Transformation of the (2-nitrophenyl)acetyl protecting group in the presence of trichloroacetonitrile and 1,8-diazabicyclo[5,4,0]-undec-7-ene

Article abstract of DOI:10.1016/j.carres.2012.11.003

When treated with trichloroacetonitrile in the presence of 1,8-diazabicyclo[5,4,0]-undec-7-ene, the (2-nitrophenyl)acetyl protecting group (NPAc) was partially transformed into mono-(NPClAc) and dichlorinated (NPCl ₂Ac) species, but no chlorina

Full text of DOI:10.1016/j.carres.2012.11.003

Carbohydrate Research 366 (2013) 1–5
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Transformation of the (2-nitrophenyl)acetyl protecting group in the presence
of trichloroacetonitrile and 1,8-diazabicyclo[5,4,0]-undec-7-ene
⇑
Jean-Claude Jacquinet
Institut de Chimie Organique et Analytique, UMR 7311 CNRS et Université d’Orléans, LabEx «SynOrg», Pôle de Chimie, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2012
Received in revised form 9 November 2012
Accepted 10 November 2012
Available online 17 November 2012
When treated with trichloroacetonitrile in the presence of 1,8-diazabicyclo[5,4,0]-undec-7-ene, the
(2-nitrophenyl)acetyl protecting group (NPAc) was partially transformed into mono-(NPClAc) and dichlo-
rinated (NPCl2Ac) species, but no chlorination occurred in the presence of solid potassium carbonate. The
monochlorinated NPClAc group, which is suitable for use in glycosylation reaction, can be selectively
removed by treatment with thiourea.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
(2-Nitrophenyl)acetyl
Chlorination
Trichloroacetonitrile
Glycosylation
The concept of orthogonal protection,1 in which any of a set of
various protecting groups can be introduced and removed selec-
tively without affecting the other present on a molecule is highly
suitable, especially in carbohydrate chemistry. Although numerous
protecting groups have been reported,2 only a few sets fulfil these
requirements. In the course of a programme dealing with the ste-
reocontrolled synthesis of oligosaccharide derivatives from the
carbohydrate–protein linkage region of proteoglycans,3 we were
looking for a robust, stable and orthogonal temporary protection
ceeded sluggishly, and sequential additions of reagents were
necessary to complete the reaction. The expected -imidate 4 was
a
isolated after chromatography and crystallization in modest yield
(58%). Careful examination of the mother liquor from crystalliza-
tion (5, not distinguishable from 4 in t.l.c.) by 1H NMR showed
unexpectedly the presence of three compounds. Two major telling
signals characteristic of a –CHCl– motif (R and S isomers) were
identified at d 6.11 and 5.97 ppm, and no signal was found for the
methylene group. HRESIMS of this mixture showed two peaks:
one (major) corresponding to a derivative of 4 containing one addi-
tional chlorine atom (NPClAc), and one (minor) containing two
additional chlorine atoms (NPCl2Ac). The monochloro/dichloro
derivative ratio was ꢀ9:1 (integrated 1H NMR). It was obvious that
under these conditions mono- and/or di-chlorination occurred at
the methylene moiety of the NPAc group. To assess this hypothesis,
fully protected compound 2 was treated under similar conditions
with sequential addition of reagents. An inseparable mixture of
compounds 6 was obtained, whose NMR and MS data matched
those reported for 5. Treatment of 6, as described for the prepara-
tion of 4 and 5, gave a mixture of imidates 5 in which the monochlo-
ro/dichloro derivative ratio was ꢀ4:1. However, when hemiacetal 3
was treated with trichloroacetonitrile but in the presence of solid
at O-4 of the D-glucuronic acid (D-GlcA) moiety allowing further
extension at these non-reducing position. The recently reported
use of the (2-nitrophenyl)acetyl group4 caught our attention. It is
easily introduced, showed apparent stability under common carbo-
hydrate transformations, and is selectively removed by assisted
cleavage through reduction of the nitro group. We would like to re-
port here the results of our observations regarding its behaviour
during the preparation of Schmidt’s trichloroacetimidates.5
Treatment of the known6 methyl(4-methoxyphenyl 2,3-di-O-
benzoyl-b-D-glucopyranosyl)uronate 1 with (2-nitrophenyl)acetic
acid, 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylamino-
pyridine (DMAP) in dichloromethane afforded readily the ester 2
in 90% yield (Scheme 1). Oxidative removal of the 4-methoxyphenyl
group with Cerium(IV) diammonium hexanitrate (CAN) gave the
hemiacetal 3 in 87% yield. This later was then treated with trichlo-
roacetonitrile and 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) in
dichloromethane, conditions that are known to give nearly exclu-
potassium carbonate,7 imidates 4
a and 4b were isolated separately
in 86% overall yield, and only traces (<3%) of chlorinated species
were observed in their 1H NMR spectra.
Although the mechanistic details of this reaction are not known,
the reaction of trichloroacetonitrile with active methylene groups,8
as well as its use as a source of positive chlorine ion9 has been
reported. In the homogeneous reaction with the amidine DBU, one
or two protons of the methylene group in the NPAc should be
sively the corresponding
a-imidate. However, the reaction pro-
⇑
Tel.: +33 238 417072; fax: +33 238 417281.
E-mail address: Jean-Claude.Jacquinet@univ-orleans.fr
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.11.003

2
J.-C. Jacquinet / Carbohydrate Research 366 (2013) 1–5
COOMe
COOMe
COOMe
a
c
O
O
O
HO
BzO
NPAcO
OMP
BzO
RO
BzO
OMP
OMP
BzO
BzO
BzO
2
1
6 : R = NPClAc + NPCl2Ac
b
b, c
COOMe
O
COOMe
c
COOMe
d
O
O
RO
NPAcO
NPAcO
BzO
BzO
BzO
OH
CCl3
O
BzO
BzO
BzO
CCl3
O
NH
3
4α + 4β
4 : R = NPAc
NH
+
5 : R = NPClAc + NPCl2Ac
H
H
Cl
O
H
Cl
O
Cl
NPAc
=
NPClAc
=
NPCl2Ac
=
O
NO2
NO2
NO2
Scheme 1. Reagents and conditions: (a) (2-Nitrophenyl)acetic acid, DCC, DMAP, CH2Cl2, rt, 1 h; (b) CAN, toluene/MeCN/H2O, rt, 15 min; (c) Cl3CCN, DBU, CH2Cl2, rt, 1 h; (d)
Cl3CCN, K2CO3, CH2Cl2, rt, 1 h.
abstracted and replaced by chlorine atom(s). In the heterogeneous
reaction with solid potassium carbonate, this side-reaction does
not occur.
MS spectra for 9 and 10 showed unambiguously that 9 was a
monochlorinated derivative (mixture of isomers) and 10 a dichlo-
rinated species.
Next was examined the behaviour of imidates 4 and 5 under
Selective removal of these modified NPAc groups was then
studied. When compounds 8, 9 and 10 were treated with zinc dust
glycosylation conditions in the preparation of the
Gal building block (Scheme 2). Coupling reaction of
known10 4-methoxyphenyl 2-O-benzyl-4,6-O-di-tert-butylsilylene-
b- -galactopyranoside 7 with imidate 4 ( ,b mixture) in the pres-
D-GlcA-D-
8
and ammonium chloride in methanol/1,4-dioxane, as reported,4
a
single alcohol 11 was isolated in 88–90% yield. When the mono-
chlorinated derivative 9 was treated with thiourea, usual condi-
tions used to remove selectively a monochloroacetyl group, the
same alcohol 11 was obtained in 87% yield.
In conclusion, care has to be taken when the NPAc group is pres-
ent on a molecule that has to be transformed into a trichloroace-
timidate using trichloroacetonitrile and DBU. Such unexpected
D
a
ence of trimethylsilyl triflate (TMSOTf) in dichloromethane gave
8 in 80% yield, the structure of which was easily deduced from
its 1H NMR spectrum. Similar coupling of imidates 5 with 7 gave
the disaccharide derivatives 9 (60%) and 10 (14%), respectively,
that were easily separated by chromatography. The 1H NMR and
Si
O
O
Si
O
O
COOMe
a
O
O
O
RO
BzO
OMP
5
HO
OMP
+
O
BzO
BzO
BzO
7
10 : R = NPCl2Ac
9 : R = NPClAc
+
+
4
b
b or c
a
Si
Si
O
O
O
O
COOMe
b
COOMe
O
O
O
O
NPAcO
BzO
HO
BzO
OMP
O
OMP
O
BzO
BzO
BzO
BzO
11
8
Scheme 2. Reagents and conditions: (a) TMSOTf, 4 Å mol. sieves, CH2Cl2, rt, 30 min; (b) Zn powder, NH4Cl, MeOH/1,4-dioxane, rt, 1 h; (c) Thiourea, pyridine/EtOH, 80 °C, 3 h.

J.-C. Jacquinet / Carbohydrate Research 366 (2013) 1–5
3
side-reaction was not encountered in the initial report since only
thioglycosides were used as glycosyl donors. Interesting enough
is the fact that the monochlorinated NPAc group (NPClAc) can be
removed selectively under two different conditions.
H-5a), 4.26 (d, 0.2H, H-5b), 3.88 (ABq, 2H, CH2CO), 3.76 (s, 3H,
COOCH3); ISMS: m/z 602.5 [M+Na]+. Anal. Calcd for C29H25NO12: C,
60.10; H, 4.35; N, 2.42. Found: C, 59.88; H, 4.41; N, 2.10.
1.4. Methyl 2,3-di-O-benzoyl-4-O-(2-nitrophenyl)acetyl-1-O-
trichloroacetimidoyl-
2,3-di-O-benzoyl-4-O-(2-nitrophenyl)chloroacetyl-1-O-
trichloroacetimidoyl- -glucopyranuronate (5)
a-D-glucopyranuronate (4a) and methyl
1. Experimental
a-D
1.1. General methods
A mixture of the hemiacetal 3 (0.6 g, 1 mmol), Cl3CCN (1.0 mL,
10 mmol) and DBU (30 L, 0.2 mmol) in anhyd CH2Cl2 (6 mL)
was stirred for 30 min at rt. More Cl3CCN (1.0 mL, 10 mmol) and
DBU (30 L, 0.2 mmol) were added, and the mixture was stirred
for 30 min, then was concentrated. Flash silica chromatography
(8:1 toluene/EtOAc, containing 0.1% of Et3N) and crystallization
Solvents were dried by standard methods, and molecular sieves
were activated prior to use by heating for 4 h at 500 °C. Melting
points were determined in capillary tubes with a Büchi apparatus
and are uncorrected. Optical rotations were measured at 20 °C with
a Perkin–Elmer 341 polarimeter. 1H and 13C NMR spectra were re-
corded at 25 °C with a Bruker Advance II 400 instrument, with
Me4Si as internal standard, unless otherwise stated. Assignments
were based on homo- and heteronuclear correlations using the
supplier’s software. Low-resolution mass spectra (ISMS) were ob-
tained on a Perkin–Elmer SCIEX API 300 spectrometer operating
in the ion-spray mode or on a Micromass Quattro Ultima spec-
trometer equipped with a Z-spray ionization source operating in
the negative mode. High-resolution mass spectra (HRESIMS) were
performed on a Bruker maXis mass spectrometer by the ‘‘Fédéra-
tion de Recherche ICOA/CBM (FR 2708) platform. Flash-silica chro-
matography was performed on Silica gel 60 (0.040–0.063 mm,
Merck, Darmstadt). The reactions were monitored by TLC on
coated aluminium sheets (silica gel 60 GF254, Merck), and spots
were detected under UV light and by charring with a 95/5 mixture
of ethanol and sulfuric acid. Elemental analyses were carried out at
the Service Central d’Analyse du CNRS (Institut des Sciences Analy-
tique, Solaize, France).
l
l
of the residue from ethyl ether gave the
a
-imidate 4
a (420 mg,
58%): mp 151–152 °C; ½a D20
ꢁ
+124 (c 1, CHCl3); 1H NMR (CDCl3,
400 MHz): d 8.64 (s, 1H, C@NH), 8.0–7.05 (m, 14H, Ar-H), 6.82 (d,
1H, J1,2 3.5 Hz, H-1), 6.07 (dd, 1H, J2,3 = J3,4 = 9.0 Hz, H-3), 5.57
(dd, 1H, J4,5 9.5 Hz, H-4), 5.50 (dd, 1H, H-2), 4.65 (d, 1H, H-5),
3.90 (ABq, 2H, CH2CO), 3.78 (s, 3H, COOCH3). Anal. Calcd for
C31H25Cl3N2O12: C, 51.43; H, 3.48; N, 3.87. Found: C, 51.27; H,
3.51; N, 3.61.
Flash silica chromatography (5:2 petroleum ether/EtOAc, con-
taining 0.1% of Et3N) of the mother liquors gave the chlorinated
derivatives 5 (152 mg, 20%) as a white foam; 1H NMR (CDCl3,
400 MHz): d 8.64, 8.63, 8.62 (3s, 1H, C@NH), 8.0–7.25 (m, 14H,
Ar-H), 6.83, 6.82 (2d, 1H, J1,2 3.5 Hz, H-1), 6.13, 6.07 (2dd, 0.9H,
J2,3 = J3,4 = 9.0 Hz, H-3), 6.11, 5.97 (2s, 0.9H, CHClCO), 5.65, 5.63,
5.62 (3dd, 1H, J4,5 9.5 Hz, H-4), 5.49, 5.47, 5.45 (3dd, 1H, H-2),
4.59, 4.55 (2d, 0.9H, H-5), 4.50 (d, 0.1H, H-5), 4.85 (s, 0.3H,
COOCH3), 4.79, 4.76 (2s, 2.7H, COOCH3); HRESIMS: Calcd for
C
31H24Cl4N2NaO12 [M+Na]+ (major): m/z 778.99755. Found:
778.99556; Calcd for C31H23Cl5N2NaO12 [M+Na]+ (minor): m/z
1.2. Methyl [4-methoxyphenyl 2,3-di-O-benzoyl-4-O-(2-
nitrophenyl)acetyl-b-
D-glucopyranosid]uronate (2)
813.96640. Found: 813.96556.
A mixture of methyl (4-methoxyphenyl 2,3-di-O-benzoyl-b-
D
-
1.5. Methyl 2,3-di-O-benzoyl-4-O-(2-nitrophenyl)chloroacetyl-
glucopyranosid)uronate 16 (5.23 g, 10 mmol), 2-nitrophenylacetic
acid (2.72 g, 15 mmol) and DMAP (0.3 g, 2.5 mmol) in anhyd CH2Cl2
(100 mL) was treated in portions with DCC (2.47 g, 12 mmol), and
the mixture was stirred for 1 h at rt. The precipitated DCU was fil-
tered off, washed with CH2Cl2, and the filtrate was washed with
cold 0.1 M HCl, satd aq NaHCO3 and water, dried (MgSO4), and con-
centrated. The solid residue was recrystallized from hot EtOAc to
D-glucopyranuronate (6)
A mixture of 2 (686 mg, 1 mmol), Cl3CCN (1.0 mL, 10 mmol) and
DBU (30
l
L, 0.2 mmol) in anhyd CH2Cl2 (6 mL) was stirred for
L,
30 min at rt. More Cl3CCN (1.0 mL, 10 mmol) and DBU (30
l
0.2 mmol) were added after 30 min, 60 min and 90 min, and the
mixture was concentrated. Flash silica chromatography (8:1 tolu-
ene/EtOAc, containing 0.1% of Et3N) gave the chlorinated deriva-
give 2 (6.18 g, 90%) as a white cotton: mp 158–159 °C; ½a D20
ꢁ
+58 (c
1, CHCl3); 1H NMR (CDCl3, 400 MHz): d 8.0–6.80 (m, 18H, Ar-H),
5.72 (dd, 1H, J2,3 = J3,4 = 9.0 Hz, H-3), 5.68 (dd, 1H, J4,5 9.5 Hz, H-4),
5.61 (dd, 1H, J1,2 7.0 Hz, H-2), 5.20 (d, 1H, H-1), 4.30 (d, 1H, H-5),
3.88 (ABq, 2H, CH2CO), 3.77, 3.72 (2s, 6H, OCH3, COOCH3); ISMS:
m/z 708.5 [M+Na]+. Anal. Calcd for C36H31NO13: C, 63.06; H, 4.56;
N, 2.04. Found: C, 62.88; H, 4.41; N, 1.89.
tives
6 (562 mg, 78%) as a
white foam: 1H NMR (CDCl3,
400 MHz): d 8.10-6.70 (m, 18H, Ar-H), 6.07, 5.95 (2s, 0.8H,
CHClCO), 5.75–5.68 (m, 1H, H-3), 5.64–554 (m, 2H, H-2,4), 5.22,
5.19 (2d, 0.8H, J1,2 7.0 Hz, H-1), 5.18 (d, 0.2H, J1,2 7.0 Hz, H-1),
4.34, 4.27 (2d, 0.8H, J4,5 9.5 Hz, H-5), 4.29 (d, 0.2H, J4,5 9.5 Hz, H-
5), 3.78, 3.76, 3.70 (3s, 3H, COOCH3).); HRESIMS: Calcd for
C
36H30ClNNaO13 [M+Na]+ (major): m/z 742.12986 Found:
742.12970; Calcd for C36H29Cl2NNaO13 [M+Na]+ (minor): m/z
1.3. Methyl 2,3-di-O-benzoyl-4-O-(2-nitrophenyl)acetyl-D-
glucopyranuronate (3)
777.09780. Found: 777.09720.
A mixture of 2 (1.09 g, 1.6 mmol) and CAN (4.39 g, 8 mmol) in
1:1.5:1 toluene/MeCN/H2O (42 mL) was stirred for 15 min at rt,
then was poured into ice-cold water (300 mL) and extracted with
CH2Cl2 (3 ꢂ 50 mL). The organic layer was washed twice with brine,
and water, dried (MgSO4), and concentrated. Flash silica chromatog-
raphy (19:1 CH2Cl2/acetone) gave hemiacetal 3 (0.80 g, 87%) as a
yellow foam. 1H NMR (CDCl3, 400 MHz): d 8.0–7.05 (m, 14H, Ar-
1.6. Methyl 2,3-di-O-benzoyl-4-O-(2-nitrophenyl)chloroacetyl-
1-O-trichloroacetimidoyl-a-D-glucopyranuronate (5)
Compound 6 (360 mg, 0.5 mmol) was treated as described for
the preparation of 3. Flash silica chromatography (1:1 EtOAc/
petroleum ether) gave the corresponding hemiacetal (277 mg,
90%) as a yellow foam. A mixture of the hemiacetal (277 mg,
H), 5.98 (dd, 0.8H, J2,3 = J3,4 = 9.0 Hz, H-3
J1,OH 4.2 Hz, H-1 ), 5.72 (dd, 0.2H, J2,3 = J3,4 = 9.0 Hz, H-3b), 5.52
(dd, 0.2H, J4,5 9.5 Hz, H-4b), 5.47 (dd, 0.8H, J4,5 9.5 Hz, H-4 ), 5.22
(ddd, 0.8 H, J2,OH 1.0 Hz, H-2 ), 4.98 (dd, 0.2H, H-2b), 4.72 (d, 0.8H,
a), 5.76 (dd, 0.8H, J1,2 3.5,
0.45 mmol), Cl3CCN (0.45 mL, 4.5 mmol) and DBU (14 lL,
a
0.1 mmol) in anhyd CH2Cl2 (6 mL) was stirred for 30 min at rt, then
was concentrated. Flash silica chromatography (2:1 petroleum
ether/EtOAc, containing 0.1% of Et3N) gave the mixture of chlori-
a
a

4
J.-C. Jacquinet / Carbohydrate Research 366 (2013) 1–5
nated derivatives 5 (266 mg, 70% from 6) as a white foam; 1H NMR
and HRESIMS data matched those reported above for 5 prepared
from 3. The ratio monochloro/dichloro was ꢀ4:1.
1.04 (2s, 18H, (CH3)3C); 13C NMR (C6D6, 100 MHz): d 166.81–
152.02 (3 C@O, GlcA C-6), 147.25, 147.15 (1C, CHClC@O), 133.51–
114.57 (30C, Ar-C), 102.23, 102.05 (2C, GlcA C-1, Gal C-1), 80.41,
80.35 (1C, Gal C-3), 73.25–70.98 (7C, GlcA C-2,3,4,5, Gal C-2,4,5),
66.89 (1C, Gal C-6), 55.46, 55.32 (1C, CHCl), 54.89 (1C, OCH3),
52.76, 52.64 (1C, COOCH3), 27.70, 27.58 (6C, (CH3)3C), 23.51,
20.87 (2C, (CH3)3C). HRESIMS: Calcd for C57H60ClKNO19Si [M+K]+ :
m/z 1164.28489. Found: 1164.28409. Anal. Calcd for C57H60ClNO19
Si: C, 60.77; H, 5.37; N, 1.24. Found: C, 60.49; H, 5.11; N, 1.09.
Next eluted was the dichloroacetyl derivative 10 (163 mg, 14%):
1.7. Methyl 2,3-di-O-benzoyl-4-O-(2-nitrophenyl)acetyl-1-O-
trichloroacetimidoyl-a,b-D-glucopyranuronate (4a,b)
A mixture of hemiacetal 3 (530 mg, 0.92 mmol), anhyd K2CO3
(500 mg) and Cl3CCN (1 mL, 10 mmol) in anhyd CH2Cl2 (8 mL) was
stirred for 1 h at rt, then was filtered through a pad of Celite and con-
centrated. Flash silica chromatography (3:2 petroleum ether/EtOAc,
mp 152–153 °C (from 2-propanol); ½a D20
ꢁ
+38 (c 1, CHCl3); 1H NMR
containing 0.1% of Et3N) gave first the crystalline
a-imidate 4a
(CDCl3, 400 MHz): d 8.06–6.60 (m, 23H, Ar-H), 5.71 (dd, 1H, J1,2 8.0,
J2,3 10.0 Hz, Gal H-2), 5.65 (dd, 1H, J3,4 9.0, J4,5 9.5 Hz, GlcA H-4),
5.58 (dd, 1H, J2,3 9.0 Hz, GlcA H-3), 5.37 (dd, 1H, J1,2 7.0 Hz, GlcA
H-2), 5.08 (d, 1H, GlcA H-1), 4.85 (d, 1H, Gal H-1), 4.68 (dd, 1H,
J3,4 3.0, J4,5 <1 Hz, Gal H-4), 4.32–4.23 (m, 2H, Gal H-6a,b), 4.16
(d, 1H, GlcA H-5), 3.92 (dd, 1H, Gal H-3), 3.82 (s, 3H, COOCH3),
3.69 (s, 3H, OCH3), 3.51 (br s, 1H, Gal H-5), 1.05 (s, 18H,
(CH3)3C); 13C NMR (C6D6, 100 MHz): d 166.31–145.91 (4 C@O, GlcA
C-6), 132.92–114.35 (30C, Ar-C), 102.06, 101.79 (2C, GlcA C-1, Gal
C-1), 82.25 (1C, CCl2CO), 80.54 (1C, Gal C-3), 73.60–70.68 (7C, GlcA
C-2,3,4,5, Gal C-2,4,5), 66.66 (1C, Gal C-6), 54.68 (1C, OCH3), 52.73
(1C, COOCH3), 27.48, 27.37 (6C, (CH3)3C), 23.32, 20.65 (2C,
(CH3)3C). HRESIMS: Calcd for C57H63Cl2N2O19Si [M+NH4]+ : m/z
1177.31658. Found: 1177.31684. Anal. Calcd for C57H59ClNO19 Si:
C, 58.96; H, 5.12; N, 1.21. Found: C, 58.80; H, 5.02; N, 1.14.
(334 mg, 50%) whose physical data matched those reported above.
Next eluted was the b-imidate 4b (240 mg, 36%): mp 130–131 °C
(from EtOAc/petroleum ether); ½a D20
ꢁ
+91 (c 1, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 8.68 (s, 1H, C@NH), 8.0–7.0 (m, 14H, Ar-H),
6.16 (d, 1H, J1,2 7.0 Hz, H-1), 5.75–5.65 (m, 2H, H-3,4), 5.62 (dd,
1H, J2,3 9.0 Hz, H-2), 4.65 (d, 1H, J4,5 9.5 Hz, H-5), 3.88 (ABq, 2H,
CH2CO), 3.78 (s, 3H, COOCH3). Anal. Calcd for C31H25Cl3N2O12: C,
51.43; H, 3.48; N, 3.87. Found: C, 51.21; H, 3.33; N, 3.58.
1.8. 4-Methoxyphenyl O-(methyl 2,3-di-O-benzoyl-4-O-(2-
nitrophenyl)acetyl-b-
D-glucopyranosyluronate)-(1?3)-
2-O-benzoyl-4,6-O-di-tert-butylsilylene-b-
D-galactopyranoside (8)
A mixture of imidate 4a
,b (655 mg, 0.90 mmol), alcohol 710
1.10. 4-Methoxyphenyl O-(methyl 2,3-di-O-benzoyl-b-
D-
(610 mg, 1.15 mmol) and powdered 4 Å molecular sieves (0.5 g)
in anhyd CH2Cl2 (10 mL) was stirred for 45 min at rt under dry
Ar. A solution of Me3SiOTf in anhyd toluene (1 M, 0.14 mL) was
added, and the mixture was stirred for 30 min at rt. Triethylamine
(0.14 mL) was added, and the mixture was filtered, and concen-
trated. Flash silica chromatography (1:1 EtOAc/petroleum ether,
containing 0.1% of Et3N) gave 8 (787 mg, 80%): mp 194–195 °C
glucopyranosyluronate)-(1?3)-2-O-benzoyl-4,
6-O-di-tert-butylsilylene-b-D-galactopyranoside (11)
From 8, 9 or 10: To a solution of esters 8, 9 or 10 (0.1 mmol) in
1,4-dioxan (1 mL) and MeOH (1.5 mL) were added Zn powder
(33 mg, 0.5 mmol) and NH4Cl (16 mg, 0.3 mmol), and the mixture
was stirred for 1 h at rt, then was filtered through a pad of Celite.
The solids were washed with MeOH, and the filtrate was concen-
trated. Flash silica chromatography (3:1 toluene/EtOAc) afforded
(from EtOAc/petroleum ether); ½a D20
ꢁ
+79 (c 1, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 8.0–6.60 (m, 23H, Ar-H), 5.72 (dd, 1H, J1,2
8.0, J2,3 10.0 Hz, Gal H-2), 5.52–5.45 (m, 2H, GlcA H-3,4), 5.42
(dd, 1H, J1,2 7.5, J2,3 9.0 Hz, GlcA H-2), 5.04 (d, 1H, GlcA H-1), 4.84
(d, 1H, Gal H-1), 4.68 (dd, 1H, J3,4 3.0, J4,5 <1 Hz, Gal H-4), 4.29–
4.19 (m, 2H, Gal H-6a,6b), 4.13 (d, 1H, J4,5 10.0 Hz, GlcA H-5),
3.92 (dd, 1H, Gal H-3), 3.84 (ABq, 2H, CH2CO), 3.75 (s, 3H, COOCH3),
3.67 (s, 3H, OCH3), 3.48 (br s, 1H, Gal H-5), 1.04 (s, 18H, (CH3)3C);
HRESIMS: Calcd for C57H61KNO19Si [M+K]+: m/z 1130.32386.
Found: 1130.32335. Anal. Calcd for C57H61NO19 Si: C, 62.68; H,
5.63; N, 1.28 Found: C, 62.49; H, 5.41; N, 1.12.
the alcohol 11 (47–48 mg, 88–90%) as a white foam: ½a D20
ꢁ
+75 (c
1, CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.95–6.60 (m, 19H, Ar-H),
5.73 (dd, 1H, J1,2 8.0, J2,3 10.0 Hz, Gal H-2), 5.40 (dd, 1H, J1,2 7.0,
J2,3 9.0 Hz, GlcA H-2), 5.30 (dd, 1H, J3,4 9.0 Hz, GlcA H-3), 5.02 (d,
1H, GlcA H-1), 4.85 (d, 1H, Gal H-1), 4.72 (dd, 1H, J3,4 3.5, J4,5
<1 Hz, Gal H-4), 4.30–4.22 (m, 2H, Gal H-6a,b), 4.19 (ddd, 1H, J4,5
9.5, J4,OH 3.2 Hz, GlcA H-4), 3.80 (s, 3H, COOCH3), 3.68 (s, 3H,
OCH3), 3.52 (br s, 1H, Gal H-5), 3.32 (d, 1H, GlcA 4-OH), 1.04 (s,
18H, (CH3)3C). HRESIMS: Calcd for C49H60O16Si [M+NH4]+ : m/z
946.36759. Found: 946.36827. Anal. Calcd for C49H56O16 Si: C,
63.65; H, 6.08. Found: C, 63.11; H, 5.95.
1.9. 4-Methoxyphenyl O-(methyl 2,3-di-O-benzoyl-4-O-(2-
nitrophenyl)chloroacetyl-b-
(1?3)-2-O-benzoyl-4,6-O-di-tert-butylsilylene-b-
-galactopyranoside (9) and 4-methoxyphenyl O-(methyl 2,3-
D-glucopyranosyluronate)-
From 9: A mixture of 9 (338 mg, 0.3 mmol) and thiourea
(76 mg, 1 mmol) in pyridine (3 mL) and EtOH (2 mL) was stirred
for 3 h at 80 °C, then was cooled and concentrated. A solution of
the residue in CH2Cl2 (30 mL) was washed with satd aq NaHCO3,
brine and water, dried (MgSO4) and concentrated. Flash silica chro-
matography (3:1 toluene/EtOAc) afforded the alcohol 11 (243 mg,
87%), whose physical data matched those reported above.
D
di-O-benzoyl-4-O-(2-nitrophenyl)dichlorochloroacetyl-b-
D-
glucopyranosyluronate)-(1?3)-2-O-benzoyl-4,
6-O-di-tert-butylsilylene-b-D-galactopyranoside (10)
A mixture of imidates 5 (758 mg, 1 mmol) and alcohol 7
(664 mg, 1.25 mmol) was treated as described for the preparation
of 8. Flash silica chromatography (3:2 petroleum ether/EtOAc, con-
taining 0.1% of Et3N) gave first the monochloroacetyl derivative 9
(676 mg, 60%) as a white foam: 1H NMR (CDCl3, 400 MHz): d 8.0–
6.60 (m, 23H, Ar-H), 6.05, 5.93 (2s, 1H, CHClCO), 5.74, 5.73 (2dd,
1H, J1,2 8.0, J2,3 10.0 Hz, Gal H-2), 5.60–5.50 (m, 2H, GlcA H-3,4),
5.39, 5.38 (2dd, 1H, J1,2 7.5, J2,3 9.0 Hz, GlcA H-2), 5.10, 5.07 (2d,
1H, GlcA H-1), 4.86 (d, 1H, Gal H-1), 4.71, 4.70 (2dd, 1H, J3,4 3.0,
J4,5 <1 Hz, Gal H-4), 4.32–4.22 (m, 2H, Gal H-6a,b), 4.21, 4.14 (2d,
1H, J4,5 10.0 Hz, GlcA H-5), 3.95 (dd, 1H, Gal H-3), 3.77, 3.73 (2s,
3H, COOCH3), 3.69 (s, 3H, OCH3), 3.52 (br s, 1H, Gal H-5), 1.05,
Acknowledgement
This research was supported by the Agence Nationale de la
Recherche (program ANR-08-BLAN ‘GAGNetwork’).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2012.11.
003.

J.-C. Jacquinet / Carbohydrate Research 366 (2013) 1–5
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