Novel amphiphilic cyclic oligosaccharides: Synthesis and self-aggregation properties

Article abstract of DOI:10.1021/jo7017087

(Chemical Equation Presented) Novel amphiphilic cyclic disaccharide analogues, in which the saccharide units are connected through stable phosphodiester linkages (CyPLOS, Cyclic Phosphate-Linked Oligosaccharides) and decorated with long lipophilic tentacl

Full text of DOI:10.1021/jo7017087

Novel Amphiphilic Cyclic Oligosaccharides: Synthesis and
Self-Aggregation Properties
Cinzia Coppola,† Vittorio Saggiomo,† Giovanni Di Fabio,†,‡ Lorenzo De Napoli,†,‡ and
Daniela Montesarchio*,†
Dipartimento di Chimica Organica e Biochimica, and Facolta’ di Scienze Biotecnologiche, UniVersita`
“Federico II” di Napoli, Complesso UniVersitario di Monte S. Angelo, Via Cintia, 4, I-80126 Napoli, Italy
daniela.montesarchio@unina.it
ReceiVed August 3, 2007
Novel amphiphilic cyclic disaccharide analogues, in which the saccharide units are connected through
stable phosphodiester linkages (CyPLOS, Cyclic Phosphate-Linked OligoSaccharides) and decorated with
long lipophilic tentacles at the 2- and 3-OH moieties, have been synthesized. Their propensity to self-
1
aggregation has been investigated by means of H and 31P NMR experiments, making it possible to
determine for these macrocycles critical aggregation concentration values in the millimolar range.
Introduction
currently devoted to amphiphilic cyclodextrins,4 obtained by
grafting hydrophobic appendages on the oligosaccharide back-
bone. Oligosaccharide-based amphiphilic molecules are cell
membrane mimics, envisaged to be biocompatible. These
compounds may be inserted into lipid systems through their
hydrophobic moieties and exploited as potential transmembrane
ion channels.5 Recent works on cyclodextrins, ad hoc derivatized
to form artificial channels, showed that, in order to be efficiently
included into membranes, they must be decorated with hydro-
phobic moieties approximately spanning the whole length of
the lipid bilayer.6 Upon adequate chemical modifications, such
as per-substitution of one face of the truncated cone by
hydrophobic tails, cyclodextrins can provide transient pores.7
Indeed, skirt- or bouquet-shaped cyclodextrins, prepared by
Macrocycles, by virtue of their intrinsic preorganization, can
show excellent recognition properties toward a wide range of
different guests and therefore be of interest in several fields,
from catalysis1 to analytical applications.2 Carbohydrates are
in general very attractive scaffolds for the construction of
macrocycles because they are rigidified building blocks, with
well-defined stereocenters displaying multiple, selectively ma-
nipulable hydroxyl functional groups. Among the plethora of
natural or artificial macrocycles known, cyclodextrins are the
most commonly used hosts, exhibiting well-recognized ability
to form stable complexes with different guests, low costs, and
reduced, if not null, toxicity.3 A great deal of attention is
† Dipartimento di Chimica Organica e Biochimica.
‡ Facolta’ di Scienze Biotecnologiche.
(4) Hedges, A. R. Chem. ReV. 1998, 98, 2035-2044.
(5) Jullien, L.; Lazrak, T.; Canceill, J.; Lacombe, L.; Lehn, J. M. J. Chem.
Soc., Perkin Trans. 2 1993, 1011-1020.
(1) For a recent review, see for example: Costamagna, J.; Ferraudi, G.;
Matsuhiro, B.; Campos-Vallette, M.; Canales, J.; Villagran, M.; Vargas,
J.; Aguirre, M. J. Coord. Chem. ReV. 2000, 196, 125-164.
(2) Molotov, Y.A. Macrocyclic Compounds in Analytical Chemistry;
Wiley: New York, 1997.
(6) Bacri, L.; Benkhaled, A.; Guegan, P.; Auvray, L. Langmuir 2005,
21, 5842-5846.
(7) Madhavan, N.; Robert, E. C.; Gin, M. S. Angew. Chem., Int. Ed.
2005, 44, 7584-7587.
(3) Szejtli, J. Chem. ReV. 1998, 98, 1743-1753 and references therein.
10.1021/jo7017087 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/08/2007
J. Org. Chem. 2007, 72, 9679-9689
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Coppola et al.
esterification with fatty acids of all hydroxyl groups of the
secondary face, or of both the primary and secondary face, are
able to form nanoparticles in water.8 Selective modification of
preformed cyclodextrins9 offers great opportunities but also
severe chemical challenges, which generally prevent their
massive exploitation. In principle, the total synthesis approach,
involving the stepwise synthesis of the linear oligomer, followed
by the circularization process, is a more general strategy, giving
access to a wider repertoire of artificially modified macrocycles.
In the context of cyclodextrins mimicry, several groups have
investigated cyclic oligosaccharide analogues having the canoni-
cal O-glycosidic bonds replaced by alternative linkages, such
as amide,10 S-glycosidic,11 acetylenic,12 or triazole13 bridges.
Recently, we described the synthesis and conformational proper-
ties of novel cyclic oligosaccharide analogues, 4,6-linked
through phosphodiester bonds, that we named CyPLOS (Cyclic
Phosphate-Linked OligoSaccharides).14 We envisioned that a
cyclic array of pyranose moieties alternated with negatively
charged phosphate groups might lead to specific recognition,
especially toward cations. These cyclic saccharide surrogates,
designed to combine some constitutive elements of both small
cyclodextrins and crown ethers and exhibiting, as a distinctive
structural motif, stable phosphodiester bonds within their
oligosaccharide core, were obtained through straightforward and
high fidelity reactions, well-optimized in oligonucleotide syn-
thesis. Cyclic dimer 2, shown to adopt a concave conformation
potentially able to bind metal ions, and key intermediate 3 are
depicted in Figure 1.
FIGURE 1. Dimer CyPLOS 2 and phosphoramidite derivative 3.
tentacles (1). In addition to providing the desired amphiphilicity,
these modifications introduce a high conformational freedom
in the cyclic skeleton. In fact, once permanently masked, the
3-OH groups of the pyranose residues are not available for
intramolecular H-bonding with the adjacent phosphate groups.
Disruption of these strong H-bonds removes the structural motif
further rigidifying the central cavity of the macrocycles, thus
leading to more flexible structures, able to cover a wide
conformational space in response to environmental stimuli.
Results and Discussion
Artificial compounds 1 are enantiopure, amphiphilic mol-
ecules endowed with a pseudo-C2 symmetry, designed to
produce reverse micellar aggregates in lipid systems, potentially
useful for the transport of cations of biological interest (e.g.,
Na+, K+, Mg2+, Ca2+, etc.) through membranes or at the
interface of water-organic solvents. In the retrosynthetic
analysis, the cyclic molecule can be prepared by intramolecular
condensation of a suitably protected linear dimer (11, Scheme
2), having at one end one phosphate moiety susceptible of
further nucleophilic attack and at the other end one free hydroxyl
group. In turn, the linear dimer is obtained by reacting phenyl-
â-D-glucopyranoside-4-O-(2-chloro-phenylphosphate) 9 with
4-phosphoramidite derivative 10, both derived from the common
precursor 6-O-DMTr-phenyl-â-D-glucopyranoside 8.
With the purpose of exploring novel amphiphilic cyclic
oligosaccharides, we reasoned that the synthesized CyPLOS
could be suitable platforms to prepare different analogues, where
the secondary hydroxyls at C-2 and C-3 of monosaccharide
building block 4 (Scheme 1) are exploited as synthetic handles
for further, selective derivatization. In this paper we report on
the synthesis of cyclic, jellyfish-shaped phosphate-linked dis-
accharides, per-substituted at the 2- and 3-OH with lipophilic
This compound was synthesized from phenyl-â-D-glucopy-
ranoside 4 in four straightforward steps, involving, respectively,
simultaneous protection of the 4- and 6-OH groups, insertion
of the desired tentacles at the 2 and 3 positions, and then
benzylidene removal followed by selective protection of the
6-OH group as 4,4′-dimethoxytritylether (Scheme 1).
In this context, as model hydrophobic tails to be attached at
the 2- and 3-OH functions, we chose linear C11 hydrocarbon
chains and tetra(ethylene glycol) (TEG) tails, thus providing a
tetra-alkylated (type a), a tetra-polyether (type b), and a mixed
dimer, containing one di-alkylated and one di-polyether-tailed
sugar (type c), respectively. These hydrophobic residues, which
in a fully extended conformation are, respectively, 15.415 and
1716 Å long, were linked via stable ether bonds. In case a, this
decoration was achieved by coupling the 4,6-benzylidene
protected sugar 5 with 1-bromoundecane in the presence of NaH
and NaI in DMF, giving 6a in 90% yields.
(8) (a) Ravoo, B. J.; Darcy, R. Angew. Chem., Int. Ed. 2000, 39, 4324-
4326. (b) Donohue, R.; Mazzaglia, A.; Ravoo, B. J; Darcy, R. Chem.
Commun. 2002, 2864-2865. (c) Mazzaglia, A.; Ravoo, B. J.; Darcy, R.;
Gambadauro, P.; Mallamace, F. Langmuir 2002, 18, 1945-1948. (d) Nolan,
D.; Darcy, R.; Ravoo, B. J. Langmuir 2003, 19, 4469-4472. (e) Falvey,
P.; Lim, C. W.; Darcy, R.; Revermann, T.; Karst, U.; Giesbers, M.; Marcelis,
A. T. M.; Lazar, A.; Coleman, A. W.; Reinhoudt, D. N.; Ravoo, B. J.
Chem.-Eur. J. 2005, 11, 1171-1180.
(9) (a) Gattuso, G.; Nepogodiev, S. A.; Stoddart, J. F. Chem. ReV. 1998,
98, 1919-1958. (b) Khan, A. R.; Forgo, P.; Stine, K. J.; D’Souza, V. T.
Chem. ReV. 1998, 98, 1977-1996. (c) Easton, C. J.; Lincoln, S. F. Modified
Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry;
Imperial College Press: London, 1999. For a recent work describing per-
2,3-di-O-alkylated cyclodextrins, see for example: Badi, N.; Jarroux, N.;
Gue´gan, P. Tetrahedron Lett. 2006, 47, 8925-8927.
(10) (a) Locardi, E.; Stockle, M.; Gruner, S.; Kessler, H. J. Am. Chem.
Soc. 2001, 123, 8189-8196. (b) van Well, R. M.; Marinelli, L.; Erkelens,
K.; van der Marel, G. A.; Lavecchia, A.; Overkleeft, H. S.; van Boom, J.
H.; Kessler, H.; Overhand, M. Eur. J. Org. Chem. 2003, 2303-2313. (c)
Bornaghi, L. F.; Wilkinson, B. L.; Kiefel, M. J.; Poulsen, S. A. Tetrahedron
Lett. 2004, 45, 9281-9284. (d) Mayes, B. A.; Stetz, R. J. E.; Ansell, C. W.
G.; Fleet, G. W. J. Tetrahedron Lett. 2004, 45, 153-156.
The analogous step to introduce the TEG chain (case b) onto
the sugar required previous synthetic elaboration of TEG, which
was first protected with the benzyl (Bn) moiety, used as a
convenient UV-vis label, leading to I, then activated at the
remaining OH group with the mesyl (Ms) group, thus yielding
(11) Fan, L.; Hindsgaul, O. Org. Lett. 2002, 4, 4503-4506.
(12) (a) Stichler-Bonaparte, J.; Vasella, A. HelV. Chim. Acta 2001, 84,
2355-2367. (b) Hoffmann, B.; Bernet, B.; Vasella, A. HelV. Chim. Acta
2002, 85, 265-287.
(13) (a) Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc. 2004,
126, 1638-1639. (b) Bodine, K. D.; Gin, D. Y.; Gin, M. S. Org. Lett.
2005, 7, 4479-4482.
(14) (a) Di Fabio, G.; Randazzo, A.; D’Onofrio, J.; Aus`ın, C.; Grandas,
A.; Pedroso, E.; De Napoli, L.; Montesarchio, D. J. Org. Chem. 2006, 9,
3395-3408. (b) D’Onofrio, J.; Coppola, C.; Di Fabio, G.; De Napoli, L.;
Montesarchio, D. Eur. J. Org. Chem. 2007, 3849-3858.
(15) Terreros, A.; Galera Gomez, P. A.; Lopez Cabarcos, E.; Muller, A.
Colloids Surf., A 2000, 164 (1), 47-53.
(16) Rumney, S. IV; Kool, E. T. J. Am. Chem. Soc. 1995, 117, 5635-
5646.
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NoVel Amphiphilic Cyclic Oligosaccharides
SCHEME 1. Synthesis of Building Blocks 9 and 10
BnO-TEG-OMs II (Scheme 3). Condensation of 5 with II in
DMF in the presence of NaH led to 6b in 85% yields.
Phosphorylation of the 4-OH of 8, followed by acidic workup
of the reaction crude, directly gave detritylated compounds 9
in 92-95% yields; 4-phosphoramidite derivative 10 was
obtained in 90% yields, essentially following protocols well-
established in the elaboration of building blocks for the
oligonucleotide synthesis.17 The dimerization step was carried
out by phosphoramidite chemistry, as described in Scheme 2.
Coupling of 9a and 10a by activation with 0.45 M tetrazole in
CH3CN, followed by oxidation, afforded 11a, obtained as a
detritylated compound after column chromatography in 80%
yield for the three steps.
In contrast, for the synthesis of 11b and 11c, the latter
obtained by mixed coupling between 9b and 10a, the building
blocks used proved to be quite reluctant to react under standard
activation conditions. The desired linear dimers were success-
fully obtained using a 0.25 M 4,5-dicyanoimidazole (DCI)
solution in CH3CN as the activator at 40 °C for 2 h. After
oxidation, the target compounds were isolated after column
chromatography in the form of detritylated dimers with 75%
yields for the three steps. Cyclization was then carried out by
exploiting a phosphotriester methodology, well-optimized both
in solution and in the solid phase, using 1-mesitylensulfonyl-
3-nitro-1,2,4-triazole (MSNT) as the condensing agent; this
strategy has been profitably exploited also for the solid-phase
synthesis of cyclic oligonucleotides18 and related analogues.19
The fully protected cyclic molecules (12a-c, Scheme 2) were
then deprotected in two steps: first, a basic, non-hydrolytic
treatment to promote â-elimination of the 2-cyanoethyl protect-
ing group (triethylamine, for 12a and 12b; a stronger base, such
as piperidine, proved to be efficient for 12c), followed by a
basic hydrolytic treatment to cleave the 2-chlorophenyl group.
The latter step, classically carried out by an overnight reaction
with aqueous ammonia at 55 °C, required in this case more
drastic basic treatments to go to completion. Optimal conditions
were found leaving overnight the cyclic compounds 13a-c in
contact with a saturated LiOH solution in dioxane/water (1:5,
v/v) at 50 °C. Following the described procedures, 1a-c could
be prepared in four steps in 50-58% yields from building blocks
9 and 10, each obtained in five steps with 62-67% yields from
phenyl-â-D-glucopyranoside 4.
All of the synthesized compounds were purified by column
chromatography, in all cases allowing the isolation of homo-
1
geneous compounds, and characterized by H, 13C (and 31P,
where present) NMR and ESI-MS data. Though ionic, the final
cyclic dimers proved to be very lipophilic tools: 1a could be
dissolved in only CHCl3 or CH2Cl2; on the contrary, final
compounds 1b and 1c were fairly soluble in most organic
solvents. On varying several solvent systems and conditions,
none of the synthesized macrocycles exhibited a marked
(18) Alazzouzi, E. M.; Escaja, N.; Grandas, A.; Pedroso, E. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1506-1508.
(19) Moggio, L.; De Napoli, L.; Di Blasio, B.; Di Fabio, G.; D’Onofrio,
J.; Montesarchio, D.; Messere A. Org. Lett. 2006, 8 (10), 2015-2018.
(17) Adinolfi, M.; De Napoli, L.; Di Fabio, G.; Iadonisi, A.; Montesar-
chio, D. Org. Biomol. Chem. 2004, 2, 1879-1886.
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Coppola et al.
SCHEME 2. Synthesis of Macrocycles 1a-c
SCHEME 3. Synthesis of BnO-TEG-OMs II
in cases a and b, a dramatic change could be observed when
converting the cyclic dimers 13a and 13b, still protected at one
phosphodiester moiety with the 2-chlorophenyl group, into final
target compounds 1a and 1b. In Figure 2, 1H and, in the insets,
31P NMR spectra of 13b are showed for comparison with those
of fully deprotected 1b.
The final cyclic compounds 1a, 1b, and 1c exhibited different
behaviors; however, they all showed concentration-dependent
NMR spectra, clearly suggesting the presence of strong inter-
molecular interactions. Compound 1a gave spectra with two
distinguishable sets of signals, as if in the presence of two
distinct species. NMR spectra of 1b showed dramatic line
broadening, diagnostic of slow equilibria on the NMR time
scale, which could be explained assuming the formation of large
aggregates in CDCl3. Similar behavior was found in all the
members of the c-series: when coupling 9b and 10a to finally
yield 1c, very broad, badly resolved signals in the NMR spectra
were obtained already at the level of linear dimer 11c, suggesting
a strong propensity toward aggregation.
tendency to form stable organogels at room temperature, though,
of the growing list of known low molecular weight gelators,
many are based on amphiphilic saccharide scaffolds.20 Even
though no gelling ability clearly emerged in these compounds,
evidence for aggregation came from investigation of their NMR
properties. CDCl3 was the solvent of choice, first of all for being
the best dissolving agent for 1a, and second, because an apolar
milieu can roughly mimic a lipid bilayer, thus offering useful,
preliminary information about the ability of these amphiphilic
macrocycles to self-assemble into ordered super-structures,
potential carriers for cations through bulk membranes.
On a general basis, a net simplification of the NMR spectra
is typically obtained when transforming an asymmetric dimer
into a molecule possessing a C2-symmetry, for which a
monomer-like spectrum is expected as a result of fast equilibria
between several conformations. Contrarily to our expectations,
Preliminary experiments to investigate the self-aggregation
properties of these amphiphilic macrocycles were carried out
by analyzing the NMR data upon varying the temperature and
concentration of the samples.21
Dimer 1a, at 14 mM concentration, typically showed two
separate signals for the anomeric protons, in approximately 1:1.2
1
ratio, in the H NMR (CDCl3, 400 MHz, 298 K) and two
distinct, sharp signals in the 31P NMR spectrum (Figure 3). In
the VT-NMR study, no difference emerged in the temperature
(20) (a) Jung, J. H.; John, G.; Masuda, M.; Yoshida, K.; Shinkai, S.;
Shimizu, T. Langmuir 2001, 17, 7229-7232. (b) Nie, X.; Wang, G. J. Org.
Chem. 2006, 71, 4734-4741. (c) John, G.; Zhu, G.; Li, J.; Dordick, J. S.
Angew. Chem., Int. Ed. 2006, 45, 4772-4775.
(21) (a) Stafford, R. E.; Fanni, T.; Dennis, E. A. Biochemistry 1989, 28,
5113-5120. (b) Babu, P.; Chopra, D.; Guru Row, T. N.; Maitra, U. Org.
Biomol. Chem. 2005, 3, 3695-3700.
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NoVel Amphiphilic Cyclic Oligosaccharides
1
FIGURE 3. 31P NMR (161.98 MHz, 298 K, CDCl3) and H NMR
(400 MHz, 298 K, CDCl3) spectra (panels A and B, respectively, with
the latter ones limited at the sugar regions) of compound 1a registered
at different concentrations (from the top to the bottom: 14.0, 7.5, 3.5,
and 1.8 mM, respectively).
FIGURE 2. 1H NMR (400 MHz, 298 K, CDCl3) and, in the inset, 31
NMR (161.98 MHz, 298 K, CDCl3) spectra of compounds 13b (panels
A and B, respectively) and 1b (panels C and D, respectively), both at
10 mM concentration.
P
spectra give the expected simplification upon dilution or by
increasing the temperature. When varying the temperature or
the concentration, the 31P NMR study gave a deeper insight
into the behavior of 1b. In detail, a very broad signal, dispersed
over a 10 ppm region, was found in the 31P NMR spectrum,
when analyzing the sample at 10 or 9 mM (CDCl3, 161.98 MHz,
298 K). This signal was significantly shrunk at 5 mM and
progressively simplified upon further dilution, thus allowing
evaluation of the critical aggregation concentration (cac)
between 6 and 8 mM (see Supporting Information).
The same trend could be observed for 1c, which in the 31P
NMR spectra registered at 9 mM concentration showed a high
number of close resonances, densely populating a region of 10
ppm. When decreasing the concentration, the chemical shift
anisotropy of the 31P NMR signals progressively reduced only
at concentrations lower than 1 mM, with an apparent cac
determined between 300 and 400 µM (see Supporting Informa-
tion).
range 273-323 K. However, when heated at 328 K, a highly
simplified system was obtained, with only one signal in the
region of the anomeric protons and one signal in the 31P NMR
spectrum (see Supporting Information).
In the concentration-dependent analysis, the 31P NMR spectra
showed the two signals coalesced into a unique, broad peak at
7 mM, giving sharp and better resolved signals upon successive
dilution. In this case the 1H NMR study was more informative,
showing the two anomeric signals to progressively overlap on
decreasing the concentration (Figure 3). A final coalescence into
a unique, sharp signal was observed at 1.8 mM concentration,
thus indicating that a fast equilibrium among the different
species was operative, with only one form finally predominating,
at a concentration between 2 and 3 mM. These spectral features
may be consistent with the aggregation into small micelles, but
they do not support the formation of large aggregates.22
On the contrary, as far as 1b and 1c are concerned, inspection
VT-31P NMR spectra showed for both 1b and 1c a tendency
toward only partial simplification of the peaks on increasing
the temperature; no apparent modification was found up to 338
K, thus indicating the formation of thermally stable aggregates
(see Supporting Information).
1
of the H and 31P spectra cleanly suggested the presence of
strongly self-aggregated systems, with typical chemical shift
1
anisotropy and line broadening. In no case did the H NMR
Taken together, these data suggest the following order in
terms of increasing preference for self-aggregation in CDCl3:
(22) Lasie, D. D. Liposomes: from Physics to Applications; Elsevier:
Amsterdam, 1993.
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Coppola et al.
H-6a and H-6b). 13C NMR (CDCl3, 75 MHz): δ 156.7, 129.5, 129.3,
128.3, 126.9, 126.2, 123.2 and 116.8 (aromatic carbons); 101.9 (Ph-
CH); 101.0 (C-1); 80.2 (C-5); 74.2 (C-3); 73.1 (C-2); 68.5 (C-4);
66.4 (C-6). ESI-MS (positive ions): calcd for C19H20O6 344.126;
m/z, found 367.19 (M + Na+), 383.25 (M + K+). HRMS (MALDI-
TOF): m/z calcd for C19H20O6Na 367.1158; found 367.1209 (M
+ Na+).
1a < 1b < 1c, with the latter two compounds able to generate
larger aggregates responsible for severe line broadening and
chemical shift anisotropy in the NMR spectra. The van der
Waals interactions between the dangling lipophilic tentacles of
these macrocycles may be in all cases indicated as the main
driving force for self-aggregation, with the TEG residues more
efficient than the sole C11 alkyl chains in promoting the
formation of stable aggregates in organic solvents.
Synthesis of 6a. Compound 5 (1.9 g, 5.65 mmol, 1 equiv),
dissolved in anhydrous N,N-dimethylformamide (35 mL), was
treated with sodium hydride (540 mg, 22.5 mmol, 4 equiv). The
mixture was left under stirring for 10 min, and then 1-bromoun-
decane (5.0 mL, 22.5 mmol, 4 equiv) and sodium iodide (425 mg,
2.82 mmol, 0.5 equiv) were sequentially added. The reaction, left
at room temperature for 4 h under stirring, was quenched by addition
of CH3OH, and the resulting mixture concentrated under reduced
pressure. The crude was then diluted with CHCl3, transferred into
a separatory funnel, washed three times with water, concentrated
under reduced pressure, and purified by column chromatography.
Eluting the column with n-hexane, containing growing amounts of
ethyl acetate (from 1 to 10%) gave pure 6a (3.3 g, 5.08 mmol) in
90% yield: white amorphous powder, Rf ) 0.8 (n-hexane/ethyl
acetate, 4:1, v/v). 1H NMR (CDCl3, 500 MHz): δ 7.50-7.03
(complex signals, 10H, aromatic protons); 5.56 (s, 1H, Ph-CH);
5.02 (d, J ) 8.0 Hz, 1H, H-1); 4.36 (dd, J ) 10.0 and 4.5 Hz, 1H,
H-6a); 3.91-3.83 [m, 2H, 1x(CH2-CH2-O-sugar)]; 3.81-3.71 [m,
3H, H-6b and 1x(CH2-CH2-O-sugar)]; 3.64 (t, J ) 9.0 and 9.5 Hz,
1H, H-4); 3.55 (t, J ) 8.5 and 9.0 Hz, 1H, H-3); 3.50 (m, 1H,
H-5); 3.45 (t, J ) 8.5 and 8.5 Hz, 1H, H-2); 1.61-1.52 [m, 4H,
(CH2-CH2-O-sugar)]; 1.31-1.24 [overlapped signals, 32H, 2x(-CH2-
)8]; 0.88 [t, 6H, 2x(CH3)]. 13C NMR (CDCl3, 100 MHz): δ 157.1,
138.3, 129.4, 128.8, 128.1, 125.9, 122.8 and 116.8 (aromatic
carbons); 102.1 (CH-Ph); 101.1 (C-1); 82.1 (C-5); 81.2 and 81.0
[2x(CH2-CH2-O-sugar)]; 73.6 (C-3); 73.5 (C-2); 68.7 (C-4); 66.2
(C-6); 31.8, 30.2, 29.6 and 26.0 [(-CH2-)8]; 22.6 [2x(CH2-CH3)];
14.0 [2x(CH3)]. ESI-MS (positive ions): calcd for C41H66O6,
654.476; m/z, found 677.49 (M + Na+), 693.44 (M + K+). HRMS
(MALDI-TOF): m/z calcd for C41H66O6Na 677.4757; found
677.4720 (M + Na+).
Synthesis of 7a. Compound 6a (3.3 g, 5.08 mmol) was treated
with 50 mL of a TFA/CH2Cl2/H2O 1:10:0.5 (v/v/v) solution. The
reaction was left at 0 °C. After 4 h, the reaction mixture was diluted
with CH2Cl2. The organic phase was washed twice with water and
concentrated under reduced pressure. The crude was purified by
column chromatography. Eluting the column with CHCl3, contain-
ing growing amounts of CH3OH (from 1 to 5%) gave pure 7a (2.4
g, 4.3 mmol) with 85% yield: white amorphous powder, Rf ) 0.5
(CHCl3/CH3OH, 95:5, v/v). 1H NMR (CDCl3, 500 MHz): δ 7.32-
6.99 (complex signals, 5H, aromatic protons); 4.97 (d, J ) 7.5 Hz,
1H, H-1); 3.97-3.91 [overlapped signals, 3H, H-6a and 1x(CH2-
CH2-O-sugar)]; 3.78 (m, 1H, H-5); 3.71-3.63 [overlapped signals,
3H, H-6b and 1x(CH2-CH2-O-sugar)]; 3.50 (m, 1H, H-4); 3.38 (t,
J ) 8.5 and 8.0 Hz, 1H, H-3); 3.30 (t, J ) 9.0 and 9.0 Hz, 1H,
H-2); 2.42 (bd, 1H, 4-OH); 2.01 (t, 1H, 6-OH); 1.61-1.52 [m, 4H,
2x(CH2-CH2-O-sugar)]; 1.31-1.23 [overlapped signals, 32H, 2x-
(-CH2-)8]; 0.88 [t, 6H, 2x(CH3)]. 13C NMR (CDCl3, 50 MHz): δ
157.2, 129.5, 122.6 and 116.6 (aromatic carbons); 101.7 (C-1); 84.2
[2x(CH2-CH2-O-sugar)]; 81.9 (C-5); 75.2 (C-3); 73.5 (C-2); 72.9
(C-4); 62.7 (C-6); 31.8, 30.3, 29.5, 29.2 and 26.1 [2x(-CH2-)8]; 22.6
[2x(CH2-CH3)]; 13.9 [2x(CH3)]. ESI-MS (positive ions): calcd for
C34H60O6, 564.439; m/z, found 587.20 (M + Na+), 603.20 (M +
K+). HRMS (MALDI-TOF): m/z calcd for C34H60O6Na 587.4288;
found 587.4301 (M + Na+).
Studies to investigate in detail the ability of these cyclic
compounds to form organized supramolecular architectures, as
well as to selectively extract metal ions from aqueous into
organic solvents, or to transport them through bulk liquid
membranes, are currently underway in our laboratories. Possible
applications of the above-described artificial structures can be
foreseen in the fields of sensory systems and drug delivery, as
well as in the development of new biocompatible functional
materials.
Conclusions
In this work, novel amphiphilic macrocycles 1a-c have been
synthesized, profitably exploiting both phosphoramidite and
phosphotriester chemistry, respectively, for the oligomerization
and the circularization reactions. Insertion of the long lipophilic
tentacles was cleanly realized by classical Williamson reactions
on the 2- and 3-OH groups of 4,6-protected sugar 5. The final
ionic compounds were fairly soluble in most organic solvents
yet displayed very different self-aggregation properties. 1H and
31P concentration-dependent and VT-NMR studies showed that
the presence of the hydrophobic TEG tentacles inserted onto
the cyclic core produces amphiphilic tools with a marked
propensity to aggregation, 1b and 1c, with critical aggregation
concentrations in the millimolar range, whereas the insertion
of the sole alkyl tails in 1a is not sufficient to generate large
self-aggregated species. Particularly, cyclic compounds conju-
gated with TEG residues may form stable inverted micellar
aggregates in CDCl3, which could account for the large
anisotropy and line broadening observed in the NMR spectra.
With the synthesis of model, cyclic molecules 1a-c we
demonstrated the feasibility of a more general synthetic platform,
giving access to a variety of diverse jellyfish-shaped oligomers,
the properties of which can be finely tuned by ad hoc varying
the nature of the monosaccharides and of the tentacles inserted
on the phosphate-linked oligosaccharide backbone.
Experimental Section
Synthesis of 5. Phenyl-â-D-glucopyranoside 4 (3.00 g, 12.0
mmol, 1 equiv) was dissolved in 25 mL of anhydrous N,N-
dimethylformamide (DMF). p-Toluensulfonic acid (PTSA, 110 mg,
0.60 mmol, 0.05 equiv) and, dropwise, benzaldehyde dimethylacetal
(4.0 mL, 26.0 mmol, 2.2 equiv) were sequentially added to the
stirred mixture, which was left at 0 °C for 48 h. The reaction mixture
was then diluted with CHCl3, transferred into a separatory funnel,
and washed twice with water. The organic phase, dried over
anhydrous Na2SO4 and filtered, was then concentrated under
reduced pressure and purified by crystallization in CHCl3, furnishing
pure 5 (3.92 g, 11.4 mmol) in 95% yield: white amorphous powder,
mp (from ethanol/acetone) 191-193 °C (lit.23 194-195 °C). Rf )
1
0.4 (CHCl3/CH3OH, 98:2, v/v). H NMR (CDCl3, 400 MHz): δ
Synthesis of 8a. Compound 7a (2.4 g, 4.3 mmol, 1 equiv),
dissolved in anhydrous pyridine (12 mL), was reacted with DMTrCl
(1.9 g, 5.6 mmol, 1.3 equiv). The reaction mixture, left at room
temperature overnight under stirring, was then diluted with CH3-
OH and concentrated under reduced pressure. The crude was next
purified on a silica gel column, eluted with CH2Cl2 containing
7.52-7.00 (complex signals, 10H, aromatic protons); 5.54 [s, 1H,
(Ph-CH)]; 5.02 (d, J ) 7.5 Hz, 1H, H-1); 4.36 (dd, J ) 6.6 and 10
Hz, 1H, H-3); 3.96-3.54 (overlapped signals, 5H, H-2, H-4, H-5,
(23) Rivaille, R.; Szabo´, L. Bull. Soc. Chim. Fr. 1963, 716-721.
9684 J. Org. Chem., Vol. 72, No. 25, 2007

NoVel Amphiphilic Cyclic Oligosaccharides
1
growing amounts of CH3OH (from 1 to 5%) in the presence of a
few drops of pyridine, affording pure 8a (3.5 g, 4.1 mmol) in 95%
yield: glassy compound, mp dec > 90 °C. Rf ) 0.7 (CHCl3/CH3-
OH, 98:2, v/v). 1H NMR (CDCl3, 400 MHz): δ 7.45-6.77
(complex signals, 18H, aromatic protons), 4.91 (d, J ) 7.5 Hz,
1H, H-1); 3.91-3.82 [overlapped signals, 3H, H-6a and 1x(CH2-
CH2-O-sugar)]; 3.77 (s, 6H, OCH3 of the DMTr group); 3.70-
3.64 [overlapped signals, 3H, H-6b and 1x(CH2-CH2-O-sugar)];
3.60-3.25 [overlapped signals, 4H, H-4, H-5, H-2 and H-3]; 1.62-
1.50 [m, 4H, 2x(CH2-CH2-O-sugar)]; 1.37-1.20 [overlapped
signals, 32H, 2x(-CH2-)8]; 0.88 [t, 6H, 2x(CH3)]. 13C NMR (CDCl3,
100 MHz): δ 158.3, 144.7, 135.8, 123.0, 129.5, 129.3, 129.0, 128.7,
128.1, 127.7, 127.0, 126.6, 124.9, 122.4, 116.9 and 113.0 (aromatic
carbons); 101.6 (C-1); 85.0 (quaternary C of the DMTr group);
84.4 [2x(CH2-CH2-O-sugar)]; 81.8 (C-5); 73.6 (C-3); 73.0 (C-2);
71.2 (C-4); 63.8 (C-6); 55.1 (OCH3 of the DMTr group); 31.8, 30.3,
29.5, 29.5, 29.2 and 26.1 [2x(-CH2-)8]; 22.6 [2x(CH2-CH3)]; 14.0
[2x(CH3)]. ESI-MS (positive ions): calcd for C55H78O8, 866.570;
m/z, found 889.20 (M + Na+), 905.18 (M + K+). HRMS (MALDI-
TOF): m/z calcd for C55H78O8Na 889.5594; found 889.5623 (M
+ Na+).
Cl2/CH3OH, 95:5, v/v). H NMR (CD3OD, 400 MHz): δ 7.60-
6.96 (complex signals, 9H, aromatic protons); 5.00 (d, J ) 7.6 Hz,
1H, H-1); 4.35 (m, 1H, H-4); 3.96-3.92 [overlapped signals, 3H,
H2-6 and 1x(CH2-CH-O-sugar)]; 3.77-3.58 [overlapped signals,
3H, 3x(CH2-CH-O-sugar)]; 3.54-3.46 (overlapped signals, 2H, H-3
and H-5); 3.34 (t, 1H, H-2); 1.60-1.52 [m, 4H, 2x(CH2-CH2-O-
sugar)]; 1.37-1.18 [overlapped signals, 36H, 2x(-CH2-)8]; 0.90-
0.88 [m, 6H, 2x(CH3)]. 13C NMR (CDCl3, 75 MHz): δ 157.5,
148.5, 146.8, 129.9, 129.4, 127.6, 123.9, 122.7, 121.2 and 116.6
(aromatic carbons); 102.2 (C-1); 83.4 [2x(CH2-CH2-O-sugar)]; 81.4
(C-5); 75.2 (C-4); 74.0 (C-3); 73.1 (C-2); 60.6 (C-6); 31.8, 30.3,
29.5, 29.4, 25.9 and 25.7 [2x(-CH2-)8]; 22.6 [2x(CH2-CH3)]; 13.9
[2x(CH3)]. 31P NMR (CD3OD, 161.98 MHz): δ -6.5. ESI-MS
(negative ions): calcd for C40H64ClO9P, 754.398; m/z, found 753.18
(M - H)-. HRMS (MALDI-TOF): m/z calcd for C40H63ClO9P
753.3898; found 753.3945 (M-H)-.
Synthesis of Linear Precursor 11a. Derivative 9a (150 mg,
0.198 mmol, 1 equiv) and compound 10a (255 mg, 0.240 mmol,
1.2 equiv), previously dried by repeated coevaporations with
anhydrous CH3CN and kept under reduced pressure, were reacted
with a 0.45 M tetrazole solution in anhydrous CH3CN (5.0 mL).
The reaction was left under stirring at room temperature and
monitored by TLC in the eluent system CH2Cl2/CH3OH, 95:5 (v/
v). After 2.0 h, a 5.5 M tert-butylhydroperoxide (t-BuOOH) solution
in decane (1.0 mL) was added to the mixture and left under stirring
at room temperature. After 30 min the reaction mixture was diluted
with CHCl3, transferred into a separatory funnel, washed three times
with water, concentrated under reduced pressure, and purified by
column chromatography eluted with CH2Cl2 containing growing
amounts of CH3OH (from 1 to 10%) in the presence of a few drops
of TFA, affording pure 11a (225 mg, 0.158 mmol) in 80% yield:
white amorphous powder, Rf ) 0.4 (CH2Cl2/CH3OH, 95:5, v/v).
1H NMR (CDCl3, 400 MHz): δ 7.58-6.80 (complex signals, 14H,
aromatic protons); 4.92 (d, J ) 7.6 Hz, 1H, H-1); 4.81 (d, J ) 7.6
Hz, 1H, H-1′); 4.45-4.22 [overlapped signals, 13H, H2-6-O-P, (-O-
CH2-CH2-CN), 1xH-4 and 4x(CH2-CH2-O-sugar)]; 3.92-3.32
[overlapped signals, 9H, H2-6-OH, 1xH-4, 2xH-2, 2xH-5 and 2xH-
3]; 2.57-2.51 [m, 2H, (-O-CH2-CH2-CN)]; 1.60-1.54 [m, 8H, 4x-
(CH2-CH2-O-sugar)]; 1.34-1.26 [overlapped signals, 64H, 4x(-CH2-
)8]; 0.87 [t, 12H, 4x(CH3)]. 31P NMR (CDCl3, 161.98 MHz): δ
Synthesis of 6-O-(4,4′-O-Dimethoxytriphenylmethyl)-2,3-di-
O-undecyl-phenyl-â-D-glucopyranoside-4-O-(2-cyanoethyl-N,N-
diisopropyl)phosphoramidite, 10a. To a solution of compound
8a (1.0 g, 1.1 mmol, 1 equiv), dissolved in anhydrous CH2Cl2 (9.4
mL) were added sequentially N,N-diisopropylethylamine (DIPEA)
(765 µL, 4.4 mmol, 4 equiv) and 2-cyanoethyl-N,N-diisopropyl-
chlorophosphoramidite (490 µL, 2.2 mmol, 2 equiv) under stirring
at room temperature. After 2 h, the reaction mixture was concen-
trated under reduced pressure. The crude was chromatographed on
a silica gel column, eluting with n-hexane containing growing
amounts of ethyl acetate (from 20 to 50%) in the presence of a
few drops of triethylamine, furnishing the desired compound 10a
(1.0 g, 0.99 mmol) in 90% yield: oil, as a mixture of diastereomers,
1
Rf ) 0.5 (n-hexane/ethyl acetate, 4:1, v/v). H NMR (CDCl3, 400
MHz): δ 7.45-6.70 (complex signals, 36H, aromatic protons); 4.94
(m, 2H, 2xH-1); 3.98-3.96 (m, 2H, 2xH-6a); 3.84-3.70 {over-
lapped signals, 18H, 4xN[CH(CH3)2]2, 2xH-6b and OCH3 of the
DMTr group}; 3.67-3.26 [overlapped signals, 20H, 2x(O-CH2-
CH2-CN), 4x(CH2-O-sugar), 2xH-4, 2xH-5, 2xH-2 and 2xH-3]; 2.64
and 2.53 [two t’s, 2H each, 2x(-O-CH2-CH2-CN)]; 1.62-1.24
[complex signals, 64H, 2x(-CH2-)8]; 1.20-1.05 {complex signals,
24H, 4xN[CH(CH3)2]2}; 0.90, 0.88 and 0.86 [s′s, 12H, 4x(CH3)].
13C NMR (CDCl3, 100 MHz): δ 158.2, 130.1, 129.3, 128.2, 127.6,
126.5, 122.3, 116.7 and 112.9 (aromatic carbons); 101.3 (C-1); 84.5
(quaternary C of the DMTr group); 82.0 (C-5); 81.8 [2x(CH2-CH2-
O-sugar)]; 75.4 and 75.3 (C-4); 73.4 and 73.1 (C-3); 72.5 (C-2);
63.9 (C-6); 60.7 (-O-CH2-CH2-CN); 55.0 (OCH3 of the DMTr
group); 43.0 {N[CH(CH3)2]2}; 31.8, 30.3, 29.6, 29.3 and 26.1 [2x-
(-CH2-)8]; 24.3 {N[CH(CH3)2]2}; 22.6 [2x(CH2-CH3)]; 14.0 [2x-
(CH3) and -O-CH2-CH2-CN]. 31P NMR (CDCl3, 161.98 MHz): δ
151.4 and 150.2. ESI-MS (positive ions): calcd for C64H95N2O9P,
1066.678; m/z, found 1067.84 (M + H+); 1105.61 (M + K+);
1168.74 (M + Et3NH+). HRMS (MALDI-TOF): m/z calcd for
C64H95N2O9PNa 1089.6673; found 1089.6684 (M + Na+).
-2.7 and -8.5. ESI-MS (negative ions): calcd for C77H126
-
ClNO17P2, 1433.819; m/z, found 1433.56 (M - H)-. HRMS
(MALDI-TOF): m/z calcd for C77H125ClNO17P2 1432.8116; found
1432.8139 (M - H)-.
Synthesis of Cyclic Dimer 12a. Derivative 11a (35 mg, 0.024
mmol, 1 equiv), previously dried by several coevaporations with
anhydrous pyridine, and MSNT (213 mg, 0.72 mmol, 30 equiv)
were dissolved in anhydrous pyridine (24 mL) and left overnight
under stirring at room temperature. The reaction mixture was then
concentrated under reduced pressure, diluted with CH2Cl2, trans-
ferred into a separatory funnel, washed three times with water,
concentrated under reduced pressure, and purified by column
chromatography. Elution with CH2Cl2 containing growing amounts
of CH3OH (from 1 to 10%) afforded pure 12a (25 mg, 0.018 mmol)
in 75% yield: white amorphous powder, Rf ) 0.5 (CH2Cl2/CH3-
OH, 97:3, v/v). 1H NMR (CDCl3, 500 MHz): δ 7.35-6.53
(complex signals, 14H, aromatic protons); 5.02 (d, J ) 7.0 Hz,
1H, H-1); 4.81 (d, J ) 7.0 Hz, 1H, H-1′); 4.70 (m, 1H, H-4); 4.58
(m, 1H, H-4′); 4.46-4.16 [overlapped signals, 6H, H2-6, (-O-CH2-
CH2-CN), H-3 and H-3′]; 3.98-3.85 (overlapped signals, 2H, H2-
6′); 3.77 [(t, 8H, 4x(-CH2-CH2-O-sugar)]; 3.68 (m, 1H, H-5); 3.54
(overlapped signals, 2H, H-5′ and H-2); 3.42 (m, 1H, H-2′); 2.70-
2.61 [m, 2H, (-O-CH2-CH2-CN)]; 1.63-1.57 [m, 8H, 4x(CH2-CH2-
O-sugar)]; 1.38-1.17 [overlapped signals, 64H, 4x(-CH2-)8]; 0.90-
0.85 [m, 12H, 4x(CH3)]. 13C NMR (CDCl3, 100 MHz): δ 156.7,
131.7, 131.7, 130.5, 129.7, 129.4, 127.6, 126.3, 123.0, 122.7, 122.1,
116.6 and 116.3 (aromatic carbons); 117.1 (CN); 101.3 and 101.3
(C-1 and C-1′); 82.0 and 81.7 (C-5 and C-5′); 81.4 [4x(CH2-CH2-
O-sugar)]; 74.6 and 74.5 (C-4 and C-4′); 73.6 and 73.5 (C-2 and
Synthesis of 2,3-Di-O-undecyl-phenyl-â-D-glucopyranoside-
4-O-(2-chlorophenylphosphate), 9a. 2-Chlorophenyl-dichloro-
phosphate (715 µL, 4.4 mmol, 4 equiv) was added dropwise to a
stirred solution of compound 8a (1.0 g, 1.1 mmol, 1 equiv), 1,2,4-
triazole (607 mg, 8.8 mmol, 8 equiv), and triethylamine (1.2 mL,
8.8 mmol, 8 equiv) in anhydrous pyridine (11 mL) at 0 °C. The
mixture was then allowed to warm to room temperature. After 3 h
the reaction was concentrated under reduced pressure. The crude
was then diluted with CHCl3, transferred into a separatory funnel,
washed three times with water, concentrated under reduced pressure,
and purified by column chromatography eluted with CH2Cl2
containing growing amounts of CH3OH (from 1 to 10%) in the
presence of a few drops of TFA, affording pure 9a (785 mg, 1.0
mmol) in 95% yield: white amorphous powder, Rf ) 0.3 (CH2-
J. Org. Chem, Vol. 72, No. 25, 2007 9685

Coppola et al.
C-2′); 72.4 and 72.1 (C-3 and C-3′); 66.1 and 65.4 (C-6 and C-6′);
62.2 (-O-CH2-CH2-CN); 31.8, 30.2, 30.0, 29.5, 29.5 and 29.2 [4x-
(-CH2-)8]; 22.6 [4x(CH2-CH2-O-sugar)]; 19.1 (-O-CH2-CH2-CN);
14.0 [4x(CH3)]. 31P NMR (CDCl3, 161.98 MHz): δ -4.9 and -9.4.
ESI-MS (positive ions): calcd for C77H124ClNO16P2, 1415.808; m/z,
found 1438.60 (M + Na+), 1454.61 (M + K+). HRMS (MALDI-
TOF): m/z calcd for C77H124ClNO16P2Na 1438.7982; found
1438.8019 (M + Na+).
in 65% yield (2.69 g, 9.47 mmol): oil, Rf ) 0.5 (ethyl acetate). 1H
NMR (CDCl3, 500 MHz): δ 7.35-7.32 (m, 5H, aromatic protons);
4.56 [s, 2H, (-CH2-Ph)]; 3.75-3.62 [overlapped signals, 14H, 3x
(-O-CH2-CH2-O-) and (-O-CH2-CH2-OH)]; 3.59 (t, J ) 4.5 and
4.5 Hz, 2H, -CH2OH). 13C NMR (CDCl3, 125 MHz): δ 138.1,
128.2, 127.6 and 127.4 (aromatic carbons); 73.1 (-CH2-Ph); 72.4,
70.5, 70.2 and 69.3 [(-O-CH2-CH2-O-)]; 61.6 (O-CH2-CH2-OH).
ESI-MS (positive ions): calcd for C15H23O5, 283.154; m/z, found
306.69 (M + Na+), 322.65 (M + K+). HRMS (MALDI-TOF): m/z
calcd for C15H23O5Na 306.1443; found 306.1460 (M + Na+).
Compound 12a (25 mg, 0.018 mmol), coevaporated several times
with anhydrous pyridine and dried under reduced pressure, was
treated with Et3N/pyridine (3 mL, 1:1, v/v) to selectively remove
the 2-cyanoethyl group and left overnight under stirring at 50 °C.
The reaction mixture was quenched by in Vacuo removal of the
solvent. The crude was purified by column chromatography, eluting
with CH2Cl2 containing growing amounts of CH3OH (from 1 to
10%), affording pure 13a (23 mg, 0.018 mmol) in an almost
quantitative yield: white amorphous powder, Rf ) 0.3 (CH2Cl2/
Synthesis of BnO-TEG-OMs (II). To 2.69 g of compound I
(9.47 mmol, 1 equiv), dissolved in 22 mL of anhydrous CH2Cl2
were sequentially added DIPEA (3.3 mL, 18.9 mmol, 2 equiv) and
mesylchloride (MsCl) (875 µL, 11.4 mmol, 1.2 equiv), and the
resulting mixture was left overnight at room temperature. The
reaction mixture was then concentrated under reduced pressure,
transferred into a separatory funnel, and washed twice with a
saturated NaCl solution. The organic phase, dried over anhydrous
Na2SO4, was filtered, concentrated under reduced pressure, and then
chromatographed on a silica gel column. Eluting with ethyl acetate/
n-hexane 9:1 (v/v) containing growing amounts of ethyl acetate
(from 90% to 100%), gave product II (3.26 g, 9.00 mmol) in 95%
1
CH3OH, 97:3, v/v). H NMR (CDCl3, 400 MHz): δ 7.70-6.83
(complex signals, 14H, aromatic protons); 4.96 (d, J ) 7.5 Hz,
1H, H-1); 4.81 (d, J ) 7.5 Hz, 1H, H-1′); 4.75 (m, 1H, H-4); 4.45-
4.02 (overlapped signals, 5H, H2-6, H-4′, H-3 and H-3′); 3.94-
3.50 (overlapped signals, 11H, 4x(-CH2-CH2-O-sugar), H2-6′ and
H-5); 3.48-3.23 (overlapped signals, 3H, H-5′, H-2 and H-2′);
1.67-1.55 [m, 8H, 4x(CH2-CH2-O-sugar)]; 1.40-1.09 [overlapped
signals, 64H, 4x(-CH2-)8]; 0.87 [m, 12H, 4x(CH3)]. 31P NMR
(CDCl3, 161.98 MHz): δ -2.5 and -9.9. ESI-MS (negative
ions): calcd for C74H121ClO16P2, 1362.781; m/z, found 1361.92 (M
- H)-. HRMS (MALDI-TOF): m/z calcd for C74H120ClO16P2
1361.7740; found 1361.7865 (M - H)-.
1
yield: oil, Rf ) 0.6 (ethyl acetate). H NMR (CDCl3, 500 MHz):
δ 7.34-7.22 (m, 5H, aromatic protons); 4.56 [s, 2H, (-CH2-Ph)];
4.36 [t, J ) 4.5 and 5.0 Hz, 2H, (-CH2-CH2-O-Ms)]; 3.75 [t, J )
4.5 and 4.0 Hz, 2H, (-CH2-CH2-O-CH2Ph)]; 3.67-3.61 [overlapped
signals, 12H, 3x (-O-CH2-CH2-O-)]; 3.05 [s, 3H, (-SO2- CH3)].
13C NMR (CDCl3, 125 MHz): δ 138.1, 128.2, 127.6 and 127.5
(aromatic carbons); 73.1 (CH2-Ph); 70.5, 70.4, 69.3 [3x(-O-CH2-
CH2-O-)]; 69.1 (-O-CH2-CH2-O-Ms); 68.9 (-O-CH2-CH2-O-Ms);
37.5 (-SO2-CH3). ESI-MS (positive ions): calcd for C16H26O7S,
362.140; m/z, found 385.69 (M + Na+), 401.65 (M + K+). HRMS
(MALDI-TOF): m/z calcd for C16H26O7SNa 385.1297; found
385.1401 (M + Na+).
Compound 13a (23 mg, 0.013 mmol), dissolved in dioxane (200
µL), was reacted with 1 mL of a saturated aqueous LiOH solution,
and the resulting mixture was left overnight under vigorous stirring
at 50 °C. Then the reaction mixture was concentrated under reduced
pressure, dissolved in CH2Cl2, transferred into a separatory funnel,
and washed three times with water. The organic phase was
concentrated under reduced pressure and purified by column
chromatography. Eluting the column with CH2Cl2 containing
growing amounts of CH3OH (from 0 to 15%) gave pure cyclic
dimer 1a (22 mg, 0.013 mmol) in an almost quantitative yield:
Synthesis of 6b. Compound 5 (774 mg, 2.25 mmol, 1 equiv)
dissolved in anhydrous N,N-dimethylformamide (15.0 mL) was
reacted with sodium hydride (162 mg, 6.75 mmol, 3 equiv). The
mixture was left under stirring for 10 min, and then 2.45 g of
compound II (6.75 mmol, 3 equiv) was added under stirring at
room temperature. After 4 h, the reaction mixture was quenched
by addition of CH3OH and concentrated under reduced pressure.
The crude was then diluted with CHCl3, transferred into a separatory
funnel and washed three times with water. The organic phase was
concentrated under reduced pressure and purified by column
chromatography. Eluting the column with ethyl acetate/n-hexane
85/15 (v/v) gave pure 6b (1.59 g, 1.80 mmol) in 80% yield: white
amorphous powder, Rf ) 0.5 (ethyl acetate/n-hexane, 85:15, v/v).
1H NMR (CDCl3, 500 MHz): δ 7.50-7.03 (complex signals, 20H,
aromatic protons); 5.54 (s, 1H, Ph-CH); 5.03 (d, J ) 7.5 Hz, 1H,
H-1); 4.56 [s, 4H, (-CH2-Ph)]; 4.36 (dd, J ) 5.0 and 5.0 Hz, 1H,
H-4); 4.08-4.04 [m, 2H, (-CH2-O-C-2)]; 4.02-3.83 (overlapped
signals, 3H, CH2-O-C-3 and H-6a); 3.78 (t, J ) 10.4 and 10.4 Hz,
1H, H-3); 3.69-3.56 [overlapped signals, 29H, 7x (O-CH2-CH2-
O) and H-6b)]; 3.52 (t, J ) 9.0 and 8.0 Hz, 1H, H-2); 3.49-3.44
(m, 1H, H-5). 13C NMR (CDCl3, 75 MHz): δ 157.2, 138.3, 137.2,
129.4, 128.9, 128.2, 128.1, 127.6, 127.5, 127.5, 126.0, 122.9, 117.1
and 116.6 (aromatic carbons); 101.9 (Ph-CH); 101.2 (C-1); 82.5
and 81.7 [(CH2-O-CH2-Ph)]; 80.7 (C-5); 73.1 [2x(-CH2-Ph)]; 72.5
and 72.4 (2xCH2-O-sugar); 70.5 [12x (O-CH2 TEG)], 69.4 (C-3);
68.6 (C-4); 66.3 (C-2); 62.5 (C-6). ESI-MS (positive ions): calcd
for C49H64O14, 876.430; m/z, found 898.98 (M + Na+), 914.95 (M
+ K+). HRMS (MALDI-TOF): m/z calcd for C49H64O14Na
899.4194; found 899.4248 (M + Na+).
1
white amorphous powder, Rf ) 0.5 (CH2Cl2/CH3OH 9:1 v/v). H
NMR (CDCl3, 400 MHz, 298 K, 14 mM): δ 7.30-6.93 (complex
signals, 10H, aromatic protons); 4.91 (d, J ) 7.6 Hz, 1H, H-1);
4.83 (d, J ) 7.6 Hz, 1H, H-1′); 4.61-4.33 (m, 2H, H-4 and H-4′);
4.20-4.09 (m, 4H, H2-6 and H2-6′); 4.03-3.98 [overlapped signals,
8H, 4x(-CH2-CH2-O-sugar)]; 3.90-3.40 (overlapped signals, 6H,
H-3 and H-3′, H-5 and H-5′, H-2 and H-2′); 1.66-1.53 [m, 8H,
4x(CH2-CH2-O-sugar)]; 1.34-1.09 [overlapped signals, 64H, 4x-
(-CH2-)8]; 0.87 [m, 12H, 4x(CH3)]. 31P NMR (CDCl3, 161.98 MHz,
298 K, 14 mM): δ 0.3 and -0.3. 1H NMR (CDCl3, 400 MHz, 298
K, 1.7 mM): δ 7.32-6.98 (complex signals, 10H, aromatic
protons); 4.94 (d, J ) 7.0 Hz, 2H, 2xH-1); 4.60-4.40 (overlapped
signals, 6H, 2xH-4 and 2xH2-6); 4.00-3.74 (overlapped signals,
10H, 2xH-3 and 4x(-CH2-CH2-O-sugar); 3.51-3.45 (overlapped
signals, 4H, 2xH-5 and 2xH-2); 1.86-1.50 [m, 8H, 4x(CH2-CH2-
O-sugar)]; 1.34-1.07 [overlapped signals, 64H, 4x(-CH2-)8]; 0.91-
[m, 12H, 4x(CH3)]. 31P NMR (CDCl3, 161.98 MHz, 298 K, 1.7
mM): δ -0.4. ESI-MS (negative ions): calcd for C68H118O16P2,
1252.789 m/z, found 1251.97 (M - H)-, 625.21 (M - 2H)2-
.
HRMS (MALDI-TOF): m/z calcd for C68H117O16P2 1251.7817;
found 1251.7885 (M - H)-.
Synthesis of BnO-TEG-OH (I). Tetra(ethylene glycol) (TEG,
Scheme 3) (2.82 g, 14.5 mmol, 1 equiv), dissolved in anhydrous
THF (8 mL), was reacted with sodium hydride (208 mg, 8.7 mmol,
1.6 equiv). The mixture was left under stirring for 10 min, and
then benzylbromide (1.5 mL, 8.7 mmol, 1.6 equiv) was added to
the stirred mixture, which was left 12 h at room temperature. The
reaction mixture was quenched by addition of CH3OH, filtered on
celite, and purified by column chromatography. Eluting the column
with ethyl acetate, target compound I was recovered in a pure form
Synthesis of 7b. Compound 6b (1.60 g, 1.80 mmol, 1 equiv)
was reacted with 5 mL of a TFA/CH2Cl2/H2O (1:10:0.5, v/v/v)
solution at 0 °C. After 4 h, the reaction mixture was diluted with
9686 J. Org. Chem., Vol. 72, No. 25, 2007

NoVel Amphiphilic Cyclic Oligosaccharides
CH2Cl2, and the resulting solution was washed twice with water
and then concentrated under reduced pressure. The crude was
purified by column chromatography. Eluting the column with ethyl
acetate, containing growing amounts of CH3OH (from 10 to 20%)
gave pure 7b (1.40 g, 1.80 mmol) in almost quantitative yield:
white amorphous powder, Rf ) 0.2 (ethyl acetate). 1H NMR (CDCl3,
400 MHz): δ 7.30-6.94 (complex signals, 15H, aromatic protons);
4.91 (d, J ) 7.2 Hz, 1H, H-1); 4.52 and 4.51 (s′s, 2H each, two
CH2-Ph); 4.10-3.92 [m, 4H, 2x(-CH2-O-sugar)]; 3.86-3.68 (over-
lapped signals, 7H, H-4, H2-6 and 2x(CH2-O-CH2-Ph)]; 3.62-3.49
[overlapped signals, 25H, H-3 and O-CH2-CH2-O TEG]; 3.42-
3.36 (m, 1H, H-5); 3.34 (t, J ) 6.0 and 7.2 Hz, 1H, H-2); 2.24 (t,
1H, CH2OH). 13C NMR (CDCl3, 100 MHz): δ 157.0, 139.0, 129.4,
128.2, 127.6, 127.5, 122.6 and 116.5 (aromatic carbons); 101.1 (C-
1); 85.8 [2x(CH2-O-CH2-Ph)]; 82.0 (C-5); 75.3 (C-4); 73.1 [2x(-
CH2-Ph)]; 72.3 (C-3); 71.9 (C-2); 70.8 and 70.5 [overlapped signals,
6x(O-CH2-CH2-O TEG)]; 69.3 (2xCH2-O-sugar); 62.9 (C-6). ESI-
MS (positive ions): calcd for C42H60O14, 788.398; m/z, found 811.49
(M + Na+), 827.50 (M + K+). HRMS (MALDI-TOF): m/z calcd
for C42H60O14Na 811.3881; found 811.3899 (M + Na+).
Synthesis of 8b. Compound 7b (1.40 g, 1.80 mmol, 1 equiv),
dissolved in anhydrous pyridine (5.4 mL), was reacted with DMTrCl
(731 mg, 2.16 mmol, 1.3 equiv). The reaction mixture, left at room
temperature overnight under stirring, was then diluted with CH3-
OH and concentrated under reduced pressure. The crude was next
purified on a silica gel column. Elution with CH2Cl2 containing
growing amounts of CH3OH (from 1 to 5%) in the presence of a
few drops of pyridine gave pure 8b (2.00 g, 1.80 mmol) in 98%
yield: glassy compound, mp dec > 90 °C. Rf ) 0.7 (CHCl3/CH3-
OH, 98:2, v/v). 1H NMR (CDCl3, 400 MHz): δ 7.54-6.82
(complex signals, 28H, aromatic protons); 5.06 (d, J ) 8.0 Hz,
1H, H-1); 4.67 and 4.63 (s′s, 2H each, two CH2-Ph); 4.30-4.20
[overlapped signals, 3H, 1x(CH2-O-sugar) and H-6a]; 4.02-3.90
[overlapped signals, 3H, 1x(CH2-O-sugar) and H-6b]; 3.85-3.82
[m, 5H, 2x(CH2-O-CH2-Ph) and H-4]; 3.80-3.60 [overlapped
signals, 32H, H-3, H-5, O-CH2-CH2-O TEG and 2x(OCH3) of the
DMTr group]; 3.54 (m, 1H, H-2). 13C NMR (CDCl3, 100 MHz):
δ 158.2, 149.7, 145.0, 138.2, 135.8, 130.0, 129.3, 128.2, 127.6,
126.4, 123.6, 122.4, 116.9, 114.7 and 112.9 (aromatic carbons);
101.2 (C-1); 86.1 (quaternary C of the DMTr group); 84.9 [2x-
(CH2-O-CH2-Ph)]; 82.1 (C-5); 75.3 (C-4); 73.1 [2x(-CH2-Ph)]; 72.3
(C-3); 71.8 (C-2); 70.5 (O-CH2-CH2-O TEG); 69.3 (2xCH2-O-
sugar); 64.0 (C-6); 55.0 (OCH3 of the DMTr group). ESI-MS
(positive ions): calcd for C63H78O16, 1090.529; m/z, found 1113.58
(M + Na+), 1129.58 (M + K+). HRMS (MALDI-TOF): m/z calcd
for C63H78O16Na 1113.5188; found 1113.5233 (M + Na+).
Synthesis of 6-O-(4,4′-Dimethoxytriphenylmethyl)-2,3-di-O-
TEG-phenyl-â-D-glucopyranoside-4-O-(2-cyanoethyl-N,N-diiso-
propyl)phosphoramidite, 10b. To a solution of compound 8b (1.0
g, 0.91 mmol, 1 equiv), dissolved in anhydrous CH2Cl2 (7 mL)
were sequentially added DIPEA (630 µL, 3.6 mmol, 4 equiv) and
2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (400 µL, 1.82
mmol, 2 equiv) under stirring at room temperature. After 2 h, the
reaction mixture was concentrated under reduced pressure. The
crude was then chromatographed on a silica gel column, eluting
with n-hexane containing growing amounts of ethyl acetate (from
20% to 50%) in the presence of a few drops of triethylamine,
furnishing desired compound 10b (993 mg, 0.77 mmol) in 85%
yield: oil, as a mixture of diastereomers, Rf ) 0.2 (CH2Cl2/CH3-
OH, 98:2, v/v). 1H NMR (CDCl3, 400 MHz): δ 7.46-6.81
(complex signals, 56H, aromatic protons); 5.07 (m, 2H, 2xH-1);
4.66 [s, 8H, 4x(-CH2-Ph)]; 4.14-3.91 [overlapped signals, 14H,
2x(-O-CH2-CH2-CN), 4x(-CH2-O-sugar) and 2xH-6a]; 3.87-3.83
(overlapped signals, 10H, 4x(CH2-O-CH2Ph) and 2xH-4); 3.79-
3.71 [overlapped signals, 64H, 2xH-6b, 2xH-3, (O-CH2-CH2-O
TEG) and 4x(OCH3) DMTr group]; 3.68-3.46 [overlapped signals,
4H, 2xH-2 and 2xH-5]; 3.40-3.29 {m, 4H, 2xN[CH(CH3)2]2};
2.48-2.35 [m, 4H, 2x(-O-CH2-CH2-CN)]; 1.18, 1.17, 1.16, 1.15,
1.11, 1.10, 0.96 and 0.95 {s′s, 3H each, 24H, 4xN[CH(CH3)2]2}.
13C NMR (CDCl3, 100 MHz): δ 158.3, 157.3, 138.3, 136.2, 130.1,
129.3, 128.2, 127.6, 126.5, 122.4, 116.9 and 112.9 (aromatic
carbons); 117.2 (CN); 101.1 (C-1); 86.0 (quaternary C of the DMTr
group); 85.0 and 84.6 [2x(CH2-O-CH2-Ph)]; 82.5 (C-5); 75.3 (C-
4); 73.1 [2x(-CH2-Ph)]; 72.3 (C-3); 72.0 (C-2); 70.5 (O-CH2-CH2-O
TEG); 69.4 (2xCH2-O-sugar); 63.8 (C-6); 60.2 (-O-CH2-CH2-CN);
55.0 (OCH3 of the DMTr group); 43.0 {N[CH(CH3)2]2}; 24.4 {N-
[CH(CH3)2]2}; 14.1 (-O-CH2-CH2-CN). 31P NMR (CDCl3, 161.98
MHz): δ 151.1 and 150.5. ESI-MS (positive ions): calcd for
C72H95N2O17P, 1290.637; m/z, found 1292.68 (M + H+), 1392.73
(M + Et3NH+). HRMS (MALDI-TOF): m/z calcd for C72H95N2O17-
PNa 1313.6266; found 1313.6296 (M + Na+).
Synthesis of 2,3-Di-O-TEG-phenyl-â-D-glucopyranoside-4-O-
(2-chlorophenylphosphate), 9b. 2-Chlorophenyl-dichlorophosphate
(590 µL, 3.64 mmol, 4 equiv) was added dropwise to a stirred
solution of compound 8b (1.0 g, 0.91 mmol, 1 equiv), 1,2,4-triazole
(503 mg, 7.28 mmol, 8 equiv), and triethylamine (1.0 mL, 7.28
mmol, 8 equiv) in anhydrous pyridine (8.8 mL) at 0 °C. The mixture
was allowed to warm to room temperature. After 3 h the reaction
mixture was concentrated under reduced pressure. The crude was
then diluted with CHCl3, transferred into a separatory funnel and
washed three times with water, then concentrated under reduced
pressure and purified by column chromatography. Elution with CH2-
Cl2 containing growing amounts of CH3OH (from 1 to 10%), with
the addition of a few drops of TFA, afforded pure 9b (810 mg,
0.84 mmol) in 92% yield: white amorphous powder, Rf ) 0.3 (CH2-
1
Cl2/CH3OH, 95:5, v/v). H NMR (CDCl3, 400 MHz): δ 7.31-
6.93 (complex signals, 19H, aromatic protons); 4.88 (d, J ) 7.6
Hz, 1H, H-1); 4.55-4.51 [m, 4H, 2x(-CH2-Ph)]; 4.02-3.88
[overlapped signals, 11H, 2x (-CH2-O-CH2Ph), 2x(CH2-O-sugar),
H-4 and H2-6]; 3.74-3.47 [overlapped signals, 27H, H-3, H-2, H-5
and (O-CH2-CH2-O TEG)]. 13C NMR (CDCl3, 100 MHz): δ 165.0,
156.6, 148.2, 141.9, 137.6, 137.2, 129.8, 129.2, 128.1, 127.4, 124.9,
124.2, 122.5, 121.7 and 116.2 (aromatic carbons); 100.8 (C-1); 85.6
and 83.8 [2x(CH2-O-CH2-Ph)]; 81.3 (C-5); 74.7 (C-4); 72.8 and
72.5 [2x(-CH2-Ph)]; 72.4 (C-2); 71.4 (C-3); 70.0, 69.8, 69.6, 69.3
and 68.8 [(O-CH2-CH2-O TEG), 2x(CH2-CH2-O-sugar)]; 67.9 (C-
6). 31P NMR (CDCl3, 161.98 MHz): δ -4.5. ESI-MS (negative
ions): calcd for C48H63ClO17P, 977.349; m/z, found 976.84 (M -
H)-. HRMS (MALDI-TOF): m/z calcd for C48H62ClO17P 976.3413;
found 976.3480 (M - H)-.
Synthesis of Linear Precursor 11b. Derivative 9b (150 mg,
0.153 mmol, 1 equiv) and compound 10b (237 mg, 0.184 mmol,
1.2 equiv), previously dried by repeated coevaporations with
anhydrous CH3CN and kept under reduced pressure, were reacted
with a 0.25 M DCI solution in anhydrous CH3CN (5.0 mL). The
reaction was left under stirring at 40 °C and monitored by TLC in
the eluent system CH2Cl2/CH3OH 94/6 (v/v). After 2.0 h, a 5.5 M
t-BuOOH solution in n-decane (1.0 mL) was added to the mixture
and left under stirring at room temperature. After 30 min the
reaction mixture was diluted with CHCl3, transferred into a
separatory funnel and washed three times with water. The organic
phase, concentrated under reduced pressure, was then purified by
column chromatography. Elution with CH2Cl2 containing growing
amounts of CH3OH (from 1 to 10%) in the presence of a few drops
of TFA afforded pure 11b (215 mg, 0.115 mmol) in 75% yield:
white amorphous powder, Rf ) 0.4 (CH2Cl2/CH3OH, 95:5, v/v).
1H NMR (CDCl3, 500 MHz): δ 7.33-6.92 (complex signals, 34H,
aromatic protons); 4.91 (d, J ) 7.5 Hz, 1H, H-1); 4.83 (d, J ) 7.5
Hz, 1H, H-1′); 4.66-4.33 [overlapped signals, 18H, H2-6-O-P, 4x-
(-CH2-O-sugar) and 4x(-CH2-Ph)]; 4.24-4.15 (m, 2H, O-CH2-CH2-
CN); 4.06-3.54 [overlapped signals, 62H, (O-CH2-CH2-O TEG),
4x(CH2-O-CH2Ph), 2xH-3, 2xH-4 and H2-6-OH]; 3.50-3.30 (par-
tially submerged, overlapped signals, 4H, 2xH-2 and 2xH-5); 2.69-
2.57 (m, 2H, O-CH2-CH2-CN). 13C NMR (CDCl3, 125 MHz): δ
157.1, 156.8, 149.1, 138.1, 137.9, 137.8, 129.8, 129.6, 129.3, 128.4,
128.3, 128.2, 127.6, 127.4, 124.8, 123.4, 122.9, 122.5, 121.3, 116.7,
116.6 and 116.4 (aromatic carbons); 117.3 (CN); 101.5 (C-1 and
C-1′); 84.4 and 82.7 [4x(CH2-O-CH2-Ph)]; 82.1 and 81.9 (C-5 and
J. Org. Chem, Vol. 72, No. 25, 2007 9687

Coppola et al.
C-5′); 75.0 and 74.7 (C-4 and C-4′); 73.1 [4x(-CH2-Ph)]; 72.7 and
72.1 (C-2 and C-2′); 72.0 and 71.9 (C-3 and C-3′); 70.8, 70.7, 70.6,
70.5, 70.4, 70.2 and 70.0 (O-CH2-CH2-O TEG); 69.3 [4x(CH2-CH2-
O-sugar)]; 68.8 (C-6-O-P); 62.0 (C-6-OH); 60.2 (-O-CH2-CH2-CN);
19.1 (-O-CH2-CH2-CN). 31P NMR (CDCl3, 161.98 MHz): δ -3.1
and -7.4. ESI-MS (negative ions): calcd for C93H126ClNO33P2,
1881.738; m/z, found 1881.35 (M - H)-. HRMS (MALDI-TOF):
m/z calcd for C93H125ClNO33P2 1880.7298; found 1880.7320 (M
- H)-.
Compound 13b (23 mg, 0.013 mmol), dissolved in dioxane (200
µL), was reacted with 1 mL of a saturated aqueous LiOH solution,
and the resulting mixture was left overnight under stirring at 50 °C.
Then the reaction mixture was concentrated under reduced pressure,
dissolved in CH2Cl2, transferred into a separatory funnel, and
washed three times with water. The organic phase was concentrated
under reduced pressure and purified by column chromatography.
Eluting the column with CH2Cl2 containing growing amounts of
CH3OH (from 0 to 15%) gave pure cyclic dimer 1b (22 mg, 0.013
mmol) in an almost quantitative yield: oil, Rf ) 0.5 (CH2Cl2/CH3-
Synthesis of Cyclic Dimer 12b. Derivative 11b (35 mg, 0.018
mmol, 1 equiv), previously dried by repeated coevaporations with
anhydrous pyridine, and MSNT (160 mg, 0.54 mmol, 30 equiv)
were dissolved in anhydrous pyridine (18 mL) and left overnight
under stirring at room temperature. The reaction mixture was then
concentrated under reduced pressure, dissolved in CH2Cl2, trans-
ferred into a separatory funnel, and washed three times with water.
The organic phase was concentrated under reduced pressure and
purified by column chromatography, eluting with CH2Cl2 containing
growing amounts of CH3OH (from 1% to 10%), affording pure
12b (25 mg, 0.013 mmol) in 75% yield: white amorphous powder,
Rf ) 0.4 (CH2Cl2/CH3OH, 95:5, v/v). 1H NMR (CDCl3, 500
MHz): δ 7.36-6.53 (complex signals, 34H, aromatic protons); 5.04
(d, J ) 7.5 Hz, 1H, H-1); 4.86 (d, J ) 7.0 Hz, 1H, H-1′); 4.72 (m,
1H, H-4); 4.55-4.46 [overlapped signals, 10H, 4x(-CH2-Ph) and
2xH-6a]; 4.42 (m, 1H, H-4′); 4.39-4.35 [m, 2H, (-O-CH2-CH2-
CN)]; 4.33-4.24 [overlapped signals, 2H, 2xH-6b); 4.14-3.93
[overlapped signals, 16H, 4x(CH2-CH2-O-sugar) and 4x(CH2-O-
CH2Ph)]; 3.90-3.75 (m, 2H, 2xH-3); 3.69-3.52 [overlapped
signals, 49H, (O-CH2-CH2-O TEG) and H-2]; 3.50-3.45 [over-
lapped signals, 3H, H-2′ and 2xH-5]; 2.68 [t, 2H, (-O-CH2-CH2-
CN)]. 13C NMR (CDCl3, 100 MHz): δ 156.8, 145.2, 138.1, 130.6,
129.5, 128.3, 128.1, 128.1, 128.0, 127.6, 127.5, 126.0, 123.1, 122.9,
121.4, 116.8 and 116.6 (aromatic carbons); 117.0 (CN); 101.1 (C-
1); 100.6 (C-1′); 82.2 and 82.0 (C-5 and C-5′); 75.4 (C-4 and C-4′);
73.1 [4x(-CH2-Ph)]; 72.9 and 72.4 (C-2 and C-2′); 72.1 (C-3 and
C-3′); 70.5 (O-CH2-CH2-O TEG); 69.3 [4x(CH2-CH2-O-sugar)];
66.0 (C-6 and C-6′); 62.4 (-O-CH2-CH2-CN); 19.1 (-O-CH2-CH2-
CN). 31P NMR (CDCl3, 161.98 MHz): δ -4.9 and -9.5. ESI-MS
(positive ions): calcd for C93H124ClNO32P2, 1863.727; m/z, found
1886.04 (M + Na+), 1906.06 (M + K+). HRMS (MALDI-TOF):
m/z calcd for C93H124ClNO32P2Na 1886.7168; found 1886.7196 (M
+ Na+).
Compound 12b (25 mg, 0.013 mmol), coevaporated several times
with anhydrous pyridine and then dried under reduced pressure,
was treated with Et3N/pyridine (3 mL, 1:1, v/v), and the resulting
mixture left overnight under stirring at 50 °C. The reaction was
quenched by in vacuo removal of the solvent. The crude was then
purified by column chromatography eluting with CH2Cl2 containing
growing amounts of CH3OH (from 1% to 10%), affording pure
13b (23 mg, 0.013 mmol) in an almost quantitative yield: white
amorphous powder, Rf ) 0.2 (CH2Cl2/CH3OH, 95:5, v/v). 1H NMR
(CDCl3, 500 MHz): δ 7.44-6.81 (complex signals, 34H, aromatic
protons); 4.92 (d, J ) 7.5 Hz, 1H, H-1); 4.81 (d, J ) 7.0 Hz, 1H,
H-1′); 4.74 (m, 1H, H-4); 4.55 [s, 8H, 4x(O-CH2-Ph)]; 4.42 (m,
2H, 2xH-6a); 4.15 (m, 1H, H-4′); 4.08-3.90 [overlapped signals,
18H, 2xH-6b, 4x(CH2-CH2-O-sugar) and 4x(CH2-O-CH2Ph)]; 3.70-
3.51 [overlapped signals, 54H, (O-CH2-CH2-O TEG), 2xH-2, 2xH-3
and 2xH-5]. 13C NMR (CDCl3, 100 MHz): δ 156.7, 138.1, 130.5,
129.4, 128.2, 127.6, 127.5, 126.7, 126.2, 123.2, 122.9, 122.5, 122.0,
120.2, 117.1 and 116.8 (aromatic carbons); 101.1 (C-1); 99.5 (C-
1′); 82.3 and 81.9 (C-5 and C-5′); 75.9 and 75.8 (C-4 and C-4′);
73.1 [4x(O-CH2-Ph)]; 72.7 and 72.3 (C-2 and C-2′); 72.2 and 72.0
(C-3 and C-3′); 70.5 (O-CH2-CH2-O TEG); 69.3 [4x(CH2-CH2-O-
sugar)]; 65.4 and 64.4 (C-6 and C-6′). 31P NMR (CDCl3, 161.98
MHz): δ -2.8 and -9.8. ESI-MS (negative ions): calcd for
C90H121ClO32P2, 1810.700; m/z, found 1809.63 (M - H)-. HRMS
(MALDI-TOF): m/z calcd for C90H120ClO32P2 1809.6926; found
1809.7000 (M - H)-.
1
OH 9:1 v/v). H NMR (CDCl3, 500 MHz) δ 7.36-7.00 (complex
signals, 30H, aromatic protons); 4.81 (broad signal, 2H, H-1 and
H-1′); 4.55-4.49 [complex, broad signals, 8H, 4x(CH2-Ph)]; 4.25-
3.83 [broad, overlapped signals, 14H, 2xH2-6, 2xH-4 and 4x(CH2-
CH2-O-sugar)]; 3.72-3.46 [overlapped signals, 62H, 4x(CH2-O-
CH2Ph), (O-CH2-CH2-O TEG), 2xH-2, 2xH-3 and 2xH-5]. 13C
NMR (CDCl3, 100 MHz) δ 156.8, 138.1, 130.4, 129.4, 128.2, 127.6,
127.5, 126.7, 126.2, 123.2, 122.9, 122.5, 122.0, 120.2, 117.1 and
116.7 (aromatic carbons); 101.2 (C-1 and C-1′); 82.3 (C-5 and C-5′);
75.8 (C-4 and C-4′); 73.1 [4x(O-CH2-Ph)]; 72.7 (C-2 and C-2′);
72.2 (C-3 and C-3′); 70.4 (O-CH2-CH2-O TEG); 69.3 [4x(CH2-
CH2-O-sugar)]; 59.4 (C-6 and C-6′). 31P NMR (CDCl3, 161.98
MHz, 9 mM): very broad signal, centered at δ -2.8. 31P NMR
(CDCl3, 161.98 MHz, 1.7 mM): sharp signal at δ -2.7. ESI-MS
(negative ions): calcd for C84H116O32P2, 1698.692; m/z, found
1698.01 (M - H)-; 849.62 (M - 2H)2-. HRMS (MALDI-TOF):
m/z calcd for C84H115O32P2 1697.6847; found 1697.6891 (M - H)-.
Synthesis of Linear Precursor 11c. Derivative 9b (150 mg,
0.153 mmol, 1 equiv) and compound 10a (265 mg, 0.184 mmol,
1.2 equiv), previously dried by repeated coevaporations with
anhydrous CH3CN and kept under reduced pressure, were reacted
with a 0.25 M DCI solution in anhydrous CH3CN (5.0 mL). The
reaction was left under stirring at 40 °C and monitored by TLC in
the eluent system CH2Cl2/CH3OH 96/4 (v/v). After 2.0 h, a 5.5 M
t-BuOOH solution in n-decane (1.0 mL) was added to the mixture
and left under stirring at room temperature. After 30 min the
reaction mixture was diluted with CHCl3, transferred into a
separatory funnel and washed three times with water. The organic
phase, concentrated under reduced pressure, was then purified by
column chromatography eluting with CH2Cl2 containing growing
amounts of CH3OH (from 1 to 10%) in the presence of a few drops
of TFA, affording pure 11c (190 mg, 0.115 mmol) in 75% yield:
white amorphous powder, Rf ) 0.4 (CH2Cl2/CH3OH, 96/4, v/v).
1H NMR (CDCl3, 500 MHz): δ 7.32-6.92 (complex signals, 24H,
aromatic protons); 4.95-4.75 (overlapped signals, 3H, 2xH-1 and
H-4); 4.55-3.14 [overlapped signals, 53H, 2xH2-6, O-CH2-CH2-
CN, 4x(-CH2-O-sugar), 2x(-CH2-Ph), 2xH-3, H-4′, (O-CH2-CH2-O
TEG), 2x(CH2-O-CH2Ph), 2xH-2 and 2xH-5]; 2.55-2.40 (broad
signals, 2H, O-CH2-CH2-CN); 1.58 [m, 4H, 2x(CH2-CH2-O-sugar)];
1.37-1.07 [overlapped signals, 32H, 2x(-CH2-)8]; 0.88 [t, 6H, 2x-
(CH3)]. 13C NMR (CDCl3, 125 MHz): δ 157.2, 156.8, 149.3, 138.2,
137.7, 131.1, 129.5, 129.3, 129.2, 129.0, 128.6, 128.3, 128.2, 128.0,
127.7, 127.6, 127.4, 124.8, 123.8, 123.4, 123.2, 122.7, 122.4, 121.7,
121.5, 116.6 and 116.3 (aromatic carbons); 117.8 (CN); 101.9 and
101.7 (C-1 and C-1′); 84.7 and 84.3 [4x(CH2-O-CH2-Ph)]; 82.2
and 81.6 (C-5 and C-5′); 73.9 and 73.5 (C-4 and C-4′); 73.0 [2x-
(-CH2-Ph)]; 72.7 and 72.4 (C-2 and C-2′); 71.9 (C-3 and C-3′);
70.4, 70.3 and 70.2 (O-CH2-CH2-O TEG); 69.3 [4x(CH2-CH2-O-
sugar)]; 66.7 and 66.0 (C-6-O-P); 63.9 and 63.0 (C-6-OH); 61.9
and 61.4 (-O-CH2-CH2-CN); 31.8, 30.2, 29.5 and 29.2
[2x(-CH2-)8]; 22.5 [2x(CH2-CH2-O-sugar)]; 19.0 (-O-CH2-CH2-CN);
13.9 [4x(CH3)]. 31P NMR (CDCl3, 161.98 MHz): δ -1.1, -4.5
and -6.9. ESI-MS (negative ions): calcd for C85H125ClNO25P2,
1656.770; m/z, found 1657.88 (M - H)-. HRMS (MALDI-TOF):
m/z calcd for C85H124ClNO25P2 1655.7626; found 1655.7811 (M
- H)-.
Synthesis of Cyclic Dimer 12c. Derivative 11c (35 mg, 0.021
mmol, 1 equiv), previously dried by repeated coevaporations with
anhydrous pyridine, 4-dimethylaminopyridine (DMAP) (2.6 mg,
9688 J. Org. Chem., Vol. 72, No. 25, 2007

NoVel Amphiphilic Cyclic Oligosaccharides
0.021 mmol, 1 equiv) and MSNT (190 mg, 0.63 mmol, 30 equiv)
were dissolved in anhydrous pyridine (20 mL) and left overnight
under stirring at room temperature. The reaction mixture was then
concentrated under reduced pressure, dissolved in CH2Cl2, trans-
ferred into a separatory funnel, and washed three times with water.
The organic phase was concentrated under reduced pressure and
purified by column chromatography eluting with CH2Cl2 containing
growing amounts of CH3OH (from 1 to 10%), affording pure 12c
(26 mg, 0.016 mmol) in 75% yield: white amorphous powder, Rf
signals, 19H, 2xH-6b, H-4′, 4x(CH2-CH2-O-sugar) and 4x(CH2-O-
CH2Ph)]; 3.70-3.44 [overlapped, broad signals, 54H, (O-CH2-
CH2-O TEG), 2xH-2, 2xH-3 and 2xH-5]; 1.65-1.48 [broad signals,
4H, 2x(CH2-CH2-O-sugar)]; 1.40-1.16 [overlapped signals, 32H,
2x(-CH2-)8]; 0.87 [t, 6H, 2x(CH3)]. 31P NMR (CDCl3, 161.98
MHz): δ -2.1 and -10.0. ESI-MS (negative ions): calcd for
C82H121ClO24P2, 1586.741; m/z, found 1585.63 (M - H)-. HRMS
(MALDI-TOF): m/z calcd for C82H120ClO24P2 1585.7333; found
1585.7379 (M - H)-.
1
) 0.4 (CH2Cl2/CH3OH, 95:5, v/v). H NMR (CDCl3, 500 MHz):
Compound 13c (23 mg, 0.014 mmol), dissolved in dioxane (200
µL), was reacted with 1 mL of a saturated aqueous LiOH solution,
and the resulting mixture was left overnight under stirring at 50
°C. Then the reaction mixture was concentrated under reduced
pressure, dissolved in CH2Cl2, transferred into a separatory funnel
and washed three times with water. The organic phase was
concentrated under reduced pressure and purified by column
chromatography. Eluting the column with CH2Cl2 containing
growing amounts of CH3OH (from 0 to 15%) gave pure cyclic
dimer 1c (22 mg, 0.013 mmol) in 93% yield: oil, Rf ) 0.5 (CH2-
δ 7.33-6.95 (complex signals, 24H, aromatic protons); 5.01-4.86
(overlapped signals, 2H, 2xH-1); 4.68 (m, 1H, H-4); 4.56-4.49
[overlapped signals, 6H, 2x(-CH2-Ph) and 2xH-6a]; 4.42 (m, 1H,
H-4′); 4.35-4.14 [overlapped signals, 4H, (-O-CH2-CH2-CN) and
2xH-6b); 4.09-3.70 [overlapped signals, 14H, 2xH-3, 4x(CH2-CH2-
O-sugar) and 2x(CH2-O-CH2Ph)]; 3.70-3.54 [overlapped signals,
24H, (O-CH2-CH2-O TEG)]; 3.53-3.35 [overlapped signals, 4H,
2xH-2 and 2xH-5]; 2.67 [t, 2H, (-O-CH2-CH2-CN)]; 1.65-1.54 [m,
4H, 2x(CH2-CH2-O-sugar)]; 1.42-1.17 [overlapped signals, 32H,
2x(-CH2-)8]; 0.89 [t, 6H, 2x(CH3)]. 13C NMR (CDCl3, 100 MHz):
δ 156.9, 153.5, 146.4, 145.9, 143.9, 141.6, 138.1, 132.8, 132.5,
132.2, 130.6, 129.6, 129.5, 128.2, 128.0, 127.8, 127.6, 126.0, 123.1,
121.4, 117.0 and 116.9 (aromatic carbons); 116.2 (CN); 101.9 (C-
1); 101.4 (C-1′); 82.2 and 81.9 [2x(CH2-O-CH2-Ph)]; 81.6 and 81.3
(C-5 and C-5′); 75.3 (C-4 and C-4′); 73.9 and 73.6 (C-2 and C-2′);
73.1 [2x(-CH2-Ph)]; 72.3 and 72.1 (C-3 and C-3′); 70.5 (O-CH2-
CH2-O TEG); 69.3 [4x(CH2-CH2-O-sugar)]; 68.1 and 66.7 (C-6 and
C-6′); 61.9 (-O-CH2-CH2-CN); 31.8, 30.1, 29.5 and 29.2 [2x(-CH2-
)8]; 22.5 [2x(CH2-CH2-O-sugar)]; 18.4 (-O-CH2-CH2-CN); 14.0 [4x-
(CH3)]. 31P NMR (CDCl3, 161.98 MHz): δ -2.1, -4.8, -7.4 and
-10.5. ESI-MS (positive ions): calcd for C85H124ClNO24P2,
1639.768; m/z, found 1663.80 (M + Na+), 1680.74 (M + K+).
HRMS(MALDI-TOF): m/zcalcdforC85H124ClNO24P2Na1662.7575;
found 1662.7610 (M + Na+).
1
Cl2/CH3OH 9:1 v/v). H NMR (CDCl3, 400 MHz): δ 7.39-6.80
(complex signals, 20H, aromatic protons); 4.98-4.62 (broad signals,
3H, 2xH-1 and H-4); 4.54 and 4.53 [two s′s, 2H each, 2x(O-CH2-
Ph)]; 4.43 (m, 2H, 2xH-6a); 4.30-3.75 [broad, overlapped signals,
11H, 2xH-6b, H-4′ and 4x(CH2-CH2-O-sugar)]; 3.72-3.30 [over-
lapped signals, 34H, (O-CH2-CH2-O TEG), 2xH-2, 2xH-3 and 2xH-
5]; 1.69-1.55 [broad signals, 4H, 2x(CH2-CH2-O-sugar)]; 1.40-
1.08 [overlapped signals, 32H, 2x(-CH2-)8]; 0.88 [t, 6H, 2x(CH3)].
31P NMR (CDCl3, 161.98 MHz, 298 K, 10 mM): a large set of
resonances is present between δ 0.7 and -7.1. 31P NMR (CDCl3,
161.98 MHz, 298 K, 100 µM): sharp signal at δ 1.6. MALDI-
TOF (negative ions): calcd for C76H116O24P2, 1474.733; m/z, found
1472.86 (M - H)-. HRMS (MALDI-TOF): m/z calcd for
C76H115O24P2 1473.7253; found 1473.7303 (M - H)-.
Compound 12c (25 mg, 0.015 mmol), coevaporated several times
with anhydrous pyridine and then dried under reduced pressure,
was treated with piperidine/DMF (3 mL, 1:5, v/v), and the resulting
mixture left overnight under stirring at 70 °C. The reaction was
quenched by in Vacuo removal of the solvent. The crude was then
purified by column chromatography eluting with CH2Cl2 containing
growing amounts of CH3OH (from 1% to 10%), affording pure
13c (23 mg, 0.014 mmol) in 96% yield: white amorphous powder,
Rf ) 0.2 (CH2Cl2/CH3OH, 95:5, v/v). 1H NMR (CDCl3, 500
MHz): δ 7.32-6.80 (complex signals, 24H, aromatic protons);
4.92-4.67 (broad signals, 3H, 2xH-1 and H-4); 4.53 [s, 4H, 2x-
(O-CH2-Ph)]; 4.43 (m, 2H, 2xH-6a); 4.23-3.90 [overlapped, broad
Acknowledgment. We thank Centro di Metodologie Chimico-
Fisiche (CIMCF), Universita` di Napoli “Federico II”, for the
MS and NMR facilities.
Supporting Information Available: General Information, cop-
ies of 1H, 13C and, where present, 31P NMR spectra for the
synthesized compounds. VT-NMR spectra for 1a, 1b, and 1c and
31P NMR spectra registered at different concentrations for 1b and
1c. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO7017087
J. Org. Chem, Vol. 72, No. 25, 2007 9689