The iodosulfonamidation of peracetylated glycals revisited: Access to 1,2-di-nitrogenated sugars

Article abstract of DOI:10.1016/j.carres.2011.01.022

Iodosulfonamidation of peracetylated glycals was investigated using either a combination of N-iodosuccinimide/iodine or iodine chloride as a source of iodonium ion. 1,2-trans- and 1,2-cis-2-deoxy-2-iodo-1-sulfonamido hexoses were, respectively, obtained d

Full text of DOI:10.1016/j.carres.2011.01.022

Carbohydrate Research 346 (2011) 577–587
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
The iodosulfonamidation of peracetylated glycals revisited: access
to 1,2-di-nitrogenated sugars
⇑
François-Moana Gautier, Florence Djedaïni-Pilard, Cyrille Grandjean
Laboratoire des Glucides, UMR CNRS 6219, Université de Picardie Jules Verne, 33 rue Saint-Leu, F-80039 Amiens Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodosulfonamidation of peracetylated glycals was investigated using either a combination of N-iodosuc-
cinimide/iodine or iodine chloride as a source of iodonium ion. 1,2-trans- and 1,2-cis-2-deoxy-2-iodo-1-
sulfonamido hexoses were, respectively, obtained depending on the reagent system used. Both series of
isomers were successfully converted to 1,2-di-nitrogenated compounds, for example, 1-azido-1,2-di-
deoxy-2-sulfonamido sugars, which are useful intermediates for the synthesis of N-linked glycoproteins
or glycoconjugates.
Received 3 December 2010
Received in revised form 17 January 2011
Accepted 20 January 2011
Available online 28 January 2011
Keywords:
Glycal
Ó 2011 Elsevier Ltd. All rights reserved.
Iodosulfonamidation
Amino sugar
Azido sugar
1. Introduction
simple straightforward amination.13 Otherwise, 1,2-di-nitrogenat-
ed compounds can be accessed either through a combination of
The 1,2-dideoxy-1,2-di-nitrogenated hexoses are important
subunits of N-glycoproteins or N-glycopeptides as well as many
glycoconjugates. For instance, N-glycans in N-glycoproteins are
linked to the proteins at asparagine residues almost exclusively
via a b-N-acetylglucosamine.1 Among the few other types of
N-glycan linkages, N-acetylgalactosamine and 2,4-diacetamido-
one among the above mentioned strategies and one method of
preparation of 2-aminosugars14 or through specific approaches.
For example, a clever approach but limited to the preparation
of 2-azido mannosylamine makes use of Burgess’s reagent.15
Alternatively, glycals have emerged as versatile intermediates
for the introduction of nitrogen substituents at C-1 and C-2 of
sugars. This can be achieved by 1,2-addition of azide on 2-nitro-
glycals.16 Metal-catalysed nitrogen transfer17 or dipolar cycload-
dition/photoisomerisation18 processes have also been reported.
However, true generalisation or application to electron-rich al-
kenes remains hitherto to be developed, respectively. Gratifyingly,
introduction of an amide at C-2 and an azide at the anomeric
centre are concomitantly accomplished following the Gin’s C-2-
amidoglycosylation procedure. However, Ferrier rearrangement
is observed when an acetyl group is present next to the unsatu-
ration.19 Kumar and Ramesh have recently described the interest-
ing iodine-catalysed 1,2-bis-sulfonamidation of glycals. While
differentiation of both sulfonamides is easily operated later dur-
ing the synthesis, their deprotection requires very large excess
of the reducing reagent.20 Therefore, in search for a general and
straightforward entry to 2-amino-1-azido sugars, we have turned
our attention to the Danishefsky’s azido-iodosulfonamidation:21
this two-steps procedure first involves the iodosulfonamidation
of a glycal, followed by azidolysis (Scheme 1).22
2,4,6-trideoxy-D-glucopyranose (bacillosamine) have also been
reported in Archaea and Bacteria.2,3 Hence access to these N-
(aspartoyl)-2-N-acetamido-glycosylamines or analogues thereof
is essential to study the structures and functions of natural and
artificial N-glycoproteins or glycopeptides. In addition, the pres-
ence of a nitrogen-based functional group at the anomeric centre
of 2-amino-2-deoxy sugars provides a unique opportunity to
modify proteins, peptides or drugs to improve their activity or
their bioavailability. Properties like aqueous solubility, oral up-
take or diversion from liver biliary clearance may be affected.4
This modification can equally be used for the preparation of
immunogens, amphiphiles, lectin ligands as well as enzyme
inhibitors or substrates.5 Anomeric azides are particularly well-
suited for these purposes: they are easily prepared from glycosyl
halide or hydrazide precursors,6 are more stable than anomeric
amines and readily react in CuI-catalysed Huisgen azide-alkyne
1,3-dipolar cycloadditions.7–9 When the parent 2-amino-2-deoxy
sugar is accessible, anomeric amines/amides can also be prepared
from glycosyl azides,10
a
-hydroxy nitriles,11 isonitriles,12 or by
The overall process is based on the intramolecular displacement
of the iodide to form an unstable aziridine which, in turn, is opened
by the incoming azide. Marked advantages of the procedure are
obviously its initial high stereoselectivity and its compatibility
⇑
Corresponding author. Tel.: +33 322828812; fax: +33 322827560.
E-mail address: cyrille.grandjean@u-picardie.fr (C. Grandjean).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.01.022

578
F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
yl-4-O-(2,3,4,6-tetra-O-b-D-galactopyranosyl)-2-deoxy-D-arabino-
RO
RO
RO
RO
I
hex-1-enitol) 1 (Scheme 2).26 This sulfonamide is expensive, but it
is deprotected in conditions (fluoride) milder and more selective
than arylsulfonamides.27,20 Besides, access to lactosamine, a motif
recognised by galectins, is essential to understand structure–
function relationships of these lectins and design effective
antagonists.28
1) Iodosulfonamidation
O
O
RO
RO
R'SO2HN
RO
2) Azidation
O
RO
RO
To minimise the anomerisation, we tried to find out experimen-
tal conditions which could promote iodosulfonamidation at lower
temperature than those reported in the literature.24 I(sym-
collidine)2ClO4 (IDCP) or NIS are the usual iodine sources employed
in the iodosulfonamidation process. However, neither of them was
effective at promoting the reaction at ꢀ10 °C. Indeed, less than 30%
conversion of starting lactal was observed after one day at this
temperature in CH2Cl2 (Table 1, entries 1 and 2). The reaction
was tentatively carried out in CH3CN, a more polar solvent com-
monly used for electrophilic addition.20,29 Compound 1 reacted
rapidly under these conditions to afford the corresponding Ferrier’s
rearranged product 2 in 82% yield. Switching back to CH2Cl2 as sol-
vent, the reaction was attempted with molecular iodine, a more
powerful electrophile. Again, rearranged compound 2 was isolated
as the sole product (Table 1, entries 3 and 4). At this stage, we rea-
soned that the electrophilic character of the reagent should ideally
be comprised between those of NIS and iodine. Along this line
interhalogen compounds have been largely used to promote glyco-
R'SO2N
RO
O
RO
RO
N3
R'SO2HN
Scheme 1. Danishefsky’s azido-sulfonamidation procedure.
with a broad range of sugars as well as protecting groups, such as
silyl and benzyl ethers, carbonates, esters and acetals as witnessed
by the numerous reported synthetic applications.23 However, it
was shown that the initially formed trans-1,2-iodosulfonamides
could rapidly and extensively isomerised into their corresponding
cis-1,2-iodosulfonamides which are claimed to be inert towards
aziridination.24 This side reaction, which considerably reduces the
scope of the iodosulfonamidation, seems to strongly depend on
the reaction temperature and duration. For example, 1-benzenesul-
fonamido-2-deoxy-2-iodo-4,6-O-isopropylidene-3-O-triethylsilyl-
-mannoside was obtained in a 10:1 or 2:5 trans:cis ratio for reaction
times of 25 min or 2.5 h, respectively. Iodosulfonamidation of 3,4,6-
tri-O-benzyl- -glucal (1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-
arabino-hex-1-enitol) using p-nitrobenzenesulfonamide gave rise
to a 5:2 trans:cis isomeric ratio at 0 °C but only the cis isomer when
conducted at rt (Chart 1).24
sylation reactions.30 When peracetyl-
D-lactal 1 was treated with
iodine chloride, whose possible implication in the bis-sulfonamida-
tion of glycals was previously suggested by Kumar and Ramesh,20b
the clean and rapid formation of the unwanted cis-1,2-iodosulfona-
mide 3b was observed at ꢀ10 °C (Table 1, entry 5). Its structure
was proposed based on the resonances of H-1 in the 1H NMR and
C-2 in the 13C NMR observed at 4.1 and 38.9 ppm, respectively,
in accordance with the previously reported data.24 Pursuing our
quest, we tried to define another system. It is well known that
the reactivity of NIS is generally enhanced in the presence of a cat-
alytic amount of acid. This property has been extensively exploited
in glycosylations31 and also in iodination of aromatic com-
pounds.32 While NIS/acid systems were not tested in this study
since acids are known to promote the Ferrier rearrangement,33
we were encouraged to test a combination of reagents. Gratify-
ingly, treatment of a mixture of compound 1 and 2-(trimethyl-
silyl)ethanesulfonamide with NIS followed by the addition of
molecular iodine afforded the expected trans-1,2-iodosulfonamide
3a in acceptable yield (Table 1, entry 6). Notably, no isomerisation
occurred in the reaction vessel, even after prolonged reaction time,
or during the flash-chromatography purification. Compared with
the cis isomer 3b, the chemical shifts of C-2 and H-1 were observed
at 26.0 ppm and at 5.40 ppm, respectively. Noteworthy, the 1C4
chair conformation seems to be substantially present as suggested
by the rather large J1,2 (7.5 Hz) as well as the small J3,4 and J4,5
D
D
D-
While glycals are easily obtained as peresterified derivatives,25
such reactants proved particularly sensitive to anomerisation,
maybe because the effective transformation of these electron-poor
derivatives usually requires higher temperature and longer reaction
times. We report herein our efforts to define new experimental con-
ditions which would limit isomerisation of peracetylated substrates
thereby avoiding laborious protecting group exchange and restoring
the full utility of the iodosulfonamidation/azidolysis procedure.
2. Results and discussion
We elected to study the addition of 2-(trimethylsilyl)ethane-
sulfonamide on hexa-O-acetyl-
D
-lactal (1,5-anhydro-3,6-di-O-acet-
O
I
O
I
(4.8 Hz) coupling constants. 4-O-(Tetra-2,3,4,6-O-acetyl-b-
D-galac-
O
O
Et3SiO
O
O
Et3SiO
NHSO2Ph
topyranosyl)-2-deoxy-2-iodo- -mannose 4 and known mannosyl-
D
succinimide 534 arising from adventitious water and competitive
addition of released succinimide were also isolated from the reac-
tion mixture in variable amounts depending on the experiments.
The exact nature of the electrophile has not been determined
but stoichiometric amount of iodine seems to be required since
diminishing the ratio to 0.2 or 0.5 equiv leads to a reaction profile
similar to the one observed for NIS alone.
PhSO2HN
25 min: trans :cis 10:1
2.5h: trans :cis 2:5
BnO
BnO
I
I
O
BnO
BnO
O
BnO
BnO
NHAr
To further confirm the observed selectivity, both reagent
systems were tested on tri-O-acetyl-
D
-glucal 6 and tri-O-acetyl-
D-
pNO2-PhSO2HN
galactal (3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-
D-lyxo-hex-1-
0°C, 2h: trans :cis 5:2
rt, 1h: cis only
enitol) 7 (Table 2). NIS/I2 treatment afforded the corresponding
trans-diaxial-1,2-iodosulfonamides 8a and 9a in shorter reaction
times and higher isolated yields, an issue being ascribed to
their lower number of electron-withdrawing substituents (Table 2,
Chart 1. Examples of temperature and reaction times dependence of iodosulfona-
mide anomerisation.

F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
579
OAc
AcO
AcO
O
O
O
AcO
AcO
2
NHSES
OAc
AcO
AcO
I
O
O
O
OAc
AcO
AcO
AcO
AcO
AcO
O
O
3a
O
NHSES
NHSES
I
?
AcO
AcO
AcO
OAc
AcO
AcO
AcO
1
I
O
O
+
O
AcO
AcO
H2NSO2CH2CH2SiMe3
3b
OAc
AcO
AcO
AcO
I
O
O
O
OH
AcO
AcO
4
O
N
AcO
OAc
O
OAc
AcO
I
O
O
O
5
AcO
AcO
Scheme 2. Disaccharides obtained from iodosulfonamidation of per-acetyl-D-glycal 1 with SESNH2.
Table 1
Products and yields (%) formed upon iodosulfonamidation of peracetyl-D-lactal 1 with SESNH2
a
Entry
Conditions
2
3a
3b
4
5
1
2
3
4
5
6
NIS (1 equiv)
IDCP (1 equiv)
30 (+ starting material)b
25
NIS (1 equiv), CH3CN
I2 (1 equiv)
82
85
ICl (2 equiv)c
40–60
20–30
30–40
NIS (1 equiv)/I2 (1 equiv)
45–30
0–15d
a
b
c
Unless otherwise mentioned, all reactions were performed at ꢀ10 °C using 1 equiv of SESNH2 in CH2Cl2.
Estimated yield from mass spectroscopy, the ratio of isomer cis:trans was not determined.
In the presence of 4 Å MS, from ꢀ10 °C to rt.
d
Only detectable in its 1C4 conformation.34,35
Table 2
Iodosulfonamidation of representative glycalsa
R2
R
R
R
2 OAc
2 OAc
2 OAc
OAc
I
I
O
O
O
O
R1
AcO
R1
R1
+
R1
AcO
NHSES
NHSES
+
AcO
AcO
CH2Cl2
I
NHSES
Xa
Xb
Xc
Entry
Compounds
Electrophile
Products (isolated yield in %)
1
2
3
4
6 R1 = OAc; R2 = H
6 R1 = OAc; R2 = H
7 R1 = H; R2 = OAc
7 R1 = H ; R2 = OAc
NIS/I2 (1 + 1 equiv)a
ICl (2 equiv)b
8a (65)c
8b (45)c
9b (19)
NIS/I2 (1 + 1 equiv)a
ICl (2 equiv)b
9a (61)c
9a (16)
9c (6)
a
b
c
4 Å MS, from ꢀ10 °C to 0 °C over 1 h then 0 °C, 1 h.
4 Å MS, ꢀ10 °C to rt.
Products of hydrolysis were not isolated.
entries 1 and 3). ICl-promoted iodosulfonamidation of glycal 6 was
also stereoselective, affording the b-1,2-trans isomer 8b in moder-
ate yield (Table 2, entry 2). Under the same conditions, compound
and b-galacto-iodosulfonamides 9c in a modest 41% overall yield
(Table 2, entry 4). This last compound was identified from the 1H
NMR proton coupling constants (J1,2 = 9.9 Hz, J2,3 = 11.3 Hz,
J3,4 = 3.2 Hz and J4,5 = 0.8 Hz) as well as from the downfield
7 was transformed into an inseparable mixture of a/b-talo- 9a/9b

580
F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
resonance of C-1 compared with the corresponding anomeric car-
bons of the talo isomers in the 13C NMR spectra (85.7 vs 80.6 and
78.9 ppm, respectively). Taken together, these data are in full
agreement with a galactopyranose derivative in a 4C1 conforma-
tion. Proton NMR coupling constants of both manno and talo deriv-
atives indicate some substantial deviation from the classical 4C1
conformations, the 1C4 conformation being predominant for
compound 9a, for which three substituents change from an axial
to an equatorial orientation.
stable cis isomers as previously suggested.24 Alternatively, the
b-cis-isomer could arise from the competitive formation of 2-
iodo-a-glycosyl chloride a-D and 2-iodo-b-glycosyl chloride b-D
which, in turn, could give the iodosulfonamides via the above men-
tioned iodocarbonium B,40 thereby suggesting an in situ isomerisa-
tion towards the b-cis isomer, or direct SN2 substitution by the
sulfonamide although anomeric halide nucleophilic substitution
is rather observed in basic medium, under Phase Transfer Catalysis
(Scheme 3, pathway b, dotted arrows).41
Stereoselectivity of the iodonium-promoted electrophile addi-
tion upon glycals is controlled, among others, by the preferred ini-
tial attack on the glycal, the ionic character of the reactive
intermediates and the stability of the products, notably in acidic
medium.
Fast and complete isomerisation of purified iodosulfonamide 3a
is observed by 13C NMR in the presence of iodine chloride at 0 °C in
CD2Cl2 as witnessed by the disappearance of the peak at 25.8 ppm
and concomitant appearance of a peak at 38.8 ppm, corresponding
to the C-2 resonance of the
a and b isomers, respectively (Fig. 1). In
It is well accepted that iodine-based electrophiles preferentially
react from the top-face of glycals in their half-chair 4H5 conforma-
tion (Scheme 3). This results in the formation of the often postu-
lated, bridged iodonium intermediate A,23,29b,36,37 whose further
trapping by nucleophiles can easily account for the regiospecificity
and the high trans stereoselectivity observed, or more likely to the
oxoniums B or C.38,39 Indeed, a computational study performed on
model compounds has shown that the open forms predominate.38
This result should still be true for the present study although the
presence of electron-withdrawing substituents (acetyl groups)
might slightly shift the equilibrium towards the A form. Among
the two open conformers, the axial iodine conformer B should be
preferred due to stabilising hyperconjugative interactions between
contrast, b-isomer 3b remains stable under these conditions while
neither compound isomerises in the presence of NIS/I2 (not
shown). These observations are fully consistent with the proposed
reactive pathway a. However, pathway b can not be totally ruled
out. Indeed, ESI-MS monitoring of the reaction reveals the presence
of isotopic profiles characteristic of chloro-derivatives, whose mass
unit could be assigned to iodo-chloro sugars. Formation of these
intermediates was further evidenced upon monitoring the ICl-
promoted sulfonamidation of 6 by 13C NMR (Fig. 2). Glucal 6
(Fig. 2a) is consumed soon after the addition of ICl to a mixture
of the former compound and SESNH2 in CDCl3 (Fig. 2b), to give a
mixture of at least three different compounds which were identi-
fied on the basis of their respective C-1 and C-2 chemical shifts.
In particular, chemical shifts at 79.8 and 37.4 ppm were as-
signed to the C-1 and C-2 signals of the 2-iodo-1-sulfonamido-b-
manno derivative 8b. These attributions were further ascertained
by comparison with the 13C NMR spectra of pure 8b (Fig. 2c) and
pure 8c (Fig. 2d). Chemical shifts at 93.9 and 92.1 as well as 26.5
and 31.4 ppm were assigned to the resonances of C-1 and C-2 of
the
nucleophile is considered to mostly proceed on the iodocarbonium
B, driven by a stereoelectronic
-anomeric effect,37 leading prefer-
entially to the formation of the -trans isomer. The NIS/I2-
r
C-I and the p⁄C–O of the oxonium.39 Thus, addition of the
a
a
promoted reaction probably follows this pathway (Scheme 3,
pathway a). The same mechanism might be invoked when using
ICl. However, in this case, the trans diaxial-1,2-iodosulfonamides
which are initially formed, further anomerise to furnish the more
the corresponding
a-1-chloro (a-D form) and b-1-chloro (b-D
form), respectively (Fig. 2b). The attribution was deduced from
Pathway a
AcO
R1
AcO
I
R1
I
O
R2
AcO
O
R2
AcO
NHSES
α-
trans
β-cis
NHSES
R2
R1
O
R1
AcO
R1
OAc
I
I
R2
AcO
R2
I
AcO
OAc
O
R2
O
O
R1
AcO
4H5
A
B
C
OAc
AcO
OAc
R1
AcO
R1
I
I
I
O
O
Pathway b
R2
AcO
O
Cl
R2
AcO
α-D
β-D
AcO
Cl
AcO
R1
R1
I
O
R2
AcO
R2
AcO
NHSES
α
β
-cis
-trans
NHSES
Scheme 3. Tentative mechanism of formation of iodosulfonamide.

F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
581
Figure 1. Facile isomerisation of 3a into 3b: 13C NMR (75.5 MHz) spectra of compound 3a in CD2Cl2 at 0 °C (a) in the absence or (b) after 5 min in the contact of 2 equiv ICl.
the crude 13C NMR spectra of ICl addition onto 6 in the absence of
the sulfonamide (Fig. 2e) since neither the -D nor the b-D form
was isolated by flash-chromatography purification. The H-1 reso-
nances, at 6.48 and 6.28 ppm, strongly support the presence of a
chlorine at the anomeric center. Moreover, these chemical shifts
significantly differ from those reported for the known 3,4,6-tri-O-
a
acetyl-2-iodo-D
-mannopyranose42 or for 1-iodo-glycopyranosides,
usually observed near 7 ppm.30 Remarkably, formation of
compound 8b is observed even if the sulfonamide is not initially
present in the NMR tube but added after the formation of the
Figure 2. 13C NMR monitoring of the ICl-promoted iodosulfonamidation of a 2 mM solution of tri-2,3,4-O-acetyl-
D-glucal 6 in CDCl3 at 0 °C: (a) spectrum of glycal 6; (b) crude
spectrum of a mixture of 6 and SESNH2 (1 equiv), followed by addition of ICl (2 equiv); (c) spectrum of pure iodosulfonamide 8b; (d) spectrum of pure iodosulfonamide 8a; (e)
crude spectrum of 6 in the presence of ICl (2 equiv); (f) crude spectrum of a mixture of 6 and ICl (2 equiv), followed by addition of SESNH2 (1 equiv).

582
F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
iodo-glycosyl chloride mixture, probing the labile character of the
C–Cl bond at the anomeric centre and beyond, possible progression
of the reaction through pathway b under these experimental con-
ditions (Fig. 2f). Compound 8a was not detected in any of these
bond cleavage,43 rotation around the N–C1 bond and cyclisation
to provide the trans-diaxial-isomer which is required to promote
the formation of the postulated aziridine intermediate. Finally,
derivatives 12 and 14 were also transformed into their correspond-
ing azides 17 and 18 in 88% and 82% yields, respectively.
experiments which is in agreement with the propensity of the
a
isomer to isomerise rapidly (see above). The iodooxonium B, in-
voked as a plausible intermediate, was not detected either cer-
tainly as a consequence of its very high reactivity. A peak which
could be assigned to this intermediate was observed during the
monitoring of the iodosulfonamidation of compound 6 but its pres-
ence might simply reflect the commonly observed fragmentation
of fragile anomeric bonds.
After 24 h at 0 °C, 8b (major) and the b-D form are the two main
sugars detected in the reaction mixture. The latter was not isolated
during chromatography purification but might account for the
presence of hydrolysed products. For comparison, activation of
thioglycosides with iodine chloride also gives rise to kinetic b-gly-
Interestingly, the transformation was not limited to azide as a
source of nucleophilic nitrogen but was also efficiently carried
out using potassium phthalimide (54% yield). Even the b-cis-isomer
8b was able to give the expected 1-phthalimido derivative 19,
showing that the epimerisation could occur in various conditions
(Table 3, entries 7 and 8). Finally, treatment of iodosulfonamide
8a with the 5-tert-butyl-2-methylthiophenol under Danishefsky’s
conditions22 gave the 2-sulfonamido thioglycoside 20 in 77% yield.
Such derivatives are key intermediates for the synthesis of com-
plex oligosaccharides from glycals.23,44
3. Conclusions
cosyl chlorides, which slowly isomerise to the thermodynamic
linked products when the reaction mixture is warmed to rt. Iodine
bromine leads exclusively to the thermodynamically favoured
glycosyl bromides.30 Though not tested, this latter reagent would
certainly give rise to the trans -2-iodo-1-bromide derivatives,
a-
In conclusion, we have developed two reagent systems for the
preparation of 2-iodo-1-sulfonamido sugars from peresterified gly-
cals. In particular, the use of a combination of NIS/I2 prevents the
anomerisation of the products which is usually associated with
the iodosulfonamidation reaction, thus increasing the scope of this
methodology. Moreover, we have shown that even the hitherto
unreactive b-cis-iodosulfonamides could be transformed into
a
-
a
ultimately leading to the formation of the b-cis products.
To further explore the scope of the NIS/I2 procedure, the reac-
tion was also applied to an acid-sensitive 6-deoxy sugar, the 3,4-
di-O-acetyl-
lated glycal, the 3,4,6-tri-O-benzoyl-
To our delight, their corresponding
D
-rhamnal 10, and a strongly deactivated, perbenzoy-
-glucal 11 (Scheme 4).
-iodosulfonamides 12 and
D
a
14 were isolated in 65% and 46% (together with 30% starting mate-
rial for the latter reaction) yield, respectively. Synthesis of 12 was
accompanied by the formation of the N-(3,4-di-O-acetyl-2,6-
Table 3
Iodine displacement using various nucleophilesa
Entry
Glycal
Conditionsa
Product (yield)
dideoxy-2-iodo-a-L-mannopyranosyl) succinimide (13) (15%) as a
by-product, but no trace of the b-isomer was detected in either
of the two crude mixtures.
OAc
AcO
AcO
AcO
O
O
b
O
1
2
3a
3b
NaN3
N3
With this series of representative iodosulfonamides in hands,
AcO
AcO
SESHN
we next envisaged the azidolysis reaction. As expected, all
a-
15
(85%)
c
trans-iodosulfonamides were converted to the corresponding b-
trans-1-azido-1,2-dideoxy-2-sulfonamides in high yields upon
treatment with sodium azide in DMF at rt (Table 3) whereas the
b-cis-iodosulfonamides were totally unreactive under the same
experimental conditions.
However, surprisingly, simple heating of the reaction mixtures
at 40 °C afforded the b-trans-1-azido-1,2-dideoxy-2-sulfonamides
in about 50% isolated yields (Table 3, entries 2 and 4). These results
NaN3
15 (45%)
OAc
O
AcO
AcO
b
3
8a
NaN3
N3
SESHN
16
(85%)
c
4
5
8b
12
NaN3
16 (48%)
N3
NHSES
O
AcO
b
NaN3
suggest the possible formation of an iminium/a-iodo-stabilised
AcO
17 (88%)
carbocation intermediate,38,39 with concomitant endocyclic C–O
OBz
O
BzO
BzO
b
N3
6
14
NaN3
SESNH
SESHN
Me
AcO
O
18 (82%)
OAc
O
OAc
12
O
I
AcO
AcO
+
KPhthal.d
KPhthal.c
O
NIS, I2
7
8
8a
8b
N
O
Me
AcO
O
SESHN
N
19 (54%)
OAc
10
O
19 (27%)
Me
AcO
O
OAc
OAc
I
O
13
AcO
AcO
9
8a
ArSHe
S
OBz
SESHN
20 (77%)
BzO
I
O
BzO
BzO
NIS, I2
O
BzO
BzO
a
b
c
All reactions were carried out in DMF.
2 equiv, rt, 2 h.
SESNH
14
2 equiv, 40 °C, 2 h.
2 equiv, ꢀ30 °C to rt, 2 h.
11
d
e
1.4 equiv, LHMDS (1.2 equiv), ꢀ30 to ꢀ20 °C, 30 min.
Scheme 4. Extension of the NIS/I2-promoted iodosulfonamidation.

F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
583
valuable intermediates when treated with sodium azide. Finally,
we have established a novel access to 1,2-bis-nitrogenated sugars.
(C-30 and C-50), 68.9 (C-20), 68.0 (C-4), 66.9 (C-40), 62.5 and 61.3 (C-
6 and C-60), 51.3 (CH2), 20.9, 20.7 (2CH3), 20.5, 10.1 (CH2), ꢀ1.91
(3CH3); HR-ESIMS m/z calcd for [C27H43NO15SSi]Na+ 704.2020,
found 704.2000.
4. Experimental methods
4.1. General methods
4.3. 3,6-Di-O-acetyl-1,2-dideoxy-2-iodo-4-O-(2,3,4,6-tetra-O-
acetyl-b-
ethanesulfonamido]-
D
-galactopyranosyl)-1-[2-(trimethylsilyl)
-mannopyranose (3a)
All reactions were monitored by TLC on Kieselgel 60 F254
(E. Merck). Detection was achieved by charring with vanillin. Silica
gel (E. Merck, 240–400 mesh) was used for chromatography. Optical
rotations were measured with a JASCO DIP-370 digital polarimeter,
using a sodium lamp (k = 589 nm) at 20 °C. All NMR experiments
were performed at 300.13 MHz using a Bruker DMX300 spectrome-
ter equipped with a Z-gradient unit for pulsed-field gradient spec-
troscopy. Assignments were performed by stepwise identification
using COSY and HSQC experiments using standard pulse pro-
grammes from the Bruker library. Chemical shifts are given relative
to external TMS with calibration involving the residual solvent
signals.
a
-D
To a ꢀ10 °C stirred suspension of hexa-O-acetyl-
D-lactal (6 g,
10.7 mmol), 2-(trimethylsilyl)ethanesulfonamide (2 g, 10.7 mmol)
and 4 Å molecular sieves in dry CH2Cl2 (30 mL) was added solid
NIS (2.42 g, 10.7 mmol) followed by I2 (2.70 g, 10.7 mmol) 2 h later.
The reaction mixture was allowed to warm to 5 °C overnight. The
mixture was then filtered and diluted with CH2Cl2. The filtrate
was washed with satd aq Na2S2O3, and brine, dried (Na2S2O4), fil-
tered and concentrated under reduced pressure. Iodosulfonamide
3a (6.20 g, 65%) was obtained following flash-chromatography
purification (eluent: ethyl acetate/cyclohexane 4:6); TLC: Rf 0.68
a]
+6.3 (c 1, CHCl3); 1H NMR
D
Low-resolution ESI mass spectra were obtained on a hybrid
quadrupole/time-of-flight (Q-TOF) instrument, equipped with a
pneumatically assisted electrospray (Z-spray) ion source (Micro-
mass). High-resolution mass spectra were recorded in positive
mode on a ZabSpec TOF (Micromass, UK) tandem hybrid mass
spectrometer with EBETOF geometry. The compounds were indi-
(ethyl acetate/cyclohexane 6:4); [
(CDCl3): dH 6.10 (d, 1H, JNH,1 = 9.6 Hz, NH), 5.40 (br d, 1H,
J3 ,4 = 2.6 Hz, H-40), 5.31 (dd, 1H, J1,2 = 7.5 Hz, H-1), 5.22 (br t, 1H,
0
0
J3,4 = 4.8 Hz, H-3), 5.17 (dd, 1H, J1 ,2 = 7.8 Hz, J2 ,3 = 10.5 Hz, H-20),
0
0
0
0
5.03 (dd, J3 ,4 = 3.4 Hz, H-30), 4.58 (d, 1H, H-10), 4.49 (dd, 1H,
J2,3 = 1.3 Hz, H-2), 4.32–4.30 (m, 2H, H-6, H-6), 4.20–4.06 (m, 3H,
H-60, H60, H-5), 3.91 (br t, 1H, J = 6.9 Hz, H-50), 3.81 (t, 1H,
J4,5 = 4.8 Hz, H-4), 3.12–3.03 (m, 2H, CH2), 2.19 (s, 3H, CH3), 2.18
(s, 3H, CH3), 2.12 (s, 3H, CH3), 2.07 (s, 6H, 2CH3), 2.00 (s, 3H,
CH3), 1.14–1.03 (m, 2H, CH2), 0.07 (s, 9H, 3CH3); 13C NMR (CDCl3):
dC (75 MHz, CDCl3) 170.6 (CO), 170.5 (CO), 170.2(CO), 170.1 (CO),
169.7(CO), 169.4(CO), 101.2 (C-10), 80.7 (C-1), 75.0 (C-4), 73.1 (C-
5), 71.7 (C-3), 71.1 (C-50), 70.6 (C-30), 68.9 (C-20), 66.9 (C-40), 61.2
(C-6 and C-60), 51.2 (CH2), 26.0 (C-2), 20.9 (CH3), 20.8 (CH3), 20.8
(CH3), 20.7 (CH3), 20.6 (CH3), 20.5 (CH3), 10.3 (CH2), ꢀ1.92
(3CH3); HR-ESIMS m/z calcd for [C29H46INO17SSi]Na+ 890.1198,
found 890.1211.
0
0
vidually dissolved in MeOH at a concentration of 10
then infused into the electrospray ion source at a flow rate of
10
L minꢀ1 at 60 °C. The mass spectrometer was operated at
l
g mLꢀ1 and
l
4 kV whilst scanning the magnet at a typical range of 4000–
100 Da. The mass spectra were collected as continuum profile data.
Accurate mass measurement was achieved using polyethylene gly-
col as an internal reference with a resolving power set to a mini-
mum of 10,000 (10% valley).
4.2. 6-O-Acetyl-1,2,3-tri-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-b-
D-
galactopyranosyl)-1-[2-(trimethylsilyl)ethanesulfonamido]-
a-
D
-erythro-hex-2-enopyranose (2)
4.4. 3,6-Di-O-acetyl-1,2-dideoxy-2-iodo-4-O-(2,3,4,6-tetra-O-
To a suspension of hexa-O-acetyl-D-lactal (1 g, 1.8 mmol), 2-(tri-
acetyl-b-
ethanesulfonamido]-b-
D
-galactopyranosyl)-1-[2-(trimethylsilyl)
-mannopyranose (3b)
methylsilyl)ethanesulfonamide (333 mg, 1.8 mmol) and 4 Å
molecular sieves in dry CH3CN (5 mL) was added solid NIS
(403 mg, 1.8 mmol) at ꢀ10 °C and the mixture was stirred at this
temperature for 30 min. The crude reaction mixture was then fil-
tered and diluted with CH2Cl2. The filtrate was washed with satd
aq Na2S2O3, and brine, dried (Na2S2O4), filtered and concentrated
under reduced pressure. Flash-chromatography purification (elu-
ent: ethyl acetate/cyclohexane 4:6) of the resulting residue pro-
vided the Ferrier’s rearranged product 2 (760 mg, 82%).
D
Hexa-O-acetyl-D-lactal (1 mmol, 560 mg), 2-trimethylsilyle-
thanesulfonamide (1 mmol, 182 mg), 4 Å MS (1 g) and CH2Cl2
(5 mL) were introduced into a 50 cm3 2-necked flask and cooled
down to ꢀ10 °C. Iodine chloride (2 mmol, 100
lL) was dissolved
in CH2Cl2 and added to the mixture. The mixture was stirred for
2.5 h at ꢀ10 °C, warmed up to rt, diluted in CH2Cl2 (50 mL) and
washed with satd aq Na2S2O3 (50 mL), satd aq NaHCO3 (50 mL)
and brine (50 mL). The organic phase was dried (Na2SO4) and evap-
orated. Flash chromatography of the crude material (ethyl acetate/
cyclohexane 1:1) afforded the compound 3b (435 mg, 50%) as a
Alternatively, to a suspension of hexa-O-acetyl-D-lactal (1 g,
1.8 mmol), 2-(trimethylsilyl)ethanesulfonamide (333 g, 1.8 mmol)
and 4 Å molecular sieves in dry CH2Cl2 (5 mL) was added I2
(450 mg, 1.8 mmol) at ꢀ10 °C and the mixture was stirred at this
temperature for 30 min. Compound 2 (788 mg, 85%) was obtained
following work-up carried as described above; TLC: Rf 0.56 (ethyl
white powder; TLC: Rf 0.50 (ethyl acetate/cyclohexane 1:1); [a]
D
ꢀ9.2 (c 1, CHCl3); 1H NMR (CDCl3): dH 5.42 (d, 1H, JNH,1 = 10.3 Hz,
NH), 5.37 (dd, 1H, J3 ,4 = 3.3 Hz, J4 ,5 = 0.7 Hz, H-40), 5.13 (dd, 1H,
acetate/cyclohexane 1:1); [a]
+ 51 (c 1, CHCl3); 1H NMR (CDCl3):
0
0
0
0
D
J1 ,2 = 7.9 Hz, J2 ,3 = 10.5 Hz, H-20), 5.02 (dd, 1H, H-30), 4.76 (dd,
1H, J1,2 = 1.3 Hz, J2,3 = 4.2 Hz, H-2), 4.61–4.56 (m, 2H, H-10, H-60),
4.47 (dd, 1H, J3,4 = 9.0 Hz, H-3), 4.21–3.91 (m, 6H, H-1, H-4, H-6,
H-6, H-50, H-60), 3.67 (m, 1H, H-5), 3.11–3.06 (m, 2H, CH2), 2.16
(s, 6H, 2CH3), 2.12 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.06 (s, 3H,
CH3), 1.98 (s, 3H, CH3), 1.07–1.02 (m, 2H, CH2), 0.08 (s, 9H,
3CH3); 13C NMR (CDCl3): dC (75 MHz, CDCl3) 170.5 (CO), 170.2
(CO), 170.1 (CO), 170.0 (CO), 169.3 (CO), 169.2 (CO), 101.1 (C-10),
79.6 (C-1), 75.3 (C-5), 74.5 (C-50), 71.6 (C-3), 70.9 (C-30), 70.7 (C-
4), 69.2 (C-20), 66.8 (C-40), 61.5 (C-60), 61.2 (C-6), 51.9 (CH2), 38.8
(C-2), 20.9 (CH3), 20.8 (CH3), 20.7 (CH3), 20.6 (2CH3), 10.2 (CH2),
0
0
0
0
dH 6.20 (br d, 1H, J2,3 = 10.2 Hz, H-3), 5.82 (br d, 1H, JNH,1 = 9.1 Hz,
NH), 5.77 (ddd, 1H, J = 2.7 Hz, J = 1.9 Hz, H-2), 5.53–5.45 (m, 1H,
H-1), 5.39 (dd, 1H, J3 ,4 = 3.5 Hz, J4 ,5 = 0.5 Hz, H-40), 5.18 (dd, 1H,
0
0
0
0
J1 ,2 = 7.8 Hz, J2 ,3 = 10.4 Hz, H-20), 5.03 (dd, 1H, H-30), 4.59 (d, 1H,
H-10), 4.26 (dd, 1H, J5,6 = 3.8 Hz, J6,6 12 Hz, H-6), 4.20–3.81 (m,
5H, H-2, H-5, H-6, H-60, H-60), 3.96 (br t, 1H, J5,6 = 6.5 Hz, H-50),
3.85–3.80 (m, 1H, H-4), 3.16–2.96 (m, 2H, CH2), 2.16 (s, 3H, CH3),
2.11 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.05 (s, 3H, CH3), 1.98 (s, 3H,
CH3), 1.16–0.95 (m, 2H, CH2), 0.07 (s, 9H, 3CH3); 13C NMR (CDCl3):
dC 171.6 (CO), 170.5 (CO), 170.2 (CO), 170.1(CO), 169.6 (CO), 132.5
(C-3), 126.0 (C-2), 102.4 (C-10), 76.9 (C-1), 72.3 (C-5), 70.8 and 70.7
0
0
0
0

584
F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
ꢀ2.0 (3CH3). HR-ESIMS m/z calcd for [C29H46INO17SSi]Na+
4.8. 3,4,6-Tri-O-acetyl-1,2-dideoxy-2-iodo-1-[2-(trimethylsilyl)
ethanesulfonamido]-b- -mannopyranose (8b)
890.1198, found 890.1174.
D
4.5. 3,6-Di-O-acetyl-2-deoxy-2-iodo-4-O-(2,3,4,6-tetra-O-acetyl-
3,4,6-Tri-O-acetyl-D-glucal (545 mg, 2 mmol), 2-trimethylsilyle-
b-
D
-galactopyranosyl)-
D
-mannose (4)
thanesulfonamide (380 mg, 2 mmol) and 4 Å MS (1 g) were dried
under vacuum for 1 h and dissolved in dry CH2Cl2 (5 mL). The mix-
ture was cooled down to ꢀ10 °C, iodine monochloride was added,
the mixture was stirred for 2 h at ꢀ10 °C, warmed up to rt and stir-
red overnight. The mixture was diluted with CH2Cl2 (100 mL),
washed with satd aq sodium thiosulfate (30 mL) and brine
(50 mL). The organic layer was dried (Na2SO4) and concentrated
under vacuum. Compound 8b (526 mg, 45%). was isolated follow-
ing flash chromatography purification (eluent: ethyl acetate/cyclo-
hexane 3:7) as a thick oil; TLC Rf 0.59 (ethyl acetate/cyclohexane
Selected data for the major b-isomer: TLC: Rf 0.24 (ethyl ace-
tate/cyclohexane 1:1; 1H NMR (CDCl3): dH 5.52 (br s, 1H, H-10),
5.36 (dd, 1H, J3 ,4 = 3.3 Hz, J4 ,5 = 0.8 Hz, H-40), 5.13 (dd, 1H,
0
0
0
0
J1 ,2 = 7.8 Hz, J2 ,3 = 10.5 Hz, H-20), 5.01 (dd, 1H, H-30), 4.79 (dd,
1H, J2,3 = 4.2 Hz, J3,4 = 8.3 Hz, H-3), 4.62 (d, 1H, H-10), 4.55 (dd,
1H, J1,2 = 2.0 Hz, H-2), 4.52–4.44 (m, 1H, H-6eq), 4.21–3.92 (m,
6H, H-4, H-5, H-50, H-60, H-6, H-60), 2.17 (s, 3H, CH3), 2.15 (s, 3H,
CH3), 2.08 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.06 (s, 3H, CH3), 1.98
(s, 3H, CH3); 13C NMR (CDCl3): dC 170.7 (CO), 170.5 (CO), 170.3
(CO), 170.1 (CO), 169.6 (CO), 169.4 (CO), 101.3 (C-10), 95.5 (C-1),
75.8 (C-4), 71.0 (C-30), 70.7 (C-50), 69.7 (C-5), 69.5 (C-3), 69.2 (C-
20), 66.9 (C-40), 62.1 and 61.2 (C-6 and C-60), 31.1 (C-2), 21.1
(CH3), 21.0 (CH3), 20.7 (CH3), 20.6 (2CH3), 20.5; HR-ESIMS m/z
calcd for [C24H33NIO16]Na+ 727.0711, found 727.0737.
0
0
0
0
1:1); [
a]
ꢀ3.1 (c 1, CHCl3); 1H NMR (CDCl3): dH 5.55 (d, 1H,
D
JNH,1 = 10.5 Hz, NH), 5.31 (t, 1H, J3,4 = J4,5 9.5 Hz, H-4), 4.77 (dd,
1H, J1,2 = 1.5 Hz, J2,3 = 4.2 Hz, H-2), 4.49 (dd, 1H, H-3), 4.25–4.19
0
(m, 2H, H-1 and H-6), 4.09 (dd, 1H, J5,6 = 4.9 Hz, J6,6 12.4 Hz, H-
60), 3.66–3.71 (m, 1H, H-5), 3.15–3.02 (m, 2H, CH2), 2.11 (s, 3 H,
CH3), 2.09 (s, 3H, CH3), 2.07 (s, 3H, CH3), 1.11–1.03 (m, 2H, CH2),
ꢀ0.07 (s, 9H, 3CH3); 13C NMR (CDCl3): dC 171.7, 170.7, 169.2,
79.8 (C-1), 74.5 (C-5), 71.6 (C-3), 66.8 (C-4), 62.0 (C-6), 51.9
(CH2), 37.5 (C-2), 20.9, 20.8, 20.7, 10.3 (CH2), ꢀ2.0 (3CH3); HR-
ESIMS m/z calcd for [C17H30INO9SSi]Na+ 602.0353, found 602.0361.
4.6. N-[3,6-Di-O-acetyl-2-deoxy-2-iodo-4-O-(2,3,4,6-tetra-O-
acetyl-b-
succinimide (5)
D-galactopyranosyl)-a-D-mannopyranosyl]
TLC: Rf 0.11 (ethyl acetate/cyclohexane 1:1); [
a
]
+7.8 (c 1,
4.9. 1,2-Dideoxy-2-iodo-3,4,6-tri-O-acetyl-1-[2-(trimethylsilyl)
D
CHCl3); 1H NMR (CDCl3): dH 5.80 (d, 1H, J1,2 = 10.5 Hz, H-1), 5.69
(m, 1H, H-3), 5.62 (dd, 1H, J2,3 = 2.6 Hz, H-2), 5.40 (dd, 1H,
ethanesulfonamido]-a-D-talopyranose (9a)
J3 ,4 = 3.4 Hz, J4 ,5 = 0.9 Hz, H-40), 5.22 (dd, 1H, J1 ,2 = 7.9 Hz,
Compound 9a (715 mg, 61%) was prepared as described for
0
0
0
0
0
0
J2 ,3 = 10.3 Hz, H-20), 5.02 (dd, 1H, H-30), 4.69 (d, 1H, H-10), 4.52–
compound 8a. TLC: Rf 0.53 (ethyl acetate/cyclohexane 4:6); [a]
D
0
0
4.42 (m, 1H, H-6), 4.24 (dd, 1H, J5 ,6 = 3.5, J6 ,6 = 12.2 Hz, H-60),
ꢀ6.7 (c 1, CHCl3); 1H NMR (CDCl3): dH 6.38 (d, 1H, JN,H1 = 10.0 Hz,
NH), 5.50 (t, 1H, J2,3 = J3,4 = 3.2 Hz, H-3), 5.30 (dd, 1H, J4,5 = 5.9 Hz,
H-4), 5.23 (br t, 1H, J1,2 = 9.5 Hz, H-1), 4.57 (dd, 1H, J5,6 = 9.1 Hz,
0
0
0
0
4.21–4.09 (m, 3H, H-5, H-6, H-60), 4.02 (dt, J5 ,6 = 6.9 Hz, H-50),
3.75 (dd, 1H, J3,4 = 1.5 Hz, J4,5 = 6.4 Hz, H-4), 2.77 (br s, 4H, 2CH2),
2.20 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.04 (s, 6H,
2CH3), 1.98 (s, 3H, CH3); 13C NMR (CDCl3): dC 176.2 (2CO), 170.6
(CO), 170.5 (CO), 170.3 (CO), 170.1 (CO), 169.6 (CO), 169.3 (CO),
101.6 (C-10), 77.5 (C-1), 77.1 (C-4), 74.0 (C-3), 73.3 (C-5), 71.2
and 70.8 (C-5 and C-30), 68.7 (C-20), 67.3 (C-40), 62.0 (C-60), 61.3
(C-6), 28.0 (2CH2), 20.9, 20.7 (2CH3), 20.6, 20.5 (2CH3), 18.6 (C-
2); HR-ESIMS m/z calcd for [C28H36NIO17]Na+ 808.0926, found
808.0907.
0
0
J6,6 = 12.2 Hz, H-6), 4.41–4.26 (m, 3H, H-2, H-5 and H-60), 3.14–
0
3.05 (m, 2H, CH2), 2.20 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.05 (s, 3H,
CH3), 1.10–1.02 (m, 2H, CH2), 0.06 (s, 9H, 3CH3); 13C NMR (CDCl3):
dC 170.7 (CO), 169.7 (CO), 169.5 (CO), 78.9 (C-1), 72.1 (C-5), 69.9 (C-
3), 66.2 (C-4), 60.1 (C-6), 51.0 (CH2), 24.7 (C-2), 21.0 (CH3), 20.9
(CH3), 20.7 (CH3), 10.3 (CH2), ꢀ1.94 (3CH3); HR-ESIMS m/z calcd
for [C17H30INO9SSi]Na+ 602.0353, found 602.0323.
4.10. 3,4,6-Tri-O-acetyl-1,2-dideoxy-2-iodo-1-[2-(trimethylsilyl)
4.7. 3,4,6-Tri-O-acetyl-1,2-dideoxy-2-iodo-1-[2-(trimethylsilyl)
ethanesulfonamido]-b-
acetyl-1,2-dideoxy-2-iodo-1-[2-(trimethylsilyl)
ethanesulfonamido]-b- -glucopyranose (9c)
D-talopyranose (9b) and 3,4,6-tri-O-
ethanesulfonamido]-
a-D
-mannopyranose (8a)
D
To a stirred suspension of tri-O-acetyl-D-glucal (1 g, 3.7 mmol),
2-(trimethylsilyl)ethanesulfonamide (731 mg, 4.04 mmol) and 4 Å
molecular sieves in dry CH2Cl2 (5 mL) was added solid NIS (826 g,
3.7 mmol) followed by I2 (922 g, 3.7 mmol) 2 h later. The reaction
mixture was kept under stirring at ꢀ10 °C overnight. The mixture
was then filtered and diluted with CH2Cl2. The filtrate was washed
with satd aq Na2S2O3, and brine, dried (Na2S2O4), filtered and con-
centrated under reduced pressure. Iodosulfonamide 8a (1.38 g,
65%) was obtained following flash-chromatography purification
(eluent: ethyl acetate/cyclohexane 3:7); TLC: Rf 0.5 (ethyl ace-
Compounds 9b and 9c have been obtained as a mixture to-
gether with compound 9a (see Supplementary data). Chemical
shift attribution has been carried out from the NMR spectra of
the mixture and comparison with the spectra of pure 9a (see Sec-
tion 4.9).
Compound 9b: 1H NMR (CDCl3): dH 5.67 (d, 1H, JN,H1 = 10.5 Hz,
NH), 5.35 (br d, 1H, J3,4 = 3.7 Hz, H-4), 4.85 (dd, 1H, J2,3 = 4.1 Hz,
H-3), 4.55 (br dd, J1,2 = 2.0 Hz, H-2), 4.36–4.29 (m, H-6eq),
4.27–4.22 (m, H-6ax), 4.22 (dd, 1H, H-1), 4.10–3.98 (m, 1H, H-5),
3.16–3.03 (m, 2H, CH2), 2.22 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.09
(s, 3H, CH3), 1.13–1.04 (m, 2H, CH2), 0.09 (s, 9H, 3CH3); 13C NMR
(CDCl3): dC 170.7, 169.5, 169.3, 80.6 (C-1), 73.7 (C-5), 68.0 (C-3),
64.2 (C-4), 61.7 (C-6), 52.1 (CH2), 29.7 (C-2), 21.0, 20.9, 20.7, 10.3
(CH2), ꢀ1.94 (3CH3);
tate/cyclohexane 4:6); [
a
]
D
ꢀ1 (c 1, CHCl3); 1H NMR (CDCl3): dH
6.68 (d, 1H, JN,H1 = 8.9 Hz, NH), 5.28 (dd, 1H, J1,2 = 4.8 Hz, H-1),
5.01 (t, 1H, J3,4 = J4,5 = 6.7 Hz, H-4), 4.69 (dd, 1H, J2,3 = 3.7 Hz, H-
3), 4.40 (dd, 1H, H-2), 4.22 (dd, 1H, J5,6 = 6.6 Hz, J6,6 = 13.1 Hz, H-
6), 4.05–3.93 (m, 2H, H-5 and H-60), 2.95–2.88 (m, 2H, CH2), 1.98
(s, 3H, CH3), 1.94 (s, 6H, 2CH3), 0.96–0.85 (m, 2H, CH2), ꢀ0.10 (s,
9H, 3CH3); 13C NMR (CDCl3): dC 170.6 (CO), 169.7 (CO), 169.5
(CO), 81.9 (C-1), 71.6, 69.7 and 67.5 (C-3, C-4 and C-5), 61.4 (C-
6), 51.0 (CH2), 27.2 (C-2), 20.9 (CH3), 20.7 (2CH3), 10.1 (CH2),
ꢀ1.93 (3CH3); HR-ESIMS m/z calcd for [C17H30INO9SSi]Na+
602.0353, found 602.0326.
Compound 9c: 1H NMR (CDCl3): dH 5.75 (d, 1H, d, 1H,
JN,H1 = 9.9 Hz, NH), 5.25 (dd, 1H, J3,4 = 3.2 Hz, J4,5 = 0.8 Hz, H-4),
5.19 (dd, 1H, J2,3 = 11.3 Hz, H-3), 4.99 (t, 1H, J1,2 = 9.9 Hz, H-1),
4.18 (dd, 1H, J5,6 = 4.7 Hz, J6,6 = 9.3 Hz, H-6), 4.09–4.01 (m, 3H,
H-2, H-5 and H-6), 3.16–3.09 (m, 2H, CH2), 2.16 (s, 3H, CH3), 2.08
(s, 3H, CH3), 2.06 (s, 3H, CH3), 1.13–1.09 (m, 2H, CH2), 0.07 (s,

F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
585
9H, 3CH3); 13C NMR (CDCl3): dC (75 MHz, CDCl3) 170.4 (CO), 169.9
(CO), 169.3 (CO), 85.7 (C-1), 74.4 (C-3), 72.7 (C-5), 67.0 (C-4), 61.4
(C-6), 51.7 (CH2), 26.3 (C-2), 20.7 (CH3), 20.6 (2CH3), 10.4 (CH2),
ꢀ1.9 (3CH3); ESI-MS m/z [C17H30INO9SSi]Na+ 602.
(CH2), 27.2 (C-2), 10.3 (CH2), ꢀ1.99 (3CH3); HR-ESIMS m/z calcd
for [C32H36INO9SSi]Na+ 788.0822, found 788.0790.
4.13. General procedure for the azidolysis
Method A: To a solution of the
a-iodosulfonamide in dry DMF
4.11. 3,4-Di-O-acetyl-2-iodo-1,2,6-tri-deoxy-1-[2-(trimethylsilyl)
(3 mL/mmol), cooled at 0 °C, was added NaN3 (2 equiv) as a solid.
The mixture was allowed to warm at rt and stirred for 3 h. The
reaction mixture was diluted in CH2Cl2, washed with 5% aq NaH-
CO3 and brine. The organic phase was dried over Na2SO4, filtered
and concentrated under reduced pressure.
Method B: To a solution of the b-iodosulfonamide in dry DMF
(3 mL/mmol), cooled at 0 °C, was added NaN3 (2 equiv) as a solid.
The mixture was heated at 40 °C and stirred for 3 h. The reaction
mixture was then diluted in CH2Cl2, washed with 5% aq NaHCO3
and brine. The organic phase was dried over Na2SO4, filtered and
concentrated under reduced pressure.
ethanesulfonamido]-
acetyl-2,6-dideoxy-2-iodo-
a
-
L
-mannopyranose (12) and N-[3,4-di-O-
-mannopyranosyl] succinimide
a-L
(13)
To
a stirred suspension of di-O-acetyl-L-glucal (300 mg,
1.40 mmol), 2-(trimethylsilyl)ethanesulfonamide (254 mg, 1.40
mmol) and 4 Å molecular sieves in dry CH2Cl2 (6 mL) was added
solid NIS (312 mg, 0.66 mmol) followed by I2 (355 mg, 1.40 mmol)
1 h later. The reaction mixture was stirred at ꢀ10 °C for 2 h. The mix-
ture was then filtered and diluted with CH2Cl2. The filtrate was
washed with satd aq Na2S2O3, and brine, dried (Na2SO4), filtered
and concentrated under reduced pressure. The crude residue was
purified by flash-chromatography (eluent: ethyl acetate/cyclohex-
ane 2.5:7.5) to give the iodosulfonamide 12 (475 mg, 65%) and then
the succinimidyl adduct 13 (92 mg, 15%);
4.13.1. 3,6-Di-O-acetyl-1-azido-1,2-dideoxy-4-O-(2,3,4,6-tetra-O-
acetyl-b-
ethanesulfonamido]-b-
D
-galactopyranosyl)-2-[2-(trimethylsilyl)
-glucopyranose (15)
D
Compound 3a (6 g, 6.92 mmol) was reacted with NaN3 follow-
ing general method A. Flash-chromatography purification (eluent:
ethyl acetate/cyclohexane 4:6) of the crude residue provided the
azide 15 (5.14 g, 95%); TLC Rf 0.40 (ethyl acetate/cyclohexane
Compound 12: TLC: Rf 0.38 (ethyl acetate/cyclohexane 3:7);
[a]
D +0.6 (c 1, CHCl3); 1H NMR (CDCl3): dH 6.54 (d, 1H, JN,H1 = 9.0 Hz,
NH), 5.45 (dd, 1H, J1,2 = 4.4 Hz, H-1), 5.01 (t, 1H, J3,4 = J4,5 = 7.3 Hz,
H-4), 4.72 (dd, 1H, J2,3 = 4.4 Hz, H-3), 4.53 (t, 1H, H-2), 4.06 (dt,
1H, J5,6 = 6.6 Hz, H-5), 3.16–2.98 (m, 2H, CH2), 2.15 (s, 3H, CH3),
2.12 (s, 3H, CH3), 1.34 (d, 3H, H-6), 1.15–0.98 (m, 2H, CH2), 0.07
(s, 9H, 3CH3); 13C NMR (CDCl3): dC (75 MHz, CDCl3) 169.9 (CO),
169.7 (CO), 81.9 (C-1), 71.8 (C-4), 70.0 (C-3), 69.6 (C-5), 62.1 (C-
6), 51.2 (CH2), 27.9 (C-2), 21.0 (CH3), 20.9 (CH3), 17.0 (C-6), 10.1
(CH2), ꢀ1.93 (3CH3); HR-ESI-MS calcd for C15H28INO7SSi (M+Na)+
544.0298, found 544.0281.
1:1); [
a
]
ꢀ18.4 (c 1, CHCl3); 1H NMR (CDCl3): dH 5.37 (br d, 1H,
D
J3 .4 = 2.5 Hz, H-40), 5.33 (d, 1H, JNH,2 = 9.4 Hz, NH), 5.12–5.04 (m,
0
0
2H, H-20 and H-3), 4.98 (dd, 1H, J2 ,3 = 10.4 Hz, H-30), 4.75 (d, 1H,
J1,2 = 9.2 Hz, H-1), 4.54–4.50 (m, 2H, H-10 and H-60), 4.20–4.08 (m,
3H, H-6, H-6, H-60), 3.94–3.79 (m, 3H, H-4, H-5, H-50), 3.38 (q,
1H, J2,3 9.3 Hz), 3.16–2.96 (m, 2H, CH2), 2.18 (s, 3H, CH3), 2.17 (s,
3H, CH3), 2.15 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.06 (s, 3H, CH3),
1.99 (s, 3H, CH3), 1.13–0.97 (m, 2H, CH2), 0.06 (s, 9H, 3CH3); 13C
NMR (CDCl3): dC 171.4, 170.3 (2CO), 170.0 (2CO), 169.5 (CO),
101.0 (C-10), 88.9 (C-1), 75.6 and 74.3 (C-4 and C-50), 73.0 (C-3),
70.8 (C-30 and C-5), 69.0 (C-20), 66.7 (C-40), 61.8 (C-60), 60.8 (C-6),
57.6 (C-2), 50.9 (CH2), 21.1 (CH3), 20.8 (CH3), 20.6 (3CH3), 20.5,
10.3 (CH2), ꢀ2.05 (3CH3); HR-ESIMS m/z calcd for [C29H46N4O17S-
Si]Na+ 805.2248, found 805.2246.
0
0
Compound 13: TLC: Rf 0.20 (ethyl acetate/cyclohexane 3:7);
[a]
+2 (c 1, CHCl3); 1H NMR (CDCl3): dH (300 MHz, CDCl3) 5.75
D
(d, 1H, J1,2 = 10.5 Hz, H-1), 5.64 (dd, 1H, J2,3 = 3.1 Hz, H-2), 5.31
(br t, 1H, H-3), 4.65 (t, 1H, J3,4 = J4,5 = 2.6 Hz H-4), 4.28 (dt, 1H,
J5,6 = 8.2 Hz, H-5), 2.67 (br s, 4H, 2CH2), 2.18 (s, 3H, CH3), 2.12 (s,
3H, CH3), 1.42 (d, 3H, H-6); 13C NMR (CDCl3): dC 176.2 (2CO),
169.6 (CO), 168.9 (CO), 74.4 (C-1), 73.2 (C-5), 72.1 (C-3), 71.0 (C-
4), 27.9 (2CH2), 22.0 (C-2), 21.0 (CH3), 20.9 (CH3), 15.8 (C-6); HR-
ESIMS m/z calcd for [C14H18INO7]Na+ 462.0026, found 462.0027.
Compound 15 was also obtained via general method B in 45%
yield.
4.13.2. 3,4,6-Tri-O-acetyl-1-azido-1,2-dideoxy-2-[2-
(trimethylsilyl)ethanesulfonamido]-b-D-glucopyranose (16)
4.12. 3,4,6-Tri-O-benzoyl-1,2-dideoxy-2-iodo-1-[2-
(trimethylsilyl)ethanesulfonamido]-
a-
D
-mannopyranose (14)
Compound 8b (100 mg, 0.17 mmol) was reacted with NaN3 fol-
lowing general method B. Compound 15 was isolated by flash chro-
matography (ethyl acetate/cyclohexane 3:7) and obtained as a
white fluffy solid (40 mg, 48%); Rf 0.47 (ethyl acetate/cyclohexane
To a stirred suspension of tri-O-benzoyl-
D
-glucal (300 mg,
0.66 mmol), 2-(trimethylsilyl)ethanesulfonamide (118 mg, 0.66
mmol) and 4 Å molecular sieves in dry CH2Cl2 (6 mL) was added
solid NIS (147 mg, 0.66 mmol) followed by I2 (167 mg, 0.66 mmol)
2 h later. The reaction mixture was warmed to 0 °C over 2 h. The
mixture was then filtered and diluted with CH2Cl2. The filtrate
was washed with satd aq Na2S2O3, and brine, dried (Na2S2O4), fil-
tered and concentrated under reduced pressure. The crude residue
was purified by flash-chromatography (eluent: ethyl acetate/cyclo-
hexane 2.5:7.5) to give unreacted glucal (91 mg, 30%) and then iod-
osulfonamide 14 (230 mg, 46%); TLC: Rf 0.5 (ethyl acetate/
1:1); [
a]
D ꢀ38.2 (c 1, CHCl3); 1H NMR (CDCl3): dH 5.19–5.11 (m, 2H,
H-3, H-4), 4.77 (d, 1H, J1,2 = 9.2 Hz, H-1), 4.31 (dd, 1H,
J5,6eq = 4.8 Hz, J6,6 = 12.4 Hz, H-6), 4.18 (dd, 1H, J 5,6 = 2.1 Hz, H-6),
3.83 (br s, 1H, H-5), 3.52–3.42 (m, 1H, H-2), 3.01–3.12 (m, 2H,
CH2), 2.15 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.06 (s, 3H, CH3), 1.09–
0.88 (m, 2H, CH2), 0.08 (s, 9H, 3CH3); 13C NMR (CDCl3): dC 171.7
(CO), 170.7 (CO), 169.2 (CO), 89.0 (C-1), 73.8 (C-5), 72.9 (C-3),
67.9 (C-4), 61.7 (C-6), 57.7 (C-2), 50.9 (CH2), 21.0 (CH3), 20.7
(CH3), 20.6 (CH3), 10.5 (CH2), ꢀ2.0 (3CH3); HR-ESIMS m/z calcd
for [C17H30N4O9SSi]Na+ 517.1400, found 517.1393.
cyclohexane 3:7); [
a]
+21.2 (c 1, CHCl3); 1H NMR (CDCl3): dH
D
8.09–7.95, 7.62–7.52 and 7.47–7.35 (m, 15H, H arom), 6.35 (d,
1H, JN,H1 = 8.1 Hz, NH), 5.90 (t, 1H, J3,4 = J4,5 = 7.5 Hz, H-4), 5.74
(dd, 1H, J1,2 = 4.0 Hz, H-1), 5.20 (dd, 1H, J2,3 = 4.0 Hz, H-3), 4.82 (t,
1H, H-2), 4.75–4.68 (m, 1H, H-6), 4.62–4.52 (m, 2H, H-5 and H-
6), 3.19–3.11 (m, 2H, CH2), 1.15–1.08 (m, 2H, CH2), 0.05 (s, 9H,
3CH3); 13C NMR (CDCl3): dC 166.1 (CO), 165.4 (CO), 165.1 (CO),
133.9, 133.7, 133.2, 129.9 (4C), 128.7 (2C), 128.5 (2C), 128.4 (2C),
82.7 (C-1), 71.5 (C-5), 70.3 (C-3), 68.3 (C-4), 62.1 (C-6), 51.5
Compound 16 was also obtained via general method A in 85%
yield.
4.13.3. 3,4-Di-O-acetyl-1-azido-1,2,6-trideoxy-2-[2-
(trimethylsilyl)ethanesulfonamido]-b-L-glucopyranose (17)
Compound 12 (100 mg, 0.19 mmol) was reacted with NaN3 fol-
lowing general method A. Flash-chromatography purification (elu-
ent: ethyl acetate/cyclohexane 3:7) of the crude residue provided

586
F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
the azide 17 (74 mg, 88%); TLC Rf 0.67 (ethyl acetate/cyclohexane
4:6); [
+22.3 (c 1, CHCl3); 1H NMR (CDCl3): dH 5.11–5.03 (m,
(Na2SO4), filtered and concentrated under reduced pressure. Flash-
chromatography (eluent: ethyl acetate/cyclohexane 1:9) of the
resulting residue provided compound 20 (180 mg, 77%); TLC Rf
a]
D
2H, NH and H-3), 4.86 (t, 1H, J3,4 = J4,5 = 9.7 Hz, H-4), 4.68 (d, 1H,
J1,2 = 9.2 Hz, H-1), 3.74–3.62 (m, 1H, H-5), 3.44 (q, 1H,
JNH,2 = J2,3 = 9.2 Hz, H-2), 3.17–2.98 (m, 2H, CH2), 2.14 (s, 3H,
CH3), 2.07 (s, 3H, CH3), 1.13–0.98 (m, 2H, CH2), 0.07 (s, 9H,
3CH3); 13C NMR (CDCl3): dC 171.7 (CO), 169.5 (CO), 88.9 (C-1),
72.9 (C-3 and C-4), 72.3 (C-5), 58.0 (C-2), 50.9 (CH2), 20.9 (CH3),
20.7 (CH3), 17.4 (C-6), 10.4 (CH2), ꢀ2.0 (3CH3); HR-ESIMS m/z calcd
for [C15H28N4O7SSi]Na+ 459.1346, found 459.1342.
0.77 (ethyl acetate/cyclohexane 1:1); [
a]
D
ꢀ4.8 (c 1, CHCl3); 1H
NMR (CDCl3): dH 7.60 (d, 1H, J = 1.9 Hz, H arom), 7.27 (dd, 1H,
J = 8.0 Hz, H arom), 7.16 (dd, 1H, H arom), 5.38 (d, 1H, JN,H2 = 9.6 Hz,
NH), 5.21 (t, 1H, J2,3 = J3,4 = 9.4 Hz, H-3), 5.12 (t, 1H, J4,5 = 9.4 Hz, H-
4), 4.76 (d, 1H, J1,2 = 10.5 Hz, H-1), 4.24 (dd, 1H, J5,6 = 4.7 Hz,
J6,6 = 12.4 Hz, H-6), 4.08 (dd, 1H, J5,6 = 2.1 Hz, H-6), 3.76 (q, 1H, H-
2), 3.74–3.66 (m, 1H,), 3.23–3.15 (m, 2H, CH2), 2.43 (s, 3H, CH3),
2.07 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.00 (s, 3H, CH3), 1.33 (s, 9H,
tBu), 1.20–1.12 (m, 2H, CH2), 0.05 (s, 9H, 3CH3); 13C NMR (CDCl3):
dC 171.8 (CO), 170.8 (CO), 169.3 (CO), 149.7 (C arom), 137.3 (C
arom), 131.6 (C arom), 130.5 (C arom), 130.1 (C arom), 125.5 (C
arom), 87.8 (C-1), 78.4 and 74.8 (C-3 and C-5), 68.4 (C-4), 62.3 (C-
6), 57.2 (C-2), 51.4 (CH2), 34.5 (CtBu), 31.3 (tBu), 21.0 (CH3), 20.8
(CH3), 20.6 (CH3), 20.5 (CH3), 10.3 (CH2), ꢀ1.94 (3CH3); HR-ESIMS
m/z calcd for [C28H45NO9S2Si]Na+ 654.2203, found 654.2207.
4.13.4. 1-Azido-3,4,6-tri-O-benzoyl-1,2-dideoxy-2-[2-
(trimethylsilyl)ethanesulfonamido]-b-D-glucopyranose (18)
Compound 14 (100 mg, 0.13 mmol) was reacted with NaN3 fol-
lowing general method A. Flash-chromatography purification (elu-
ent: ethyl acetate/cyclohexane 2:8) of the crude residue provided
the azide 18 (75 mg, 82%); TLC Rf 0.35 (ethyl acetate/cyclohexane
3:7); [
a
]
D
ꢀ30.9 (c 0.5, CHCl3); 1H NMR (CDCl3): dH 8.08–7.90
and 7.63–7.32 (m, 15H, H arom), 5.70 (br t, 1H, J3,4 = J4,5 = 9.8 Hz,
H-4), 5.56 (br t, 1H, J3,2 = 9.8 Hz, H-3), 5.12–5.04 (m, 2H, H-20 and
H-3), 5.00–4.96 (m, 1H, NH), 4.82 (d, 1H, J1,2 = 9.2 Hz, H-1), 4.68
(dd, 1H, J5,6 = 3.0 Hz, J6,6 = 12.2 Hz, H-6), 4.52 (dd, 1H, J5,6 = 5.0 Hz,
H-6), 4.24–4.19 (m, 1H, H-5), 3.08–2.93 (m, 2H, CH2), 1.13–0.97
(m, 2H, CH2), 0.06 (s, 9H, 3CH3); 13C NMR (CDCl3): dC 167.2 (CO),
166.0 (CO), 165.0 (CO), 133.9 (C arom), 133.6 (C arom), 133.3 (C
arom), 130.1 (2C arom), 129.8 (4C arom), 128.6 (2C arom), 128.5
(4C arom), 89.7 (C-1), 74.2 (C-5), 73.3 (C-3), 69.0 (C-4), 62.7 (C-
6), 58.0 (C-2), 51.2 (CH2), 10.3 (CH2), ꢀ2.21 (3CH3); HR-ESIMS m/
z calcd for [C32H36N4O9SSi]Na+ 703.1870, found 703.1898.
Acknowledgement
The authors are grateful to the Conseil Régional de Picardie for
financial support to F.-M.G.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.01.022.
4.14. 3,4,6-Tri-O-acetyl-1,2-dideoxy-1-phthalimido-2-[2-
(trimethylsilyl)ethanesulfonamido]-b-D-glucopyranose (19)
References
1. (a) Dwek, R. A. Chem. Rev. 1996, 96, 683–720; (b) Zuber, C.; Roth, J. In The Sugar
Code Fundamental of Glycosciences; Gabius, H.-J., Ed.; Wiley-Blackwell:
Weinheim, Germany, 2009; pp 87–110. Chapter 6; (c) Stanley, P.; Schachter,
H.; Taniguchi, N., 2nd ed. In Essentials of Glycobiology; Varki, A., Cummings, R.
D., Esko, J. D., Freeze, H. H., Stanley, P., Bertozzi, C. R., Hart, G. W., Etzler, M. E.,
Eds.; Cold Spring Harbor Laboratory Press: New York, 2009; pp 101–114.
Chapter 8.
2. (a) Kärcher, U.; Schröder, H.; Haslinger, E.; Allmeier, G.; Schreiner, R.; Wieland,
F.; Haselbeck, A.; König, H. J. Biol. Chem 1993, 268, 26821–26826; (b) Eichler, J.;
Adams, M. W. W. Microb. Mol. Biol. Rev. 2005, 69, 393–425; (c) Bejugam, M.;
Flitsch, S. L. Org. Lett. 2004, 6, 4001–4004.
3. (a) Paul, G.; Lottspeich, F.; Wieland, F. J. Biol. Chem. 1986, 261, 1020–1024; (b)
Young, M. N.; Brisson, J. R.; Kelly, J.; Watson, D. C.; Tessier, L.; Lanthier, P. H.;
Jarrell, H. C.; Cadotte, N.; St Michael, F.; Aberg, E.; Szymanski, C. M. J. Biol. Chem.
2002, 277, 42530–42539.
4. For some articles mentioning N-linked 2-amino-2-deoxy sugars, see: (a)
Arsequell, G.; Haurum, J. S.; Elliott, T.; Dwek, R. A.; Lellouch, A. C. J. Chem.
Soc., Perkin Trans. 1 1995, 1739–1745; (b) Honda, T.; Kato, M.; Inoue, M.;
Shimamoto, T.; Shima, K.; Nakanishi, T.; Yoshida, T.; Noguchi, T. J. Med. Chem.
1988, 31, 1295–1305; (c) Harrison, A. W.; Fisher, J. F.; Guido, D. M.; Couch, S. J.;
Lawson, J. A.; Sutter, D. M.; Williams, M. V.; DeGraaf, G. L.; Rogers, J. E.; Pals, D.
T.; DuCharme, D. W. Bioorg. Med. Chem. 1994, 2, 1339–1361; (d) Courtney, S. M.
PCT Int. Appl. WO 9700882, 1997.
5. (a) Mieszala, M.; Kogan, G.; Jennings, H. J. Carbohydr. Res. 2003, 338,
167–175; (b) Boullanger, P.; Maunier, V.; Lafont, D. Carbohydr. Res. 2000, 324,
97–106; (c) Zeng, X.; Murata, T.; Kawagishi, H.; Usui, T.; Kobayashi, K. Biosci.
Biotechnol. Biochem. 1998, 62, 1171–1178; (d) Masaka, R.; Ogata, M.; Misawa,
Y.; Yano, M.; Hashimoto, C.; Murata, T.; Kawagishi, H.; Usui, T. Bioorg. Med.
Chem. 2010, 18, 621–629; (e) Ogata, M.; Hidari, K. I. P. J.; Kozaki, W.; Murata, T.;
Hiratake, J.; Park, E. Y.; Suzuki, T.; Usui, T. Biomacromolecules 2009, 10, 1894–
1903; (f) O’Reilly, M. K.; Collins, B. E.; Han, S.; Liao, L.; Rillahan, C.; Kitov, P. I.;
Bundle, D. R.; Paulson, J. C. J. Am. Chem. Soc. 2008, 130, 7736–7745; (g) Vetter,
D.; Tate, E. M.; Gallop, M. A. Bioconjugate Chem. 1995, 6, 319–322; (h) Park, S.;
Lee, M.; Pyo, S.-J.; Shin, I. J. Am. Chem. Soc. 2004, 126, 4812–4819; (i) Bridiau, N.;
Benmansour, M.; Legoy, M. D.; Maugard, T. Tetrahedron 2007, 63, 4178–4183;
(j) Hu, H.; Xue, J.; Swarts, B. M.; Wang, Q.; Wu, Q.; Guo, Z. J. Med. Chem. 2009,
52, 2052–2059; (k) de las Heras, F. G.; Alonso, R.; Alonso, G. J. Med. Chem. 1979,
22, 496–501; (l) Rawe, S. L.; Doyle, D.; Zaric, V.; Rozas, I.; McMahon, K.; Tosin,
M.; Müller Bunz, H.; Murphy, E. P.; O’Boyle, K. M.; Murphy, P. V. Carbohydr. Res.
2006, 341, 1370–1390.
Compound 8b (100 mg, 0.17 mmol) and potassium phthalimide
(22 mg, 0.34 mmol) were dissolved in DMF (5 mL). The mixture
was heated to 40 °C under argon for 3 h, cooled down to rt, diluted
in CH2Cl2 (50 mL), washed with water (30 mL) and brine (30 mL),
dried (Na2SO4) and concentrated under reduced pressure. Com-
pound 19 was isolated following flash chromatography purifica-
tion (eluent: ethyl acetate/cyclohexane 3:7) as a white solid
(29 mg, 27%). Rf 0.38 (ethyl acetate/cyclohexane 1:1); [
a
]
ꢀ14.1
D
(c 1, CHCl3); 1H NMR (CDCl3): dH 8.04–7.91 (m, 2H, H arom),
7.83–7.77 (m, 2H, H arom), 5.57 (d, 1H, J1,2 9.7 Hz, H-1), 5.42 (t,
1H, J2,3 = J3,4 = 9.7 Hz, H-3), 5.30 (t, 1H, J4,5 = 9.7 Hz, H-4), 5.26 (d,
1H, JNH,2 = 9.7 Hz, NH), 4.73 (q, 1H, J1,2 = 9.7 Hz, H-2), 4.26–4.24
(m, 2H, H-6, H-6), 3.99 (ddd, 1H, J5,6 = 1.1 Hz, J5,6 = 2.9 Hz, H-5),
2.77–2.72 (m, 2H, CH2), 2.16 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.11
(s, 3H, CH3), 0.86–0.80 (m, 2H, CH2), ꢀ0.12 (s, 9H, 3CH3); 13C
NMR (CDCl3): dC 176.0 (2C), 171.1 (CO), 170.8 (CO), 169.5 (CO),
134.8–134.4 (C arom), 124.1–123.9 (C arom), 79.5 (C-1), 74.4 (C-
5), 73.7 (C-3), 68.5 (C-4), 61.9 (C-6), 53.6 (C-2), 50.7 (CH2), 20.9
(CH3), 20.8 (CH3), 20.7 (CH3), 10.1 (CH2), ꢀ2.2 (3CH3); HR-ESIMS
m/z calcd for [C25H34N2O11SSi]Na+ 621.1550, found 621.1569.
4.15. (5-tert-Butyl-2-methyl)phenyl 3,4,6-tri-O-acetyl-1,2-
dideoxy-1-thio-2-[2-(trimethylsilyl)ethanesulfonamido]-b-D-
glucopyranoside (20)
To a solution of 5-tert-Butyl-2-methyl-phenyl sulfide (93.65 mg,
0.52 mmol) in DMF (1 mL) was added LiHMDS (1 M in THF, 445 L,
l
0.46 mmol) dropwise under Ag at ꢀ30 °C. The suspension was then
transferred to a solution of compound 8a (215 mg, 0.38 mmol) in
DMF (1 mL) at ꢀ30 °C. The reaction mixture was allowed to warm
at ꢀ20 °C over 30 min. The reaction mixture was diluted in CH2Cl2
and quenched by addition of satd aq NH4Cl. The organic layer was
washed with 5% aq Na2S2O3 and brine. The organic phase was dried
6. For examples, see: (a) Kumar, R.; Maulik, P. R.; Misra, A. K. Glycoconjugate J.
2008, 25, 595–602; (b) Gudmundsdottir, A. V.; Nitz, M. Org. Lett. 2008, 10,
3461–3463.

F.-M. Gautier et al. / Carbohydrate Research 346 (2011) 577–587
587
7. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
2021; (b) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064.
Tetrahedron 2006, 62, 4954–4978; (h) Nagorny, P.; Fasching, B.; Li, X.; Chen, G.;
Aussedat, B.; Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, 5792–5799.
24. Owens, J. M.; Yeung, B. K. S.; Hill, D. C.; Petillo, P. A. J. Org. Chem. 2001, 66,
1484–1486.
8. For a review on application of the click-chemistry to carbohydrates, see:
Dedola, S.; Nepogodiev, A. S.; Field, R. A. Org. Biomol. Chem. 2007, 5, 1006–1017.
9. For some application on 2-amino-1-azido sugars, see: (a) Lee, D. J.; Mandal, K.;
Harris, P. W. R.; Brimble, M. A.; Kent, S. B. H. Org. Lett. 2009, 11, 5270–5273; (b)
Macmillan, D.; Blanc, J. Org. Biomol. Chem. 2006, 4, 2847–2850; (c) Valverde, I.
E.; Delmas, A. F.; Aucagne, V. Tetrahedron 2009, 65, 7597–7602; (d) Ortega-
Munoz, M.; Perez-Balderas, F.; Morales-Sanfrutos, J.; Hernandez-Mateo, F.;
Isac-García, J.; Santoyo-Gonzalez, F. Eur. J. Org. Chem. 2009, 2454–2473; (e)
Joosten, J. A. F.; Tholen, N. T. S.; Ait El Maate, F.; Brouwer, A. J.; van Esse, G. W.;
Rijkers, D. T. S.; Liskamp, R. M. J.; Pieters, R. J. Eur. J. Org. Chem. 2005, 3182–
3185; (f) Marotte, K.; Sabin, C.; Préville, C.; Moumé-Pymbock, M.; Wimmerová,
M.; Mitchell, E. P.; Imberty, A.; Roy, R. ChemMedChem 2007, 2, 1328–1338; (g)
Marotte, K.; Préville, C.; Sabin, C.; Moumé-Pymbock, M.; Imberty, A.; Roy, R.
Org. Biomol. Chem. 2007, 5, 2953–2961; (h) Gouin, S. G.; Vanquelef, E.; García
Fernández, J. M.; Ortiz Mellet, C.; Dupradeau, F.-Y.; Kovensky, J. J. Org. Chem.
2007, 72, 9032–9045; (i) Wilkinson, B. L.; Bornaghi, L. F.; Poulsen, S.-A.;
Houston, T. A. Tetrahedron 2006, 62, 8115–8125; (j) Wilkinson, B. L.; Bornaghi,
L. F.; Houston, T. A.; Innocenti, A.; Supuran, C. T.; Poulsen, S.-A. J. Med. Chem.
2006, 49, 6539–6548; (k) Zhang, J.; Garrossian, M.; Gardner, D.; Garrossian, A.;
Chang, Y.-T.; Kim, Y. K.; Chang, C.-W. T. Bioorg. Med. Chem. Lett. 2008, 18, 1359–
1363; (l) Lin, H.; Walsh, C. T. J. Am. Chem. Soc. 2004, 126, 13998–14003.
10. For the preparation of N-(aspartoyl)-2-N-acetamido-glycosylamines, see: (a)
Dunstan, D.; Hough, L. Carbohydr. Res. 1972, 245, 246–248; (b) Tanaka, M.;
Yamashina, I. Carbohydr. Res. 1973, 27, 175–183.
25. (a) Priebe, W.; Grynkiewicz, G. In Glycoscience: Chemistry and Biology; Fraser-
Reid, B. O., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, 2001; Vol. 1, pp
749–783; (b) Fischer, E.; Zach, K. Sitzungsber. Kl. Preuss. Akad. Wiss. 1913, 27, 311–
317; (c) Roth, W.; Pigman, W. In Methods in Carbohydrate Chemistry; Whistler, R.
L., Wolfrom, M. L., Eds.; Academic Press: New York, 1963; Vol. 2, pp 405–408; (d)
Zhao, J.; Wei, S.; Ma, X.; Shao, H. Carbohydr. Res. 2010, 345, 168–171.
26. (a) Bergmann, M. Liebigs Ann. 1923, 434, 79–110; (b) Kent, P. W.; Dimitrijevich,
S. D. J. Fluor. Chem. 1977, 10, 455–478.
27. (a) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett. 1986, 27, 2099–
2102; (b) Ribière, P.; Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2006, 106,
2249–2269.
28. Klyosov, A. A. In Galectins; Klyosov, A. A., Witczak, Z. J., Platt, D., Eds.; Wiley:
Hoboken, 2008; pp 33–69. Chapter 3.
29. (a) Liu, M.; Young, V. G., Jr.; Lohani, S.; Live, D.; Barany, G. Carbohydr. Res. 2005,
340, 1273–1285; (b) Lafont, D.; Descotes, G. Carbohydr. Res. 1987, 166, 195–
209; (c) Gammon, D. W.; Kinfe, H. H.; De Vos, D. E.; Jacobs, P. A.; Sels, B. F.
Tetrahedron Lett. 2004, 45, 9533–9536.
30. (a) Kartha, K. P. R.; Cura, P.; Aloui, M.; Readman, S. K.; Rutherford, T. J.;
Field, R. A. Tetrahedron: Asymmetry 2000, 11, 581–593; (b) Marsh, S. J.;
Kartha, K. P. R.; Field, R. A. Synlett 2003, 1376–1378; (c) van Well, R. M.;
Kartha, K. P. R.; Field, R. A. J. Carbohydr. Chem. 2005, 24, 463–474; (d) van
Well, R. M.; Kärkkäinen, T. S.; Kartha, K. P. R.; Field, R. A. Carbohydr. Res.
2006, 341, 1391–1397.
11. (a) Nishiyama, T.; Isobe, M.; Ichikawa, Y. Angew. Chem., Int. Ed. 2005, 44, 4372–
4375; (b) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 15446–15448.
12. Dorsey, A. D.; Barbarow, J. E.; Trauner, D. Org. Lett. 2003, 5, 3237–3239.
13. (a) Likhosherstov, L. M.; Novikova, O. S.; Derevitskaja, V. A.; Kochetkov, N. K.
Carbohydr. Res. 1986, 146, C1–C5; (b) Urge, L.; Otvos, L., Jr.; Lang, E.;
Wroblewski, K.; Laczko, I.; Hollosi, M. Carbohydr. Res. 1992, 235, 83–93; (c)
Vetter, D.; Gallop, M. A. Bioconjugate Chem. 1995, 6, 316–318.
14. (a) Banoub, J.; Boullanger, P.; Lafont, D. Chem. Rev. 1992, 92, 1167–1195; (b)
Bongat, A. F. G.; Demchenko, A. V. Carbohydr. Res. 2007, 342, 374–406.
15. Nicolaou, K. C.; Snyder, S. A.; Nalbandian, A. Z.; Longbottom, D. A. J. Am. Chem.
Soc. 2004, 126, 6234–6236.
31. (a) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31,
4313–4316; (b) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331–1334.
32. Castanet, A.-S.; Colobert, F.; Broutin, P.-E. Tetrahedron Lett. 2002, 43, 5047–
5048.
33. (a) Yadav, J. S.; Subba Reddy, B. V.; Premalatha, K.; Swamy, T. Tetrahedron Lett.
2005, 46, 2687–2690; (b) Colinas, P. A.; Bravo, R. D. Carbohydr. Res. 2007, 342,
2297–2302.
34. (a) Thiem, J.; Köpper, S.; Schwentner, J. Liebigs Ann. 1985, 11, 2135–2150; (b)
Laupichler, L.; Endres Sowa, C.; Thiem, J. Bioorg. Med. Chem. 1994, 2, 1281–
1294.
16. Schmidt, R. R.; Vankar, Y. D. Acc. Chem. Res. 2008, 41, 1059–1073.
17. (a) Snider, B. B.; Lin, H. Synth. Commun. 1998, 28, 1913–1922; (b) Du Bois, J.;
Tomooka, C. S.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179–3180;
(c) Guthikonda, K.; When, P. M.; Caliando, B. J.; Du Bois, J. Tetrahedron 2006, 62,
11331–11342; (d) Kan, C.; Long, C. M.; Paul, M.; Ring, C. M.; Tully, S. E.; Rojas, C.
M. Org. Lett. 2001, 3, 381–384.
35. (a) De Castro, M.; Marzabadi, C. H. Tetrahedron Lett. 2004, 45, 6501–6504; (b)
De Castro, M.; Marzabadi, C. H. J. Carbohydr. Chem. 2005, 24, 179–185.
36. Horton, D.; Priebe, W.; Sznaidman, M. Carbohydr. Res. 1990, 205, 71–86.
37. (a) Belluci, G.; Chiappe, C.; D’Andrea, F.; Lo Moro, G. Tetrahedron 1997, 53,
3417–3424; (b) Boschi, A.; Chiappe, C.; De Rubertis, A.; Ruasse, M. F. J. Org.
Chem. 2000, 65, 8470–8477.
18. Dahl, R. S.; Finney, N. S. J. Am. Chem. Soc. 2004, 126, 8356–8357.
19. (a) Liu, J.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 9789–9797; (b) Liu, J.; Di
Bussolo, V.; Gin, D. Y. Tetrahedron Lett. 2003, 44, 4015–4018.
20. (a) Kumar, V.; Ramesh, N. G. Chem. Commun. 2006, 4952–4954; (b) Kumar, V.;
Ramesh, N. G. Org. Biomol. Chem. 2007, 5, 3847–3858.
38. Bravo, F.; Viso, A.; Alcázar, E.; Molas, P.; Bo, C.; Castillón, S. J. Org. Chem. 2003,
68, 686–691.
39. (a) Billings, S. B.; Woerpel, K. A. J. Org. Chem. 2006, 71, 5171–5178; (b)
Rodriguez, M. A.; Boutureira, O.; Matheu, M. I.; Diaz, Y.; Castillón, S.; Seeberger,
P. H. J. Org. Chem. 2007, 72, 8998–9001.
21. McDonald, F. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1992, 114, 7001–7002.
22. Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 5811–5819.
23. For a review, see: (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
1996, 108, 1380–1419; For some more recent examples, see: (b) Dudkin, V. Y.;
Miller, J. S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 736–738; (c) Geng, X.;
Dudkin, V. Y.; Mandal, M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2004, 43,
2562–2565; (d) Deshpande, P. P.; Kim, H. M.; Zatorski, A.; Park, T.-K.;
Ragupathi, G.; Livingston, P. O.; Live, D.; Danishefsky, S. J. J. Am. Chem. Soc.
1998, 120, 1600–1614; (e) Kwon, O.; Danishefsky, S. J. J. Am. Chem. Soc. 1998,
120, 1588–1599; (f) Roberge, J. Y.; Beebe, X.; Danishefsky, S. J. J. Am. Chem. Soc.
1998, 120, 3915–3927; (g) Wang, Z.-G.; Warren, J. D.; Dudkin, V. Y.; Zhang, X.;
Iserloh, U.; Visser, M.; Eckhardt, M.; Seeberger, P. H.; Danishefsky, S. J.
40. (a) Suzuki, K.; Sulikowski, G. A.; Friesen, R. W.; Danishefsky, S. J. J. Am. Chem.
Soc. 1990, 112, 8895–8902; (b) Durham, T. B.; Roush, W. R. Org. Lett. 2003, 5,
1871–1874.
41. Roy, R.; Tropper, F. D.; Cao, S.; Kim, J. M. In Phase-Transfer Catalysis, ACS
Symposium Series; Halpern, M. E., Ed.; American Chemical Society, 1997; Vol.
659, pp 163–180. Chapter 13.
42. Miljkovic´, D.; Djurendic´, E.; Vukojevic´, N.; Gaši, K.; Csanádi, J. Carbohydr. Res.
1992, 233, 251–253.
43. For an example of an anomerisation in basic medium, see: Benito, J. M.; Ortiz
Mellet, C.; Sadalapure, K.; Lindhorst, T. K.; Defaye, J.; García Fernández, J. M.
Carbohydr. Res. 1999, 320, 37–48.
44. Boulineau, F. P.; Wei, A. J. Org. Chem. 2004, 69, 3391–3399.