 (5) was used as the glycosyl
donor, and trimethylsilyl triflate was the promoter.
Under these reaction conditions, allyl 2-acetamido-3-O-
acetyl-4,6-O-benzylidene-2-deoxy-a-D-glucopyranoside
of disaccharides, 2,3,4,6-tetra-O-acetyl-a-D-glucopyran-
osyl bromide (6) was used as the model compound
(Reaction 3). After the reaction of 2 with 6 in the
* Corresponding author. Fax: +48-585-3410357
E-mail address: januszm@chemik.chem.univ.gda.pl (J.
Madaj).
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00207-0

1496
J. Madaj et al. / Carbohydrate Research 337 (2002) 1495–1498
presence of silver triflate, a more complex mixture was
formed. Apart from substrates and a small amount of
the desired disaccharide (about 5%), two major prod-
ucts were formed. The first, allyl 2-acetamido-3-O-acet-
amido-3,6-di-O-bezyl-2-deoxy-D-glucopyranoside (13
and 14) in acetonitrile. In both cases the expected
disaccharide was formed in small amounts (about 5%).
Beside products of O-acetyl migration, which were
formed in almost 30% yield, both anomers of N-acetyl-
yl-4,6-O-benzylidene-2-deoxy-a- -glucopyranoside (7)
D
was isolated in 17% yield. Its presence, as before, could
be explained as a result of intermolecular migration of
the O-acetyl group. The second product 9, formed in a
yield similar to that of compound 7, was a derivative of
compound 2 in which the 3-OH group was protected by
an unknown residue. The presence of signals of N-ace-
tyl, O-benzylidene and O-allyl groups in the NMR
spectra and the absence of the free hydroxyl group
signal in the infrared spectrum confirmed that it is a
derivative of 2. There were two additional signals in the
2,3,4-tri-O-acetyl-
L
-fucopyranosylamine
(15)
were
formed in about 30% yield. Their structures were confi-
rmed by NMR spectroscopy. Three singlets of CH3/
OAc and a doublet of three protons bonded to C-6 in
1
the H NMR spectrum indicated a tri-O-acetylfucopy-
ranosyl structure. An addition, a singlet of CH3/NAc at
l 1.99 (2.03 for b anomer), coupled with the H-1
doublet of NH/NAc at l 6.34 (b 6.74) and doublet of
doublets of the anomeric proton at l 5.13 (b 5.87; J1a.2
3.2, J1b,2 7.2, J1a,NH 9.2, J1b,NH 8.0 Hz) confirm the
presence of an N-acetyl group bonded to C-1. The
presence of an N-acetyl group in this compound was
confirmed by signals of CH3/NAc at l 20.79 (b 20.88)
and a carboxyl carbon atom at l 170.03 (b 169.60) in
the 13C NMR spectrum.
1
NMR spectra. In the H spectrum, we found the signal
of one proton at 8.11 ppm and in the 13C spectrum, the
signal of a carbon atom at 160.96 ppm. A DEPT
spectrum of 9 indicated that this additional carbon
atom is bonded to one proton. Signals of coupling
between the proton at 8.11 ppm and C-3 and H-3 and
the carbon at 160.96 on the HMBC spectrum proved
the allyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-
Similar results were obtained when 10 reacted with
allyl or propyl 2-acetamido-3,4-di-O-benzyl-2-deoxy-D-
glucopyranoside (18 and 19) in acetonitrile. Products of
migration of the O-acetyl group at C-6 and 15 were
formed in about 40 and 50% yield, respectively. When
reactions of 10 with 18 or 19 were carried out in
dichloromethane, the expected disaccharides allyl and
formyl-a- -glucopyranoside structure for 9. Pozsgay
D
and Nanasi6 reported the formation of a 6-O-formyl
derivative as a side product of glycosidation, what they
explained as a Vilsmeier-type formylation with N,N-
dimethylformamide. In our case, we did not use DMF,
so the mechanism for the formation of 9 must be some
other reaction. Additionally we carried out the reaction
propyl
2,3,4-tri-O-acetyl-
L
-fucopyranosyl-(1“6)-2-
-glucopypanoside
acetamido-4,6-di-O-benzyl-2-deoxy-
D
(22 and 23) were formed in good yield, and 15 was not
found. These results indicate that 15 is a side product of
the reaction of a very reactive 10 in acetonitrile as a
solvent. In order to prevent this problem, another
solvent (e.g., dichloromethane) should be used (Scheme
2).
of 2 with 2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl
trichloroacetimidate in DMF, and the expected disac-
charide was formed with almost 70% yield, which will
be described in another article.
Next we prepared a very reactive glycosyl donor,
2,3,4-tri-O-acetyl- -fucopyranosyl bromide (10). In the
L
reaction of 10 with 2 or 4, we state formation of desired
disaccharides with almost 50% yield and as side prod-
ucts 7 and 8, respectively. Much more interesting were
products of reaction of 10 with allyl or propyl 2-acet-
1. Experimental
General methods.—All reactions were carried out in
commercially available dry solvents (Fluka, water
B0.005%). Thin-layer chromatography (TLC) was per-
formed with E. Merck pre-coated Silica Gel 60 F254
plates, and detection of compounds was achieved by
charring after spraying with 5% H2SO4 in EtOH. Silica
gel (70–230 mesh) and redistilled solvents were used for
column chromatography. 1H and 13C NMR spectra
were recorded at 25 °C with a Varian Mercury spec-
trometer at 400 and 100 MHz, respectively, with Me4Si
as internal standard. Assignments were based on
homonuclear decoupling experiments, and homo- and
heteronuclear correlation. Infrared spectra were
recorded on a Bruker IFS-66 instrument. Optical rota-
tions were measured with a JASCO J-20 polarimeter.
Elemental analyses were carried out on a Carlo–Erba
apparatus.
Scheme 1.

J. Madaj et al. / Carbohydrate Research 337 (2002) 1495–1498
1497
Scheme 2.
Reaction 1.—A mixture of allyl 2-acetamido-4,6-O-
benzylidene-2-deoxy-a- -glucopyranoside (2) (80 mg,
0.23 mmol, prepared adopting the Warren and Jeanloz
procedure7), methyl 2,3,4-tri-O-acetyl-a-
-glucopyran-
osyluronate trichloroacetimidate (5) (128 mg, 0.27
Reaction 2.—Propyl 2-acetamido-4,6-O-benzylidene-
2-deoxy-a- -glucopyranoside (4) (250 mg, 0.71 mmol)
in a mixture of dry 15:1 CH2Cl2–acetonitrile (16 mL)
was stirred at rt under dry nitrogen, and silver triflate
(400 mg, 1.55 mmol) was added. After 15 min, methyl
D
D
D
,
mmol), and powdered 4 A molecular sieves (0.1 g) in
2,3,4-tri-O-acetyl-a-D-glucopyranosyluronate bromide
anhyd CH2Cl2 (5 mL) was stirred at rt under a dry
nitrogen atmosphere. The mixture was cooled to −
60 °C, and trimethylsilyl triflate (TMSOTf, 40 L) was
added. The mixture was stirred for 1 h at −60 °C, and
then for 16 h at rt. Diisopropylethylamine (0.1 mL) was
then added, and the mixture was diluted with CH2Cl2
(10 mL), filtered and concentrated. The residue was
eluted from a column of silica gel with 2:1 EtOAc–tol-
uene to give allyl 2-acetamido-3-O-acetyl-4,6-O-benzyl-
(3) (380 mg, 0.96 mmol) in dry CH2Cl2 (10 mL) was
added dropwise, and the mixture was stirred for 24 h at
rt. Diisopropylethylamine (0.4 mL) was then added,
and the mixture was diluted with CH2Cl2 (15 mL),
filtered, washed with 10% brine, satd aq NaHCO3, and
water, dried with magnesium sulfate, and concentrated.
The residue was eluted from a column of silica gel with
20:4:1 toluene–acetone–MeOH to give propyl 2-acet-
amido-3-O-acetyl-4,6-O-benzylidene-2-deoxy-a-D-
idene-2-deoxy-a-
D
-glucopyranoside (7) (46 mg, 51%) as
glucopyranoside (8) (54 mg, 19%) as an oil: [h]D +51°
1
1
an oil: [h]D +67° (c 0.9, CHCl3); H NMR (CDCl3): l
7.45–7.35 (m, 5 H, Ph), 5.91 (m, 1 H, ꢀCHꢁ), 5.83 (d,
1 H, NH), 5.53 (s, 1 H CHꢂ), 5.30 (m, 2 H, ꢀCH2),
4.88 (d, 1 H, J1,2 3.6 Hz, H-1), 4.35 (m, 1 H, J2,3 10.0
Hz, H-2), 4.29 (q, 1 H, H-6%), 4.21 (m, 1 H, OCH2), 4.01
(m, 1 H, OCH2), 3.94 (m, 1 H, J4,5 10.0 Hz, H-4), 3.77
(m, 2 H, H-5,6), 3.73 (t, 1 H, H-3), 2.07 (s, 3 H,
OCOCH3), 1.98 (s, 3 H, NCOCH3). 13C NMR: l
171.43 (OCOCH3), 170.07 (NCOCH3), 137.02 (CHꢀ),
133.23–126.26 (Ph), 118.48 (CH2ꢀ), 101.72 (CHPhꢂ),
97.26 (C-1), 79.19 (C-4), 70.50 (C-3), 69.07 (OCH2),
68.91 (C-6), 63.22 (C-5), 52.82 (C-2), 23.59 (OCOCH3),
21.28 (NCOCH3). Anal. Calcd for C20H25NO7: C,
61.38; H, 6.39; N, 3.58. Found: C, 61.73; H, 6.44; N,
3.46.
(c 1.6, CHCl3); H NMR (CDCl3): l 7.47–7.32 (m, 5
H, Ph), 5.79 (d, 1 H, NH), 5.53 (s, 1 H, CHꢂ), 5.31 (t,
1 H, J3,4 10.0 Hz, H-3), 4.82 (d, 1 H, J1,2 3.6 Hz, H-1),
4.32 (m, 1 H, J2,3 10.4 Hz, H-2), 4.28 (q, 1 H, H-6%),
3.90 (m, 1 H, J5,6 10.4 Hz, H-5), 3.77 (t, 1 H, H-6), 3.73
(q, 1 H, J4,5 9.6 Hz, H-4), 3.67 (m, 1 H, OCH2), 3.38
(m, 1 H, OCH2), 2.06 (s, 3 H, OCOCH3), 1.96 (s, 3 H,
NCOCH3), 1.64 (m, 2 H, CH2), 0.96 (t, 3 H, CH3). 13C
NMR:
l 171.45 (OCOCH3), 170.01 (NCOCH3),
137.14–126.28 (Ph), 101.73 (CHꢂ), 98.04 (C-1), 79.30
(C-4), 70.68 (C-3), 70.28 (OCH2), 69.18 (C-6), 63.12
(C-5), 52.99 (C-2), 23.55 (OCOCH3), 22.99 (CH2),
21.27 (NCOCH3), 10.98 (CH3). Anal. Calcd for
C20H27NO7: C, 61.07; H, 6.87; N, 3.56. Found: C,
60.92; H, 6.67; N, 3.34.

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J. Madaj et al. / Carbohydrate Research 337 (2002) 1495–1498
The desired disaccharide propyl (methyl 2,3,4-tri-O-
acetyl-b- -glucopyranosyl)uronate-(1“3)-2-acetamido-
4,6-O-benzylidene-2-deoxy-a- -glucopyranoside was
obtained as an oil only in 4.7% yield.
Reaction 3.—Allyl 2-acetamido-4,6-O-benzylidene-2-
deoxy-a- -glucopyranoside (2) (2.0 g, 5.7 mmol) in a
mixture of dry 2:1 CH2Cl2–CH3CN (60 mL) was
stirred at rt under dry nitrogen, and silver triflate (3.7 g,
14.2 mmol) was added. After 15 min, 2,3,4,6-tetra-O-
The residue was eluted from a column of silica gel with
D
20:4:1 toluene–acetone–MeOH, and then the second
fraction was eluted again with 2:1 EtOAc–toluene to
give three compounds. The first was allyl 2-acetamido-
6-O-acetyl-3,4-di-O-benzyl-2-deoxy-a-D-glucopyran-
oside (20) (49 mg, 40.7%) as an oil; the second and the
third compounds were both anomers of N-acetyl-2,3,4-
D
D
tri-O-acetyl- -fucopyranosylamine (15) (129 mg, 43%;
L
a:b 1:2.7). a anomer: 1H NMR (CDCl3): l 6.34 (d, 1 H,
NH), 5.13 (dd, 1 H, J1,2 3.2, J1,NH 9.2 Hz, H-1), 5.19 (t,
1 H, H-2), 5.09 (dd, 1 H, J3,4 9.2 Hz, H-3), 5.29 (dd, 1
H, J4,5 8.4 Hz, H-4), 3.94 (m, 1 H, J5,6 6.8 Hz, H-5),
1.20 (d, 3 H, H-6, H-6% and H-6%%), 2.18–2.00 (9 H,
3×OCOCH3); 13C NMR: l 171.69–170.58 (3 C,
OCOCH3), 170.03 (NHCOCH3), 78.53 (C-1), 68.60
(C-2), 71.39 (C-3), 70.49 (C-4), 70.95 (C-5), 16.26 (C-6),
23.59–20.82 (3 C, OCOCH3), 20.79 (NHCOCH3); b
acetyl-a- -glucopyranosyl bromide (6) (5.1 g, 12.4
D
mmol) in dry CH2Cl2 (15 mL) was added dropwise, and
the mixture was stirred for 24 h at rt. Diisopropylethy-
lamine (1 mL) was added, and the mixture was diluted
with CH2Cl2 (30 mL), filtered, washed with 10% brine,
satd aq NaHCO3, and water, dried with magnesium
sulfate, and concentrated. The residue was eluted from
a column of silica gel with 20:4:1 toluene–acetone–
MeOH, then the second fraction was eluted again with
2:1 EtOAc–toluene to give two compounds. The first
was allyl 2-acetamido-3-O-acetyl-4,6-O-benzylidene-2-
1
anomer: H NMR (CDCl3): l 6.74 (d, 1 H, NH), 5.87
(dd, 1 H, J1,2 7.2, J1,NH 8.0 Hz, H-1), 5.39 (dd, 1 H,
H-2), 5.27 (m, 2 H, H-3, H-4), 3.99 (dd, 1 H, J5,6 6.4
Hz, H-5), 1.15 (d, 3 H, H-6, H-6% and H-6%%), 2.19–2.04
(9 H, 3×OCOCH3); 13C NMR: l 174.18–170.92 (3 C,
OCOCH3), 169.60 (NHCOCH3), 74.76 (C-1), 69.10
(C-2), 70.75 (C-3), 68.27 (C-4), 65.68 (C-5), 16.29 (C-6),
23.59–20.94 (3 C, OCOCH3), 20.88 (NHCOCH3).
Anal. Calcd for C14H21NO8: C, 50.76; H, 6.34; N, 4.23.
Found: a anomer C, 50.46; H, 6.24; N, 4.08; b anomer
C 50.61; H 6.23; N 4.17.
deoxy-a-
The second compound was allyl 2-acetamido-4,6-O-
benzylidene-2-deoxy-3-O-formyl-a- -glucopyranoside
D
-glucopyranoside (7) (0.32 g, 17%) as an oil.
D
(9) (0.38 g, 19%) as an oil: [h]D +66° (c 1.1, CHCl3);
1H NMR (CDCl3): l 8.11 (s, 1 H, CHO), 7.46–7.34 (m,
5 H, Ph), 5.90 (m, 1 H, ꢀCH), 5.79 (d, 1 H, NH), 5.53
(s, 1 H, CHꢂ), 5.43 (t, 1 H, J3,4 10.4 Hz, H-3), 5.29 (m,
2 H, ꢀCH2), 4.88 (d, 1 H, J1,2 4.0 Hz, H-1), 4.43 (m, 1
H, J2,3 9.6 Hz, H-2), 4.29 (q, 1 H, H-6%), 4.21 (m, 1 H,
OCH2), 4.01 (m, 1 H, OCH2), 3.95 (m, 1 H, J5,6 10.4
Hz, H-5), 3.79 (t, 1 H, J6,6% 12.0 Hz, H-6), 3.76 (t, 1 H,
J4,5 10.0 Hz, H-4), 1.97 (s, 3 H, NCOCH3). 13C NMR:
l 170.00 (NCOCH3), 160.96 (CHO), 136.91 (CHꢀ),
133.17–126.25 (Ph), 118.61 (CH2ꢀ), 101.79 (CHPhꢂ),
97.37 (C-1), 79.12 (C-4), 0.22 (C-3), 69.05 (OCH2),
69.00 (C-6), 63.24 (C-5), 52.39 (C-2), 23.58 (NCOCH3).
Anal. Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71.
Found: C, 60.04; H, 6.11; N, 3.45.
Acknowledgements
This work was supported by the Polish State Com-
mittee for Scientific Research (KBN-T T09A 083 20).
References
The third compound, allyl 2,3,4,6-tetra-O-acetyl-b-
glucopyranosyl-(1“3)-2-acetamido-4,6-O-benzylidene-
-glucopyranoside, was obtained in 4.8%
yield after column chromatography.
Reaction 4.—A mixture of allyl 2-acetamido-3,4-di-
D-
1. Leigh, D. A.; Smart, J. P.; Truscello, A. M. Carbohydr. Res.
1995, 276, 417–424.
2. Belot, F.; Jacquinet, J. C. Carbohydr. Res. 1996, 276,
79–86.
3. Urban, F. J.; Moore, B. S.; Breitenbach, R. Tetrahedron
Lett. 1990, 16, 4421–4424.
4. Ziegler, T.; Kovacˇ, P.; Glaudemans, C. P. J. Justus Liebigs
Ann. Chem. 1990, 613–615.
5. Hough, L.; Lewis, A. W. Carbohydr. Res. 1975, 42,
173–174.
6. Pozsgay, V.; Nanasi, P. Carbohydr. Res. 1979, 68, 157–160.
7. Warren, Ch. D.; Jeanloz, R. W. Carbohydr. Res. 1977, 53,
67–84.
2-deoxy-a-
D
O-benzyl-2-deoxy-a-
0.25 mmol, prepared from allyl 2-acetamido-3-O-ben-
zyl-4,6-O-benzylidene-2-deoxy-a- -glucopyranoside by
D
-glucopyranoside (18) (110 mg,
D
cleavage the O-benzylidene ring with NaBH3CN) in dry
acetonitrile (12 mL), was stirred at rt under dry nitro-
gen, and silver triflate (280 mg, 1.08 mmol) was added.
After 15 min, 2,3,4-tri-O-acetyl-L-fucopyranosyl bro-
8. Bowering, W. D.; Timell, T. E. J. Am. Chem. Soc. 1960,
mide (10) (320 mg, 0.91 mmol) in dry CH3CN (8 mL)
was added dropwise, and the mixture was stirred for 24
h at rt. Next diisopropylethylamine (1 mL) was added,
and the mixture was diluted with CH2Cl2 (30 mL),
filtered, washed with 10% brine, satd aq NaHCO3, and
water, dried with magnesium sulfate, and concentrated.
82, 2827–2830.
9. Jacquinet, J. C. Carbohydr. Res. 1990, 199, 153–181.
10. Dasgupta, F.; Anderson, L. Carbohydr. Res. 1990, 202,
239–255.
11. Nakahara, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28,
2731–2734.
12. Lo¨nn, H.; Lo¨nngren, J. Carbohydr. Res. 1984, 132, 39–44.