The synthesis of cyclic imidates from amides of glucuronic acid and investigation of glycosidation reactions

Article abstract of DOI:10.1016/j.carres.2006.10.023

The synthesis of novel cyclic glycosyl imidates and an investigation of their potential as donors in glycosidation reactions is described. The results show that 1,2-cis glycosides obtained from the reactions of glycosyl acetates or cyclic imidates, each d

Full text of DOI:10.1016/j.carres.2006.10.023

Carbohydrate Research 342 (2007) 111–118
Note
The synthesis of cyclic imidates from amides of glucuronic acid
and investigation of glycosidation reactions
Linda Cronin, Manuela Tosin, Helge Muller-Bunz and Paul V. Murphy*
¨
UCD School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology,
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
Received 30 August 2006; accepted 25 October 2006
Available online 1 November 2006
Abstract—The synthesis of novel cyclic glycosyl imidates and an investigation of their potential as donors in glycosidation reactions
is described. The results show that 1,2-cis glycosides obtained from the reactions of glycosyl acetates or cyclic imidates, each derived
from amides of glucuronic acid, result from the anomerisation of initially formed 1,2-trans glycosides.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Imidates; Glycosidation; Anomerisation; Glucuronic acid; Amides; Lewis acid
Stereoselective glycoside synthesis has long been of
interest because of the biological and medical relevance
of oligosaccharides, glycoproteins, glycolipids1 and
other carbohydrate derivatives2 and a range of strate-
gies, including the application of imidate donors, have
been investigated and developed.3,4 Glycosyl azide 2
with a-configuration was the major product (after
16 h) from the SnCl4 promoted reaction of acid 1 with
azidotrimethylsilane (Scheme 1).5 The 1,6-anhydro
derivative 4, formed during the reaction of 1 with SnCl4,
provided 2 and 3 in a similar yield and ratio to that ob-
served from 1 when it is reacted with silylated acceptors
in the presence of SnCl4.6 As the reaction of glucuronic
acid anilide 5 proceeded to give 1,2-cis glycosides 6,5
there is also the possibility that cyclic imidate 7 is an
intermediate in this glycosidation reaction; however,
up to now 7 was not obtained in sufficiently high purity
for confirmation of its structure and investigation of its
SnCl4 catalysed glycosidation reactions. Herein, we
describe the synthesis of novel cyclic imidates and show
O
O
O
OH
O
O
OH
O
OH
O
O
SnCl4, TMSN3,
CH2Cl2, 16 h
OAc
O
AcO
AcO
AcO
AcO
AcO
+
OAc
N3
AcO
AcO
OAc
N3
AcO
OAc OAc
~4:1
2
3
1
4
PhN
O
O
NHPh
O
O
NHPh
O
OAc
O
SnCl4, TMSN3,
CH2Cl2, 16 h
AcO
AcO
AcO
AcO
OAc
AcO
OAc
N3
OAc OAc
6
5
7
Scheme 1.
*
Corresponding author. Fax: +353 1 7162127; e-mail: Paul.V.Murphy@ucd.ie
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.10.023

112
L. Cronin et al. / Carbohydrate Research 342 (2007) 111–118
that they can be donors in glycosidation reactions cata-
lysed by SnCl4. The evidence presented supports the
proposal that a-glycosides obtained from the reactions
of glycosyl acetates 5 or cyclic imidates 7 are, as in the
case of 1 and 4, formed by anomerisation of the initially
formed 1,2-trans glycosides.
H
N
H
N
O
O
R
R
HBr-AcOH
O
O
AcO
AcO
OAc
AcO
AcO
AcO
OAc
Br
8a R = Ph
13 R = iPr
14a R = Ph, 90%
14b R = iPr, 73%
The reaction of amide 8a in dichloromethane cata-
lysed by SnCl4 in the presence of azidotrimethylsilane
was re-examined and the experiments showed that the
ratio of 9a:10a (75–90%) present in the mixture varied
depending on the reaction time (Scheme 2). Thus b-azide
10a was the major component observed after 1.75 h
(9a:10a = 1:2), whereas a-anomer 9a predominated after
12 h (9a:10a >100:1). a-Acetate 11 and a-chloride 12
AgClO4
Ag2CO3
CH2Cl2
Mol. Sieves
H
RN
O
R
N
O
OAc
O
O
+
AcO
AcO
AcO
OH
OAc OAc
1
(11+12 = 10–25%) were also detected by H NMR dur-
15a R = Ph, 35%
15b R = iPr, 35%
16a R = Ph
16b R = iPr
ing the course of this reaction. The reactions of tertiary
amide 8b also showed evidence that anomerisation was
occurring; after 2 h only b-anomer 10b was present,
whereas after 12 h a 1:1 mixture of 9b and 10b was
obtained.
Scheme 3. Synthesis of cyclic imidates.
O8
The possibility that cyclic imidate 15a could be an
intermediate in the glycosidation reaction of 8a was next
explored. Efforts to synthesise 15a directly from 8a using
SnCl4 led only to recovery of the starting compound or
to isolation of impure fractions containing 15a. The gly-
cosyl bromides 14a and 14b were prepared by the reac-
tion of 8a and 13, respectively, with HBr–AcOH. The
formation and isolation of 15a (35%) and 15b (35%)
was achieved after activation of a-bromides 14a and
14b, respectively, using a mixture of silver carbonate
and silver perchlorate in CH2Cl2 in the presence of
molecular sieves (Scheme 3). Hemi-acetals 16a and 16b
were the major side products obtained from both reac-
tions, and presumably arise from a competing hydrolysis
reaction of the bromide that occurs in the presence of
water. The X-ray crystal structure of 15a is shown
(Fig. 1).
C11
O6
C4
C8
C10
O7
C9
O5
C5
C18
C17
C3
O1
C12
N1
C13
C16
C15
C2
C14
O2
O3
C6
C1
O4
C7
Figure 1. X-ray crystal structure of imidate 15a. Thermal ellipsoids are
drawn at the 50% probability level. The pyranose ring adopts a chair
conformation in the solid state and the imine has the Z-configuration.
by TMSOTf gave, respectively, b-glycosides 10a and
17 (Chart 1) as the major products of the reaction.
Hemi-acetal 16a was the main by-product from both
reactions. When these reactions were carried out in the
presence of molecular sieves, normally added to reac-
The glycosidation reactions of 15a and 15b catalysed
by SnCl4 were next investigated and the results are sum-
marised in Table 1. The reaction of 15a with azidotri-
methylsilane and TMSOPh as nucleophiles promoted
R1
R1
O
R1
N
O
O
Ph
N
Ph
N
Ph
SnCl4
TMSN3
CH2Cl2
O
O
O
AcO
AcO
AcO
N3
OAc
AcO
AcO
AcO
AcO
OAc
OAc
N3
8a R = H
8b R = Me
9a R = H
9b R = Me
10a R = H
10b R = Me
H
O
H
O
N
Ph
AcO
N
Ph
AcO
O
O
AcO
AcO
AcO
AcO
OAc
Cl
12
11
Scheme 2. Synthesis of glycosyl azides from amides of glucuronic acid.

L. Cronin et al. / Carbohydrate Research 342 (2007) 111–118
113
Table 1. Reactions of cyclic imidatesa
Entry
Nucleophile
Time (h)
Imidate
Temp (ꢁC)
Promoter (equiv)
Product (isolated yield, %) ratiob
1
2
3
4
5
6
7
8
TMSN3
TMSOPh
PhOH
PhOH
PhOH
TMSN3
TMSOPh
TMSOCy
1
4
24
1
24
24
5
15a
15a
15a
15a
15a
15b
15b
15b
0
20
20
20
20
20
20
20
SnCl4 (0.5)
SnCl4 (0.5)
SnCl4 (0.5)
TMSOTf (2.5), SnCl4 (0.5)
TMSOTf (2.5), SnCl4 (0.5)
SnCl4 (0.5)
SnCl4 (0.5)
SnCl4 (0.5)
10a (66), 16a 5:1
16a, 17 (22) 1:3
16a, 17 2:1c
16a, 17, 18 1:1.2:2c
18 (63)
16b, 19 (75) 1:14
21 (40)
22 (40)
24
a All reactions were carried out in CH2Cl2.
b Ratios were determined by 1H NMR analysis of crude product mixtures.
c Yields were not obtained.
H
N
H
N
H
O
O
Ph
AcO
O
Ph
N
O
O
O
AcO
AcO
AcO
O
AcO
N3
AcO
AcO
AcO
AcO
O
17
18
19
H
N
H
O
O
N
O
AcO
AcO
O
O
AcO
AcO
AcO
AcO
O
21
22
Chart 1. Structures of 17–22.
tions as a drying reagent, only 16a was obtained. The
efficient in situ anomerisation of b-glycoside 10a, formed
from 15a, could be promoted by the addition of
TMSOTf (1 equiv) to the reaction mixture and gave
9a. a-Glycoside 18 was obtained in high yield from the
reactions of 15a with phenol carried out in the presence
of SnCl4 and TMSOTf after 24 h. If this reaction was
stopped after 2 h, a mixture of 16a, 17 and 18 was ob-
tained. Hemi-acetal 16a most likely undergoes a Fischer
type glycosidation to give initially 17 and subsequently
18 under these conditions. In the absence of TMSOTf,
the reaction of 15a with PhOH is less effective. Attempts
to carry out glycosidation reactions of 15a using
BF3(OEt)2 or TMSOTf as promoters in the absence of
SnCl4 were unsuccessful. The structure of 17 was con-
firmed by its independent synthesis by reaction of aniline
with the acid chloride prepared from phenyl 2,3,4-tri-O-
acetyl-a-D-glucopyranosiduronic acid.5 Removal of the
protecting groups from 18 and characterisation of the
unprotected compound confirmed the assignment of
the a-configuration to 17.
from the reaction of 15b with PhOTMS. a-Glycoside
22 (40%) was isolated from the reaction of 15b with
CyOTMS.
A recent study from our group has shown that the
tin(IV) chloride catalysed reaction of silylated nucleo-
philes with 4 can provide 1,2-trans glycosides or 1,2-cis
glycosides, even when 2-acyl protecting groups are pres-
ent.7 When 1,2-cis glycoside formation occurs, this is
due to the SnCl4 catalysed anomerisation of the initially
formed 1,2-trans glycosides. This anomerisation of b-
glucopyranosiduronic acids was found to be faster than
the anomerisation of related b-D-glucopyranosiduronic
acid esters and b-glucopyranoside derivatives and the
rates depend on the electron affinity of the aglycon,
being faster for more electropositive aglycon groups
(OCy faster than OPh).7,8 The results observed herein
indicate that anomerisation of the initially formed b-gly-
cosides accounts for the formation of a-glycosides (e.g.,
formation of 9 from 10, 18 from 17), displaying a pat-
tern of behaviour similar to that observed in the reac-
tions of 1 and 4.7 A chelated intermediate 23 has been
suggested to account for the anomerisation of interme-
diates generated from 4. The anomerisation of b-glyco-
side intermediates generated from the reaction of cyclic
imidates is slower than that from b-glycosides generated
from glucuronic acid amides (comparing the reaction of
The reaction of imidate 15b with TMSN3 in the pres-
ence of SnCl4 gave b-azide 19 (75%). This observation
contrasts with the previous observation that the reaction
of 13 under similar conditions and reaction time gave
only the a-azide.5 b-Glycoside 21 (40%) was isolated

114
L. Cronin et al. / Carbohydrate Research 342 (2007) 111–118
O
SnL
n
O
O
PO
PO
OR
OP
23
R
N
R
N
A
H
H or SnLn
or TMSOTf
O
NHR
O
O
AcO
O
-A
O
AcO
AcO
OH
AcO
AcO
Nu
Nu
AcO
AcO
Nu
OAc
OAc
A = H or TMS or SnLn
24
25
26
Scheme 4. Structure for 23–26 and a mechanistic proposal for anomerisation.
TMSN3 with 135 and 15b). The reason for this is not
clear to us. To explain the anomerisation of b-glucu-
ronic acid amides a general acid catalysis9 type mecha-
nism, related to that proposed7 for the anomerisation
of b-D-glucopyranosiduronic acids, can be invoked
and this involves coordination of the amide carbonyl
group of 24 to SnCl4 leading to increased acidity10 of
the amide proton, subsequent protonation of the pyra-
nose oxygen and cleavage of the C-1–O-5 bond giving
an open chair intermediate11 25 that ultimately gives
26 (Scheme 4). This would explain the observation that
10b anomerises more slowly than 10a.
In summary, 1,2-cis glycosides, when they are
obtained from SnCl4 catalysed 2-O-acyl-protected
glucopyranosiduronic acid amides,12 result from the
anomerisation of initially formed 1,2-trans glyco-
sides. Cyclic imidates may be intermediates but they
also would predominantly give 1,2-trans glycosides
initially.
and the spots were visualised by UV and charring with
1:20 H2SO4–EtOH. Chromatography was carried out
with Silica Gel 60 (0.040–0.630 mm, E. Merck) and
employed a stepwise solvent polarity gradient, which
correlated with the TLC mobility. Chromatography
solvents used were EtOAc (Riedel-deHaen), cyclohexane
and MeOH (Sigma Aldrich). CH2Cl2 (Riedel-deHaen)
was freshly distilled from calcium hydride, MeOH was
distilled from Mg.
1.2. Preparation of glycosyl azides from glucuronic acid
amides
To a soln of the amide in dry CH2Cl2 (0.1 g/mL) under
N2 atmosphere, TMSN3 (2.5 equiv) and SnCl4
(0.5 equiv) were added and the reaction mixture was stir-
red for the required time (see Scheme 2). Dilution with
CH2Cl2 followed and the soln was vigorously stirred
for further 30–40 min in the presence of an equal volume
of satd aq NaHCO3; a white emulsion formed and the
organic and aq layers can be separated after filtration
through a layer of Celite. The azide was obtained after
purification by column chromatography (EtOAc–cyclo-
hexane gradient).
1. Experimental
1.1. General
Optical rotations were determined with a Perkin–Elmer
1
241 model polarimeter at 23 ꢁC. H NMR spectra were
1.3. 2,3,4-Tri-O-acetyl-1-azido-1-deoxy-a/b-D-gluco-
pyranuronic acid, N-phenylamide 9a/10a
recorded with a Varian Inova 300 or 500 MHz spec-
trometer; 13C NMR spectra were recorded at 75 MHz.
Chemical shifts are reported relative to internal Me4Si
A 1:2 mixture of a-anomer 9a and b-anomer 10a11 was
obtained from 8a after 2 h. a-Anomer 9a (72%) was ob-
tained from 8a13 after 12 h; Rf 0.21 (1:2 EtOAc–cyclo-
hexane); [a]D +81.1 (c 0.38, CHCl3); 1H NMR
(300 MHz, CDCl3): d 8.02 (s, 1H, NH), 7.49 (dd, 2H,
J 8.5, J 1.2, Ar H), 7.33 (t, 2H, J 7.5, Ar H), 7.14 (t,
1H, J 7.5, Ar H), 5.77 (d, 1H, J1,2 4.3, H-1), 5.49 (t,
1H, J2,3 = J3,4 9.5, H-3), 5.22 (t, 1H, J4,5 10.3, H-4),
4.96 (dd, 1H, J1,2 4.3, J2,3 9.5, H-2), 4.50 (d, 1H, J5,4
10.3, H-5), 2.13, 2.09, 2.04 (each s, each 3H, each
1
in CDCl3 (d 0.0) or HOD for D2O, (d 4.79) for H,
and (d 77.16) for 13C. 13C signals were assigned with
1
the aid of DEPT-135. H NMR signals were assigned
with the aid of COSY. IR spectra were recorded with
a Mattson Galaxy Series IR 3000 using either thin film
between NaCl plates or KBr discs, as specified. Mass
spectra were recorded on a Micromass LCT KC420 or
Micromass Quattro. TLC was performed on aluminium
sheets precoated with Silica Gel 60 (HF254, E. Merck)

L. Cronin et al. / Carbohydrate Research 342 (2007) 111–118
115
COCH3); HRESIMS calcd for C18H19O8N4 419.1203,
found m/z 419.1213 [MꢀH]ꢀ.
CDCl3): d 169.8, 169.6, 169.5 (each s, each COCH3),
164.7 (s, CONH), 84.6 (d, C-1), 72.0, 70.4, 69.3, 68.5
(each d, C-2–5), 41.3 (d, CH(CH3)2), 22.4, 22.3 (each
q, each CH(CH3)2), 20.6, 20.5, 20.5 (each q, each
COCH3); HRESIMS: calcd for C15H22O8NBrNa
446.1, found m/z 446.0 [M+Na]+.
1.4. 2,3,4-Tri-O-acetyl-1-bromo-1-deoxy-a-D-gluco-
pyranosiduronic acid, N-phenylamide 14a
To a soln of 8a11 (2.49 g, 5.7 mmol) in acetic acid
(5 mL), 30% HBr in acetic acid (8 mL, 40 mmol) was
added slowly and the mixture was stirred overnight.
Ice and water (80 mL) were added and the mixture
was allowed to stand until a creamy precipitate had
formed, which was filtered off and washed with cold
water. The solid obtained was dissolved in EtOAc
(40 mL) and stirred with NaHCO3 (60 mL) for 1 h.
The organic layer was then washed with water, dried
(MgSO4), filtered and the solvent removed under dimin-
ished pressure. Recrystallisation (EtOAc–cyclohexane)
gave 14a as a white solid (2.35 g, 90%); Rf 0.4
(EtOAc–cyclohexane 2:3); mp 160–161 ꢁC; [a]D +159.5
(c 1.12, CH2Cl2); IR (KBr) cmꢀ1 3473, 3361, 1763,
1735, 1702, 1607, 1554, 1499, 1448, 1369, 1307, 1242,
1.6. 2,3,4-Tri-O-acetyl-1,6-anhydro-6-Z-phenylimino-b-
D-glucopyranose 15a
To a soln of bromide 14a (2.28 g, 4.96 mmol) in dry
˚
CH2Cl2, activated 4 A molecular sieves, silver carbonate
(3 g, 10.9 mmol) and silver perchlorate (0.1 g, 0.48
mmol) were added and the soln was allowed to stir over-
night. The soln was filtered through Celite, dried
(MgSO4), filtered and the solvent was removed. Chro-
matography (4:1 cyclohexane–EtOAc) of the residue
gave 15a as a white solid (0.64 g, 35%); Rf 0.28 (2:1
cyclohexane–EtOAc); mp 129–130 ꢁC; [a]D +113 (c
0.39, CH2Cl2); IR (KBr) cmꢀ1 1746, 1354, 1217, 1183,
1041, 957, 787, 721, 523, 433; 1H NMR (300 MHz,
CDCl3): d 7.35 (t, 2H, J 7.3, Ar H), 7.26 (d, 2H, J 7.3,
Ar H), 7.16 (t, 1H, J 7.3, Ar H), 5.90 (s, 1H, H-1),
4.97 (m, 2H, H-3, H-4), 4.90 (t, 1H, J2,3 1.9, H-2),
4.76 (d, 1H, J4,5 1.2, H-5), 2.21, 2.19, 1.99 (each s, each
3H, each COCH3); 13C NMR (75 MHz, CDCl3): d
169.3, 169.2, 168.5 (each s, each COCH3), 151.8 (s,
CONPh), 144.4 (s, Ar C), 128.7, 125.2, 123.1 (each d),
101.6 (d, C-1), 73.7, 69.2, 67.5, 66.3 (each d, C-2–5),
20.8, 20.6, 20.5 (q, COCH3); HRESIMS: calcd for
C18H20O8N 378.1189, found m/z 378.1204 [M+H]+.
Anal. Calcd for C18H19O8N: C, 57.29; H, 5.08; N,
3.71. Found: C, 57.13; H, 5.09; N, 3.65. Chromato-
graphy also gave 2,3,4-tri-O-acetyl-D-glucopyranuronic
acid, phenylamide 16a (1.22 g, 65%); Rf 0.14 (3:2 cyclo-
hexane–EtOAc), mp 116–117.5 ꢁC; [a]D +55.7 (c 0.24,
CH2Cl2); IR (KBr) cmꢀ1 3490 (OH), 3359 (NH), 1698,
1
1201, 1099, 1046, 885; H NMR (300 MHz, CDCl3): d
7.91 (s, 1H, NH), 7.47 (d, 2H, J 8.0, Ar H), 7.34 (t,
2H, J 8.0, Ar H), 7.14 (t, 1H, J 8.0, Ar H), 6.71 (d,
1H, J1,2 4.2, H-1), 5.66 (t, 1H, J3,2 10.0, J3,4 9.6, H-3),
5.33 (t, 1H, J4,3 9.6, H-4), 4.85 (dd, 1H, J2,1 4.2,
J2,310.0, H-2), 4.61 (d, 1H, J5,4 10.3, H-5), 2.12, 2.11,
2.06 (each s, each 3H, each COCH3); 13C NMR
(75 MHz, CDCl3): d 169.9, 169.6, 169.5 (each s, each
COCH3), 163.5 (s, CONH), 136.3 (s, Ar C), 129.0,
125.1, 120.5 (each d, Ar C), 84.3 (d, C-1), 72.2, 70.5,
69.3, 68.5 (each d, C-2–5), 20.6, 20.5 (overlapping
signals, each q, each COCH3); HRESIMS: calcd for
C15H22O8N 458.0451, found m/z 458.0472 [M+H]+.
1.5. 2,3,4-Tri-O-acetyl-1-bromo-1-deoxy-a-D-gluco-
pyranosiduronic acid, N-isopropylamide 14b
1
1627, 1581, 1467, 1395, 1209, 1019, 751, 685; H NMR
To a soln of amide 1311 (2.32 g, 5.9 mmol) in acetic acid
(6 mL), 30% HBr in acetic acid (7 mL, 41.3 mmol) was
added slowly and the soln was stirred overnight. Ice
and water (80 mL) were added and the mixture was
allowed to stand until a creamy precipitate formed,
which was filtered and washed with cold water. The so-
lid, which was collected was dissolved in EtOAc (40 mL)
and stirred with NaHCO3 (60 mL) for 1 h. The organic
layer was then washed with water, dried (MgSO4),
filtered and solvent removed. Recrystallisation
(EtOAc–cyclohexane) gave 14b as a white solid (1.83 g,
(500 MHz, CD3OD, a-anomer): d 7.42 (d, 2H, J 7.5,
Ar H), 7.31 (t, 2H, J 7.5, Ar H), 7.13 (t, 1H, J 7.5, Ar
H), 5.64 (t, 1H, J2,3 10.0, J3,4 9.8, H-3), 5.55 (d, 1H,
J1,2 3.5, H-1), 5.17 (t, 1H, J4,3 9.8, H-4), 4.87 (dd, 1H,
J2,13.5, J2,310.0, H-2), 4.54 (d, 1H, J5,4 10.1, H-5),
2.08, 2.07, 2.07, (each s, each 3H, each COCH3); 13C
NMR (125 MHz, CD3OD): d 172.5, 171.9, 169.3 (each
s, each COCH3), 139.6 (s, CONH), 130.7 (s, Ar C),
126.8, 122.9, 120.7 (each d, Ar C), 92.3 (d, C-1), 73.4,
72.6, 71.9, 71.4 (each d, C-2–5), 21.5, 21.4 (overlapping
signals, each q, each COCH3); HRESIMS: calcd for
C18H20O9N 394.1165, found m/z 394.1153 [MꢀH]ꢀ.
1
73%); H NMR (300 MHz, CDCl3): d 6.64 (d, 1H, J1,2
4.06, H-1), 6.06 (d, 1H, JCH–NH 7.65, NH), 5.61 (t,
1H, J2,3 10.0, J3,4 9.6, H-3), 5.21 (t, 1H, J4,3 9.6, H-4),
4.81 (dd, 1H, J2,1 4.06, J2,3 10.0, H-2), 4.43 (d, 1H, J5,4
10.3, H-5), 4.04 (m, 1H, CH(CH3)2), 2.11, 2.09, 2.05
(each s, each 3H, each COCH3), 1.16 and 1.14 (2 · d,
1.7. Methods for X-ray crystal structure determination
Crystal data were collected using a Bruker SMART
APEX CCD area detector diffractometer. A full sphere
of the reciprocal space was scanned by phi-omega scans.
6H, JCH;CH 6.6, CH(CH3)2); 13C NMR (75 MHz,
3

116
L. Cronin et al. / Carbohydrate Research 342 (2007) 111–118
Semi-empirical absorption correction based on redun-
dant reflections was performed by the program
SADABS.14 The structures were solved by direct methods
COCH3); HRESIMS: calcd for C15H22O8N 344.1345,
found m/z 344.1352 [M+H]+.
15
using SHELXS-97 and refined by full matrix least-
1.10. Phenyl 2,3,4-tri-O-acetyl-b-D-glucopyranosiduronic
acid, N-phenylamide 17
squares on F2 for all data using SHELXL-97.16 All hydro-
gen atoms were added at calculated positions and
refined using a riding model. Their isotropic tempera-
ture factors were fixed to 1.2 times (1.5 times for methyl
groups) the equivalent isotropic displacement para-
meters of the carbon atom to which the H-atom is attached.
Imidate 15a (0.082 g, 0.22 mmol) was dissolved in anhyd
CH2Cl2, and SnCl4 (0.014 mL, 0.12 mmol) and
TMSOPh (0.1 mL, 0.55 mmol) were added and the mix-
ture was stirred at room temp for 1 h. CH2Cl2 was
added and the mixture was then stirred in the presence
of satd aq NaHCO3 (20 mL) and then water (20 mL).
The organic layer was dried (MgSO4), filtered and the
solvent was removed. Chromatography (1:10 cyclo-
hexane–EtOAc) of the residue gave the title compound
as a colourless oil (25 mg, 22%); Rf 0.39 (3:2 cyclo-
1.8. Crystal data and structure refinement for 15a
Molecular formula, C18H19NO8; M = 377.34. Tempera-
˚
ture, 100(2) K. Wavelength, 0.71073 A. Crystal system,
triclinic. Space group, P1 (#1). Unit cell dimensions,
1
˚
˚
a = 7.390(3) A, a = 89.454(6)ꢁ; b = 8.596(3) A, b =
hexane–EtOAc); H NMR (300 MHz, CDCl3): d 8.06
˚
77.219(6)ꢁ; c = 14.777(6) A, c = 78.456(6)ꢁ. Volume,
(s, 1H, NH), 7.90–7.00 (m, 10H, Ar H), 5.50–5.10 (m,
4H, H-1–4), 4.28 (d, 1H, J4,5 9.4, H-5), 2.19, 2.18, 2.12
(each s, each 3H, each COCH3); HRESIMS: calcd for
C24H24O9N 470.1451, found m/z 470.1444 [MꢀH]ꢀ.
The title compound was dissolved in MeOH (5 mL),
and a 1 M NaOMe soln in MeOH was then added drop-
wise. The soln was stirred with Amberlite IR-120,
filtered and the solvent removed under diminished
pressure to give phenyl b-D-glucopyranosiduronic acid,
N-phenylamide; Rf 0.4 (30:1 EtOAc–MeOH); [a]D
3
3
˚
896.4(6) A . Z, 2. Density (calculated), 1.398 Mg/m .
Absorption coefficient, 0.111 mmꢀ1
.
F(000), 396.
Crystal size, 0.80 · 0.30 · 0.20 mm3. Theta range for
data collection, 2.42–28.37ꢁ. Index ranges, ꢀ9 6 h 6 9,
ꢀ11 6 k 6 11, ꢀ19 6 l 6 19. Reflections collected,
15,186. Independent reflections, 8082 [R(int) = 0.0168].
Completeness to theta = 26.00ꢁ, 99.8%. Absorption cor-
rection, semi-empirical from equivalents. Max. and min.
transmission, 0.9781 and 0.8513. Refinement method,
full-matrix least-squares on F2. Data/restraints/para-
meters, 8082/3/493. Goodness-of-fit on F2, 1.022. Final
R indices [I > 2r(I)], R1 = 0.0378, wR2 = 0.0936. R
indices (all data), R1 = 0.0392, wR2 = 0.0947. Absolute
structure parameter, 0.0(5). Largest diff. peak and hole,
1
ꢀ204 (c 0.24, CH3OH); H NMR (300 MHz, CD3OD):
d 7.59 (dd, 2H, J 1.2, J 8.8, Ar H), 7.30–6.99 (m, 8H, Ar
H), 5.01 (d, 1H, J1,2 7.5, H-1), 4.02 (d, 1H, J5,4 9.5, H-5),
3.73 (t, 1H, J4,3 = J4,5 = 9.5, H-4), 3.61–3.5 (m, 2H, H-2,
H-3); 13C NMR (125 MHz, CD3OD): d 167.9 (s,
CONH), 157.6, 137.8 (each s, each Ar C), 129.2, 128.5,
124.4, 122.5, 120.3, 116.8 (each Ar C), 101.4 (d, C-1),
76.3, 76.2, 73.2, 71.7 (each d, C-2–5); HRESIMS: calcd
for C18H18O6N 344.1134, found m/z 344.1141 [MꢀH]ꢀ.
ꢀ3
˚
0.387 and ꢀ0.191 e A
.
1.9. 2,3,4-Tri-O-acetyl-1,6-anhydro-6-isopropylimino-b-
D-glucopyranose 15b
To a soln of bromide 14b (0.27 g, 0.64 mmol) in dry
CH2Cl2, activated 4 A molecular sieves, silver carbonate
1.11. Phenyl 2,3,4-tri-O-acetyl-a-D-glucopyranuronic
acid, N-phenylamide 18
˚
(0.39 g, 1.4 mmol) and silver perchlorate (0.013 g,
0.063 mmol) were added and the mixture was stirred
overnight. The soln was then filtered through a layer
of Celite and dried (MgSO4), filtered and the solvent
removed under diminished pressure. Flash chromatog-
raphy (8:1 CH2Cl2–EtOAc) of the residue gave 15b as a
white solid (75 mg, 35%); Rf 0.36 (8:1 CH2Cl2–EtOAc);
[a]D +89.7 (c 0.5, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d 5.83 (m, 1H, H-1), 4.90 (m, 1H, H-3), 4.84
(m, 1H, H-4), 4.69 (m, 1H, H-2), 4.64 (m, 1H, H-5),
3.90 (m, 1H, CH(CH3)2), 2.18, 2.17, 2.08 (each s, each
An analytical sample of 18 was prepared from
phenyl 2,3,4-tri-O-acetyl-a-D-glucopyranosiduronic acid.5
Thus, to an ice-cold soln of phenyl 2,3,4-tri-O-acetyl-
a-D-glucopyranosiduronic acid (0.135 g, 0.34 mmol) in
freshly distilled CH2Cl2 (5 mL), oxalyl chloride
(0.03 mL, 0.34 mmol) and DMF (0.05 mL) were added.
The soln was stirred for 30 min at 0 ꢁC and for 1 h at
room temp. In a separate flask, a suspension of aniline
(0.031 mL, 0.34 mmol) and anhyd pyridine (0.028 mL,
0.34 mmol) in CH2Cl2 (1 mL) was stirred in the presence
˚
3H, each COCH3), 1.17 and 1.15 (2 · d, 6H, JCH;CH
of 4 A molecular sieves. The acid chloride soln was
3
6.4, CH(CH3)2); 13C NMR (300 MHz, CDCl3): d
169.4, 169.1, 168.5 (each s, each COCH3), 150.5 (s,
CON), 100.5 (d, C-1), 72.9, 69.5, 67.8, 66.9 (each d, C-
2–5), 48.4 (d, CH(CH3)2), 23.3, 23.2 (each q, each
CH(CH3)2), 21.0 (q, COCH3), 20.8, 20.7 (each q, each
cooled to 0 ꢁC again and the amine suspension was
slowly poured into it. The mixture was stirred for
30 min at 0 ꢁC and for a further 1.5 h at room temp,
then it was transferred into a separatory funnel where
it was washed with satd aq NaHCO3 (7 mL). The

L. Cronin et al. / Carbohydrate Research 342 (2007) 111–118
117
organic layer was washed with dilute HCl (0.1 M,
7 mL), dried (Na2SO4) and filtered. Removal of the sol-
vent and chromatography (1:2 EtOAc–cyclohexane) of
the residue gave 18 as a white solid (0.13 g, 86%); Rf
0.31 (0.5:12 EtOAc–CH2Cl2); mp 188–189 ꢁC; [a]D
OCy (40 lL, 0.25 mmol) were added and the mixture
was stirred at room temp for 25 h. CH2Cl2 was then
added and the mixture stirred in the presence of satd
aq NaHCO3 (20 mL) and then water (20 mL). The
organic layer was dried (MgSO4), filtered and the solvent
removed and chromatography (2:1 cyclohexane–EtOAc)
of the residue gave the title compound as a colourless
syrup (15 mg, 40%); Rf 0.2 (1:1 cyclohexane–EtOAc);
[a]D +56.8 (c 0.185, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d 6.16 (d, 1H, JCH,NH 8.2, NH), 5.57 (t, 1H,
J3,4 9.8, H-3), 5.29 (d, 1H, J1,2 3.7, H-1), 5.04 (t, 1H,
J4,3 9.8, H-4), 4.76 (dd, 1H, J2,3 10.0, J2,1 3.7, H-2),
4.24 (d, 1H, J5,4 10.0, H-5), 4.01 (m, 1H, CH(CH3)2),
3.98 (m, 1H, C5H10CHO, OCy), 2.08, 2.06, 2.02 (each
s, each 3H, each COCH3), 1.78 and 1.28 (each m,
10H, cyclohexyl protons), 1.16 and 1.14 (2 · d, 6H,
JCH;ðCH 6.4, CH(CH ) ); 13C NMR (125 MHz, CDCl3):
d 170.4, 169.9, 169.8 (each s, each COCH3), 166.7 (s,
CONH), 93.7 (d, C-1), 76.8 (d, cyclohexyl CH), 71.2,
70.2, 69.4, 68.4 (each d, C-2–5), 41.1 (d, CH(CH3)2),
33.1, 31.2, 25.4 (each t, cyclohexyl CH2), 22.5, 22.5 (each
q, each CH(CH3)2), 20.8, 20.7, 20.6 (each q, each CH3);
HRESIMS: calcd for C21H34O9N 444.2234, found m/z
444.2234 [M+H]+.
1
+65.5 (c 3.2, CH2Cl2); H NMR (300 MHz, CDCl3): d
7.99 (br s, 1H, NH), 7.46–7.03 (m, 10H, Ar H), 5.93
(d, 1H, J1,2 3.7, H-1), 5.83 (t, 1H, J3,4 9.5, J3,2 10.1, H-
3), 5.31 (dd, 1H, J4,5 10.3, J4,3 9.5, H-4), 5.02 (dd, 1H,
J2,1 3.7, J2,3 10.1, H-2), 4.47 (d, 1H, J5,4 10.3, H-5),
2.10, 2.08, 2.07 (each s, each 3H, each COCH3); 13C
NMR (75 MHz, CDCl3): d 170.3, 169.8, 169.7 (each s,
each COCH3), 164.6 (s, CONH), 155.7, 136.5 (each s,
each Ar C), 129.8, 128.9, 124.9, 123.5, 120.3, 116.6
(overlapping signals, each s, each Ar C), 94.1 (d, C-1),
70.4, 69.6, 69.2, 69.1 (each d, C-2–5), 20.8, 20.7, 20.6
(each q, each COCH3); HRESIMS: calcd for
C24H24O9N 470.1451, found m/z 470.1474 [MꢀH]ꢀ.
Anal. Calcd for C24H25O9N: C, 61.1; H, 5.34; N, 2.97.
Found: C, 60.84; H, 5.49; N, 2.82.
3Þ
3 2
1.12. Phenyl 2,3,4-tri-O-acetyl-b-D-glucopyranosiduronic
acid, N-isopropylamide 21
Imidate 15b (36 mg, 0.1 mmol) was dissolved in anhyd
CH2Cl2, and SnCl4 (6 lL, 0.05 mmol) and TMSOPh
(0.048 mL, 0.25 mmol) were added and the mixture
was stirred at room temp for 5 h. CH2Cl2 was added
and the mixture then stirred in the presence of satd aq
NaHCO3 (20 mL) and then water (20 mL). The organic
layer was dried (MgSO4), filtered and the solvent re-
moved under diminished pressure and column chroma-
tography (2.5:1 cyclohexane–EtOAc) of the residue
gave the title compound as a colourless oil (20 mg,
40%); Rf 0.29 (1:1 cyclohexane–EtOAc); [a]D ꢀ21.6 (c
Acknowledgements
The authors are grateful for financial support from
Science Foundation Ireland (04/BR/C0192) and the
Programme for Research in Third Level Institutions
Cycle 3 administered by the HEA.
1
Supplementary data
0.185, CH2Cl2); H NMR (300 MHz, CDCl3): d 7.40
(t, 2H, J 7.5, Ar H), 7.05 (t, 1H, Ar H), 7.03 (d, 2H,
Ar H), 6.17 (d, 1H, JCH–NH 7.5, NH), 5.42 (t, 1H, J3,2
8.8, J3,4 9.1, H-3), 5.33 (t, 1H, J1,2 7.5, J2,3 8.8, H-2),
5.27 (t, 1H, J4,3 9.1, H-4), 5.23 (d, 1H, J1,2 7.5, H-1),
4.08 (d, 1H, J5,4 9.7, H-5), 4.04 (m, 1H, CH(CH3)2),
2.15, 2.13, 2.11 (each s, each 3H, each COCH3), 1.17
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2006.10.023.
(d, 6H, JCHðCH
6.6, JCH
4.0, CH(CH3)2); 13C
3Þ2
3–CH3
References
NMR (75 MHz, CDCl3): d 169.9, 169.7, 169.4 (each s,
each COCH3), 165.4 (s, CONH), 156.6 (s, Ar C),
129.8, 123.7, 116.8 (each s, each Ar C), 98.8 (d, C-1),
72.8, 71.8, 71.2, 69.4 (each d, C-2–5), 41.3 (d,
CH(CH3)2), 22.4, 22.3 (each q, each CH(CH3)2), 20.7,
20.6, 20.5 (each q, each COCH3); HRESIMS: calcd
for C21H28O9N 438.1764, found m/z 438.1780 [M+H]+.
1. Varki, A. Glycobiology 1993, 3, 97.
2. Schweizer, F.; Hindsgaul, O. Curr. Opin. Chem. Biol. 1999,
3, 291.
3. Schmidt, R. R. Angew. Chem., Int. Ed. 1986, 25, 212.
4. Demchenko, A. V. Synlett 2003, 1225.
5. Tosin, M.; Murphy, P. V. Org. Lett. 2002, 4, 3675.
´
´
6. Polakova, M.; Pitt, N.; Tosin, M.; Murphy, P. V. Angew.
Chem., Int. Ed. 2004, 43, 2518.
´
´
7. O’Brien, C.; Polakova, M.; Pitt, N.; Tosin, M.; Murphy, P.
V. Chem. Eur. J., in press, doi:10.1002/chem.200601111.
8. (a) Timell, T. E.; Enterman, W.; Spencer, F.; Soltes, E. J.
Can. J. Chem. 1965, 43, 2296; (b) Saunders, M. D.; Timell,
T. E. Carbohydr. Res. 1967, 5, 453; (c) Saunders, M. D.;
1.13. Cyclohexyl 2,3,4-tri-O-acetyl-a-D-glucopyranosid-
uronic acid, N-isopropylamide 22
Imidate 15b (35 mg, 0.1 mmol) was dissolved in anhyd
CH2Cl2, and SnCl4 (5.9 lL, 0.05 mmol) and then TMS-
´
Timell, T. E. Carbohydr. Res. 1968, 6, 12; (d) Bleriot, Y.;

118
L. Cronin et al. / Carbohydrate Research 342 (2007) 111–118
Vadivel, S. K.; Herrera, A. J.; Greig, I. R.; Kirby, A. J.;
Sinay, P. Tetrahedron 2005, 60, 6813.
9. Capon, B. Tetrahedron Lett. 1963, 14, 911.
13. Tosin, M.; O’Brien, C.; Fitzpatrick, G. M.; Muller-Bunz,
¨
H.; Glass, W. K.; Murphy, P. V. J. Org. Chem. 2005, 70,
4096–4106.
¨
10. Lemieux, R. U.; Hindsgaul, O. Carbohydr. Res. 1980, 82,
14. Sheldrick, G. M. SADABS; Bruker AXS: Madison, WI,
2000.
195.
11. Janson, J.; Lindberg, B. Acta Chem. Scand. 1960, 14,
15. Sheldrick, G. M. SHELXS-97: Program for Crystal Struc-
ture Solution; Go¨ttingen; 1997.
877.
12. Tosin, M.; Murphy, P. V. J. Org. Chem. 2005, 70, 4107–
16. Sheldrick, G. M. SHELXS-97: Program for Crystal Struc-
ture Refinement, Release 2, Go¨ttingen; 1997.
4117.