A urea-linked glucosamine dimer as a building block for the synthesis of linear and cyclic neosaccharides

Article abstract of DOI:10.1002/ejoc.201000292

A novel urea-linked glucosamine dimer was obtained through a modification of the standard oxazolidinone closure reaction on a 2,3-amino alcohol monomer and fully characterized by NMR spectroscopy and by molecular mechanics and dynamics techniques. A mechanism was proposed for the dimerization reaction that was based on the formation of a 2,3-bis[(p-nitrophenoxy)carbonyl] intermediate, Chemoselective manipulations on the orthogonal protecting group pattern of the dimer - especially on its unprecedented oxazolidinone-urea-oxazolidinone system - gave an alcohol building block that was useful for access to higher linear and cyclic neosaccharides, The conformational features and 3Dcharacterization of a novel carbamate-linked neodisaccharide macrocycle was accomplished through molecular mechanics and dynamics calculations.

Full text of DOI:10.1002/ejoc.201000292

FULL PAPER
DOI: 10.1002/ejoc.201000292
A Urea-Linked Glucosamine Dimer as a Building Block for the Synthesis of
Linear and Cyclic Neosaccharides
Luigi Cirillo,[a] Alba Silipo,[a] Emiliano Bedini,*[a] and Michelangelo Parrilli[a]
Keywords: Carbohydrates / Glycoconjugates / Macrocycles / Oligosaccharides / Reaction mechanisms
A
novel urea-linked glucosamine dimer was obtained
pattern of the dimer – especially on its unprecedented oxaz-
olidinone–urea–oxazolidinone system gave an alcohol
building block that was useful for access to higher linear and
cyclic neosaccharides. The conformational features and 3D-
through a modification of the standard oxazolidinone closure
reaction on a 2,3-amino alcohol monomer and fully charac-
terized by NMR spectroscopy and by molecular mechanics
and dynamics techniques. A mechanism was proposed for
the dimerization reaction that was based on the formation of
a 2,3-bis[(p-nitrophenoxy)carbonyl] intermediate. Chemose-
lective manipulations on the orthogonal protecting group
–
characterization of
a novel carbamate-linked neodisac-
charide macrocycle was accomplished through molecular
mechanics and dynamics calculations.
syl trichloroacetamides with an amine.[3k] Sugar carboxylic
acids were also used in the Curtius rearrangement,[3j] in the
presence of a nucleophile, to afford both carbamato- and
urea-linked pseudosaccharides. A particular area of interest
in glycomimetics is that of neosaccharides, which are oligo-
saccharides linked together without using the anomeric cen-
tre.[6] To the best of our knowledge, urea-linked neosac-
charides have seldom been reported,[3b,3f,3j,3k] and have been
synthesized according to only two methods. The first was
based on the acid-catalysed addition of water to diglycosyl-
carbodiimides, which were in turn synthesized by the Staud-
inger/aza-Wittig reaction of a protected azide with a sugar
isothiocyanate in the presence of triphenylphosphane
(Scheme 1a).[3b] Alternatively, neosaccharides have been ob-
tained by coupling of per-O-acetylated sugar isocyanates
with amino sugars (Scheme 1b).[3f] Herein, we report a
method of accessing a novel class of neosaccharides starting
from an unprecedented urea-linked glucosamine dimer ob-
tained from amino alcohol 1 through a modification of the
known[7] oxazolidinone closure reaction.
Introduction
Oligosaccharides and glycoconjugates play a central role
in many biological processes, including cellular recognition
phenomena. For this reason, the synthesis of biologically
relevant carbohydrates is a topic of wide interest in sugar
chemistry.[1] In the last decade, increasing effort was also
dedicated to obtaining sugar mimics. These molecules, usu-
ally termed glycomimetics, resemble carbohydrates but have
some structural differences.[2] They are very interesting
compounds because they can be recognized in biological
processes involving carbohydrates, but show a different re-
sponse due to the structural modification.
Recently, researchers have focused their synthetic efforts
on the obtainment of compounds – termed pseudosaccha-
rides – having the acid-labile glycosidic bonds substituted
with non-acetal linkages. Among these compounds, urea-
linked pseudosaccharides captured an increasing share of
interest in the last decade[3] due to the occurrence of these
linkages in natural antibiotics such as glycocinnamoyl-
spermidines[4] as well as their potential application in the
field of aminoglycosides.[5] Most urea-linked pseudosac-
charides have a tether involving at least one anomeric posi-
tion, and are typically obtained from unstable glycosyl iso-
cyanates by reaction with an amine.[3a,3d,3e,3g] Very recently,
alternative methods were developed that employ the reac-
tion of Steyermark’s glycosyl-1,2-oxazolidinone[3h] or glyco-
Results and Discussion
Glucosamine Dimerization
The standard conditions used to protect a 2,3-amino
alcohol sugar derivative as its oxazolidinone uses excess 4-
nitrophenyl chloroformate (NPCC) at 0 °C for 3 h, produc-
ing a mixture of the desired oxazolidinone and uncyclized
carbamate that is converted into the fully protected material
by an additional step with Amberlyst IR-120 Na ion-ex-
change resin.[7b] We studied the dependence of the reaction
of 1 – available from N-acetyl glucosamine in three stan-
[a] Dipartimento di Chimica Organica e Biochimica, Università
di Napoli “Federico II”, Complesso Universitario Monte
S. Angelo,
Via Cintia 4, 80126 Napoli, Italy
Fax: +39-081-674393
E-mail: ebedini@unina.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000292.
[8]
dard steps – on the temperature of the reaction. By con-
4062
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4062–4074

Synthesis of Linear and Cyclic Neosaccharides
Scheme 1. Literature examples of urea-linked neosaccharide synthesis.
ducting the reaction at 40 °C, no uncyclized carbamate 3 ble tetraol 7/8 (73% yield), which was subjected to detailed
1
was detected by H NMR analysis of the crude mixture, NMR analysis and molecular mechanics and dynamics cal-
and 2,3-oxazolidinone 2 was recovered in 80% isolated culations to discriminate between the two possible struc-
yield. In contrast, at 0 °C, only uncyclized carbamate 3 was tures and, in addition, to evaluate the conformational be-
obtained when the reaction was conducted for short times havior of the novel neosaccharide in aqueous solution.
(Scheme 2 and Table 1). Compound 3 was recovered by
Ring conformations have been defined by the analysis of
simple extraction and then treated with sodium hydride in 3JH,H coupling constants obtained from one-dimensional
N,N-dimethylformamide (DMF) at 30 °C. No oxazolid- 1H NMR and two dimensional DQF-COSY spectra, and
inone 2 was recovered, whereas a new compound was iso- supported by analysis of the inter-residual NOE contacts
lated as the major product (62% yield over two steps) to- present in the T-ROESY spectrum. GlcN residues were
gether with N-aryloxycarbonyl-oxazolidinone 4 (26% from found in the 4C1 chair conformation in which carbon atoms
1).
C-4 and C-1 are, respectively, above and below the plane
1H NMR spectra of the unknown compound presented defined by carbons C-2, C-3, C-5, and the intra-ring oxygen
a single set of carbinolic signals, with those from H-2 and O-5. Due to the symmetry of the spectra it was not possible
H-3 downfield shifted at δ = 3.99 and 4.94 ppm, respec- to distinguish between potential intra and inter-residual
tively. The 13C NMR spectrum was characterized by two NOE contacts. Moreover, the pattern of NOEs were those
signals at δ = 150.4 and 150.0 ppm, with the first signal typical of an α-configured glucopyranose residue and not
intensity approximately double that of the second. The indicative of any particular spatial contact between the two
MALDI-MS spectrum gave a [M + Na+] peak at m/z = symmetric units.
715. According to these data, a C2-symmetric dimeric struc-
On the other hand, the dependence of long range cou-
ture could be hypothesized, with two 2,3-oxazolidinone- pling constants on dihedral angles is well known, and the
protected glucosamines linked by an ureido bridge (see 5). general behavior is described by the Karplus equation in
An alternative, less probable hypothesis could be a structure six-membered rings. A number of empirical correlations be-
with two glucosamines linked by both an ureido and two tween the magnitude of these coupling constants and the
carbamate bridges (see 6). To assign an unequivocal struc- geometric features of the chemical structure have been es-
3
ture to the new compound, the benzylidene rings were tablished; these studies have concluded that JC,H coupling
cleaved with CSA in dioxane/water to afford the water-solu- is most significantly affected.[9] Taking into account the dif-
Eur. J. Org. Chem. 2010, 4062–4074
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4063

L. Cirillo, A. Silipo, E. Bedini, M. Parrilli
FULL PAPER
were determined from two different NMR experiments: J-
HMBC and HSQMBC. The former provides cross peaks J-
scaled in the carbon dimension, and can be used for deter-
mination of CH long-range coupling constants via splitting
in F1,[10] whereas the latter technique provides cross peaks
J-scaled in F2.[11] Relevant data obtained from these experi-
ments are presented in Table 2. To check which structure
(7 or 8) best match these data, both were constructed and
subjected to extensive molecular mechanics and molecular
dynamics calculations with Amber* force field, followed by
the calculation of weighted averages heteronuclear long-
range coupling constants; the results were then compared
to the experimental values. The whole conformation of
structure 7 is essentially defined by the relative orientation
of the two sugar moieties around the ureido bridge, and a
key step was the definition of the geometry around the par-
tial double bonds of this group. Several maps were calcu-
lated, taking into account the possible orientations of the
allylic groups (not shown) and different orientations of the
2,3-oxazolidinone-glucosamines with respect to the ureido
bridge. The resulting adiabatic energy maps are displayed
in Figure 1. These surfaces provided a rough estimation of
the conformational states that could be adopted. It was ob-
Table 2. Experimental and theoretical values for selected 3JC,H cou-
pling constants [Hz] of structures 7 and 8.
Coupling
constant
7/8
7
8
(NMR data) (MD data)[a] (MD data)[a]
3JCO ureido, H–2
1.6/1.7[b]
absent
absent
1.6
0.9
0.9
5.1
6.5
7.7
3JCO carbamate, H–2
3JCO carbamate, H–3
3
[a] The values correspond to the weighted average JC,H coupling
constant calculated from the molecular dynamics simulation. [b]
3
The two values correspond to the JC,H coupling constants ob-
tained from HSQMBC and J-HMBC experiments, respectively.
Scheme 2. Synthesis of urea-linked neodisaccharide from amino
alcohol 1.
Table 1. Oxazolidinone 2 versus uncyclized carbamate 3 formation
from 1 with NPCC (5 equiv.) and NaHCO3 (5 equiv.) in 2:3 (v/v)
H2O/CH3CN.
Entry
T [°C]
Time [min]
2/3[a]
1
2
3
4
5
6
40
20
0
0
0
30
100:0
19:81
17:83
6:94
0:100
0:100
180
180
120
50
0
30
[a] Percent molar ratio determined by 1H NMR analysis of the
crude mixture.
ferences in the spatial orientation of the bridges with re-
spect to the sugar moieties in 7 and in 8, long range cou-
pling constants JC,H across the carbonyl of these groups around the partial double bond of the ureido bridges in 7.
Figure 1. Relaxed energy maps for the symmetric dihedral angles
3
4064
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4062–4074

Synthesis of Linear and Cyclic Neosaccharides
Figure 2. Scatter plots of Φ versus Ψ values of 7 starting from minima (a) A/B and (b) C/D obtained from molecular mechanics calcula-
tions.
served that the energy maps covered a large area, represent- ima obtained with the molecular mechanics approach. The
ing a high number of conformational states. The lowest en- Φ/Ψ scatter plots of the torsion angles for both minima A/
ergy regions were located around two symmetric groups of B and C/D are displayed in Figure 2.
energy minima separated by a low energy barrier (below
The simulation confirmed the existence, for A/B, of a
2 kJ/mol): minima A/B located around 18/–128 and –128/ compact energy-well located in the region spanning the two
18, respectively, corresponding to symmetric isomers with minima and predicted by the molecular mechanics calcula-
E,Z and Z,E geometry around the partial double bond of tions; for minima C/D, during the molecular dynamics sim-
the ureido bridge, and minima C/D located around –144/ ulation an oscillation between the two predicted values was
–130 and –130/–144, respectively, corresponding to E,E dis- observable starting from both C and D minima, as con-
position around the partial ureido double bond. The con- firmed by the analysis of the scatter plot. It is worth noting
formational space available for the regions was then investi- that no interconversion between the two groups of minima
gated by molecular dynamics simulations. Computational was observed. A further examination of these data provided
models were generated using the two groups of energy min- other useful information. Ensemble average inter-proton
Figure 3. View of representative structures of 7 with (a) E,E and (b) E,Z disposition around the ureido bridge.
Eur. J. Org. Chem. 2010, 4062–4074
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4065

L. Cirillo, A. Silipo, E. Bedini, M. Parrilli
FULL PAPER
distances were extracted and translated into predicted
NOEs by a full-matrix relaxation approach. The predicted
NOEs were then compared to those experimentally col-
lected to assess the reliability of the simulation data, and the
corresponding average distances obtained for the simulation
from Ͻr-6Ͼ values were compared to those collected exper-
imentally. A satisfactory agreement was observed between
the calculated and the experimental values (data not
3
shown). Average-weighted JC,H coupling constants were
then calculated for the lowest energy families corresponding
to the local minima A/B and C/D (Table 2). The experimen-
tal values were in agreement with the conformations
adopted by both families, and also confirmed that, in both
cases, the predicted coupling constant for H-2 and H-3 with
oxazolidinone carbonyl was close to zero. Snapshots of the
most representative conformers of 7 corresponding to the
two groups of minima are depicted in Figure 3. E,Z/Z,E
and E,E conformers adopted conformations with different
shapes. Conformers with E,E geometry assumed a more ex-
tended shape in which a significant cleft was observable. On
the other side, conformers with a E,Z geometry adopted a
more constricted spatial disposition that was characterized
by a contracted structure with an ‘L’-shaped conformation
corresponding to a quasi-perpendicular disposition of the
sugar moieties.
The same molecular mechanics and dynamics calcula-
tions protocol was also used to characterize the structure 8.
3
Average-weighted JC,H coupling constants (Table 2) were
calculated from the molecular dynamics simulation and
compared with the experimental results. These data estab-
lish that – as expected – only 7 was in agreement with exper-
imental data. The formation of 8 was excluded because the
calculated data were in discordance with those measured in
the NMR experiments. In fact, in the case of 8, predictable
and strong cross-peaks between the carbonyl of the ureido
bridge with H-2 and H-3 as well as of the carbonyl of carb-
amate groups with H-2 should have been visible due to their
high long-range heteronuclear coupling constant.
Scheme 3. Proposed mechanism for the formation of 5.
gested that this pathway had to be discarded. Instead, the
formation of derivative 11 was proposed as a pathway that
operates in competition with oxazolidinone formation.
Compound 11 could then be converted into isocyanate 12,
which, unlike 9, cannot undergo the intramolecular reac-
tion. On the contrary, it can be subjected to nucleophilic
addition by oxazolidinone 2 to form a dimer that could
easily react further to give the final product 5. Indeed, when
pure compound 11[13] was mixed with 2 in the presence of
excess NaH, dimer 5 was obtained exclusively (95% isolated
yield). However, a more in-depth study is in progress to
develop the details of the proposed mechanism.
Mechanism Investigation
The dimerization process of amino alcohol 1 into 5 is
strictly dependent on the presence of excess NPCC in the
reaction mixture. Indeed, uncyclized carbamate 3 was reco-
vered pure by column chromatography (87% yield from 1)
and then subjected to NaH/DMF treatment. No dimer 5
was detected in this case. The reaction produced oxazolidi-
none 2 exclusively in 91% yield, in accordance with similar
known transformations.[7d,8,12] On the basis of this result,
a mechanism was hypothesized in which, after the initial
formation of oxazolidinone 2 through the reactive isocyan-
ate 9, N-aryloxycarbonyl-oxazolidinone 4 is produced and
then coupled to 3 (Scheme 3).
Chemoselective Reactions on the Oxazolidinone–Urea–
Oxazolidinone System
Nonetheless, by mixing pure 3 and 4 in the presence of
NaH in DMF, no dimer species were detected. Moreover,
by treating pure 2 under dimerization conditions in the
A case study of selective reactions on the oxazolidinone–
presence of excess NPCC, only compound 4 was recovered urea–oxazolidinone system of dimer 5 was then pursued.
together with starting oxazolidinone. These results sug- To the best of our knowledge, this system is unprecedented.
4066
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4062–4074

Synthesis of Linear and Cyclic Neosaccharides
Scheme 4. Chemoselective cleavage of the oxazolidinone–urea–oxazolidinone system 5.
Table 3. Chemoselective cleavage of the oxazolidinone–urea–oxazolidinone system 5.
Entry
Reaction conditions
Products[a]
1
2
3
4
5
6
LiOH, H2O2, 7:2 v/v THF/H2O, –40 °C to 0 °C, 15 min
LiOH, LiCl, 3:1 v/v THF/H2O, 0 °C, 75 min
NaOMe, 9:1 v/v CH2Cl2/MeOH, –60 °C, 40 min
14:6:1 v/v/v CHCl3/MeOH/Et3N, room temp., 2 d
14:6:1:1 v/v/v/v CHCl3/1,4-dioxane/H2O/Et3N, room temp., 2 d 14a R = H (81%)
6:2:1 v/v/v 1,4-dioxane/H2O/Et3N, 80 °C, 14 h 15a R = H (76%)
2 (42%), 14a R = H (20%)
2 (41%), 14a R = H (33%), 15a R = H (21%)
14b R = COOMe (34%), 15b R = COOMe (34%)
15b R = COOMe (54%)
[a] Isolated yield.
Mild conditions were sought for the chemoselective cleav-
age of one or both oxazolidinone rings with respect to the
ureido bridge (Scheme 4). Solvolysis of 5 was conducted un-
der several conditions, as indicated in Table 3. Reaction
conditions employed for the chemoselective deprotection of
N-acetyl-2,3-N,O-oxazolidinone of glucosamine[14] gave un-
satisfactory results on 5 (entries 1–3). Interestingly, chemo-
selective cleavage of one or both carbamates with respect to
the ureido bridge was accomplished by employing mild
Et3N-mediated hydrolysis or methanolysis. The C2-symmet-
ric urea-linked neodisaccharide 15a was obtained in 76%
yield by reaction of 5 in 6:2:1 (v/v/v) 1,4-dioxane/H2O/Et3N
at 80 °C (entry 6). A very interesting compound – alcohol
14a – was obtained in 81% yield by reaction in 14:6:1:1
(v/v/v/v) CHCl3/1,4-dioxane/H2O/Et3N (entry 5). This com-
pound could be used as a glycosyl acceptor to access higher
neooligosaccharides. For example, a glycosylation reaction
between 14a and donor 16[15] afforded neotrisaccharide 17
(76%), which was deprotected in two steps (Scheme 5). A
chemoselective cleavage of the residual oxazolidinone ring
was possible under the conditions developed above. Indeed,
hydrolysis in 6:2:1 (v/v/v) dioxane/water/Et3N gave alcohol
18 (58%). A subsequent transfer hydrogenation under Per-
lin conditions[16] furnished water-soluble urea-linked neotri-
saccharide 19 in 72% yield. Alcohol 14a was a useful build-
ing block that could also be used to access the first repre-
sentative example of a novel class of carbamate-linked
macrocyclic analogues of cyclodextrins.[3j,3k,17] Indeed,
when treated with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) in DMF, 14a gave carbamate-linked macrocycle 20
in 43% yield (51% based on recovered starting material;
Scheme 6). The detection of oxazolidinone 2 as the sole by-
product in the crude reaction mixture suggested that the
mechanism could proceed through attack of the alcoholate
ion on the ureido carbonyl group, giving the macrocycle 20
after a subsequent rearrangement of the amine intermediate
(path a,a) or could lead directly to the oxazolidinone 2 Scheme 5. Synthesis of neotrisaccharide 19.
Eur. J. Org. Chem. 2010, 4062–4074
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4067

L. Cirillo, A. Silipo, E. Bedini, M. Parrilli
FULL PAPER
Scheme 6. Synthesis of carbamate-linked cyclic neodisaccharide 21.
(path b). The latter compound could also be obtained of the molecule, the trans disposition of the amide protons
1
through the amine intermediate (paths a, b). Benzylidene in relation to the H-2 atoms and the C4 chair conforma-
cleavage of 20 with CSA in 4:1 (v/v) 1,4-dioxane/water at tion, two possible low energy structures were built that dif-
60 °C afforded the water-soluble macrocycle 21 (98%). Its fered in the relative orientation of the NH and C=O bonds
NMR characterization indicated a symmetric dimeric struc- (structures here named as syn and anti species).
4
ture in which glucosamine residues were found in the C1
NMR-derived data and extensive molecular mechanics
chair conformation, as defined by the analysis of 3JH,H cou- and dynamics calculations with Amber* force field in GB/
pling constants. The 1H NMR spectra in 9:1 (v/v) H2O/D2O SA water solvation model were used to distinguish between
3
allowed the anti orientation of the amide NH protons with the two conformers. NMR-derived homonuclear JH-2,NH
respect to H-2 to be defined.[18]
coupling constants and heteronuclear long-range 3JC,H cou-
Actually, the amide proton showed a large vicinal cou- pling constants from the ureido bridge carbonyl with H-2
pling constant (3JH,NH = 9.5 Hz) with H-2 of GlcN, which and H-3 atoms were compared with average-weighted cou-
restricts the torsion angle to Ϯ162°, as calculated from the pling constants obtained from molecular dynamics simula-
Karplus equation.[9] Taking into account the C2-symmetry tion performed on both candidate conformers. The data al-
Figure 4. View of a representative conformer of 21.
4068
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4062–4074

Synthesis of Linear and Cyclic Neosaccharides
phase-sensitive COSY experiments were performed using spectral
widths of either 3600 in both dimensions or data sets of 4096ϫ256
points. Quadrature indirect dimensions were achieved through the
States-TPPI method; spectra were processed by applying an un-
shifted Qsine function to both dimensions and the data matrix was
zero-filled by a factor of two before Fourier transformation. Cou-
pling constants were determined on a first order basis from high
resolution 1D spectra or by 2D phase-sensitive DQF-COSY.
TOCSY were performed with spinlock times from 20 to 100 ms,
using data sets (t1ϫt2) of 4096ϫ256 points. T-ROESY experi-
ments were recorded using data sets (t1ϫt2) of 4096ϫ256 points
with mixing times of between 200 ms and 700 ms. Interproton dis-
tances were obtained by employing the isolated spin pair approxi-
mation as described.[19] In these homonuclear experiments, the data
matrix was zero-filled in the F1 dimension to give a matrix of
4096ϫ2048 points and was resolution-enhanced in both dimen-
sions by a 90° shifted Qsine function before Fourier transforma-
lowed us to demonstrate the exclusive existence of the anti
species. In fact, a very satisfactory agreement was observed
for the anti species between calculated and experimental
values (Table 4), that were far from the experimental data
in case of the syn species.
Table 4. Experimental and theoretical values for selected 3JC,H and
3JH,H coupling constants [Hz] of compound 21.
Coupling
constant
21
21
21
(NMR data)
anti (MD data)[a] syn (MD data)[a]
3JCO ureido, H-2
3JCO ureido, H-3
3J2,NH
8.0
3.4
9.5
7.0
3.3
9.8
4.7
8.0
6.1
3
3
[a] The values correspond to the weighted average JC,H and JH,H
coupling constant calculated from the molecular dynamics simula-
tion.
1
tion. HSQC experiments were measured in the H-detected mode
via single quantum coherence with proton-decoupling in the 13C
domain, using data sets of 2048ϫ256 points. In these heteronuclear
experiments the data matrix was extended to 2048ϫ1024 points
using forward linear prediction extrapolation. Two different meth-
Molecular dynamics simulation also allowed us to esti-
mate the conformational behavior of structure 21. This
cyclodextrin mimic possesses an elliptical cavity in which
the major and minor axes have an average length of 4.43
and 3.03 Å, respectively (Figure 4).
3
ods were used to measure long-range heteronuclear JC,H coupling
constants: J-HMBC and HSQMBC. J-HMBC spectra were ac-
quired using data sets of 4096ϫ512 points transformed after zero
filling to 4096ϫ4096 complex points applying an unshifted cosine
function to both F1 and F2 dimensions. The long-range coupling
constant used for the evolution of long-range connectivities was
varied from 2 to 10 Hz. For HSQMBC experiments, spectra were
acquired with 8192ϫ256 points transformed after zero filling to
16384ϫ4096 complex points applying a cosine function to both
F1 and F2 dimensions. Software TOPSPIN was used to measure
homonuclear and heteronuclear coupling constants.
Conclusions
In conclusion, the synthesis of a novel urea-tethered glu-
cosamine neodisaccharide building block by dimerization
of a simple 2,3-amino alcohol monomer through a modifi-
cation of the standard oxazolidinone closure reaction has
been reported. The dimer was fully characterized by NMR
spectroscopy as well as by molecular mechanics and dy-
namics calculations. The behavior of the oxazolidinone–
urea–oxazolidinone moiety of the dimer under mild solvol-
ysis conditions was studied. The chemoselective cleavage of
only one oxazolidinone afforded an alcohol building block
that was used for the synthesis of a higher neoligosacchar-
ide as well as a carbamate-bridged cyclic neosaccharide.
The latter compound represents the first example of a novel
class of cyclodextrin analogues. Its 3D-geometry was
studied with both NMR spectroscopy and by using molecu-
lar mechanics and dynamics techniques. Work is in progress
to apply the urea-dimerization approach to obtain a large
family of linear and cyclic amino sugar neosaccharides as
well as to develop these molecules as tools for carbo-
hydrate-based supramolecular chemistry.
Positive MALDI-MS spectra were recorded with an Applied Biosy-
stem Voyager DE-PRO MALDI-TOF mass spectrometer in the
positive mode: compounds were dissolved in CH3CN at a concen-
tration of 1 mg/mL, and 1 µL of these solutions was mixed with
1 µL of a 20 mg/mL solution of 2,5-dihydroxybenzoic acid in 7:3
(v/v) CH3CN/0.1  trifluoroacetic acid. Analytical thin layer
chromatography (TLC) was performed on aluminium plates pre-
coated with Merck Silica Gel 60 F254 as the adsorbent. The plates
were developed with 5% H2SO4 ethanolic solution and then heat-
ing to 130 °C. Flash chromatography was performed using Merck
Kieselgel 60 (63–200 mesh).
Molecular Mechanics calculations were performed using the
AMBER* force field as included in MacroModel 8.0. A dielectric
constant of 80 was used. For each disaccharide structure, both Φ
and Ψ were varied incrementally using a grid step of 18°, each
(Φ, Ψ) point of the map was optimized using 2000 P.R. conjugate
gradients. The Molecular Dynamics simulations were run by using
the AMBER* force field; bulk water solvation was simulated by
using MacroModel generalized Born GB/SA continuum solvent
model. All simulations were performed at 300 K, structures were
initially subjected to an equilibration time of 300 ps, then a 3000 ps
molecular dynamic simulation was performed with a dynamic time-
step of 1.5 fs, a bath constant (t) of 0.2 ps and the SHAKE protocol
to the hydrogen bonds. Trajectory coordinates were sampled every
picosecond, and a total of 3000 structures were collected for every
simulation. Ensemble average-interproton distances were calculated
using the NOEPROM program by applying the isolated spin pair
approximation as described.[19] Coordinate extractions were per-
formed with the program SuperMap, supplied with the NOEP-
ROM package, and data was visualized with ORIGIN software.
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded with
Varian XL-200 (1H: NMR 200 MHz, 13C: NMR 50 MHz), Bruker
DRX-400 (1H NMR: 400 MHz, 13C NMR: 100 MHz) or Varian
INOVA 500 (1H NMR: 500 MHz, 13C NMR: 125 MHz) instru-
1
ments in CDCl3 (CHCl3 as internal standard, H NMR: CHCl3 at
δ = 7.26 ppm; 13C NMR: CDCl3 at δ = 77.0 ppm). Compounds 7,
19 and 21 were analysed in D2O [acetone as internal standard, 1H:
(CH3)2CO at δ = 2.22 ppm; 13C: (CH3)2CO at δ = 31.0 ppm]. Ex-
tensive NMR analysis on compounds 7 and 21 were made with
a Bruker-600 DRX (1H NMR: 600 MHz, 13C NMR: 150 MHz)
instrument equipped with a cryo probe. Double quantum-filtered
Eur. J. Org. Chem. 2010, 4062–4074
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4069

L. Cirillo, A. Silipo, E. Bedini, M. Parrilli
FULL PAPER
Solvent-accessible surfaces were calculated with the Surface utility
of Macromodel and with Molecular Surface displays of the
Chem3D package.
The crude gummy solid was dissolved in DMF (6.4 mL) and heated
to 30 °C. NaH (60% dispersion in oil, 261 mg, 6.53 mmol) was then
added portion-wise to avoid sudden overheating. The yellow mix-
ture was stirred for 45 min at 30 °C, then cooled to 0 °C and treated
dropwise with a little water until production of gas ceased. The
mixture was diluted with CH2Cl2 (150 mL) and washed with water.
The organic layer was collected, dried and concentrated. The resi-
due was subjected to flash chromatography (hexane/ethyl acetate,
6:1 to 2:3) to give 4 (179 mg, 26%) as the first eluted compound,
as white amorphous crystals. [α]D = +64.7 (c = 1.0; CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 8.29 (d, J3Ј,2Ј = 9.1 Hz, 2 H, 2 ϫ 3Ј-
H pNO2-Ar), 7.51–7.38 (m, 7 H, benzylidene, 2 ϫ 2Ј-H pNO2-Ar),
5.88 (m, 1 H, OCH2CH=CH2), 5.64 (s, 1 H, CHPh), 5.63 (d, J1,2
= 2.7 Hz, 1 H, 1-H), 5.32 (br. d, Jvic = 17.2 Hz, 1 H, trans
OCH2 CH=CHH), 5.22 (br. d, Jv i c = 10.3 Hz, 1 H, cis
OCH2CH=CHH), 4.90 (t, J3,2 = J3,4 = 11.0 Hz, 1 H, 3-H), 4.30
( m , 2 H , 6 a -H , O C HH C H = C H2 ) , 4 . 1 1 ( m , 2 H , 4- H ,
OCHHCH=CH2), 4.05 (dd, J2,3 = 11.0, J2,1 = 2.7 Hz, 1 H, 2-H),
3.92 (m, 2 H, 5-H, 6b-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
154.3, 145.8 (2 ϫ Cipso), 150.3, 148.9 (2 ϫ NCOO), 136.2 (Cipso
benzylidene), 132.7 (OCH2CH=CH2), 129.3, 128.4, 126.1, 125.4,
122.2 (C-Ar), 118.8 (OCH2CH=CH2), 101.5 (CHPh), 95.5 (C-1),
79.5, 74.0, 69.7, 68.4, 65.4, 60.9 (C-2, C-3, C-4, C-5, C-6,
OCH2CH=CH2) ppm. MALDI TOF-MS: unstable. C24H22N2O10
(498.13): calcd. C 57.83, H 4.45, N 5.62; found C 57.70, H 4.40, N
5.56.
Allyl 4,6-O-Benzylidene-2,3-N,O-carbonyl-2-deoxy-α-D-glucopyr-
anoside (2): Compound 1 (95.4 mg, 0.310 mmol) was suspended in
2:1 (v/v) water/CH3CN (1.12 mL) and then heated to 40 °C.
NaHCO3 (128 mg, 1.52 mmol) and then a solution of 4-nitrophenyl
chloroformate (314 mg, 1.56 mmol) in CH3CN (750 µL) were
added. After 30 min stirring at 40 °C, the mixture was diluted with
ethyl acetate (50 mL) and washed with 1  NaHCO3. The organic
layer was collected, dried with anhydrous Na2SO4 and concen-
trated. Purification by flash chromatography (petroleum ether/ethyl
acetate, 5:1 to 1:1 v/v) afforded 2 (82.3 mg, 80%) as a white powder.
[α]D = +33 (c = 0.3; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ =
7.51–7.36 (m, 5 H, Ar-H), 5.91 (m, 1 H, OCH2CH=CH2), 5.62 (s,
4
1 H, CHPh), 5.35 (ddd, Jvic = 17.2, JH,H = 3.0, Jgem = 1.5 Hz, 1
H, trans OCH2CH=CHH), 5.28 (dd, Jvic = 10.4, Jgem = 1.5 Hz, 1
H, cis OCH2CH=CHH), 5.15 (d, J1,2 = 2.9 Hz, 1 H, 1-H), 5.07 (br.
s, 1 H, NH), 4.84 (dd, J3,2 = 11.3, J3,4 = 10.2 Hz, 1 H, 3-H), 4.29
(m,
2 H, 6a-H, OCHHCH=CH2), 4.09 (m, 2 H, 4-H,
OCHHCH=CH2), 3.90 (m, 2 H, 5-H, 6b-H), 3.74 (dd, J2,3 = 11.3,
J2,1 = 2.9 Hz, 1 H, 2-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
159.1 (NCOO), 136.5 (Cipso), 132.8 (OCH2CH=CH2), 129.2, 128.3,
126.2 (C-Ar), 118.5 (OCH2CH=CH2), 101.4 (CHPh), 95.5 (C-1),
80.1, 75.6, 69.1, 68.5, 65.5, 59.5 (C-2, C-3, C-4, C-5, C-6,
OCH2CH=CH2) ppm. MALDI TOF-MS: calcd. for C17H19NO6
333.12; found 334.16 [M + H]+. C17H19NO6 (333.12): calcd. C
61.26, H 5.75, N 4.20; found C 61.06, H 5.58, N 4.11.
Second eluted compound 5 (299 mg, 62%) was recovered as a white
powder. [α]D = +60 (c = 0.9; CH2Cl2). 1H NMR (400 MHz,
CDCl3 ): δ = 7 . 5 0– 7. 36 (m, 5 H, Ar-H), 5. 85 (m, 1 H,
OCH2CH=CH2), 5.61 (s, 1 H, CHPh), 5.53 (d, J1,2 = 2.8 Hz, 1 H,
Allyl 4,6-O-Benzylidene-2,3-N,O-carbonyl-2-deoxy-2-[(p-nitrophen-
oxy)carbonylamino]-α-
allyl-4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-α-
D
-glucopyranoside (4) and N,NЈ-Bis(1-O-
-glucopyranos-
4
1-H), 5.31 (ddd, Jvic = 17.3, JH,H = 3.1, Jgem = 1.3 Hz, 1 H, trans
D
4
OCH2CH=CHH), 5.22 (ddd, Jvic = 10.4, JH,H = 2.4, Jgem
1.3 Hz, 1 H, cis OCH2CH=CHH), 4.94 (dd, J3,2 = 11.4, J3,4
=
=
2-yl)urea (5): Compound 1 (430 mg, 1.40 mmol) was suspended in
2:1 (v/v) water/CH3CN (6.0 mL) and then cooled to 0 °C. NaHCO3
(585 mg, 6.96 mmol) and then a solution of 4-nitrophenyl chloro-
formate (1.83 g, 6.80 mmol) in CH3CN (4.0 mL) were added. After
45 min stirring at 0 °C, the mixture was diluted with ethyl acetate
(300 mL) and washed with 1  NaHCO3. The organic layer was
collected, dried with anhydrous Na2SO4 and concentrated to give
a white gummy solid.
10.0 Hz, 1 H, 3-H), 4.28 (m, 2 H, 6a-H, OCHHCH=CH2), 4.07
(m, 2 H, 4-H, OCHHCH=CH2), 3.99 (dd, J2,3 = 11.4, J2,1 = 2.8 Hz,
1 H, 2-H), 3.92 (m, 2 H, 5-H, 6b-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 150.4 (OCON), 150.0 (NCON), 136.4 (Cipso), 132.3
(OCH 2 CH= CH 2 ) , 1 2 9 . 4 , 1 2 8 . 4 , 1 2 6 . 2 ( C - A r ) , 1 1 8 . 0
(OCH2CH=CH2), 101.4 (CHPh), 94.6 (C-1), 79.5, 74.0, 69.3, 68.4,
65.2, 61.0 (C-2, C-3, C-4, C-5, C-6, OCH2CH=CH2) ppm. MALDI
TOF-MS: calcd. for C35H36N2O13 692.22; found 715.25 [M +
Na]+. C35H36N2O13 (692.22): calcd. C 60.09, H 5.24, N 4.04; found
C 60.49, H 5.09, N 3.97.
To obtain pure allyl 4,6-O-benzylidene-2-deoxy-2-[(p-nitrophen-
oxy)carbonylamino]-α--glucopyranoside (3) for analytical pur-
poses, flash chromatography (petroleum ether/ethyl acetate, 15:1 to
2:1) was performed: [α]D = +22.4 (c = 1.4; CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 8.25 (d, J3Ј,2Ј = 8.8 Hz, 2 H, 2 ϫ 3Ј-H N,NЈ-Bis(1-O-allyl-2,3-N,O-carbonyl-2-deoxy-α-
D-glucopyranos-2-
pNO2-Ar), 7.51–7.35 (m, 7 H, Ar-H benzylidene, 2 ϫ 2Ј-H pNO2- yl)urea (7): Compound 5 (44.7 mg, 64.6 µmol) was dissolved in 4:1
Ar), 5.94 (m, 1 H, OCH2CH=CH2), 5.58 (s, 1 H, CHPh), 5.47 (d, (v/v) 1,4-dioxane/water (1.2 mL) and then treated with (Ϯ)-cam-
JH,NH = 7.8 Hz, 1 H, NH), 5.35 (br. d, Jvic = 17.2 Hz, 1 H, trans phor-10-sulfonic acid (35.0 mg, 151 µmol). After 4 h stirring at
OCH2 CH=CHH), 5.29 (br. d, Jv i c = 10. 4 Hz, 1 H, cis 60 °C, silica gel (500 mg) was added and the mixture was evapo-
OCH2CH=CHH), 5.00 (d, J1,2 = 3.0 Hz, 1 H, 1-H), 4.30 (dd, Jgem
= 10.2, J6a,5 = 4.7 Hz, 1 H, 6a-H), 4.25 (dd, Jgem = 12.3, Jvic
4.7 Hz, 1 H, OCHHCH=CH2), 4.06 (dd, Jgem = 12.3, Jvic = 4.7 Hz, powder. [α]D = +134 (c = 0.8; H2O). H NMR (400 MHz, D2O): δ
rated. The residue was subjected to flash chromatography (chloro-
=
form/methanol, 94:6 to 90:10) to afford 7 (24.3 mg, 73%) as a white
1
1 H, OCHHCH=CH2), 4.02 (m, 2 H, 2-H, 3-H), 3.89 (dt, J5,4
J5,6b = 10.2, J5,6a = 4.7 Hz, 1 H, 5-H), 3.78 (t, Jgem = J6b,5
=
=
= 5.86 (m, 1 H, OCH2CH=CH2), 5.54 (d, J1,2 = 2.9 Hz, 1 H, 1-H),
5.32 (dd, Jvic = 17.3, Jgem = 1.1 Hz, 1 H, trans OCH2CH=CHH),
10.2 Hz, 1 H, 6b-H), 3.61 (t, J4,3 = J4,5 = 10.2 Hz, 1 H, 4-H), 2.58 5.25 (dd, Jvic = 10.5, Jgem = 0.8 Hz, 1 H, cis OCH2CH=CHH), 4.81
(br. s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.7 (dd, J3,2 = 12.0, J3,4 = 10.0 Hz, 1 H, 3-H), 4.30 (dd, Jgem = 13.2,
(NCOO), 153.3, 145.1, 136.9 (3 ϫ Cipso), 133.1 (OCH2CH=CH2), Jvic = 5.0 Hz, 1 H, OCHHCH=CH2), 4.19 (dd, J2,3 = 12.0, J2,1
=
129.4, 128.4, 126.2, 125.1, 121.9 (C-Ar), 118.4 (OCH2CH=CH2), 2.9 Hz, 1 H, 2-H), 4.11 (m, 2 H, 4-H, OCHHCH=CH2), 3.86 (m,
102.0 (CHPh), 97.0 (C-1), 81.8, 70.2, 68.8, 68.7, 62.7, 55.7 (C-2, C- 2 H, 6a-H, 6b-H), 3.73 (m, 1 H, 5-H) ppm. 13C NMR (50 MHz,
3, C-4, C-5, C-6, OCH2CH=CH2) ppm. MALDI TOF-MS: calcd.
D2O): δ = 153.4 (OCON), 149.8 (NCON), 134.0 (OCH2CH=CH2),
for C23H24N2O9 472.15; found 495.28 [M + Na]+. C23H24N2O9 118.8 (OCH2CH=CH2), 94.3 (C-1), 78.6 (C-3), 75.3 (C-5), 69.6
(472.15): calcd. C 58.47, H 5.12, N 5.93; found C 58.30, H 5.01, N
5.85.
(OCH2CH=CH2), 67.9 (C-4), 60.6 (C-2), 60.4 (C-6) ppm. MALDI
TOF-MS: calcd. for C21H28N2O13 516.16; found 539.32 [M +
4070
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4062–4074

Synthesis of Linear and Cyclic Neosaccharides
Na]+. C21H28N2O13 (516.16): calcd. C 48.84, H 5.46, N 5.42; found
C 48.77, H 5.28, N 5.35.
C34H38N2O12 (666.24): calcd. C 61.25, H 5.75, N 4.20; found C
61.06, H 5.57, N 4.11.
Allyl 4,6-O-Benzylidene-2-deoxy-3-(p-nitrophenoxycarbonyl)-2-[(p-
nitrophenoxy)carbonylamino]-α-D-glucopyranoside (11): Compound
N,NЈ-Bis(1-O-allyl-4,6-O-benzylidene-2-deoxy-α-D-glucopyranos-2-
yl)urea (15a): A solution of compound 5 (172 mg, 0.25 mmol) in
3:1 (v/v) 1,4-dioxane/water (8.0 mL) was treated with triethylamine
(1.0 mL). After 14 h stirring at 80 °C, silica gel (1.25 g) was added.
The mixture was immediately cooled to room temp. and concen-
trated. Flash chromatography (chloroform/methanol, 99:1 to 96:4)
afforded 15a (122 mg, 76%) as a white powder. [α]D = +32 (c =
0.5; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.50–7.34 (m, 5 H,
Ar-H), 5.91 (m, 1 H, OCH2CH=CH2), 5.55 (s, 1 H, CHPh), 5.32
(br. d, Jvic = 17.2 Hz, 1 H, trans OCH2CH=CHH), 5.24 (br. d, Jvic
= 10.4 Hz, 1 H, cis OCH2CH=CHH), 4.88 (d, J1,2 = 3.0 Hz, 1 H,
1-H), 4.26 (dd, Jgem = 9.9, J6a,5 = 4.5 Hz, 1 H, 6a-H), 4.20 (dd,
Jgem = 12.8, Jvic = 5.2 Hz, 1 H, OCHHCH=CH2), 4.01 (dd, Jgem
= 12.8, Jvic = 5.2 Hz, 1 H, OCHHCH=CH2), 3.93 (m, 2 H, 2-H,
3-H), 3.83 (dt, J5,4 = J5,6b = 9.9, J5,6a = 4.5 Hz, 1 H, 5-H), 3.74 (t,
Jgem = J6b,5 = 9.9 Hz, 1 H, 6b-H), 3.56 (t, J4,3 = J4,5 = 9.9 Hz, 1
H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.1 (NCON),
137.2 (Cipso), 133.4 (OCH2CH=CH2), 129.1, 128.2, 126.4 (C-Ar),
118.2 (OCH2CH=CH2), 102.0 (CHPh), 97.5 (C-1), 82.2, 71.5, 68.9,
68.8, 62.6, 55.7 (C-2, C-3, C-4, C-5, C-6, OCH2CH=CH2) ppm.
MALDI TOF-MS: calcd. for C33H40N2O11 640.26; found 641.39
[M + H]+. C33H40N2O11 (640.26): calcd. C 61.86, H 6.29, N 4.37;
found C 62.02, H 6.40, N 4.45.
1 (143 mg, 0.466 mmol) was treated as described above to give
crude 3, which was then dissolved in DMF (3.3 mL) and treated at
5 °C with DMAP (28.5 mg, 0.233 mmol). After 1 h stirring at 5 °C,
the solution was diluted with CH2Cl2 (50 mL) and washed with
0.1  HCl and water. The organic layer was collected, dried and
concentrated. The residue was subjected to column chromatog-
raphy (toluene/ethyl acetate, 12:1 to 9:1) to give 11 (68.4 mg, 23%)
as white amorphous crystals. [α]D = –15 (c = 0.9; CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 8.23 (d, J3Ј,2Ј = 9.1 Hz, 2 H, 2 ϫ 3Ј-
H pNO2-Ar), 8.20 (d, J3Ј,2Ј = 9.1 Hz, 2 H, 2 ϫ 3Ј-H pNO2-Ar),
7.49–7.39 (m, 5 H, Ar-H benzylidene), 7.28 (d, J2Ј,3Ј = 9.1 Hz, 2 H,
2 ϫ 2Ј-H pNO2-Ar), 7.27 (d, J2Ј,3Ј = 9.1 Hz, 2 H, 2 ϫ 2Ј-H pNO2-
Ar), 5.94 (m, 1 H, OCH2CH=CH2), 5.61 (d, JH,NH = 10.0 Hz, 1
H, NH), 5.59 (s, 1 H, CHPh), 5.37 (br. d, Jvic = 17.2 Hz, 1 H, trans
OCH2 CH=CHH), 5.32 (br. d, Jv i c = 10. 6 Hz, 1 H, cis
OCH2CH=CHH), 5.27 (t, J3,2 = J3,4 = 9.9 Hz, 1 H, 3-H), 5.05 (d,
J1,2 = 3.8 Hz, 1 H, 1-H), 4.35 (dd, Jgem = 10.3, J6a,5 = 4.8 Hz, 1 H,
6a-H), 4.28 (m, 2 H, 2-H, OCHHCH=CH2), 4.09 (dd, Jgem = 12.6,
Jvic = 6.5 Hz, 1 H, OCHHCH=CH2), 4.01 (dt, J5,4 = J5,6b = 10.3,
J5,6a = 4.8 Hz, 1 H, 5-H), 3.88 (t, J4,3 = J4,5 = 10.3 Hz, 1 H, 4-H),
3.83 (t, Jgem = J6b,5 = 10.3 Hz, 1 H, 6b-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.3, 155.2, 145.5, 144.8 (4 ϫ Cipso), 152.9,
152.5 (NCOO, OCOO), 136.6 (Cipso benzylidene), 132.7
(OCH2CH=CH2), 129.3–121.6 (C-Ar), 118.9 (OCH2CH=CH2),
101.8 (CHPh), 96.8 (C-1), 78.5, 76.3, 68.8, 68.6, 62.7, 54.2 (C-2, C-
3, C-4, C-5, C-6, OCH2CH=CH2) ppm. MALDI TOF-MS: un-
stable. C30H27N3O13 (637.15): calcd. C 56.52, H 4.27, N 6.59; found
C 56.38, H 4.19, N 6.50.
N-(1-O-Allyl-4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-α-
copyranos-2-yl)-NЈ-(1-O-allyl-4,6-O-benzylidene-2-deoxy-3-meth-
oxycarbonyl-α- -glucopyranos-2-yl)urea (14b) and N,NЈ-Bis(1-O-
allyl-4,6-O-benzylidene-2-deoxy-3-methoxycarbonyl-α- -glucopyr-
D-glu-
D
D
anos-2-yl)urea (15b): Compound 5 (32.3 mg, 46.7 µmol) was dis-
solved in CH2Cl2 (1.4 mL), cooled to –60 °C and treated with a
1.5  solution of NaOMe in MeOH (155 mL). After 40 min stirring
at –60 °C, sat. NH4Cl (5 mL) was added. The mixture was immedi-
ately diluted with EtOAc (30 mL), warmed to room temp. and
washed with water. The organic layer was collected, dried with an-
hydrous Na2SO4, filtered and concentrated to give a residue, that,
after flash chromatography (toluene/ethyl acetate, 7:1 to 5:1), af-
forded, 14b (11.5 mg, 34%) as the first eluted compound as a white
powder. [α]D = +66 (c = 0.5; CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.91 (d, JH,NH = 9.5 Hz, 1 H, NH), 7.49–7.34 (m, 10
N-(1-O-Allyl-4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-α-
D-glu-
copyranos-2-yl)-NЈ-(1-O-allyl-4,6-O-benzylidene-2-deoxy-α- -gluco-
D
pyranos-2-yl)urea (14a): A solution of compound 5 (45.6 mg,
65.9 µmol) in chloroform (1.5 mL) was treated with water (110 µL),
triethylamine (110 µL) and finally with 1,4-dioxane (660 µL). After
3 d stirring at room temp., the mixture was treated at 0 °C with
some drops of 0.1  HCl, then quickly diluted with dichlorometh-
ane (40 mL) and washed with water. The organic layer was col-
lected, dried with anhydrous Na2SO4 and concentrated to give a
residue, that, after flash chromatography (toluene/ethyl acetate, 6:1
H, Ar-H), 5.90 (m, 2 H, 2 ϫ OCH2CH=CH2), 5.75 (d, J1,2
=
to 2:1), afforded 14a (35.6 mg, 81%) as a white powder. [α]D
=
2.8 Hz, 1 H, 1A-H), 5.62 (s, 1 H, CHPh), 5.52 (s, 1 H, CHPh), 5.33
+81.4 (c = 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.89 (dd, Jvic = 17.2, Jgem = 1.5 Hz, 1 H, trans OCH2CH=CHH), 5.30
(d, JH,NH = 8.7 Hz, 1 H, NH), 7.51–7.36 (m, 10 H, Ar-H), 5.90 (m, (dd, Jvic = 17.2, Jgem = 1.5 Hz, 1 H, trans OCH2CH=CHH), 5.23
2 H, 2 ϫ OCH2CH=CH2), 5.76 (d, J1,2 = 2.8 Hz, 1 H, 1A-H), 5.62
(m, 3 H, 3B-H, 2 ϫ cis OCH2CH=CHH), 4.91 (d, J1,2 = 3.7 Hz, 1
H, 1B-H), 4.80 (dd, J3,2 = 11.7, J3,4 = 10.1 Hz, 1 H, 3A-H), 4.36–
4.21 (m, 6 H, 2B-H, 6aA-H, 6aB-H, 6bA-H, 2 ϫ OCHHCH=CH2),
4.15 (dd, Jgem = 12.8, Jvic = 5.9 Hz, 1 H, OCHHCH=CH2), 4.05
(m, 2 H, 4A-H, OCHHCH=CH2), 3.98 (td, J5,6a = J5,6b = 10.3, J5,4
(s, 1 H, CHPh), 5.56 (s, 1 H, CHPh), 5.32 (dd, Jvic = 17.2, Jgem
1.5 Hz, 1 H, trans OCH2CH=CHH), 5.29 (dd, Jvic = 17.2, Jgem
1.5 Hz, 1 H, trans OCH2CH=CHH), 5.24 (dd, Jvic = 10.3, Jgem
1.5 Hz, 1 H, cis OCH2CH=CHH), 5.22 (dd, Jvic = 10.5, Jgem
=
=
=
=
1.5 Hz, 1 H, cis OCH2CH=CHH), 4.91 (d, J1,2 = 3.8 Hz, 1 H, 1B- = 9.4 Hz, 1 H, 5B-H), 3.90 (d, J5,4 = 6.8 Hz, 1 H, 5A-H), 3.87 (dd,
H), 4.83 (dd, J3,2 = 11.7, J3,4 = 10.1 Hz, 1 H, 3A-H), 4.26 (m, 4 H, J2,3 = 11.7, J2,1 = 2.8 Hz, 1 H, 2A-H), 3.78 (t, J6,5 = Jgem = 10.3 Hz,
6 a A - H , 3 ϫ O C H H C H = C H 2 ) , 4 . 1 6 ( m , 2 H , 2 A - H , 1 H, 6bB-H), 3.76 (s, 3 H, OCH3), 3.74 (t, J4,3 = J4,5 = 9.4 Hz, 1
OCHHCH=CH2), 4.04 (m, 3 H, 5A-H, 5B-H, 6aB-H), 3.91 (m, 4 H, 4B-H) ppm. 13C NMR (50 MHz, CDCl3): δ = 155.3, 154.7, 151.8
H, 2B-H, 3A-H, 4A-H, 4B-H), 3.76 (d, Jgem = J6,5 = 10.3 Hz, 1 H,
6bA-H), 3.59 (d, Jgem = J6,5 = 9.9 Hz, 1 H, 6bB-H) ppm. 13C NMR
(COOCH3, NCON, OCON), 136.9, 136.4 (2 ϫ Cipso), 133.1, 133.0
(2 ϫ OCH2CH=CH2), 129.3, 129.1, 128.3, 128.2, 126.2, 126.1 (C-
(100 MHz, CDCl3): δ = 154.9 (OCON), 152.5 (NCON), 137.0, Ar), 118.5, 118.3 (2 ϫ OCH2CH=CH2), 101.6, 101.4 (2 ϫ CHPh),
136.4 (2 ϫ Cipso), 133.2, 133.1 (2 ϫ OCH2CH=CH2), 129.3–126.1 97.0, 96.3 (C-1A, C-1B), 79.8, 79.2, 74.6, 74.0, 69.7, 69.0, 68.7, 68.5,
(C-Ar), 118.4, 118.3 (2 ϫ OCH2CH=CH2), 102.0, 101.4 (2 ϫ 65.4, 62.9, 60.9, 55.2, 52.9 (C-2A, C-2B, C-3A, C-3B, C-4A, C-4B, C-
CHPh), 96.9, 96.5 (2 ϫ C-1), 81.9, 79.8, 74.1, 70.5, 69.9, 68.9, 68.8, 5A, C-5B, C-6A, C-6B, 2 ϫ OCH2CH=CH2, OCH3) ppm. MALDI
68.5, 65.4, 62.6, 60.9 (C-2A, C-3A, C-3B, C-4A, C-4B, C-5A, C-5B, TOF-MS: calcd. for C36H40N2O14 724.25; found 747.11 [M +
C-6A, C-6B, 2 ϫ OCH2CH=CH2), 54.7 (C-2B) ppm. MALDI TOF-
Na]+. C36H40N2O14 (724.25): calcd. C 59.66, H 5.56, N 3.87; found
C 59.48, H 5.47, N 3.80.
MS: calcd. for C34H38N2O12 666.24; found 689.39 [M + Na]+.
Eur. J. Org. Chem. 2010, 4062–4074
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4071

L. Cirillo, A. Silipo, E. Bedini, M. Parrilli
FULL PAPER
Second eluted compound 15b (12.1 mg, 34%) was recovered as a
white powder. [α]D = +84.1 (c = 1.5; CH2Cl2). 1H NMR (400 MHz,
CDCl3 ): δ = 7 . 4 6– 7. 35 (m, 5 H, Ar-H), 5. 87 (m, 1 H,
OCH2CH=CH2), 5.52 (s, 1 H, CHPh), 5.30 (br. d, Jvic = 17.2 Hz,
96.5 (C-1A, C-1B, C-1C), 80.6, 79.8, 79.4, 77.9, 76.0, 74.7, 73.6, 73.3,
72.2, 71.7, 69.1, 69.0, 68.9, 68.5, 66.7, 65.1, 62.9, 61.2, 55.0 (C-2A,
C-2B, C-2C, C-3A, C-3B, C-3C, C-4A, C-4B, C-4C, C-5A, C-5B, C-5C,
C-6A, C-6B, 3 ϫ OCH2Ph, 2 ϫ OCH2CH=CH2), 16.3 (C-6C) ppm.
1 H, trans OCH2CH=CHH), 5.23 (br. d, Jvic = 10.3 Hz, 1 H, cis MALDI TOF-MS: calcd. for C61H66N2O16 1082.44; found 1105.21
OCH2CH=CHH), 5.09 (t, J3,2 = J3,4 = 10.0 Hz, 1 H, 3-H), 4.90 (d,
[M + Na]+. C61H66N2O16 (1082.44): calcd. C 67.64, H 6.14, N 2.59;
J1,2 = 3.6 Hz, 1 H, 1-H), 4.85 (d, JH,NH = 9.6 Hz, 1 H, NH), 4.27 found C 67.48, H 6.00, N 2.50.
(dd, Jgem = 10.2, J6a,5 = 4.8 Hz, 1 H, 6a-H), 4.18 (m, 2 H, 2-H,
N-[3-O-(2,3,4-Tri-O-benzyl-α-
ylidene-2-deoxy-α- -glucopyranos-2-yl]-NЈ-(1-O-allyl-4,6-O-benzyl-
idene-2-deoxy-α- -glucopyranos-2-yl)urea (18): A solution of com-
L-fucopyranosyl)-1-O-allyl-4,6-O-benz-
OCHHCH=CH2), 4.00 (dd, Jgem = 12.8, Jvic = 6.1 Hz, 1 H,
OCHHCH=CH2), 3.91 (dt, J5,4 = J5,6b = 9.9, J5,6a = 4.8 Hz, 1 H,
5-H), 3.75 (m, 5 H, 4-H, 6b-H, OCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.2, 155.9 (COOCH3, NCON), 137.0 (Cipso), 133.2
(OCH 2 CH= CH 2 ) , 1 2 9 . 1 , 1 2 8 . 3 , 1 2 6 . 2 ( C - A r ) , 1 1 8 . 2
(OCH2CH=CH2), 101.6 (CHPh), 97.6 (C-1), 79.1, 74.5, 68.8, 68.7,
62.9, 55.1, 53.4 (C-2, C-3, C-4, C-5, C-6, OCH2CH=CH2, OCH3)
ppm. MALDI TOF-MS: calcd. for C37H44N2O15 756.27; found
779.38 [M + Na]+. C37H44N2O15 (756.27): calcd. C 58.72, H 5.86,
N 3.70; found C 58.50, H 5.68, N 3.65.
D
D
pound 17 (36.6 mg, 33.8 µmol) in 3:1 (v/v) 1,4-dioxane/water
(2.1 mL) was treated with triethylamine (260 µL). After 30 h stir-
ring at 80 °C, silica gel (600 mg) was added. The mixture was imme-
diately cooled to room temp. and concentrated. Flash chromatog-
raphy (toluene/ethyl acetate, 6:1 to 2:1) afforded 18 (20.8 mg, 58%)
as white amorphous crystals. [α]D = –3 (c = 0.7; CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.40–7.27 (m, 25 H, Ar-H), 5.88 (m, 1 H,
OCH2CH=CH2), 5.78 (m, 1 H, OCH2CH=CH2), 5.54 (s, 2 H, 2 ϫ
CHPh), 5.30 (dd, Jv i c = 17.2, Jg e m = 1.4 Hz, 1 H, trans
OCH2CH=CHH), 5.28 (d, J1,2 = 3.1 Hz, 2 H, 1A-H, 1B-H), 5.23
(dd, Jvic = 10.4, Jgem = 1.4 Hz, 1 H, cis OCH2CH=CHH), 5.17 (dd,
Jvic = 17.2, Jgem = 1.4 Hz, 1 H, trans OCH2CH=CH2), 5.14 (dd,
Jvic = 10.4, Jgem = 1.4 Hz, 1 H, cis OCH2CH=CHH), 5.05 (br. s, 2
Alternatively, compound 15b could be obtained by dissolving 5
(42.4 mg, 61.3 µmol) in chloroform (1.4 mL) and then treating it
with methanol (0.6 mL) and triethylamine (0.1 mL). The solution
was stirred at room temp. for two days. The reaction was quenched
by adding a few drops of 0.1  HCl. The mixture was immediately
diluted with CH2Cl2 (25 mL) and washed with water. The organic
layer was collected, dried and concentrated. Column chromatog-
raphy (toluene/ethyl acetate, 7:1 to 5:1) of the residue afforded 15b
(24.9 mg, 54%).
H, 2 ϫ NH), 5.01 (d, J1,2 = 3.8 Hz, 1 H, 1C-H), 4.89 (d, Jgem
=
11.5 Hz, 1 H, OCHHPh), 4.82 (d, Jgem = 11.9 Hz, 1 H, OCHHPh),
4.75 (s, 2 H, OCH2Ph), 4.65 (d, Jgem = 11.5 Hz, 1 H, OCHHPh),
4.57 (d, Jgem = 11.9 Hz, 1 H, OCHHPh), 4.28 (dd, J2,3 = 10.0, J2,1
= 3.5 Hz, 1 H, 2A-H), 4.23 (dd, J2,3 = 10.0, J2,1 = 3.5 Hz, 1 H, 2B-
H), 4.16 (dd, Jgem = 13.4, Jvic = 6.8 Hz, 1 H, OCHHCH=CH2),
4.09–3.68 (m, 16 H, 2C-H, 3A-H, 3B-H, 3C-H, 4A-H, 4B-H, 5A-H,
5B-H, 5C-H, 6aA-H, 6bA-H, 6aB-H, 6bB-H, 3 ϫ OCHHCH=CH2),
3.53 (d, J4,3 = 2.0 Hz, 1 H, 4C-H), 0.96 (d, J6,5 = 6.4 Hz, 3 H, 6C-
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 158.9 (NCON), 138.7,
138.5, 137.6, 137.3, 137.1 (3 ϫ Cipso Bn, 2 ϫ Cipso benzylidene),
133.7, 133.2 (2 ϫ OCH2CH=CH2), 129.0–125.9 (C-Ar), 118.4,
117.9 (2 ϫ OCH2CH=CH2), 101.7, 101.1 (2 ϫ CHPh), 97.9, 97.4,
97.3 (C-1A, C-1B, C-1C), 81.7, 81.5, 79.2, 79.1, 77.5, 74.9, 74.5, 73.7,
73.3, 71.8, 71.7, 68.8, 68.7, 68.6, 67.2, 63.0, 62.5, 55.6, 55.1 (C-2A,
C-2B, C-2C, C-3A, C-3B, C-3C, C-4A, C-4B, C-4C, C-5A, C-5B, C-5C,
C-6A, C-6B, 3 ϫ OCH2Ph, 2 ϫ OCH2CH=CH2), 16.5 (C-6C) ppm.
MALDI TOF-MS: calcd. for C60H68N2O15 1056.46; found 1078.61
[M + Na]+. C60H68N2O15 (1056.46): calcd. C 68.17, H 6.48, N 2.65;
found C 68.08, H 6.42, N 2.60.
N-[3-O-(2,3,4-Tri-O-benzyl-α-
ylidene-2-deoxy-α- -glucopyranos-2-yl]-NЈ-(1-O-allyl-4,6-O-benzyl-
idene-2,3-N,O-carbonyl-2-deoxy-α- -glucopyranos-2-yl)urea (17): A
L-fucopyranosyl)-1-O-allyl-4,6-O-benz-
D
D
mixture of 14a (39.0 mg, 58.6 µmol) and 16 (70.8 mg, 117 µmol)
was coevaporated three times with toluene, the residue was dried
and then mixed with freshly activated molecular sieves (AW-300,
4 Å), suspended under argon in 1:1 (v/v) CH2Cl2/THF (1.5 mL).
The mixture was stirred at –30 °C for 15 min. A solution of
TMSOTf in CH2Cl2 (24.6 mg/mL, 27.4 µL, 3.0 µmol) was then
added. The mixture was stirred for 75 min at –30 °C, then a few
drops of Et3N were added. The mixture was filtered through a Ce-
lite pad and concentrated. The residue was subjected to column
chromatography (toluene/ethyl acetate, 12:1 to 8:1) to give 17
(48.1 mg, 76%) as a colorless oil. [α]D = +23.1 (c = 1.7; CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, JH,NH = 10.0 Hz, 1 H,
NH), 7.39–7.25 (m, 25 H, Ar-H), 5.86 (m, 1 H, OCH2CH=CH2),
5.69 (m, 2 H, 1A-H, OCH2CH=CH2), 5.54 (s, 1 H, CHPh), 5.51 (s,
1 H, CHPh), 5.35 (d, J1,2 = 3.6 Hz, 1 H, 1C-H), 5.31 (dd, Jvic
17.2, Jgem = 1.5 Hz, 1 H, trans OCH2CH=CHH), 5.22 (dd, Jvic
10.5, Jgem = 1.5 Hz, 1 H, cis OCH2CH=CHH), 5.09 (dd, Jvic
17.0, Jgem = 1.5 Hz, 1 H, trans OCH2CH=CH2), 5.06 (dd, Jvic
10.5, Jgem = 1.5 Hz, 1 H, cis OCH2CH=CH2), 4.89 (d, Jgem
=
=
=
=
=
N-(1-O-Allyl-3-O-α-
yl)-NЈ-(1-O-allyl-2-deoxy-α-
tion of 18 (10.0 mg, 9.5 µmol) in 9:1 (v/v) MeOH/HCOOH
(500 µL) was treated with Pd/C (3 mg) under an Ar atmosphere.
After 1 h in an ultrasound bath, the mixture was filtered through
L
-fucopyranosyl-2-deoxy-α-
D-glucopyranos-2-
D-glucopyranos-2-yl)urea (19): A solu-
11.5 Hz, 1 H, OCHHPh), 4.87 (d, J1,2 = 3.5 Hz, 1 H, 1B-H), 4.83 a Celite pad and concentrated. The residue was lyophilized to give
(d, Jgem = 11.7 Hz, 1 H, OCHHPh), 4.73 (d, Jgem = 11.6 Hz, 1 H, pure 19 (4.2 mg, 72%) as a white foam. [α]D = +37 (c = 0.3; H2O).
OCHHPh), 4.66 (d, Jgem = 11.7 Hz, 1 H, OCHHPh), 4.65 (t, J3,4
J3,2 = 10.0 Hz, 1 H, 3A-H), 4.56 (d, Jgem = 11.6 Hz, 1 H,
=
1H NMR (400 MHz, D2O): δ = 5.04 (d, J1,2 = 3.9 Hz, 1 H, 1-H),
4.89 (d, J1,2 = 3.4 Hz, 1 H, 1-H), 4.82 (d, J1,2 = 3.6 Hz, 1 H, 1-H),
OCHHPh), 4.55 (d, Jgem = 11.5 Hz, 1 H, OCHHPh), 4.35 (dt, 4.34 (q, J5,6 = 6.6 Hz, 1 H, 5C-H), 3.88–3.40 (m, 19 H, 2A-H, 2B-
J2,3 = J2,NH = 10.0, J2,1 = 3.5 Hz, 1 H, 2B-H), 4.31–4.17 (m, 5 H,
2A-H, 6aA-H, 6bA-H, OCH2CH=CH2), 4.12 (q, J5,6 = 6.4 Hz, 1 H,
5C-H), 4.05–3.72 (m, 11 H, 2C-H, 3B-H, 3C-H, 4A-H, 4B-H, 5A-H,
H, 2C-H, 3A-H, 3B-H, 3C-H, 4A-H, 4B-H, 4C-H, 5A-H, 5B-H, 6A-
H, 6B-H, 2 ϫ OCH2CH2CH3), 1.62 (m, 4 H, 2 ϫ OCH2CH2CH3),
1.16 (d, J6,5 = 6.6 Hz, 3 H, 6C-H), 0.93 (t, Jvic = 7.4 Hz, 6 H, 2
5B-H, 6aB-H, 6bB-H, OCH2CH=CH2), 3.49 (d, J4,3 = 2.0 Hz, 1 H, ϫ OCH2CH2CH3) ppm. 13C NMR (100 MHz, D2O): δ = 160.1
4C-H), 0.88 (d, J6,5 = 6.4 Hz, 3 H, 6C-H) ppm. 13C NMR (NCON), 100.0, 98.3 (C-1A, C-1B, C-1C), 79.0, 72.6, 72.5, 70.9,
(100 MHz, CDCl3): δ = 154.9, 152.4 (OCON, NCON), 139.0,
138.6, 138.2, 137.3, 136.4 (3 ϫ Cipso Bn, 2 ϫ Cipso benzylidene),
133.4, 133.0 (2 ϫ OCH2CH=CH2), 129.3–125.9 (C-Ar), 118.0,
70.8, 70.7, 69.3, 68.9, 67.8, 61.4 (C-2C, C-3A, C-3B, C-3C, C-4A, C-
4B, C-4C, C-5A, C-5B, C-5C, C-6A, C-6B, OCH2CH2CH3), 55.0, 54.7
(C-2A, C-2B), 22.8 (OCH2CH2CH3), 16.0 (C-6C), 10.7
117.9 (2 ϫ OCH2CH=CH2), 101.6, 101.4 (2 ϫ CHPh), 97.2, 96.6, (OCH2CH2CH3) ppm. MALDI TOF-MS: calcd. for C25H46N2O15
4072
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4062–4074

Synthesis of Linear and Cyclic Neosaccharides
614.29; found 637.10 [M + Na]+. C25H46N2O15 (614.29): calcd. C
48.85, H 7.54, N 4.56; found C 48.60, H 7.78, N 4.39.
[3]
a) Y. Ichikawa, T. Nishiyama, M. Isobe, J. Org. Chem. 2001,
66, 4200–4205; b) M. I. García-Moreno, J. M. Benito, C. Or-
tiz Mellet, J. M. García Fernández, J. Org. Chem. 2001, 66,
7604–7614; c) C. Böttcher, K. Burger, Tetrahedron Lett. 2003,
44, 4223–4226; d) D. Prosperi, S. Ronchi, L. Lay, A. Rencurosi,
G. Russo, Eur. J. Org. Chem. 2004, 395–405; e) Y. Ichikawa, Y.
Matsukawa, T. Nishiyama, M. Isobe, Eur. J. Org. Chem. 2004,
586–591; f) M. Ávalos, R. Babiano, P. Cintas, M. B. Hurst-
house, J. L. Jiménez, M. E. Light, J. C. Palacios, E. M. S. Pérez,
Eur. J. Org. Chem. 2006, 657–671; g) Y. Ichikawa, F. Ohara,
H. Kotsuki, K. Nakano, Org. Lett. 2006, 8, 5009–5012; h) Y.
Ichikawa, Y. Matsukawa, M. Isobe, J. Am. Chem. Soc. 2006,
128, 3934–3938; i) D. Sawada, S. Sasayama, H. Takahashi, S.
Ikegami, Tetrahedron Lett. 2006, 47, 7219–7223; j) J. M. Benito,
D. Rodríguez-Lucena, J. L. Jiménez-Blanco, C. Ortiz Mellet,
J. M. García Fernández, J. Inclusion Phenom. Macrocyclic
Chem. 2007, 57, 147–150; k) D. Rodríguez-Lucena, J. M. Be-
nito, E. Álvarez, C. Jaime, J. Perez-Miron, C. Ortiz Mellet,
J. M. García Fernández, J. Org. Chem. 2008, 73, 2967–2979; l)
D. Sawada, S. Sasayama, H. Takahashi, S. Ikegami, Tetrahe-
dron 2008, 64, 8780–8788; m) P. Spanu, F. Ulgheri, Curr. Org.
Chem. 2008, 12, 1071–1092; n) N. H. Park, H. M. Nguyen,
Org. Lett. 2009, 11, 2433–2436; o) N. Felföldi, M. Tóth, E. D.
Chrysina, M.-D. Charavgi, K. M. Alexacou, L. Somsák, Car-
bohydr. Res. 2010, 345, 208–213.
1-O-Allyl-4,6-O-benzylidene Cyclic Neodisaccharide (20): Com-
pound 14a (36.8 mg, 55.2 µmol) was dissolved in DMF (2.0 mL)
under an Ar atmosphere. The solution was treated with DBU
(10.2 µL, 68.4 µmol) and then heated to 50 °C. After overnight stir-
ring, the reaction was cooled to room temp., diluted with ethyl
acetate (20 mL) and washed with 0.1  HCl and then water. The
organic layer was collected, dried with anhydrous Na2SO4, filtered
and concentrated to give a residue, that, after flash chromatography
(toluene/ethyl acetate, 6:1 to 2:1), afforded 20 (15.7 mg, 43%) as a
1
white powder. [α]D = +32 (c = 0.9; CH2Cl2). H NMR (400 MHz,
CDCl3):
δ = 7.49–7.33 (m, 5 H, Ar-H), 5.85 (m, 1 H,
OCH2CH=CH2), 5.52 (s, 1 H, CHPh), 5.28 (m, 3 H, 3-H,
OCH2CH=CH2), 5.00 (d, JH,NH = 9.8 Hz, 1 H, NH), 4.92 (d, J1,2
= 3.8 Hz, 1 H, 1-H), 4.29 (dd, Jgem = 10.2, J6a,5 = 4.8 Hz, 1 H, 6a-
H), 4.20 (dd, Jgem = 12.5, Jvic = 5.4 Hz, 1 H, OCHHCH=CH2),
4.07 (dt, J2,3 = JH,NH = 9.8, J2,1 = 3.8 Hz, 1 H, 2-H), 3.99 (dd, Jgem
= 12.5, Jvic = 5.4 Hz, 1 H, OCHHCH=CH2), 3.94 (ddd, J5,6b
10.3, J5,4 = 9.6, J5,6a = 4.8 Hz, 1 H, 5-H), 3.77 (t, Jgem = J6b,5
=
=
10.3 Hz, 1 H, 6b-H), 3.73 (t, J4,3 = J4,5 = 9.6 Hz, 1 H, 4-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.5 (OCON), 136.8 (Cipso),
132.7 (OCH2CH=CH2), 129.2, 128.2, 126.3 (C-Ar), 119.2
(OCH2CH=CH2), 101.8 (CHPh), 96.6 (C-1), 78.3, 75.1, 68.9, 68.8,
63.2, 56.4 (C-2, C-3, C-4, C-5, C-6, OCH2CH=CH2) ppm. MALDI
TOF-MS: calcd. for C34H38N2O12 666.24; found 689.37 [M + Na]
+. C34H38N2O12 (666.24): calcd. C 61.25, H 5.75, N 4.20; found C
61.08, H 5.66, N 4.11.
[4]
[5]
a) G. A. Ellestad, D. B. Cosulich, R. W. Broschard, J. H. Mar-
tin, M. P. Kunstmann, G. O. Morton, J. E. Lancaster, W.
Fulmor, F. M. Lovell, J. Am. Chem. Soc. 1978, 100, 2515–2524;
b) K. Dobashi, K. Nagaoka, Y. Watanabe, M. Nishida, M.
Hamada, H. Naganawa, T. Takita, T. Takeuchi, H. Umezawa,
J. Antibiot. 1985, 38, 1166–1170.
H. A. Kirst, in: Burger’s Medicinal Chemistry and Drug Discov-
ery (Ed.: M. E. Wolff), Wiley-VCH, Weinheim, 1996, pp. 463–
525.
1-O-Allyl Cyclic Neodisaccharide (21): Compound 20 (36.0 mg,
54.1 µmol) was dissolved in 4:1 (v/v) 1,4-dioxane/water (1.0 mL)
and then treated with (Ϯ)-camphor-10-sulfonic acid (31.1 mg,
134 µmol). After 4 h stirring at 60 °C, silica gel (500 mg) was added
and the mixture was evaporated. The residue was subjected to flash
chromatography (chloroform/methanol, 95:5 to 86:14) affording 21
[6]
[7]
T. Akhtar, I. Cumpstey, Tetrahedron Lett. 2007, 48, 8673–8677,
and references cited therein.
a) K. Benakli, C. Zha, R. J. Kerns, J. Am. Chem. Soc. 2001,
123, 9461–9462; b) D. Crich, A. U. Vinod, Org. Lett. 2003, 5,
1297–1300; c) S. Manabe, K. Ishii, Y. Ito, J. Am. Chem. Soc.
2006, 128, 10666–10667; d) Y. Geng, L.-H. Zhang, X.-S. Ye,
Tetrahedron 2008, 64, 4949–4958; e) J. D. M. Olsson, L. Eriks-
son, M. Lahmann, S. Oscarson, J. Org. Chem. 2008, 73, 7181–
7188; f) Y. Nagai, N. Ito, I. Sultana, T. Sagai, Tetrahedron 2008,
64, 9599–9606.
1
(25.9 mg, 98%) as a white powder. [α]D = +104 (c = 0.9; H2O). H
NMR (400 MHz, D2O): δ = 6.00 (m, 1 H, OCH2CH=CH2), 5.38
(d, Jvic = 17.2 Hz, 1 H, trans OCH2CH=CHH), 5.28 (d, J1,2
3.7 Hz, 1 H, cis OCH2CH=CHH), 5.07 (d, J1,2 = 3.7 Hz, 1 H, 1-
H), 4.87 (dd, J3,2 = 10.0, J3,4 = 9.2 Hz, 1 H, 3-H), 4.25 (dd, Jgem
=
=
12.7, Jvic = 5.5 Hz, 1 H, OCHHCH=CH2), 4.15 (dd, J2,3 = 10.0,
J2,1 = 3.7 Hz, 1 H, 2-H), 4.09 (dd, Jgem = 12.7, Jvic = 5.5 Hz, 1 H,
OCHHCH=CH2), 3.91–3.73 (m, 4 H, 4-H, 5-H, 6a-H, 6b-H) ppm.
[8]
[9]
O. Gavard, Y. Hersant, J. Alais, V. Duverger, A. Dilhas, A.
Bascou, D. Bonnaffé, Eur. J. Org. Chem. 2003, 3603–3620.
13C NMR (50 MHz, D2O):
δ
=
158.6 (OCON), 134.0
a) M. J. Karplus, J. Am. Chem. Soc. 1963, 85, 2870–2871; b)
M. Barfield, W. B. Smith, J. Am. Chem. Soc. 1992, 114, 1574–
1581; c) M. J. Clément, A. Imberty, A. Phalipon, S. Pérez, C.
Simenel, L. A. Mulard, M. Delepierre, J. Biol. Chem. 2003,
278, 47928–47936; d) V. Lacerda, G. da Silva, M. G. Con-
stantino, C. Tormena, T. Williamson, B. Marquez, Magn. Re-
son. Chem. 2006, 44, 95–98; e) V. Lacerda, G. da Silva, C. Tor-
mena, T. Williamson, B. Marquez, Magn. Reson. Chem. 2007,
45, 82–86; f) M. Tafazzoli, M. Ghiasi, Carbohydr. Res. 2007,
342, 2086–2096; g) V. Lacerda, G. da Silva, M. G. Constantino,
R. B. Dos Santos, E. V. R. De Castro, R. Silva, Magn. Reson.
Chem. 2008, 46, 268–273.
(OCH2CH=CH2), 119.1 (OCH2CH=CH2), 96.4 (C-1), 79.6, 72.4,
69.2, 67.3, 60.8, 55.8 (C-2, C-3, C-4, C-5, C-6, OCH2CH=CH2)
ppm. MALDI TOF-MS: calcd. for C20H30N2O12 490.18; found
513.00 [M + Na]+. C20H30N2O12 (490.18): calcd. C 48.98, H 6.17,
N 5.71; found C 48.78, H 6.04, N 5.61.
Supporting Information (see also the footnote on the first page of
1
this article): Copies of H and 13C NMR spectra for all new com-
pounds. Copies of HSQBMC spectra of compounds 7 and 21 as
well as of J-HMBC spectrum of compound 7.
[10]
[11]
A. Meissner, O. W. Soerensen, Magn. Reson. Chem. 2001, 39,
49–52.
a) R. T. Williamson, B. L. Marquez, W. H. Gerwick, K. E.
Kover, Magn. Reson. Chem. 2000, 38, 265–273; b) B. L. Mar-
quez, W. H. Gerwick, R. T. Williamson, Magn. Reson. Chem.
2001, 39, 499–530.
Acknowledgments
NMR and MS facilities of the Centro Interdipartimentale di Meto-
dologie Chimiche Fisiche (CIMCF) are acknowledged.
[12]
a) T. Sugawara, M. Narisada, Carbohydr. Res. 1989, 194, 125–
138; b) S. Manabe, K. Ishii, Y. Ito, J. Am. Chem. Soc. 2006,
128, 10666–10667; c) A. Bodlenner, A. Alix, J.-M. Weibel, P.
Pale, E. Ennifar, J.-C. Paillart, P. Walter, R. Marquet, P.
Dumas, Org. Lett. 2007, 9, 4415–4418; d) G. Chen, P. Pan, Y.
[1] T. J. Boltje, T. Buskas, G.-J. Boons, Nature Chem. 2009, 1, 611–
622.
[2] State of the art, see: Carbohydr. Res. 2007, 342, 1537–1982 (spe-
cial issue on Glycomimetics).
Eur. J. Org. Chem. 2010, 4062–4074
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4073

L. Cirillo, A. Silipo, E. Bedini, M. Parrilli
FULL PAPER
Yao, Y. Chen, X. Meng, Z. Li, Tetrahedron 2008, 64, 9078–
9087.
3298; k) G. Di Fabio, A. Randazzo, J. D’Onofrio, C. Ausín, E.
Pedroso, A. Grandas, L. De Napoli, D. Montesarchio, J. Org.
Chem. 2006, 71, 3395–3408; l) K. S. Kim, B.-Y. Lee, S. H.
Yoon, H. J. Jeon, J. Y. Baek, K.-S. Jeong, Org. Lett. 2008, 10,
2373–2376; m) S. Muthana, H. Yu, H. Chao, J. Cheng, X.
Chen, J. Org. Chem. 2009, 74, 2928–2936; n) S. Paul, S. Ragho-
thama, N. Jayaraman, Carbohydr. Res. 2009, 344, 177–186; o)
Y.-C. Hsieh, J.-L. Chir, W. Zou, H.-H. Wu, A.-T. Wu, Car-
bohydr. Res. 2009, 344, 1020–1023; p) S. Porwanski, A. Mar-
sura, Eur. J. Org. Chem. 2009, 2047–2050; q) D. Rodríguez-
Lucena, C. Ortiz Mellet, C. Jaime, K. K. Burusco, J. M.
García Fernández, J. M. Benito, J. Org. Chem. 2009, 74, 2997–
3008; r) C. L. Romero Zaliz, O. Varela, Tetrahedron Lett. 2009,
50, 5677–5680.
[13] Compound 11 was obtained by reacting 3 with DMAP and
excess NPCC in DMF at 5 °C.
[14] P. Wei, R. J. Kerns, Tetrahedron Lett. 2005, 46, 6901–6905.
[15] D. Comegna, E. Bedini, A. Di Nola, A. Iadonisi, M. Parrilli,
Carbohydr. Res. 2007, 342, 1021–1029.
[16] V. S. Rao, A. S. Perlin, Carbohydr. Res. 1980, 83, 175–177.
[17] a) G. Gattuso, S. A. Nepogodiev, J. F. Stoddart, Chem. Rev.
1998, 98, 1919–1958; b) P. Y. Chong, P. A. Petillo, Org. Lett.
2000, 2, 1093–1096; c) J. Stichler-Bonaparte, A. Vasella, Helv.
Chim. Acta 2001, 84, 2355–2367; d) E. Locardi, M. Stöckle, S.
Gruner, H. Kessler, J. Am. Chem. Soc. 2001, 123, 8189–8196; e)
L. Fan, O. Hindsgaul, Org. Lett. 2002, 4, 4503–4506; f) R. M.
van Well, L. Marinelli, K. Erkelens, G. A. van der Marel, A.
Lavecchia, H. S. Overkleeft, J. van Boom, H. Kessler, M. Over-
hand, Eur. J. Org. Chem. 2003, 2303–2313; g) B. A. Mayes,
R. J. E. Stetz, C. W. G. Ansell, G. W. J. Fleet, Tetrahedron Lett.
2004, 45, 153–156; h) T. Velasco-Torrijos, P. V. Murphy, Tetra-
hedron: Asymmetry 2005, 16, 261–272; i) K. D. Bodine, D. Y.
Gin, M. S. Gin, Org. Lett. 2005, 7, 4479–4482; j) M. Ménand,
J.-C. Blais, J.-M. Valéry, J. Xie, J. Org. Chem. 2006, 71, 3295–
[18] Water suppression was achieved by using excitation sculpting
with gradients. For details, see: T. L. Hwang, A. J. Shaka,
Magn. Res. A 1995, 112, 275–279.
[19] M. Rance, O. W. Sørensen, G. Bodenhausen, G. Wagner, R. R.
Ernst, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983,
117, 479–485.
Received: March 3, 2010
Published Online: June 14, 2010
4074
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4062–4074