Versatile and self-assembling urea-linked neosaccharides from sugar aminoalcohols

Article abstract of DOI:10.1016/j.tet.2012.12.005

The increasing interest in urea compounds as self-assembling molecules, ion transporters and organocatalysts prompted several efforts towards synthetic urea-linked glycomimetics. In this frame we studied in details a novel two steps dimerization reaction of sugar vicinal aminoalcohol building blocks, opening a synthetic path to a series of urea-linked neosaccharides. Glucosamine neodisaccharide possessing an oxazolidinone-urea-oxazolidinone system could be transformed into both cyclic and higher linear neosaccharides. Furthermore, a series of six urea-linked glucosamine and galactosamine neodisaccharides was tested for self-assembling properties by measuring NMR spectra at different temperatures and concentrations as well as by gelation of several organic solvents.

Full text of DOI:10.1016/j.tet.2012.12.005

Tetrahedron 69 (2013) 1285e1296
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Versatile and self-assembling urea-linked neosaccharides from sugar
aminoalcohols
y
*
Emiliano Bedini , Luigi Cirillo , Michelangelo Parrilli
ꢀ
Dipartimento di Scienze Chimiche, Universita di Napoli “Federico II”, Complesso Universitario Monte S. Angelo, Via Cintia 4, I-80126 Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 August 2012
Received in revised form 13 November 2012
Accepted 3 December 2012
Available online 8 December 2012
The increasing interest in urea compounds as self-assembling molecules, ion transporters and organo-
catalysts prompted several efforts towards synthetic urea-linked glycomimetics. In this frame we studied
in details a novel two steps dimerization reaction of sugar vicinal aminoalcohol building blocks, opening
a synthetic path to a series of urea-linked neosaccharides. Glucosamine neodisaccharide possessing an
oxazolidinoneeureaeoxazolidinone system could be transformed into both cyclic and higher linear
neosaccharides. Furthermore,
a series of six urea-linked glucosamine and galactosamine neo-
Keywords:
disaccharides was tested for self-assembling properties by measuring NMR spectra at different tem-
peratures and concentrations as well as by gelation of several organic solvents.
Ó 2012 Elsevier Ltd. All rights reserved.
Neosaccharide
Sugar dimerization
Urea
Aminosugar
Self-assembly
Organogelation
1. Introduction
linkages (thioether, amine, amide, olefin, etc.) have been reported.
In the last decade urea-linked glycomimetics captured an in-
Carbohydrates are involved in a myriad of biological processes
that involve the recognition of glycans by specific receptors. The
study of such interactions in vivo and in vitro as well as their ex-
ploitation for the development of carbohydrate-based functional
materials is a ‘hot topic’ nowadays.1 However, a clear drawback of
natural occurring oligosaccharides is their metabolic instability in
biological systems. For this reason, the study of carbohydrate
mimics (glycomimetics)dmolecules resembling carbohydrates but
with some different properties (e.g., recognized but not hydrolyzed
by a glycosidase)dhas become a research area of great interest.2
Much effort has been spent on the development of practicable
ways to the synthesis of glycomimetics, which can serve as func-
tional materials or as biochemical and biomedical tools.3
Among glycomimetics, attention has been mainly focused on
the attainment of compoundsdtermed pseudosaccharidesdhav-
ing the acid-labile glycosidic bonds substituted with non-acetal
linkages.4 Oligosaccharide mimics with linkages between mono-
saccharides not involving the anomeric position are termed neo-
saccharides. Pseudo- and neosaccharides with several kinds of
creasing share of interest5 due to the occurrence of these linkages
in natural antibiotics, such as glycocinnamoyl-spermidines.6 Fur-
thermore, several urea compounds have recently staged a remark-
able re-emergence in several fields of chemistry, after being almost
ignored during 20th century. This renaissance is mainly associated
with the exploitation of urea compounds as powerful, geo-
metrically ordered hydrogen-bond donors and acceptors for the
design of self-assembling supramolecular structures, ion trans-
porters and organocatalysts, as well as coordinating molecules for
promoting several reactions in metallation chemistry.7
Most urea-linked pseudosaccharides have been obtained by the
reaction of glycosyl amines with unstable glycosyl isocyanates or
their more stable synthetic equivalents, such as Steyermark’s gly-
cosyl-1,2-oxazolidinone or glycosyl trichloroacetamides.8 Glycosyl
amines were also used in a Curtius rearrangement in the presence
of sugar carboxylic acids to afford urea-linked pseudosaccharides.9
Urea-linked neosaccharides have been also reported, by two dif-
ferent synthetic routes. The first was based on the acid-catalyzed
addition of water to diglycosyl-carbodiimides, obtained in turn by
a tandem Staudinger/aza-Wittig reaction of a protected azide with
a sugar isocyanate in the presence of triphenylphosphine.10 Alter-
natively, urea-linked neosaccharides were obtained by coupling
sugar isocyanates with aminosugars.11
* Corresponding author. Tel.: þ39 (0)81674153; fax: þ39 (0)81674393; e-mail
address: ebedini@unina.it (E. Bedini).
y
Very recently, we reported the conversion of glucosamine 2,3-
Present address: Novartis Farma S.p.A., Lg. Umberto Boccioni 1, I-21040 Origgio
(VA), Italy.
aminoalcohol 1 into symmetric N,N0-urea-linked neodisaccharide
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.005

1286
E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
2 by slightly modifying12 the reaction conditions usually employed
for the closure of an oxazolidinone cycle (Scheme 1a).13 It is worth
noting that a few scattered examples can be found in the literature
on the formation of N,N0-urea-linked dimers from sugar building
blocks, as byproducts of diverse reactions (Scheme 1b).14 This is
usually attributed to adventitious hydrolysis of intermediate iso-
cyanates or synthetic equivalents thereof by moisture, followed by
addition of the resulting amine to another isocyanate molecule.
Nonetheless, no study on the dependence of neodisaccharide for-
mation on reaction conditions was conducted.
In this work we studied the dependence of urea-linked dimer
versus oxazolidinone monomer species formation on several re-
action conditions, starting from 1 or other sugar vicinal amino-
alcohols. The obtained urea-linked neodisaccharides were
demonstrated to be very versatile scaffolds for the synthesis of
higher linear and cyclic neosaccharides and for the attainment of
neosaccharide derivatives possessing self-assembling properties.
Ph
O
O
O
O
Ph
Ph
O
O
O
O
O
HO
HO
H2N
H2N
H2N
HO
O
O
O
1
4
5
OBn
O
H2N
PMBO
BnO
O
Ph
O
O
OBn
N
O
HO
3 O
6
7
HO
OMe
H2N
O
Fig. 1. Sugar vicinal aminoalcohols on which urea-linked dimerization was tested.
O
Ph
O
O
a)
Ph
O
Ph
+
O
O
OCOCl
NaHCO3
O2N
O
N
O
O
O
O
O
NaH
O
O
O
N
HO
O
O
O
DMF
30°C
H2O-CH3CN
rt
ref. 12 and this work
N
H2N
O
O
O
O
1
O
O
O
Ph
O2N
2: 17-97%
3: 0-26%
b)
Ph
N
O
O
HO
O
NH
N
N
N
OBn
Ph
O
Ph
+
O
O
O
O
O
O
O
OBn
HO
THF, rt
ref. 14a
OBn
O
HN
O
NH2
NH
OH
BnO
O
O
O
Ph
13%
87%
O
Ph
O
O
O
Pb(OAc)4
t-BuOH
Ph
+
Ph
O
O
O
O
O
O
HN
BocHN
OCH3
CN
OCH3
O
CN
DMF, reflux
ref. 14b
O
OCH3
OCH3
OMe
CN
H2N
CN
NH
O
19%
76%
O
Ph
AcO
AcO
AcO
AcO
AcO
O
O
O
AcO
AcO
AcO
O
NHFmoc
OMe
OMe
O
DIPEA
AcO
+
HS
Ph
+
NH
HN
O
CH2Cl2, rt
ref. 14c
NCO
HN
Ph
30%
NHFmoc
OAc
OAc
OAc
MeO
O
45%
Scheme 1. Examples of urea-linked neosaccharide dimers as reaction byproducts.
2. Results and discussion
excess 4-nitrophenyl chloroformate (NPCC) in the presence of
NaHCO3 in H2OeCH3CN at 0 ꢀC for 3 h, producing a mixture of the
desired oxazolidinone and uncyclized carbamate. The latter could
be converted into the former by an additional step with Amberlyst
IR-120 Naþ ion-exchange resin.13b We investigated the dependence
on temperature and time of the reaction on glucosamine amino-
alcohol 1. The exclusive formation of oxazolidinone 9 could be
obtained at 40 ꢀC (Table 1, entry 1), whereas a lower reaction
temperature (entries 5 and 6) afforded only uncyclized carbamate 8
(Scheme 2). By increasing the reaction time from 30 min to 2e3 h,
2.1. Synthesis of neosaccharides
The urea-linked dimerization reaction was investigated on the
sugar vicinal aminoalcohols depicted in Fig. 1. They were obtained
through standard literature procedures from commercially avail-
able carbohydrates.15e19
The standard conditions used in carbohydrate chemistry to
protect a vicinal aminoalcohol moiety as an oxazolidinone uses

E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
1287
Table 1
In the presence of a strong base, such as NaH, compound 8 (or
analogously 10) could be rapidly converted into oxazolidinone 9
through isocyanate 15, in accordance with similar known trans-
formations.13c,d,20 In the absence of NPCC in the reaction mixture,
only this pathway can operate. Consistently, when the reaction was
conducted on pure uncyclized carbamates 8 and 10, oxazolidinone
species 9 (Table 2, entry 7) and 13 (Table 3, entries 7 and 8) were
obtained exclusively. On the contrary, when excess NPCC was
present in the reaction mixture, isocyanate 16 could also be formed.
An intramolecular nucleophilic addition cannot occur in 16,
whereas oxazolidinone 9 could act as external nucleophile to form
a dimer, that could easily react furtherdagain through an iso-
cyanate speciesdto give the final product 2. Oxazolidinone 9 can
Uncyclized carbamate 8 versus oxazolidinone 9 formation from 1
Entrya
T
Time
9/8b
1
40 ꢀC
20 ꢀC
0
0
0
0
30 min
3 h
3 h
2 h
50 min
30 min
100:0
19:81
17:83
6:94
0:100
0:100
2
3c
4
ꢀC
ꢀC
ꢀC
ꢀC
5
6
a
Reactions conducted with NPCC (5 equiv) and NaHCO3 (5 equiv) in 3:2 v/v
CH3CN/H2O.
b
Percent molar ratio determined by 1H NMR analysis of the crude mixture after
extractive work-up.
c
Ref. 13b reaction conditions.
O
Ph
a
O
O
Ph
+
O
O
O
+
3
HO
b
O
1
2
HN
O
NH
O
O
O
O
9
8
O2N
Ph
Ph
Ph
Ph
O
O
O
O
O
O
O
O
O
O
c
O
NH
O
d
O
+
4
N
+
O
HO
O
O
O
O
O
HN
N
O
O
O
O
O
O
N
O
O
O
O
O
13
O2N
10
11
O
12
O
O
O2N
Ph
Scheme 2. Reagents and conditions: (a) see Table 1; (b) see Table 2; (c) NPCC, NaHCO3, 3:2 v/v CH3CN/H2O, 0 ꢀC, 30 min; (d) see Table 3.
a mixture of oxazolidinone and uncyclized carbamate products was
obtained at both 0 ꢀC and 20 ꢀC (entries 2e4). After a simple ex-
tractive work-up of the reaction conducted at 0 ꢀC for 30 min (entry
6), the obtained mixture of 8 and excess NPCC was treated with
sodium hydride in DMF. Depending on the conditions used, column
chromatography of the crude reaction mixture afforded the ex-
pected oxazolidinone 9 and/or two other products (2 and 3), that
were fully characterized by 1H and 13C NMR spectroscopy as well as
MALDI-MS. In particular, a peak at 715 m/z ([MþNaþ]) in the
MALDI-MS spectrum, together with the downfield shift of the H-2
Table 2
Screening of reaction conditions for urea-linked glucosamine neosaccharide
synthesis
2
Entrya
T
[8]
2b
3b
9b
1
2
3
4
5
6
7c
ꢁ30 ꢀC
220 mM
220 mM
220 mM
220 mM
72 mM
41%
7%
26%
0
ꢀC
51%
62%
21%
97%
17%
30 ꢀC
50 ꢀC
30 ꢀC
30 ꢀC
24 mM
220 mM
55%
91%
0
ꢀC
and H-3 signals (
d
3.99 and 4.94 ppm, respectively) and the pres-
150.4 and
a
Reaction conducted on crude 8 with NaH (5 equiv) in the presence of excess
ence in the 13C NMR spectrum of two signals at
d
NPCC (approx. 4 equiv) unless otherwise stated.
b
Isolated yield.
Reaction conducted on pure 8 without NPCC.
150.0 ppmdwith the first one approximately of double intensity in
comparison with the seconddsuggested the urea-linked dimeric
structure for compound 2. The structure was confirmed by a de-
tailed comparison of NMR data with those arising from molecular
mechanics and dynamics calculations.12
c
Table 3
The effect of the temperature on the formation of urea-linked
dimer 2 was first investigated. Once it was found that a tempera-
ture of 30 ꢀC was the best choice (Table 2, entries 1e4), the effect of
the concentration of 8 was studied (entries 3, 5, 6), revealing that it
is highly determinant for the attainment of 2 in high yields. Similar
results were obtained by searching the optimal reaction conditions
for the synthesis of urea-linked galactosamine dimer 11 from
aminoalcohol 4 via NaH induced rearrangement of uncyclized
carbamate 10 in DMF in the presence of excess NPCC (Scheme 2 and
Table 3).
Screening of reaction conditions for urea-linked galactosamine neosaccharide 11
synthesis
Entrya
T
0
[10]
11b
12b
13b
1
2
3
4
ꢀC
220 mM
220 mM
220 mM
220 mM
650 mM
72 mM
9%
30%
43%
42%
78%
33%
42%
43%
27%
27%
13%
46%
14%
30 ꢀC
50 ꢀC
70 ꢀC
30 ꢀC
30 ꢀC
5
6
7c
8c
0
ꢀC
30 ꢀC
650 mM
650 mM
65%
68%
The high dependence of the dimerization process on the con-
centration parameter as well as on the presence of excess NPCC in
the reaction mixture could be explained by the proposed mecha-
nism for the formation of urea-linked neodisaccharide (Scheme 3).
a
Reaction conducted on crude 10 with NaH (5 equiv) in the presence of excess
NPCC (approx. 4 equiv) unless otherwise stated.
b
Isolated yield.
Reaction conducted on pure 10 without NPCC.
c

1288
E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
Having optimized the dimerization conditions for glucosamine
O
Ph
O
O
and galactosamine building blocks 1 and 4, the study was then ex-
panded to other sugar aminoalcohols. Allosamine 5 and mannos-
amine 6 were treated with NaHCO3 and NPCC in CH3CNewater at
0 ꢀC for a short time to give crude carbamates 18 and 19, respectively.
Surprisingly, their treatment with NaH in DMF in the presence of
excess NPCC under the temperature and concentration conditions
already optimized for glucosamine and galactosamine species, did
not furnished any neodisaccharide product. Only oxazolidinones 20
and 21 were obtained21 (Scheme 4), thus suggesting that a trans
configuration of the vicinal aminoalcohol moiety is essential for
dimerization. This is probably due to a stereoelectronic effect, that
decreases the CeN partial double bond character in the strained
trans-configured oxazolidinone ring, and in turn increases the nu-
cleophilic strength of the nitrogen atom. On the contrary, in the cis-
configured oxazolidinones 20 and 21 the higher CeN partial double
bond character, due to a more favourable stereoelectronic feature,
decreases the nucleophilic strength of the nitrogen atom, that is not
able to attack the isocyanate or NPCC species, thus affording neither
urea-linked dimer nor N-aryloxycarbonyl-oxazolidinone. Di-
merizationwas then tested on disaccharide 7 possessing a 2,3-GlcN-
aminoalcohol moiety. Its trans configuration allowed the di-
merization reaction furnishing neotetrasaccharide 23 in 35% unop-
timized yield together with a minor amount of disaccharide 24.
Glucosamine and galactosamine dimers 2 and 11 were very
versatile scaffolds, that could be suitably manipulated to enlarge
the chemical diversity of these urea-linked neosaccharides. Indeed,
a broad number of modifications on their structure were possible
(Scheme 5). Benzylidene rings were useful for phase-tagging the
neosaccharides. They could be hydrolytically removed to give
water-soluble neosaccharide 25 (73%).12 Benzylidene rings could
also be cleaved under reductive conditions with Et3SiH/TFA in the
HO
HN
O
O
O
8
O2N
pNO2PhOCOCl
O
Ph
O
O
O
Ph
O
O
O
O
HO
HN
O
O
O
N
O
C
O
O
O
14
15
O2N
O2N
pNO2PhOCOCl
O
Ph
O
O
O
Ph
O
O
O
O
O
N
NH
O
C
O
O
O
9
16
O2N
9
pNO2PhOCOCl
O
Ph
O
O
NO2
Ph
O
O
O
Ph
O
N
O
O
O
O
N
O
O
O
O
HN
O
O
O
O
O
O
O
17
O2N
3
O
Ph
O
O
O
ꢁ
presence of 4 A molecular sieves to give symmetrical diol 26 (54%).
N
O
O
The regioselectivity of benzylidene opening was demonstrated by
O
O
a downfield shift (d
5.42 ppm) of H-4 signal in 1H NMR spectrum of
O
N
O
acetylated derivative 27. Diol 26 could be employed as a glycosyl
O
O
acceptor to further access higher neooligosaccharides. For example,
Ph
O
2
26 was coupled with donor 2822 to give stereoselectively
a,a-linked
neotetrasaccharide 29 in good yield (82%), in spite of the low nu-
cleophilicity of the 4-hydroxy group in several GlcN acceptors,23 as
well as the high rate of glycosyl donor leaving group release in
some reported fucosylations.22 It is worth noting that the obtained
fucosylated neosaccharide could be a useful building block en route
to the synthesis of a urea-linked dimeric Lewis A mimic.
Scheme 3. Proposed mechanism for the formation of products of Table 2.
give also addition on NPCC, thus affording 3, that could not convert
into dimer 2, as demonstrated by mixing pure 3 and 9 under di-
merization conditions. No urea-linked neodisaccharide formation
was detected in this case. Furthermore, by treating pure 9 with NaH
in DMF, no dimer species were detected again. It is worth noting
that alternative mechanisms for the formation of 2, relying upon
the adventitious hydrolysis of intermediate isocyanates 15 and/or
16 by moisture, followed by dimerization through addition of the
resulting amine to another isocyanate molecule, cannot be ruled
out. However, when oxazolidinone 9 was mixed with pure com-
pound 14dobtained in turn from 8 by reaction with DMAP and
excess NPCC in DMF at 5 ꢀCdin the presence of NaH in DMF at
30 ꢀC, neodisaccharide 2 was obtained exclusively (95% isolated
yield) and neither residual oxazolidinone 9 nor 3 could be found.
This strongly suggested that, even in the presence of adventitious
partial hydrolysis of isocyanate species, the proposed mechanism is
active in the formation of neodisaccharide 2.
In accordance with the proposed mechanism, concentration is
a key parameter for glucosamine and galactosamine neodisaccharides
(2 and 11, respectively) versus monomer species (3, 9 and 12, 13, re-
spectively) formation. Indeed, the intramolecular oxazolidinone clo-
sure reaction affording the monomer species was favoured in dilute
solutions, whereas higher concentrations allowed the prevalent for-
mation of dimer species (see Tables 2 and 3).
Desymmetrization of
2 was possible by mild hydrolysis
(14:6:1:1 v/v/v/v CHCl3/1,4-dioxane/H2O/Et3N at rt)12 of only one
oxazolidinone ring, preserving the urea linkage. The obtained al-
cohol 30 (81%) was employed as a glycosyl acceptor to again access
higher neooligosaccharides, such as neotrisaccharide 31. Alterna-
tively, 30 could be treated with DBU in DMF to give carbamate-
linked macrocycle 32. By conducting the hydrolysis of the
oxazolidinone-urea-oxazolidinone system of 2 with an increased
amount of Et3N (6:2:1 v/v/v 1,4-dioxane/H2O/Et3N) at higher
temperatures (80 ꢀC), both oxazolidinone rings of 2 could be
cleaved, but the ureido linkage still remained intact (signal at
d
159.1 ppm in 13C NMR spectrum), thus affording symmetrical diol
33 in 76% yield.
Similarly, galactosamine neodisaccharide diol 34 was obtained in
64% yield from 11 (Scheme 6). The chemical diversity of this series of
urea-linked neosaccharides was further increased by the de-
rivatization of glucosamine and galactosamine diols 33 and 34 with
ether-linked appendages at position 3. Treatment of 33 and 34 with
1-bromoundecane in the presence of NaH and NaI in DMF afforded
neodisaccharides 35 and 36, respectively (56e66%), bearing two
long-chain hydrocarbon moieties. Analogously, a methyl or a benzyl
group could be installed (compounds 37 and 38).

E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
1289
O
Ph
O
O
O
Ph
O
a
b
O
5
NH
O
HO
O
O
NH
O
O
O
18
20
O2N
NO2
O
O
O
NH
O
Ph
O
a
HN
O
O
Ph
b
O
6
O
O
HO
OMe
21
19
OMe
OBn
O
PMBO
BnO
OBn
N3
OBn
O
O
O
PMBO
BnO
O
N
OBn
O
N3
O
23
a
O
b
O
O
O
7
O
HO
N
NH
O
O
O
+
O
N3
O
O
O
BnO
OBn
OBn
OPMB
O2N
O
PMBO
BnO
22
BnO
OBn
N3
O
O
O
24
NH
O
O
Scheme 4. Reagents and conditions: (a) NPCC, NaHCO3, 3:2 v/v CH3CN/H2O, 0 ꢀC, 30 min; (b) NaH, NPCC, DMF, 30 ꢀC, 45 min, 26% for 20 from 5, 50% for 21 from 6, 35% for 23 from 7,
13% for 24 from 7.
BnO
O
BnO
RO
HO
HO
O
O
O
O
O
O
OBn
N
O
O
N
OBn
BnO
N
O
O
d
O
O
O
O
b
O
O
O
O
O
OBn
BnO
O
O
O
BnO
N
O
c
O
N
N
O
O
O
OR
O
OH
OH
OBn
O
O
OBn
a
29
25
26: R=H
27: R=Ac
2
e
g
OC(NPh)CF3
OBn
O
OBn
28
O
O
O
Ph
Ph
O
O
BnO
Ph
O
Ph
O
O
HO
RO
O
O
NH
O
HN
O
O
f
O
NH
O
O
O
O
O
HN
O
O
N
O
HN
O
O
OR
O
O
O
O
Ph
O
O
Ph
32
O
O
30
33: R=H
35: R=CH2(CH2)9CH3
d
h
O
O
Ph
O
O
HN
O
O
OBn
O
O
O
N
OBn
BnO
O
O
O
Ph
O
31
12
Scheme 5. Reagents and conditions: (a) CSA, 4:1 v/v 1,4-dioxane/H2O, 60 ꢀC, 4 h, 73%; (b) Et3SiH, TFA, AW-300 4 A MS, CH2Cl2, 0 ꢀC, overnight, 54%; (c) Ac2O, py, rt, overnight, 97%;
(d) 28, TMSOTf, 1:1 v/v CH2Cl2/THF, ꢁ30 ꢀC, 90 min, 82% for 29, 76% for 31; (e) 14:6:1:1 v/v/v/v CHCl3/1,4-dioxane/H2O/Et3N, rt, 3 days, 81%;12 (f) DBU, DMF, 50 ꢀC, overnight, 43%;12
(g) 6:2:1 v/v/v 1,4-dioxane/H2O/Et3N, 80 ꢀC, overnight, 76%; (h) 1-bromoundecane, NaH, NaI, DMF, 0 ꢀC, overnight, 66%.
ꢁ

1290
E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
Ph
O
O
O
RO
a
HN
O
11
O
O
HN
OR
O
O
O
Ph
34: R=H
b
c
d
36: R=CH2(CH2)9CH3
37: R=Bn
38: R=CH3
Scheme 6. Reagents and conditions: (a) 6:2:1 v/v/v 1,4-dioxane/H2O/Et3N, 80 ꢀC, 2
days, 64%; (b) 1-bromoundecane, NaH, NaI, DMF, 0 ꢀC, overnight, 56%; (c) BnBr, NaH,
DMF, 0 ꢀC, 6 h, 60%; (d) CH3I, NaH, DMF, 0 ꢀC, 7 h, 61%.
2.2. Self-association properties
Compounds 33e38 presented a RNHCONHR urea system that
could form aggregates via geometrically ordered intermolecular
hydrogen bonding interactions. The self-association behaviour of
these ureas was characterized in solution by 1H NMR spectroscopy
in CDCl3. Spectra were measured at different temperatures and the
chemical shifts of the urea NH moieties were plotted against the
temperature (Fig. 2). The upfield shifts showed with increasing
temperature are a signature of hydrogen bonding.
Fig. 3. (a)1 H NMR chemical shift of urea NeH protons in CDCl3 at 298 K plotted
against concentration of 33e38; (b) 1H NMR chemical shift of hydroxyl protons in
CDCl3 at 298 K plotted against concentration of 33 and 34.
bonds with an adjacent urea NH, especially at lower concentra-
tions.26 Consistently, the plot of chemical shift of the hydroxyl
proton against the concentration of 33 and 34 showed again
a horizontal plateau at lower concentrations, whereas a downfield
shift was observed with increasing neodisaccharide concentration
(Fig. 3b).
The self-association behaviour of urea-linked neodisaccharides
was tested for organogelation ability. Indeed, the presence of self-
complementary, geometrically ordered intermolecular in-
teractions enforcing the self-assembly is one of the general prin-
ciples guiding gelator design. Furthermore, the not too close
association between the urea functions could facilitate the disper-
sion of the neosaccharide assemblies in the solvent, thus enabling
the organogelation process.27 Moreover, some sugar derivatives
possessing a 4,6-O-benzylidene protecting group exhibited good
properties as low molecular weight gelators.28,29 The ability of
neodisaccharides 33e38 to behave as organogelators was screened
in nine solvents by the test tube inversion method. Three different
stimuli were employed to trigger the gelation: thermic, ultrasonic
and combined thermic-ultrasonic. The critical gelation concentra-
tion of neodisaccharides was determined from the minimum
amount of gelator required to induce gel formation. The observed
organogelation abilities are summarized in Table 4.
Neodisaccharides 33e36 were able to form gels, whereas com-
pounds 37 and 38 gave clear solutions or precipitates but no gel was
observed. The ability of 33e36 to form organogels parallels their
urea groups driven self-association behaviour observed in 1H NMR
spectra at different concentrations. Analogously, the inability of
compounds 37 and 38 to act as organogelators finds a comparison
with the absence of self-association showed in their 1H NMR
spectra at different concentrations. In the case of neodisaccharides
35 and 36, van der Waals interactions between n-undecyl chains of
neighbouring molecules could consolidate the self-aggregation
process. Indeed, among screened compounds, galactosamine neo-
disaccharide 36 was able to induce gelation of the broadest variety
of organic solvents, from the nonpolar toluene to the polar
Fig. 2. 1H NMR chemical shift of urea NeH protons of 33e38 in CDCl3 ([C]¼10 mM)
plotted against temperature.
More details on the self-association behaviour of 33e38 were
obtained by measuring the chemical shifts of the urea NH moieties
at different concentrations (Fig. 3a). With the exception of benzyl-
and methyl-appended compounds 37 and 38 exhibiting a concen-
tration-insensitive NH chemical shift, a downfield shift with in-
creasing neodisaccharide concentration was observed. This implies
that intermolecular hydrogen bonds were formed between urea
functions of neighbouring neodisaccharides and they became
stronger as the concentration increased. This effect was particularly
marked for galactosamine neodisaccharide 34, that covered
a chemical shift range of approx. 0.35 ppm, whereas the range for
compounds 33, 35 and 36 not exceeded 0.1 ppm.24 At lower con-
centrations the chemical shifts reached a horizontal plateau, in-
dicating that neodisaccharides were unassociated at such
concentrations. No plateau was observed at the higher concentra-
tions. This suggests that self-association did not reach equilibrium
even in saturated solutions, that is a typical behaviour of ureas
aggregated with a low association constant.25 This could be due to
the aliphatic nature of our ureas, and, in the case of neo-
disaccharides 33 and 34, also to the presence of two hydroxyls, that
could form intramolecular five- and seven-membered hydrogen

E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
1291
Table 4
to understand, which are the relationships between urea-linked
neodisaccharide structure and environmental factors that allow
the organogelation process. Further studies are therefore planned
with this in mind. The results will be reported in due time.
Organogelation abilities of neodisaccharides 33e38
Solventa
33b
Gc,d,e (5)
34b
35b
36b
37b
38b
Acetone
Ethyl acetate
CH2Cl2
CHCl3
THF
CH3CN
Toluene
CH3OH
S
P
S
S
S
S
P
P
P
P
Gc,e (2.5)
Gce (1)
S
P
P
P
S
P
P
P
P
P
S
P
S
S
P
S
P
S
P
P
Ge (5)
4. Experimental section
4.1. General
Gc,e (5)
Gc,e (5)
S
S
P
P
P
P
P
Gd (2.5)
P
P
P
P
Gc,e (3)
Gc,e (5)
Gc,e (2.5)
Gc,e (4)
Gc,d,e (4)
Gc,e (4)
1H and 13C NMR spectra were recorded on Varian XL-200 (1H
NMR: 200 MHz, 13C NMR: 50 MHz), Bruker DRX-400 (1H NMR:
400 MHz, 13C NMR: 100 MHz) and Varian INOVA 500 (1H NMR:
500 MHz, 13C NMR: 125 MHz) instruments in CDCl3 (internal
(CH3)2CHOH
a
ꢁ
The solvent was dried before use on 4 A molecular sieves.
P¼precipitate at 5% wt/vol concentration; S¼soluble at 5% wt/vol concentration;
b
G¼gelation (minimum gelator % wt/vol concentrations are indicated in parenthesis).
standard, for 1H: CHCl3 at 7.26; for 13C: CDCl3 at
d d 77.0). J values are
c
Gel formed upon slow cooling to rt after a thermic stimulus (60 ꢀC, 60 s).
Gel formed upon standing at rt after an ultrasonic stimulus (37 kHz, 60 s).
Gel formed upon slow cooling to rt after a combined thermic-ultrasonic stim-
d
given in Hertz. MALDI-MS spectra were recorded on an Applied
Biosystem Voyager DE-PRO MALDI-TOF mass spectrometer: com-
pounds were dissolved in CH3CN at a concentration of 0.1 mg/mL
e
ulus (60 ꢀC, 37 kHz, 60 s).
and 1 mL of these solutions were mixed with 1 mL of a 20 mg/mL
solution of 2,5-dihydroxybenzoic acid in 7:3 CH3CN/H2O. Optical
rotations were measured on a JASCO P-1010 polarimeter. Infrared
spectra were measured on a Thermo Nicolet 5700 FT-IR spec-
trometer. Melting points were measured on a Gallenkamp melting
point apparatus. Elemental analyses were performed on a Carlo
Erba 1108 instrument. Centrifugations were performed with an
Eppendorf 5804R centrifuge. Thermic, ultrasonic and combined
thermic-ultrasonic stimuli triggering the organogelation processes
were provided with an Elma Elmasonic S 30 H instrument. Ana-
lytical thin layer chromatographies (TLCs) were performed on al-
uminium plates precoated with Merck Silica Gel 60 F254 as the
adsorbent. The plates were developed with 10% H2SO4 ethanolic
solution and then heating to 130 ꢀC. Column chromatographies
were performed on Kieselgel 60 (63e200 mesh).
methanol and acetonitrile. This result ties in with the already re-
ported higher ability of methyl 4,6-O-benzylidene
a- and b-gal-
actopyranosides to act as gelators when compared to their gluco-
counterparts.28 Interestingly, glucosamine neodisaccharide 35
showed organogelation abilities somehow complementary to its
galactosamine counterpart 36. Indeed, among the screened sol-
vents, compound 35 revealed gelation properties exclusively in
chloroform and THF, that were two of the three solvents not gelified
by 36. It is also worth noting that the stimulus triggering the gel-
ification process varied in dependence of the neodisaccharide-
solvent couple under examination. Most gels were formed upon
slow cooling after a conventional thermic stimulus at 60 ꢀC,
whereas the gelification process of 33 in CH2Cl2 and of 35 in THF
required exclusively a combined thermic-ultrasonic stimulus con-
sisting of an ultrasound irradiation at 60 ꢀC. By submitting these
two gelator-solvent systems to a thermic or ultrasound stimulus
separately, precipitation was observed and no gel was obtained. A
similar behaviour was recently reported for some urea-
functionalized quinacridone derivatives, that formed organogels
exclusively after a thermic stimulus quickly followed by ultrasonic
irradiation, inducing the formation of initial aggregates that spon-
taneously propagated to well-ordered clusters.30
4.2. General procedure for aminoalcohol dimerization
Aminoalcohol (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 chloroformate
(1.83 g, 6.80 mmol) in CH3CN (4.0 mL) were added. After 30 min
stirring at 0 ꢀC, the mixture was diluted with ethyl acetate (300 mL)
and washed with 1 M NaHCO3. The organic layer was collected,
dried over anhydrous Na2SO4 and concentrated to give a white
gummy solid, that was dissolved in DMF (see Tables 2 and 3) and
heated/cooled to the temperature indicated in Tables 2 and 3. NaH
(60% dispersion in oil) (261 mg, 6.53 mmol) was then added por-
tionwise to avoid sudden overheating. The yellow mixture was
stirred for 45 min at the indicated temperature, then cooled to 0 ꢀC
and treated dropwise with water until production of gas ceased.
The mixture was diluted with CH2Cl2 (150 mL) and washed with
water. The organic layer was collected, dried over anhydrous
Na2SO4, filtered and concentrated. The residue was subjected to
flash-chromatography (6:1 to 2:3 v/v hexane/ethyl acetate).
3. Conclusion
The reaction conditions influencing the urea-linked di-
merization of sugar building blocks possessing a vicinal amino-
alcohol moiety have been studied in detail. The dimerization
process was demonstrated to be highly dependent on reaction
temperature as well as on concentration and configuration of the
starting sugar aminoalcohol. The obtained neodisaccharides were
shown to be very versatile scaffolds for affording cyclic and higher
linear neosaccharides. Furthermore, a series of six urea-linked
glucosamine and galactosamine neodisaccharides was synthe-
sized and their self-association properties were studied by mea-
suring NMR spectra at different temperatures and concentrations.
The four compounds showing self-association were able to induce
gelation of several organic solvents at relatively low concentration.
Depending on whether the neosaccharide possessed a gluco- or
galacto-configuration as well as long-chain alkyl appendages or not,
the organogelation abilities changed in terms of both the gelified
solvent and the kind of stimulus triggering the process. This paves
the way for preparing a larger library of neosaccharide derivatives,
that in dependence of small structural variations, could be able to
gelate solvents in a selective way and in response to a well-defined
stimulus. However, more detailed information on the supramo-
lecular assembly of the synthesized derivatives is needed in order
4.3. Characterization data for aminoalcohol dimerization
products
4.3.1. N,N0-Bis(1-O-allyl-4,6-O-benzylidene-2,3-N,O-carbonyl-2-
22
deoxy-
a
-
D
-glucopyranos-2-yl)urea (2). White powder. [
a
]
þ60 (c
D
0.9 in CH2Cl2). nmax (powder) 2917, 1802, 1615, 1575, 1371, 1108,
1027 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
7.50e7.36 (10H, m, HeAr),
5.89e5.81 (2H, m, OCH2CH]CH2), 5.61 (2H, s, CHPh), 5.53 (2H, d,
4
J1,2 2.8, 1-H), 5.31 (2H, ddd, Jvic 17.3, JH,H 3.1, Jgem 1.3, trans
4
OCH2CH]CHH), 5.22 (2H, ddd, Jvic 10.4, JH,H 2.4, Jgem 1.3, cis
OCH2CH]CHH), 4.94 (2H, dd, J3,2 11.4, J3,4 10.0, 3-H), 4.31e4.25 (4H,
m, 6a-H, OCHHCH]CH2), 4.10e4.04 (4H, m, 4-H, OCHHCH]CH2),
3.99 (2H, dd, J2,3 11.4, J2,1 2.8, 2-H), 3.96e3.88 (4H, m, 5-H, 6b-H). 13
C

1292
E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
NMR (100 MHz, CDCl3):
d
150.4 (OCON), 150.0 (NCON), 136.4 (Cipso),
Jgem 1.5, trans OCH2CH]CHH), 5.22 (1H, dd, Jvic 10.4, Jgem 1.5, cis
OCH2CH]CHH), 4.88 (1H, dd, J3,2 12.1, J3,4 2.5, 3-H), 4.70 (1H, dd, J2,3
12.1, J2,1 2.8, 2-H), 4.68 (1H, d, J4,3 2.5, 4-H), 4.37 (1H, dd, Jgem 12.7,
J6a,5 1.1, 6a-H), 4.30 (1H, dd, Jgem 12.9, Jvic 6.5, OCHHCH]CH2), 4.18
(1H, dd, Jgem 12.7, J6b,5 1.7, 6b-H), 4.14 (1H, dd, Jgem 12.9, Jvic 6.5,
OCHHCH]CH2), 3.76 (1H, br s, 5-H). 13C NMR (100 MHz, CDCl3):
132.3 (OCH2CH]CH2), 129.4, 128.4, 126.2 (CeAr), 118.0 (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). MS (MALDI TOF): m/z 715.25
[MþNa]þ. Anal. Calcd for C35H36N2O13: C, 60.09, H 5.24, N, 4.04.
Found C, 60.49, H 5.09, N 3.97.
d
154.4 (Cipso), 150.2, 148.9 (2 NCOO), 145.8 (Cipso), 136.8 (Cipso
4.3.2. Allyl 4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-2-(p-nitro-
benzylidene), 133.1 (OCH2CH]CH2), 129.3, 128.3, 126.1, 125.4, 122.1
(CeAr), 118.5 (OCH2CH]CH2), 100.3 (CHPh), 96.1 (C-1), 73.5, 71.6,
69.8, 69.6, 63.6, 55.4 (C-2, C-3, C-4, C-5, C-6, OCH2CH]CH2). MS
(MALDI TOF): unstable. Anal. Calcd for C24H22N2O10: C, 57.83, H
4.45, N, 5.62. Found C, 57.47, H 4.61, N 5.44.
phenoxycarbonylamino)-a-D-glucopyranoside (3). White powder.
[
a]
22 þ64.7 (c 1.0 in CH2Cl2). nmax (powder) 2896, 1797, 1742, 1521,
D
1344, 1218, 997 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 8.29 (2H, d, J3 ,2
0 0
9.1, 2ꢂ 30-H pNO2eAr), 7.51e7.38 (7H, m, HeAr benzylidene, 2ꢂ 20-
H pNO2eAr), 5.92e5.84 (1H, m, OCH2CH]CH2), 5.64 (1H, s, CHPh),
5.63 (1H, d, J1,2 2.7, 1-H), 5.32 (1H, br d, Jvic 17.2, trans OCH2CH]
CHH), 5.22 (1H, br d, Jvic 10.3, cis OCH2CH]CHH), 4.90 (1H, t,
J3,2¼J3,4 11.0, 3-H), 4.33e4.27 (2H, m, 6a-H, OCHHCH]CH2),
4.14e4.08 (2H, m, 4-H, OCHHCH]CH2), 4.05 (1H, dd, J2,3 11.0, J2,1
2.7, 2-H), 3.95e3.89 (2H, m, 5-H, 6b-H). 13C NMR (100 MHz, CDCl3):
4.3.6. Allyl 2-amino-4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-
a-D-galactopyranoside (13). White powder. nmax (powder) 2910,
22
1772, 1117, 1020, 1006 cmꢁ1. [
(500 MHz, CDCl3):
a]
þ120 (c 0.4 in CH3CN). 1H NMR
D
d
7.52e7.36 (5H, m, HeAr), 5.95e5.87 (1H, m,
OCH2CH]CH2), 5.64 (1H, s, CHPh), 5.33 (1H, br d, Jvic 17.0, trans
OCH2CH]CHH), 5.26 (1H, d, JNH,2 2.0, NH), 5.25 (1H, d, Jvic 10.5, cis
OCH2CH]CHH), 5.05 (1H, br s, H-1), 4.81 (1H, dd, J3,2 12.0, J3,4 2.5,
3-H), 4.61 (1H, br s, 4-H), 4.39 (1H, dd, J2,3 12.0, J2,NH 2.0, 2-H), 4.33
(1H, br d, Jgem 12.5, 6a-H), 4.29 (1H, dd, Jgem 13.5, Jvic 5.5, OCHHCH]
CH2), 4.17e4.11 (2H, m, 6b-H, OCHHCH]CH2), 3.69 (1H, br s, 5-H).
d
154.3, 145.8 (2Cipso), 150.3, 148.9 (2 NCOO), 136.2 (Cipso benzyli-
dene), 132.7 (OCH2CH]CH2), 129.3, 128.4, 126.1, 125.4, 122.2
(CeAr), 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). MS
(MALDI TOF): unstable. Anal. Calcd for C24H22N2O10: C, 57.83, H
4.45, N, 5.62. Found C, 57.70, H 4.40, N 5.56.
13C NMR (125 MHz, CDCl3):
d 158.8 (NCOO), 137.0 (Cipso), 133.1
(OCH2CH]CH2), 129.2, 128.2, 126.2 (CeAr), 118.2 (OCH2CH]CH2),
100.3 (CHPh), 96.1 (C-1), 75.0, 72.1, 70.0, 69.1, 63.7, 53.3 (C-2, C-3, C-
4, C-5, C-6, OCH2CH]CH2). MS (MALDI TOF): m/z 334.07 [MþH]þ.
Anal. Calcd for C17H19NO6: C, 61.26, H 5.75, N, 4.20. Found C, 61.00,
H 5.92, N 4.02.
4.3.3. Allyl 2-amino-4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-
a
-
D
-glucopyranoside (9). White powder. [
a
]
22 þ33 (c 0.3 in CH2Cl2).
D
nmax (powder) 2885, 1842, 1745, 1100, 1030, 968 cmꢁ1
.
1H NMR
(400 MHz, CDCl3):
d 7.51e7.36 (5H, m, HeAr), 5.95e5.87 (1H, m,
OCH2CH]CH2), 5.62 (1H, s, CHPh), 5.35 (1H, ddd, Jvic 17.2, 4JH,H 3.0,
Jgem 1.5, trans OCH2CH]CHH), 5.28 (1H, dd, Jvic 10.4, Jgem 1.5, cis
OCH2CH]CHH), 5.15 (1H, d, J1,2 2.9, 1-H), 5.07 (1H, br s, NH), 4.84
(1H, dd, J3,2 11.3, J3,4 10.2, 3-H), 4.32e4.26 (2H, m, 6a-H, OCHHCH]
CH2), 4.12e4.06 (2H, m, 4-H, OCHHCH]CH2), 3.93e3.87 (2H, m, 5-
H, 6b-H), 3.74 (1H, dd, J2,3 11.3, J2,1 2.9, 2-H). 13C NMR (125 MHz,
4.3.7. Allyl 2-amino-4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-
a-D-allopyranoside (20). White powder. nmax (powder) 2904, 1764,
22
1705, 1355, 1220, 998 cmꢁ1. [
(500 MHz, CDCl3):
a]
þ104 (c 0.8 in CH3CN). 1H NMR
D
d
7.51e7.33 (5H, m, HeAr), 5.93e5.85 (1H, m,
OCH2CH]CH2), 5.59 (1H, s, CHPh), 5.33 (1H, d, Jvic 17.0, trans
OCH2CH]CHH), 5.27e5.20 (2H, m, NH, cis OCH2CH]CHH),
4.94e4.90 (2H, m, 1-H, 3-H), 4.37 (1H, dd, Jgem 10.5, J6a,5 5.5, 6a-H),
4.25e4.19 (2H, m, 5-H, OCHHCH]CH2), 4.00 (1H, dd, Jgem 13.0, Jvic
5.5, OCHHCH]CH2), 3.95 (1H, t, J2,3¼J2,1 5.5, 2-H), 3.82 (1H, dd, Jgem
10.5, J6b,5 3.5, 6b-H), 3.73 (1H, t, J4,5¼J4,3 10.0, 4-H). 13C NMR
CDCl3):
d 159.1 (NCOO), 136.5 (Cipso), 132.8 (OCH2CH]CH2), 129.2,
128.3, 126.2 (CeAr), 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). MS (MALDI TOF): m/z 334.16 [MþH]þ. Anal. Calcd for
C
17H19NO6: C, 61.26, H 5.75, N, 4.20. Found C, 61.06, H 5.58, N 4.11.
(125 MHz, CDCl3):
d 160.1 (OCON), 137.2 (Cipso), 132.9 (OCH2CH]
4.3.4. N,N0-Bis(1-O-allyl-4,6-O-benzylidene-2,3-N,O-carbonyl-2-
CH2), 129.4, 128.3, 126.4, 125.4, 121.8 (CeAr), 117.9 (OCH2CH]CH2),
102.7 (OCHPh), 94.8 (C-1), 75.5, 73.0, 68.9, 68.5, 59.9, 53.6 (C-2, C-3,
C-4, C-5, C-6, OCH2CH]CH2). MS (MALDI TOF): m/z 334.26
[MþH]þ. Anal. Calcd for C17H19NO6: C, 61.26, H 5.75, N, 4.20. Found
C, 60.88, H 5.84, N 4.07.
22
deoxy-
a
-
D
-galactopyranos-2-yl)urea (11). White powder. [
a]
þ45
D
(c 0.5 in CH2Cl2). nmax (powder) 2902, 1810, 1620, 1581, 1385, 1096,
1019 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
7.54e7.37 (10H, m, HeAr
benzylidene), 5.86e5.78 (2H, m, OCH2CH]CH2), 5.64 (2H, s, CHPh),
5.60 (2H, d, J1,2 2.6, 1-H), 5.25 (2H, dd, Jvic 17.1, Jgem 1.3, trans
OCH2CH]CHH), 5.15 (2H, dd, Jvic 10.5, Jgem 1.3, cis OCH2CH]CHH),
4.89 (2H, dd, J3,2 12.2, J3,4 2.3, 3-H), 4.64e4.58 (4H, m, 2-H, 4-H),
4.35 (2H, br d, Jgem 12.6, 6a-H), 4.22 (2H, dd, Jgem 13.0, Jvic 5.1,
OCHHCH]CH2), 4.15 (2H, br d, Jgem 12.6, 6b-H), 4.08 (2H, dd, Jgem
13.0, Jvic 5.1, OCHHCH]CH2), 3.70 (2H, br s, 5-H). 13C NMR
4.3.8. Methyl 2-amino-4,6-O-benzylidene-2,3-N,O-carbonyl-2-
deoxy-
2905, 1755, 1716, 1387, 1240, 1014 cmꢁ1. [
1H NMR (400 MHz, CDCl3):
a-D-mannopyranoside (21). White powder. nmax (powder)
a]
22 ꢁ45 (c 0.4 in CH3CN).
D
d
7.50e7.36 (5H, m, HeAr), 6.07 (1H, br
s, NH), 5.59 (1H, s, CHPh), 4.78 (1H, s,1-H), 4.76 (1H, t, J3,4¼J3,2 7.7, 3-
H), 4.36e4.31 (1H, m, 6a-H), 4.12 (1H, d, J2,3 7.7, 2-H), 3.92 (1H, t,
J4,5¼J4,3 7.7, 4-H), 3.83e3.77 (2H, m, 5-H, 6b-H), 3.38 (3H, s, OCH3).
(100 MHz, CDCl3): d 150.6 (OCON), 149.1 (NCON), 137.0 (Cipso), 133.1
(OCH2CH]CH2), 129.3, 128.3, 126.2 (CeAr), 117.9 (OCH2CH]CH2),
100.4 (CHPh), 95.2 (C-1), 73.4, 71.7, 69.9, 69.4, 63.4, 55.5 (C-2, C-3,
C-4, C-5, C-6, OCH2CH]CH2). MS (MALDI TOF): m/z 715.08
[MþNa]þ. Anal. Calcd for C35H36N2O13: C, 60.09, H 5.24, N, 4.04.
Found C, 59.79, H 5.42, N 3.92.
13C NMR (125 MHz, CDCl3):
d 159.0 (OCON), 136.8 (Cipso), 129.2,
128.3, 126.1 (CeAr), 101.9 (OCHPh), 98.0 (C-1), 78.7, 75.0, 68.8, 59.5,
56.4, 55.2 (C-2, C-3, C-4, C-5, C-6, OCH3). MS (MALDI TOF): m/z
308.19 [MþH]þ. Anal. Calcd for C15H17NO6: C, 58.63, H 5.58, N, 4.56.
Found C, 58.87, H 5.72, N 4.41.
4.3.5. Allyl 4,6-O-benzylidene-2,3-N,O-carbonyl-2-deoxy-2-(p-nitro-
phenoxycarbonylamino)-
a
-D-galactopyranoside (12). White pow-
4.3.9. N,N0-Bis[(2-azido-3,6-di-O-benzyl-2-deoxy-4-O-p-methox-
der. nmax (powder) 2919, 1839, 1735, 1522, 1344, 1220, 1113,
ybenzyl-
a-D-glucopyranosyl)-(1/4)-1-O-allyl-6-O-benzyl-2,3-N,O-
1025 cmꢁ1. [
a
]
22 þ55.3 (c 2.0 in CH2Cl2). 1H NMR (400 MHz, CDCl3):
carbonyl-2-deoxy-a-D-glucopyranos-2-yl]urea (23). Colourless oil.
D
0
0
d
8.30 (2H, d, J3 ,2 7.0, 2ꢂ 30-H pNO2eAr), 7.54e7.37 (7H, m, ben-
[
a
]
22 þ35 (c 0.4 in CH2Cl2). 1H NMR (500 MHz, CDCl3):
d 7.40e7.26
D
zylidene, 2ꢂ 20-H pNO2eAr), 5.91e5.84 (1H, m, OCH2CH]CH2),
(30H, m, HeAr), 7.05 (4H, d, Jvic 8.0, HeAr PMB), 6.81 (4H, d, Jvic 8.0,
HeAr PMB), 5.86e5.78 (2H, m, OCH2CH]CH2), 5.49 (2H, d, J1,2 2.5,
5.72 (1H, d, J1,2 2.8, H-1), 5.67 (1H, s, CHPh), 5.30 (1H, dd, Jvic 17.2,

E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
1293
1A-H), 5.41 (2H, d, J1,2 3.5, 1B-H), 5.27 (2H, d, Jgem 17.0, trans
OCH2CH]CHH), 5.19 (2H, d, Jgem 10.5, cis OCH2CH]CHH), 4.91 (2H,
t, J3,2¼J3,4 9.5, 3A-H), 4.86 (4H, s, OCH2Ph PMB), 4.69 (2H, d, Jgem 10.0,
OCHHPh), 4.56 (2H, d, Jgem 12.0, OCHHPh), 4.52 (2H, d, Jgem 11.5,
OCHHPh), 4.50 (2H, d, Jgem 11.5, OCHHPh), 4.41 (2H, d, Jgem 10.0,
OCHHPh), 4.37 (2H, t, J4,3¼J4,5 9.5, 4A-H), 4.32 (2H, d, Jgem 12.0,
OCHHPh), 4.21 (2H, dd, Jgem 13.0, Jvic 5.5, OCHHCH]CH2), 4.03 (2H,
dd, Jgem 13.0, Jvic 5.5, OCHHCH]CH2), 3.92 (2H, dd, J2,3 9.5, J2,1 2.5,
2A-H), 3.88e3.67 (18H, m, 3B-H, 4B-H, 5A-H, 5B-H, 6aA-H, 6bA-H,
OCH3), 3.51 (2H, d, Jgem 10.0, 6aB-H), 3.45 (2H, dd, J2,3 10.0, J2,1 3.5,
2B-H), 3.37 (2H, d, Jgem 10.0, 6bB-H). 13C NMR (125 MHz, CDCl3):
9.2, 2ꢂ 30-H pNO2eAr), 7.50e7.25 (9H, m, benzylidene, 4ꢂ 20-H
pNO2eAr), 5.97e5.90 (1H, m, OCH2CH]CH2), 5.71 (1H, d, JH,NH 9.9,
NH), 5.59 (1H, s, CHPh), 5.37 (1H, dd, Jvic 16.1, Jgem 1.4, trans
OCH2CH]CHH), 5.30 (1H, dd, Jvic 10.3, Jgem 1.4, cis OCH2CH]CHH),
5.28 (1H, t, J3,4¼J3,2 10.0, 3-H), 5.06 (1H, d, J1,2 3.8, 1-H), 4.33e4.27
(2H, m, 6a-H, OCHHCH]CH2), 4.14e4.08 (2H, m, 2-H, OCHHCH]
CH2), 4.01 (1H, dd, J6b,5 10.0, Jgem 4.8, 6b-H), 3.89 (1H, q,
J5,4¼J5,6a¼J5,6b 10.0, 5-H), 3.83 (1H, t, J4,5¼J4,3 10.0, 4-H). 13C NMR
(100 MHz, CDCl3):
d 155.3, 155.2 (2Cipso), 152.9, 152.5 (NCOO,
OCOO), 145.6, 144.9 (2Cipso), 136.6 (Cipso benzylidene), 132.7
(OCH2CH]CH2), 129.3, 128.3, 126.1, 125.2, 121.8, 121.6 (CeAr), 118.9
(OCH2CH]CH2),101.8 (CHPh), 96.8 (C-1), 78.5, 76.3, 68.9, 68.6, 62.7,
54.2 (C-2, C-3, C-4, C-5, C-6, OCH2CH]CH2). MS (MALDI TOF):
unstable. Anal. Calcd for C30H27N3O13: C, 56.52, H 4.27, N, 6.59.
Found C, 56.26, H 4.43, N 6.31.
d
159.3 (Cipso PMB) 150.4 (OCON), 149.0 (NCON), 137.9 (3Cipso Bn),
132.9 (OCH2CH]CH2), 130.2 (Cipso PMB), 129.6e127.3 (CeAr), 117.8
(OCH2CH]CH2), 113.7 (CeAr PMB), 96.3, 93.7 (C-1A, C-1B), 80.2,
75.4, 74.7, 74.6, 73.5, 73.4, 71.8, 71.6, 70.9, 70.3, 69.1, 68.1, 67.8, 63.2,
60.2, 55.3 (C-2A, C-2B, C-3A, C-3B, C-4A, C-4B, C-5A, C-5B, C-6A, C-6B,
3OCH2Ph, OCH2Ph PMB, OCH2CH]CH2, OCH3). MS (MALDI TOF):
m/z 1693.36 [MþNa]þ. Anal. Calcd for C91H98N8O23: C, 65.38, H 5.91,
N, 6.70. Found C, 65.06, H 6.05, N 6.83.
4.5. N,N0-Bis(1-O-allyl-6-O-benzyl-2,3-N,O-carbonyl-2-deoxy-
a-
D-glucopyranos-2-yl)urea (26)
Compound 2 (254.2 mg, 367
m
mol) was coevaporated three
4.3.10. Allyl
ybenzyl-
(2-azido-3,6-di-O-benzyl-2-deoxy-4-O-p-methox-
times with anhydrous toluene (3 mL). The residue was dried, then
mixed with freshly activated AW-300 4 A molecular sieves and
ꢁ
a
-
D
-glucopyranosyl)-(1/4)-2-amino-6-O-benzyl-2,3-N,O-
22
carbonyl-2-deoxy-
a-D
-glucopyranoside (24). Yellowish oil.
[a
]
suspended in CH2Cl2 (10 mL) under Ar atmosphere. The mixture
D
þ40.1 (c 1.5 in CH2Cl2). 1H NMR (500 MHz, CDCl3):
d
7.38e7.26 (15H,
was cooled to 0 ꢀC, treated with Et3SiH (591
mL, 3.67 mmol) and
m, HeAr), 7.04 (2H, d, Jvic 8.5, HeAr PMB), 6.81 (2H, d, Jvic 8.5, HeAr
PMB), 5.93e5.85 (1H, m, OCH2CH]CH2), 5.46 (1H, d, J1,2 3.5, 1B-H),
5.32 (1H, dd, Jgem 17.5, Jvic 1.5, trans OCH2CH]CHH), 5.27e5.21 (2H,
m, NH, cis OCH2CH]CHH), 5.12 (1H, d, J1,2 2.5, 1A-H), 4.86 (2H, s,
OCH2Ph PMB), 4.81 (1H, dd, J3,2 11.5, J3,4 10.0, 3A-H), 4.69 (1H, d, Jgem
10.5, OCHHPh), 4.55 (1H, d, Jgem 11.5, OCHHPh), 4.54 (1H, d, Jgem
10.0, OCHHPh), 4.51 (1H, d, Jgem 10.5, OCHHPh), 4.42 (1H, d, Jgem
10.0, OCHHPh), 4.36e4.31 (2H, m, 4A-H, OCHHPh), 4.26 (1H, dd, Jgem
12.5, Jvic 5.0, OCHHCH]CH2), 4.08 (1H, dd, Jgem 12.5, Jvic 5.0,
OCHHCH]CH2), 3.86e3.64 (10H, m, 2A-H, 3B-H, 4B-H, 5A-H, 5B-H,
6aA-H, 6bA-H, OCH3), 3.53 (1H, d, Jgem 11.0, J6a,5 3.0, 6aB-H), 3.45 (1H,
dd, J2,3 10.0, J2,1 3.5, 2B-H), 3.40 (1H, d, Jgem 11.0, 6bB-H). 13C NMR
then with 3 M TFA in CH2Cl2 (1.43 mL, 4.51 mmol). After stirring
overnight, the mixture was heated to rt, filtered on a Celite pad,
diluted with CH2Cl2 (100 mL) and washed with 1 M NaHCO3. The
organic layer was collected, dried over anhydrous Na2SO4, filtered
and concentrated. The obtained residue was subjected to flash-
chromatography (6:1 to 1:1 v/v n-hexane/ethyl acetate) to give
26 (138.8 mg, 54%) as a yellowish oil. [
a
]
22 þ64 (c 0.4 in CH2Cl2). 1H
D
NMR (400 MHz, CDCl3):
d
7.37e7.30 (10H, m, HeAr), 5.85e5.78 (2H,
m, OCH2CH]CH2), 5.45 (2H, d, J1,2 2.8, 1-H), 5.26 (2H, ddd, Jvic 17.2,
4JH,H 3.1, Jgem 1.5, trans OCH2CH]CHH), 5.16 (2H, ddd, Jvic 10.5, 4JH,H
2.7, Jgem 1.4, cis OCH2CH]CHH), 4.75 (2H, dd, J3,2 11.9, J3,4 9.9, 3-H),
4.64 (2H, d, Jgem 12.0, OCHHPh), 4.55 (2H, d, Jgem 12.0, OCHHPh), 4.19
(2H, dd, Jgem 13.2, Jvic 8.1, OCHHCH]CH2), 4.12 (2H, t, J4,3¼J4,5 9.9, 4-
H), 4.03 (2H, dd, Jgem 13.2, Jvic 8.1, OCHHCH]CH2), 3.89 (2H, dd, J2,3
11.9, J2,1 2.8, 2-H), 3.81 (2H, dd, Jgem 9.7, J6a,5 6.0, 6a-H), 3.77e3.73
(2H, m, 5-H), 3.70 (2H, dd, Jgem 9.7, J6b,5 4.2, 6b-H). 13C NMR
(125 MHz, CDCl3):
d 159.3, 159.0 (Cipso PMB, OCON), 137.9 (3Cipso
Bn), 133.0 (OCH2CH]CH2), 130.2 (Cipso PMB), 129.6e127.3 (CeAr),
118.2 (OCH2CH]CH2), 113.8 (CeAr PMB), 96.2, 94.6 (C-1A, C-1B),
80.3, 79.2, 77.6, 75.4, 74.7, 73.5, 73.4, 72.0, 71.7, 70.9, 69.3, 68.3, 67.9,
63.3, 58.4, 55.3 (C-2A, C-2B, C-3A, C-3B, C-4A, C-4B, C-5A, C-5B, C-6A,
C-6B, 3OCH2Ph, OCH2Ph PMB, OCH2CH]CH2, OCH3). MS (MALDI
TOF): m/z 823.28 [MþH]þ. Anal. Calcd for C45H50N4O11: C, 65.68, H
6.12, N, 6.81. Found C, 65.39, H 7.00, N 6.69.
(50 MHz, CDCl3):
d 151.2 (OCON), 148.8 (NCON), 137.7 (Cipso), 133.1
(OCH2CH]CH2), 128.5, 127.9, 127.7 (CeAr), 117.6 (OCH2CH]CH2),
93.8 (C-1), 77.4, 73.6, 72.9, 69.0, 68.7, 60.5, 60.0 (C-2, C-3, C-4, C-5,
C-6, OCH2Ph, OCH2CH]CH2). MS (MALDI TOF): m/z 719.14
[MþNa]þ. Anal. Calcd for C35H40N2O13: C, 60.34, H 5.81, N, 4.02.
Found C, 60.00, H 5.94, N 3.96.
4.4. Allyl 4,6-O-benzylidene-2-deoxy-2-(p-nitro-phenox-
ycarbonylamino)-3-O-(p-nitro-phenoxycarbonyl)-a-D-gluco-
pyranoside (14)
4.6. N,N0-Bis(4-O-acetyl-1-O-allyl-6-O-benzyl-2,3-N,O-car-
bonyl-2-deoxy-a-D-glucopyranos-2-yl)urea (27)
Compound 1 (197 mg, 643
mmol) was suspended in 2:1 v/v
water/CH3CN (3.0 mL), cooled to 0 ꢀC and treated with NaHCO3
(268 mg, 3.19 mmol) and then with a solution of 4-nitrophenyl
chloroformate (631 mg, 3.13 mmol) in CH3CN (1.4 mL). After
30 min stirring at 0 ꢀC, the mixture was diluted with ethyl acetate
(100 mL) and washed with 1 M NaHCO3. The organic layer was
collected, dried over anhydrous Na2SO4 and concentrated. The
obtained gummy solid was dissolved in DMF (3.3 mL), cooled to
Compound 26 (9.8 mg, 14.1
mmol) was treated with pyridine
(250 L) and Ac2O (250 L). The solution was stirred overnight at rt,
m
m
then diluted with CH2Cl2 (20 mL) and washed with 1 M HCl and
then with water. The organic layer was collected, dried over an-
hydrous Na2SO4, filtered and concentrated to give 27 (10.7 mg, 97%)
22
as a yellowish oil. [
a
]
þ85 (c 0.4 in CH2Cl2). 1H NMR (400 MHz,
D
CDCl3):
d
7.34e7.29 (10H, m, HeAr), 5.85e5.78 (2H, m, OCH2CH]
0
ꢀC and then treated with DMAP (28.5 mg, 233
mmol). After 1 h
CH2), 5.50 (2H, d, J1,2 2.8, 1-H), 5.42 (2H, t, J4,3¼J4,5 9.9, 4-H), 5.26
(2H, ddd, Jvic 17.2, 4JH,H 3.0, Jgem 1.5, trans OCH2CH]CHH), 5.19 (2H,
dd, Jvic 10.5, Jgem 1.3, cis OCH2CH]CHH), 4.81 (2H, dd, J3,2 11.7, J3,4
10.3, 3-H), 4.61 (2H, d, Jgem 12.0, OCHHPh), 4.48 (2H, d, Jgem 12.0,
OCHHPh), 4.21 (2H, dd, Jgem 13.1, Jvic 5.9, OCHHCH]CH2), 4.05 (2H,
dd, Jgem 13.1, Jvic 5.9, OCHHCH]CH2), 4.02 (2H, dd, J2,3 11.7, J2,1 2.8, 2-
H), 3.87 (2H, dt, J5,4 9.4, J5,6a¼J5,6b 3.5, 5-H), 3.60e3.55 (4H, m, 6a-H,
stirring at 0 ꢀC, CH2Cl2 (50 mL) was added. The solution was washed
with 0.1 M HCl and then with water. The organic layer was col-
lected, dried over anhydrous Na2SO4, filtered and concentrated to
give a residue, that was subjected to flash-chromatography (8:1 to
5:2 v/v n-hexane/ethyl acetate) to give 14 (102 mg, 25%) as amor-
22
phous white crystals. Mp 126e128 ꢀC. [
a
]
ꢁ15 (c 0.9 in CH2Cl2).
D
nmax (powder) 1720,1532,1519,1490,1211 cmꢁ1. 1H NMR (400 MHz,
6b-H), 1.98 (6H, s, COCH3). 13C NMR (125 MHz, CDCl3):
d
169.1
0
0
0
0
CDCl3):
d
8.21 (2H, d, J3 ,2 9.1, 2ꢂ 30-H pNO2eAr), 8.18 (2H, d, J3 ,2
(COCH3), 150.3 (OCON), 148.6 (NCON), 137.5 (Cipso), 132.8

1294
E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
(OCH2CH]CH2), 128.4, 128.0, 127.9 (CeAr), 118.0 (OCH2CH]CH2),
93.7 (C-1), 75.1, 73.6, 71.2, 69.3, 68.1, 67.4, 60.0 (C-2, C-3, C-4, C-5, C-
6, OCH2Ph, OCH2CH]CH2), 23.7 (COCH3). MS (MALDI TOF): m/z
803.20 [MþNa]þ. Anal. Calcd for C39H44N2O11: C, 59.99, H 5.68, N,
3.59. Found C, 59.70, H 5.90, N 3.46.
4.9. N,N0-Bis(1-O-allyl-4,6-O-benzylidene-2-deoxy-
a-D-gal-
actopyranos-2-yl)urea (34)
A solution of 11 (74.8 mg, 0.108 mmol) in 3:1 v/v 1,4-dioxane/
water (3.6 mL) was treated with triethylamine (450 mL). After two
days stirring at 80 ꢀC, SiO2 (600 mg) was added. The mixture was
immediately cooled to rt and concentrated to give a residue, that
was subjected to flash-chromatography (99:1 to 98:2 v/v CHCl3/
4.7. N,N0-Bis[(4-O-(2,3,4-tri-O-benzyl-
a-L-fucopyranosyl)-1-O-
allyl-6-O-benzyl-2,3-N,O-carbonyl-2-deoxy-a-D-glucopyranos-
2-yl]urea (29)
MeOH) to afford 34 (44.2 mg, 64%) as a white powder. [
a
]
22 þ126.1
D
(c 2.0 in acetone). nmax (powder) 2905, 1653, 1601, 1250, 1014 cmꢁ1
.
1H NMR (500 MHz, CDCl3):
d 7.52e7.35 (10H, m, HeAr), 5.90e5.83
A mixture of 27 (20.5 mg, 29.4 mmol) and 28 (74.5 mg, 123 mmol)
(2H, m, OCH2CH]CH2), 5.56 (2H, s, CHPh), 5.27 (2H, br d, Jvic 17.0,
trans OCH2CH]CHH), 5.19 (2H, br d, Jvic 10.0, cis OCH2CH]CHH),
5.01 (2H, d, J1,2 3.5, 1-H), 4.92 (2H, br s, NH), 4.26 (2H, d, Jgem 11.0,
6a-H), 4.23e4.20 (4H, m, 2-H, 4-H), 4.18 (2H, dd, Jgem 13.0, Jvic 5.0,
OCHHCH]CH2), 4.07 (2H, d, Jgem 11.0, 6a-H), 4.00 (2H, dd, Jgem 13.0,
Jvic 5.0, OCHHCH]CH2), 3.88 (2H, td, J3,2¼J3,OH 8.0, J3,4 3.5, 3-H),
3.69 (2H, br s, 5-H), 3.39 (2H, br s, OH). 13C NMR (100 MHz, CDCl3):
was coevaporated three times with anhydrous toluene (2 mL). The
ꢁ
residue was dried, mixed with freshly activated AW-300 4 A mo-
lecular sieves and suspended in 1:1 v/v CH2Cl2/THF (2.0 mL) under
Ar atmosphere. The mixture was stirred at ꢁ30 ꢀC for 15 min. A
10.4 mg/mL solution of TMSOTf in CH2Cl2 (130 mL, 6.1 mmol) was
then added. The mixture was stirred for 90 min at ꢁ30 ꢀC. A drop of
Et3N was then added. The mixture was filtered over a Celite pad and
concentrated. The residue was subjected to column chromatogra-
d
159.6 (NCON), 137.8 (Cipso), 133.6 (OCH2CH]CH2), 128.9, 128.0,
126.4 (CeAr), 117.6 (OCH2CH]CH2), 101.1 (CHPh), 98.0 (C-1), 75.6,
69.2, 69.0, 68.5, 63.0, 51.4 (C-2, C-3, C-4, C-5, C-6, OCH2CH]CH2).
phy (8:1 to 3:1 v/v n-hexane/ethyl acetate) to give 29 (36.8 mg,
22
82%) as a white powder. [
(400 MHz, CDCl3):
a
]
D
þ0.2 (c 1.0 in CH2Cl2). 1H NMR
MS (MALDI TOF): m/z 641.13 [MþH]þ. Anal. Calcd for C33H40N2O11
:
d
7.40e7.26 (40H, m, HeAr), 5.83e5.76 (2H, m,
C, 61.86, H 6.29, N, 4.37. Found C, 61.53, H 6.37, N 4.29.
OCH2CH]CH2), 5.46 (2H, d, J1,2 2.6, 1GlcN-H), 5.24 (2H, dd, Jvic 17.2,
Jgem 1.5, trans OCH2CH]CHH), 5.17 (2H, dd, Jvic 10.5, Jgem 1.5, cis
OCH2CH]CHH), 4.99 (2H, d, J1,2 3.7, 1Fuc-H), 4.96 (2H, d, Jgem 11.5,
4.10. N,N0-Bis(1-O-allyl-4,6-O-benzylidene-2-deoxy-3-O-n-un-
decyl-a-D-glucopyranos-2-yl)urea (35)
OCHHPh), 4.96 (2H, d, Jgem 11.7, OCHHPh), 4.79e4.73 (6H, m, 3GlcN
-
H, 2ꢂ OCHHPh), 4.65 (2H, d, Jgem 11.5, OCHHPh), 4.63 (2H, d, Jgem
A solution of 33 (29.9 mg, 46.7
to 0 ꢀC. It was treated with 1-bromoundecane (52
NaH (60% dispersion in oil) (9.5 mg, 236 mol) and finally with NaI
(3.5 mg, 23.0
mol). After overnight stirring at 0 ꢀC, some drops of
m
mol) in DMF (1.0 mL) was cooled
11.6, OCHHPh), 4.47 (2H, d, Jgem 11.9, OCHHPh), 4.36 (2H, d, Jgem 11.9,
m
L, 0.234 mol),
m
OCHHPh), 4.22 (2H, t, J4,5¼J4,3 9.7, 4GlcN-H), 4.19e4.14 (4H, m, 5Fuc
-
m
H, OCHHCH]CH2), 4.07 (2H, dd, J2,3 10.2, J2,1 3.7, 2Fuc-H), 4.02e3.94
(8H, m, 2GlcN-H, 3Fuc-H, 6aGlcN-H, OCHHCH]CH2), 3.84 (2H, d, J5,4
9.7, 5GlcN-H), 3.73 (2H, br s, 4Fuc-H), 3.59 (2H, d, Jgem 10.7, 6bGlcN-H),
m
water were added. The mixture was diluted with CH2Cl2 (25 mL)
and washed with water. The organic layer was collected, dried over
anhydrous Na2SO4, filtered and concentrated. The residue was
subjected to flash-chromatography (99:1 to 98:2 v/v CH2Cl2/
MeOH). The product was further purified by dissolving it into
CH2Cl2 (1.0 mL) and then adding n-hexane dropwise. The obtained
precipitate was collected by centrifugation (4 ꢀC, 6000 rpm,
1.19 (6H, d, J6,5 6.4, 6Fuc-H). 13C NMR (100 MHz, CDCl3):
d 150.9
(OCON), 148.6 (NCON), 138.6, 138.5, 138.3, 137.9 (4Cipso), 133.0
(OCH2CH]CH2), 128.4e127.4 (CeAr), 117.7 (OCH2CH]CH2), 99.3
(C-1Fuc), 93.5 (C-1GlcN), 79.9, 77.6, 76.3, 75.7, 74.9, 74.4, 73.7, 73.3,
72.9, 72.7, 68.9, 67.3, 67.1, 60.3 (C-2Fuc, C-2GlcN, C-3Fuc, C-3GlcN, C-
4
Fuc, C-4GlcN, C-5Fuc, C-5GlcN, C-6GlcN, 4OCH2Ph, OCH2CH]CH2), 16.3
10 min), giving pure 35 (29.4 mg, 66%) as a white powder. [
a
]
22 þ16
D
(C-6Fuc). MS (MALDI TOF): m/z 1551.31 [MþNa]þ. Anal. Calcd for
C89H96N2O21: C, 69.88, H 6.33, N, 1.83. Found C, 69.69, H 6.44, N
1.80.
(c 0.5 in CH2Cl2). nmax (powder) 2914, 2851, 1629, 1588, 1371, 1080,
983 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d 7.49e7.36 (10H, m, HeAr),
5.95e5.87 (2H, m, OCH2CH]CH2), 5.57 (2H, s, CHPh), 5.32 (2H, d,
Jvic 17.0, trans OCH2CH]CHH), 5.22 (2H, d, Jvic 10.0, cis OCH2CH]
CHH), 5.07 (2H, br s, NH), 4.90 (2H, d, J1,2 4.0, 1-H), 4.27 (2H, dd, Jgem
10.0, J6a,5 4.5, 6a-H), 4.19 (2H, dd, Jgem 12.5, Jvic 5.5, OCHHCH]CH2),
3.98 (2H, dd, Jgem 12.5, Jvic 5.5, OCHHCH]CH2), 3.87e3.80 (8H, m, 2-
H, 5-H, 6b-H, OCHH(CH2)9CH3), 3.67e3.59 (6H, m, 3-H, 4-H,
OCHH(CH2)9CH3), 1.62e1.54 (8H, m, 4ꢂ OCH2(CHH)9CH3), 1.26e1.17
(28H, m, 14ꢂ OCH2(CHH)9CH3), 0.88 (6H, t, Jvic 6.0, OCH2(CH2)9CH3).
4.8. N,N0-Bis(1-O-allyl-4,6-O-benzylidene-2-deoxy-
a-D-gluco-
pyranos-2-yl)urea (33)
A solution of 2 (172 mg, 0.250 mmol) in 3:1 v/v 1,4-dioxane/
water (8.0 mL) was treated with triethylamine (1.0 mL). After
overnight stirring at 80 ꢀC, SiO2 (1.25 g) was added. The mixture
was immediately cooled to rt and concentrated. Flash-
13C NMR (125 MHz, CDCl3):
d 158.0 (NCON), 137.4 (Cipso), 133.5
chromatography (99:1 to 96:4 v/v CHCl3/MeOH) afforded 33
(OCH2CH]CH2), 128.9, 128.2, 126.0 (CeAr), 117.9 (OCH2CH]CH2),
101.2 (CHPh), 98.1 (C-1), 82.3, 78.0, 72.8, 69.0, 68.7, 62.9, 54.7 (C-2,
C-3, C-4, C-5, C-6, OCH2CH]CH2, OCH2(CH2)9CH3), 31.9, 30.3,
29.7e29.3, 26.0, 22.7 (OCH2(CH2)9CH3), 14.1 (OCH2(CH2)9CH3). MS
(MALDI TOF): m/z 971.38 [MþNa]þ. Anal. Calcd for C55H84N2O11: C,
69.59, H 8.92, N, 2.95. Found C, 69.37, H 8.86, N 2.90.
22
(122 mg, 76%) as a white powder. [
a
]
þ32 (c 0.5 in CH2Cl2). nmax
D
(powder) 2920, 2849, 1643, 1583, 1055 cmꢁ1
.
1H NMR (400 MHz,
CDCl3): 7.50e7.34 (10H, m, HeAr), 5.95e5.88 (2H, m, OCH2CH]
d
CH2), 5.55 (2H, s, CHPh), 5.32 (2H, br d, Jvic 17.2, trans OCH2CH]
CHH), 5.27e5.21 (4H, m, NH, cis OCH2CH]CHH), 4.88 (2H, d, J1,2 3.0,
1-H), 4.26 (2H, dd, Jgem 9.9, J6a,5 4.5, 6a-H), 4.20 (2H, dd, Jgem 12.8, Jvic
5.2, OCHHCH]CH2), 4.01 (2H, dd, Jgem 12.8, Jvic 5.2, OCHHCH]CH2),
3.95e3.91 (4H, m, 2-H, 3-H), 3.83 (2H, dt, J5,4¼J5,6b 9.9, J5,6a 4.5, 5-H),
3.74 (2H, t, Jgem¼J6b,5 9.9, 6b-H), 3.64 (2H, br s, OH), 3.56 (2H, t,
4.11. N,N0-Bis(1-O-allyl-4,6-O-benzylidene-2-deoxy-3-O-n-un-
decyl-a-D-galactopyranos-2-yl)urea (36)
J4,3¼J4,5 9.9, 4-H). 13C NMR (100 MHz, CDCl3):
d
159.1 (NCON), 137.2
A solution of 34 (43.8 mg, 68.4
cooled to 0 ꢀC. It was then treated with 1-bromoundecane (54.3
258 mol), NaH (60% dispersion in oil) (10.3 mg, 257 mol) and
finally with NaI (5.1 mg, 33.1
mol). After overnight stirring at 0 ꢀC,
m
mol) in DMF (750
mL) was
(Cipso), 133.4 (OCH2CH]CH2), 129.1, 128.2, 126.4 (CeAr), 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). MS (MALDI TOF): m/z
641.39 [MþH]þ. Anal. Calcd for C33H40N2O11: C, 61.86, H 6.29, N,
4.37. Found C, 62.02, H 6.40, N 4.45.
mL,
m
m
m
some drops of water were added. The mixture was diluted with
CH2Cl2 (25 mL), heated to rt and washed with water. The organic

E. Bedini et al. / Tetrahedron 69 (2013) 1285e1296
1295
layer was collected, dried over anhydrous Na2SO4, filtered and
concentrated to give a residue, that was subjected to flash-
H), 4.21 (2H, br s, 2-H), 4.13 (2H, dd, Jgem 13.0, Jvic 5.5, OCHHCH]
CH2), 4.07 (2H, dd, Jgem 12.0, J6b,5 1.0, 6b-H), 3.99 (2H, dd, Jgem 13.0,
Jvic 5.5, OCHHCH]CH2), 3.65 (2H, br s, 5-H), 3.55 (2H, dd, J3,2 10.5,
chromatography (5:1 to 1:2 v/v n-hexane/ethyl acetate) to afford
22
36 (36.1 mg, 56%) as a white powder. [
a
]
þ92 (c 0.9 in CH2Cl2).
J3,4 3.0, 3-H), 3.44 (6H, s, OCH3). 13C NMR (125 MHz, CDCl3):
d 158.6
D
nmax (powder) 2912, 2849, 1643, 1584, 1258, 1013 cmꢁ1
.
1H NMR
(NCON), 137.8 (Cipso), 133.6 (OCH2CH]CH2), 128.8, 128.1, 126.4
(CeAr), 117.7 (OCH2CH]CH2), 101.0 (CHPh), 97.9 (C-1), 72.3, 69.5,
68.9, 62.8, 56.7, 50.2 (C-2, C-3, C-4, C-5, C-6, OCH2CH]CH2, OCH3).
MS (MALDI TOF): m/z 691.09 [MþNa]þ. Anal. Calcd for
(500 MHz, CDCl3): 7.52e7.32 (10H, m, HeAr), 5.85e5.77 (2H, m,
d
OCH2CH]CH2), 5.55 (2H, s, CHPh), 5.21 (2H, d, Jvic 17.0, trans
OCH2CH]CHH), 5.13e5.07 (6H, m, 1-H, NH, cis OCH2CH]CHH),
4.30e4.25 (4H, m, 4-H, 6a-H), 4.14e4.07 (6H, m, 2-H, 6b-H,
OCHHCH]CH2), 3.96 (2H, dd, Jgem 13.0, Jvic 6.5, OCHHCH]CH2),
3.65 (2H, br s, 5-H), 3.62e3.56 (4H, m, 3-H, OCHH(CH2)9CH3), 3.46
(2H, q, Jgem¼Jvic 7.0, OCHH(CH2)9CH3), 1.59e1.53 (6H, m, 3ꢂ
OCH2(CHH)9CH3), 1.28e1.19 (30H, m, 15ꢂ OCH2(CHH)9CH3), 0.88
C35H44N2O11: C, 62.86, H 6.63, N, 4.19. Found C, 62.72, H 6.69, N 4.15.
4.14. General procedure for 1H NMR titration
ꢁ
A measured amount of CDCl3, that was freshly dried over 4 A
molecular sieves, was added to a weighed amount of neosaccharide
(36e41) in a NMR tube. 1H NMR data were collected at 298 K and
500 MHz. A further measured amount of solvent was added and,
after mixing, the 1H NMR spectrum was recorded again. The pro-
cedure was iterated until signal to noise ratio obtained after 32
scans was judged unsatisfactory.
(6H, t, Jvic 6.7, OCH2(CH2)9CH3). 13C NMR (50 MHz, CDCl3):
d 158.8
(NCON), 137.9 (Cipso), 133.7 (OCH2CH]CH2), 128.8, 128.0, 126.3
(CeAr), 117.7 (OCH2CH]CH2), 101.0 (CHPh), 98.0 (C-1), 75.9, 73.1,
69.6, 69.1, 68.8, 62.9, 50.3 (C-2, C-3, C-4, C-5, C-6, OCH2CH]CH2,
OCH2(CH2)9CH3), 31.9, 29.9e29.3, 26.0, 22.7 (OCH2(CH2)9CH3), 14.1
(OCH2(CH2)9CH3). MS (MALDI TOF): m/z 971.16 [MþNa]þ. Anal.
Calcd for C55H84N2O11: C, 69.59, H 8.92, N, 2.95. Found C, 69.30, H
8.81, N 2.89.
4.15. General procedure for organogelation testing
4.12. N,N0-Bis(1-O-allyl-3-O-benzyl-4,6-O-benzylidene-2-
deoxy-
a
-D
-galactopyranos-2-yl)urea (37)
The organogelation ability of the neosaccharide (33e38) was
tested at a starting concentration of 5% wt/vol in a glass vial. Sol-
ꢁ
A solution of 34 (46.1 mg, 72.0
to 0 ꢀC. The solution was treated with benzyl bromide (171
1.44 mmol) and then with NaH (60% dispersion in oil) (16.2 mg,
404
mol). The mixture was stirred at 0 ꢀC for 6 h, then treated with
some drops of water, diluted with CH2Cl2 (25 mL) and heated to rt.
The organic layer was washed with water, collected, dried over
m
mol) in DMF (470
m
L) was cooled
vents used were dried over 4 A molecular sieves. After a 60 s
mL,
thermic (60 ꢀC), ultrasonic (37 kHz) or combined thermic-
ultrasonic (60 ꢀC-37 KHz) stimulus, the vial was left standing for
some minutes at rt and then inverted to check gel formation.
Gelator-solvent couples that gave a positive response to the in-
version test, were evaporated to dryness and the procedure was
then repeated at a lower concentration. The process was iterated
until no gel formation was observed. Minimum gelator concen-
tration was recorded as the lowest gelator concentration for which
an unstable gel (gel or part of the gel felt apart during inversion
test) was formed.
m
anhydrous
Na2SO4,
filtered
and
concentrated.
Flash-
chromatography (99:1 to 98:2 v/v CH2Cl2/MeOH) afforded 37
(35.4 mg, 60%) as a white powder. [
a]
22 þ117.4 (c 1.0 in CH2Cl2). nmax
D
(powder) 2940, 1630, 1576, 1244, 1051, 995 cmꢁ1
.
1H NMR
(500 MHz, CDCl3):
d 7.54e7.22 (20H, m, HeAr), 5.86e5.78 (2H, m,
OCH2CH]CH2), 5.44 (2H, s, CHPh), 5.20 (2H, d, Jvic 18.0, trans
OCH2CH]CHH), 5.11 (2H, d, Jvic 10.5, cis OCH2CH]CHH), 5.08 (2H,
d, J1,2 3.5, 1-H), 5.06 (2H, br s, NH), 4.51 (4H, br s, CH2Ph), 4.30 (2H,
br s, 2-H), 4.24 (2H, d, Jgem 12.0, 6a-H), 4.14e4.09 (4H, m, 4-H,
OCHHCH]CH2), 3.99 (2H, d, Jgem 12.0, 6b-H), 3.95 (2H, dd, Jgem 12.5,
Jvic 6.0, OCHHCH]CH2), 3.61 (2H, br d, J3,2 11.0, 2-H), 3.57 (2H, s, 5-
Acknowledgements
The authors thank Mr. Marco Meoli for help in synthetic work
and organogelation tests. NMR and MS facilities of CIMCF (Centro
Interdipartimentale di Metodologie Chimiche Fisiche) of University
of Naples ‘Federico II’ are acknowledged.
H). 13C NMR (100 MHz, CDCl3):
d 158.4 (NCON), 138.5, 137.9 (Cipso),
133.7 (OCH2CH]CH2), 128.8e126.3 (CeAr), 117.7 (OCH2CH]CH2),
101.1 (CHPh), 98.0 (C-1), 75.7, 73.2, 70.8, 69.5, 68.8, 62.9, 50.2 (C-2,
C-3, C-4, C-5, C-6, OCH2CH]CH2, OCH2Ph). MS (MALDI TOF): m/z
843.18 [MþNa]þ. Anal. Calcd for C47H52N2O11: C, 68.76, H 6.38, N,
3.41. Found C, 68.42, H 6.53, N 3.32.
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methyl-a-D-galactopyranos-2-yl)urea (38)
ꢂ
ꢂ
A solution of 34 (38.9 mg, 60.8
cooled to 0 ꢀC and treated with CH3I (75.8
with NaH (60% dispersion in oil) (6.8 mg, 170
m
mol) in DMF (400
L, 1.22 mmol) and then
mol). After 7 h
mL) was
m
m
stirring at 0 ꢀC, some drops of water were added. The mixture was
diluted with CH2Cl2 (25 mL) and heated. The organic layer was
washed with water, collected, dried over anhydrous Na2S2O4, fil-
tered and concentrated. The residue was subjected to flash-
chromatography (99:1 to 98:2 v/v CH2Cl2/MeOH) to give 38
22
(24.6 mg, 61%) as a white powder. [
a
]
D
þ122.7 (c 2.0 in CH2Cl2).
nmax (powder) 2915, 1639, 1585, 1258, 1050, 1015 cmꢁ1
.
1H NMR
(500 MHz, CDCl3): 7.54e7.32 (10H, m, HeAr), 5.88e5.80 (2H, m,
d
OCH2CH]CH2), 5.57 (2H, s, CHPh), 5.24 (2H, dd, Jvic 17.0, Jgem 1.0,
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CHH), 4.34 (2H, d, J4,3 3.0, 4-H), 4.26 (2H, dd, Jgem 12.0, J6a,5 1.5, 6a-
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