Building multivalent iminosugar-based ligands on calixarene cores via nitrone cycloadditions

Article abstract of DOI:10.1021/jo301155p

A novel and challenging approach for the construction of multivalent iminosugar architectures directly on calixarene scaffolds is presented, which exploits multiple cycloaddition reactions of a carbohydrate-derived nitrone on diversely functionalized cali

Full text of DOI:10.1021/jo301155p

Article
pubs.acs.org/joc
Building Multivalent Iminosugar-Based Ligands on Calixarene Cores
via Nitrone Cycloadditions
Francesca Cardona,‡ Giovanni Isoldi,‡ Francesco Sansone,† Alessandro Casnati,*,† and Andrea Goti*,‡
‡Dipartimento di Chimica “Ugo Schiff”, Polo Scientifico e Tecnologico, Universita
̀
di Firenze, Via della Lastruccia 13, 50019 Sesto
Fiorentino (FI), Italy
†Dipartimento di Chimica Organica e Industriale, Universita
̀
degli Studi, Parco Area delle Scienze 17/A, 43124 Parma, Italy
S
* Supporting Information
ABSTRACT: A novel and challenging approach for the
construction of multivalent iminosugar architectures directly
on calixarene scaffolds is presented, which exploits multiple
cycloaddition reactions of a carbohydrate-derived nitrone on
diversely functionalized calix[4]arenes. Regardless of the 4-fold
reiteration on a single calixarene, the reactions take place with
high regio- and stereoselectivity, demonstrating this method as
an appealing one for the synthesis of calixarene-based
neoglycoconjugates.
recently for a fullerene decorated with 12 iminosugar residues
(up to 2150-fold)8 and for a series of cyclodextrins conjugated
with 7 and 14 iminosugars (up to 4 orders of magnitude).9,10
These results demonstrated that the use of multivalent ligands
can be applied, beyond carbohydrate−lectin recognition
processes, to glycomimetic-enzyme inhibition for modulating
the activity as well as the selectivity in the design of more
potent glycosidase inhibitors from iminosugars, a class of
compounds with several therapeutic applications.11
Following these findings, we wish to report here our results
on the synthesis of novel enantiopure iminosugars linked to
calix[4]arenes via highly selective 1,3-dipolar cycloaddition
reactions of enantiopure cyclic nitrones to calix[4]arenes
functionalized at the upper or the lower rim.
INTRODUCTION
■
Carbohydrate−lectin interactions are intensively investigated as
they play a pivotal role in a host of biological events.
Monovalent carbohydrates typically bind to their lectin
receptors with low affinity.1 Nature has circumvented this
tight binding limitation by exposing sugar residues in a
multivalent fashion at the surface of cells. This multivalent or
cluster glycoside effect is the affinity enhancement obtained
with multivalent ligands compared to their monovalent
counterparts, which is greater than predicted from the sum of
every single saccharide-receptor recognition event.2 On this
basis, hundreds of multivalent glycomimetics have been
synthesized for studying carbohydrate−lectin interactions.3,4
Conversely, the concept of multivalency has remained
essentially unexplored concerning specific glycosidase inhib-
ition using iminosugars as glycomimetics. The different nature
of the enzyme receptors involved, which usually have a single
and deep active site and therefore do not appear prone to
accept multivalent substrates, reasonably accounts for the
paucity of studies on this subject. However, although a strong
multivalent or cluster effect is generally associated with the
interaction of receptors bearing multiple recognition sites with
multivalent sugar ligands, significant affinity enhancements have
also been observed for systems where the receptors possess a
single binding site. In this case, an “intrinsic” multivalent effect
associated with local concentration effects may be producti-
ve.2c,5
RESULTS AND DISCUSSION
■
Multiple glycosylations of calix[4]arene platforms to give
glycoclusters have been extensively investigated in recent
years.12,13 Concerning the synthetic strategies adopted, they
usually involve conjugation of a preformed sugar moiety to the
calixarene scaffold through suitable linkers. In contrast, our
approach to iminosugar decorated calixarenes is particularly
innovative and challenging, regarding the direct construction of
nascent iminosugars on the calixarene skeleton. Thus, an
intriguing selectivity issue arises: several novel stereogenic
centers are created in the same key step when the iminosugar
moieties are generated on the calixarene. For the success of this
strategy, availability of a highly selective reaction for formation
of the iminosugars was essential in order to avoid complex
Early attempts to use multivalent iminosugar inhibitors were
not encouraging,6 apart from the results reported with a
trivalent derivative of 1-deoxynojirimycin, which showed a 6-
fold affinity enhancement toward jack bean-α-mannosidase.7
Conversely, dramatic enhancement effects were reported more
Received: June 10, 2012
© XXXX American Chemical Society
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Scheme 1
mixtures of products. We demonstrate the feasibility of this
approach through highly regio- and diasterostereoselective
multiple cycloaddition reactions of nitrone 2 to calix[4]arenes
3,5 and 4,6 (Scheme 1) functionalized, respectively, at the
lower and the upper rim with terminal double bonds.
Dipolarophiles 7 and 8 were chosen as model substrates of
calixarenes 3,5 and 4,6, respectively, in order to investigate the
optimal reaction conditions for the cycloaddition reaction.
Compound 8 was synthesized from 7, obtained in turn by
allylation of xylenol, through a Claisen−Cope rearrangement
followed by methylation of the phenolic hydroxy group with
CH3I in THF (Scheme 2).14
Scheme 3
Scheme 2
Hz was detected between protons H-3a and H-4, indicative of
their trans relationship.17a,b
Calixarenes 3−6 were synthesized following literature
procedures.23 When performing the cycloaddition reaction on
these multifuctionalized calixarenes, the stereoselectivity issue
becomes crucial. Indeed, in the case of difunctionalized
calixarenes 3 and 4, formation of a diadduct will generate
four novel stereocenters on the same molecule. Thus, assuming
a complete regioselectivity and taking into account symmetry
considerations, the reaction may afford up to 10 stereoisomers,
besides the 4 possible monoadducts. The number of possible
stereoisomers increases dramatically on going to the
tetrafunctionalized calixarenes 5 and 6. In this case, eight
novel stereocenters are generated in a single synthetic step, in
principle giving rise to 70 tetraadducts (strongly reduced from
the theoretical 28 = 256 for symmetry reasons), besides the 64
possible trisubstituted adducts, 26 diadducts (16 vicinal + 10
distal) and 4 monoadducts, for a total of 164 possible products.
In this quite complex scenario, it is essential that all the
dipolarophiles react and the stereoselectivity of each cyclo-
addition reaction has to be virtually complete. This may happen
if highly stereoselective reactions are chosen and the
dipolarophilic moieties in the calixarene behave independently
of each other; that is, each subsequent cycloaddition is not
influenced by the already installed stereocenters in terms of
stereoselectivity. On the basis of the results obtained with
model compounds 7 and 8, nitrone 2 appeared more suited
than 1 for this study. Indeed, nitrone 1 reacted with calixarene
323b slightly faster than 2 but considerably less selectively. The
Cycloaddition of nitrone 115 to lower rim model allyl ether 7
in toluene as solvent went to completion in 3 days at room
temperature. Among various diastereoisomers visible in the
crude mixture, one major adduct 9 was collected after flash
column chromatography (FCC) in 48% yield (Scheme 3).16
The structure of 9 was assigned as derived from an exo/anti
approach of the dipole to the dipolarophile, on the basis of the
1
analogy of its H NMR spectrum to those of similar adducts
from the same nitrone.17 Cycloaddition of nitrone 218 to the
same model compound 7 required heating at 60 °C in
toluene.19 After 24 h, a single regio- and stereoisomer 10 was
detected and isolated in 52% yield (Scheme 3), which was also
assigned a structure deriving from an exo/anti approach on the
basis of a correlation peak between H-2 and H-6 observed in
the 1D NOESY spectrum (see Supporting Information, Figure
S6). This stereochemical outcome was in agreement to those
reported for other cycloaddition reactions of the same
nitrone.17c,20 Thus, nitrone 2 appeared to be, at least with
model compound 7, less reactive but more selective.21 The
upper rim calixarene model dipolarophile 8 was less reactive
than 7. Indeed, cycloaddition with nitrone 2 required 3 days at
60 °C for completion.22 A single regio- and stereoisomeric
adduct 11 was isolated in 65% yield (Scheme 3), again resulting
from an exo/anti approach of the reacting partners. In both
adducts 10 and 11, a small vicinal coupling constant J = 4.0−4.6
B
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Scheme 4
Scheme 5
Scheme 6
reaction was complete after two days at 60 °C, but several TLC
spots were detected on the crude; luckily, the major exo/anti
diadduct 12 could be isolated by FCC, albeit with a moderate
29% yield (Scheme 4).24
between H-2 and H-6 of the pyrroloisoxazole nucleus (see
Supporting Information, Figure S18), in analogy with the
model system. As shown in the Supporting Information (Figure
1
S14), the H NMR spectrum of 13 showed a high symmetry,
Conversely, calixarene 3 reacted with 2 equiv of nitrone 2 in
toluene at 60 °C to give, after 3 days,25 the only detectable
compound 13, obtained in a satisfactory 52% yield after
purification by FCC (Scheme 4). It is worth noting that the
recovered yields of diadducts 12 and 13 are in line with those
obtained with the model dipolarophiles, considering the
different selectivities of nitrones 1 and 2. These results
confirmed that nitrone 1 is unsuitable for synthesizing multiple
cycloadducts and justified continuing this study with the
nitrone 2 exclusively. The structure of 13 was confirmed by 1D
according to the anticipation that both cycloadditions
proceeded with the same type of approach, thus providing a
C2 symmetric molecule. At least other two adducts were
detected in the crude mixture by TLC, but they could be
isolated only in traces, and they were not further characterized.
In order to obtain calixarenes functionalized at the upper rim,
calixarene 423a was reacted with 2 equiv of nitrone 2 in toluene
at 60 °C, affording a single adduct 14 isolated in 59% yield after
1
FCC (Scheme 5). Again, the H NMR spectrum was highly
symmetric (see Supporting Information, Figure S19). The
structure of 14 was confirmed to derive from an exo/anti
approach of both 1,3-dipole molecules on the basis of 1D and
2D NMR spectra. In particular, the 2D NOESY spectrum
1
and 2D H NMR experiments, and derived from an exo/anti
approach of both allylic moieties of calixarene 3 to nitrone 2, as
demonstrated by the presence of NOESY correlation peaks
C
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Figure 1. Spin systems for methylene protons in calixarenes 13 and 14 (relative positions within the couples A, B and X, Y have been indicated
1
arbitrarily) and a section of H NMR spectrum (400 MHz) of 13 (a) and 14 (b).
1
showed correlation peaks of H-2 with H-6 and H-4 and of H-3a
with H-5 (see Supporting Information, Figure S21).
on alumina. Compound 15 showed a more complex H NMR
spectrum with some broadened signals (see Supporting
Information, Figure S22), presumably as a consequence of
higher energy barriers for the conformational mobility of the
pyrroloisoxazole nuclei crowding at the lower rim of the
macrocycle calixarene. However, the simplicity of NMR spectra
with a limited number of signals show again that the newly
formed stereocenters in each cycloaddition reaction did not
influence the stereoselectivity of the subsequent cycloadditions,
and each cycloaddition was established to proceed with an exo/
Tetrafunctionalization at lower and upper rim of calixarenes
523c and 6,23a respectively, has been also achieved (Scheme 6).
Four equivalents of nitrone 2 were reacted either with
calixarene 5 or 6 in toluene at 60 °C, affording complete
conversions after 3 days in both cases. However, isolation and
purification of these tetrafunctionalized calixarenes was not a
trivial task, mainly due to instability of the products on silica
gel. Calixarene 15 was obtained in 49% yield after purification
D
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anti approach, thus affording a C4 symmetric compound.
Purification of 16, obtained by addition of 2 to the upper rim
functionalized calixarene 6 was even more difficult, and the
adduct 16 could be isolated in a poor 14% yield (Scheme 6) via
FCC on silica, while purification on alumina did not give any
improvement.
between H-2 and H-4 in its 2D NOESY spectrum (see
Supporting Information, Figure S34) and furnished a
confirmation of the previous structural assignment to the
parent cycloadduct.
Unfortunately, catalytic hydrogenation of calixarene adducts
13 and 14 did not give any positive result. On reacting 13 with
H2 and Pd/C in the presence of conc. HCl in MeOH as solvent
for 15 h, only decomposition products were obtained after
treatment with ion-exchange resin. This may be ascribed to a
sensitivity of the product to the acidic conditions, or to
instability to the resin. Alternatively, catalytic hydrogenation
performed without addition of HCl did not succeed in
removing all the benzyl groups, even reacting for 4 days with
200% catalyst in weight, and thus confirming the difficulties
observed, in some cases, in the debenzylation of calixarene
derivatives.27 We then turned to investigate the possibility to
selectively cleave the N−O bond. A mixture of calixarene 13
and Zn in CH3COOH/H2O 9:1 was thus heated at 45 °C for
1.5 h as reported for similar cycloadducts to nitrone 2,18,20,28
affording amino alcohol 19 in 66% yield. Analogously,
isoxazolidine ring cleavage of adduct 14 under the same
conditions afforded compound 20 in 86% yield after
purification on silica gel (Scheme 8). Unfortunately, when
this reaction was performed on tetra-adduct 15 under the same
conditions, no product was recovered, due to instability of the
amino alcohol on silica gel.
1
The H NMR patterns originated by the protons of the
methylene units connecting the aryl rings in the different
calixarene adducts 13, 14, 15 and 16 deserve a further
comment. In the starting calixarenes 3−6, the presence of bulky
groups (and hydrogen-bonding for compounds 3 and 4) fixes
the calixarene in the cone structure, inducing diastereotopicity
in the four axial and four equatorial protons that give rise to an
AX spin system.26
When a homochiral moiety is introduced in two distal
positions in a calixarene, as it happens in adducts 13 and 14, the
symmetry planes are lost, and this generates two different spin
systems AX and BY for the methylene bridge protons, as is
apparent from the 1H NMR spectrum of compound 13 (Figure
1a), which shows two couples of doublets at around 4.4 and 3.4
ppm. This effect is not observed for 14, probably due to the
larger distance of the homochiral moieties, which are placed in
the upper rim, from the methylene protons, resulting in an
accidental isochronism for their signals, with only two doublets,
respectively at 4.42 and 3.12 ppm (Figure 1b).
When the homochiral moiety is introduced in all of the
arenes, as it happens for tetraadducts 15 and 16, the methylene-
bridge spin system does not change after the cycloaddition
reaction with respect to the starting calixarenes 5 and 6: two
Scheme 8
1
doublets are observed in the H NMR spectrum, which reflect
the AX spin system of the methylene protons. In conclusion,
apart from accidental isochronisms, the observed spin systems
are a proof of the symmetry of compounds 13−16, thus
confirming that each cycloaddition has occurred with the same
stereoselective mode. With adducts in hand, we attempted at
their further elaboration. Catalytic hydrogenation of model
adducts 10 and 11 with Pd/C in MeOH as solvent and in
presence of conc. HCl afforded the deprotected amino alcohols
17 and 18 after treatment with ion-exchange resin DOWEX
50WX8, by eluting with ammonia. However, while 17 was
obtained pure and in high yield (97%) after the treatment with
the resin, compound 18 required a further purification on silica
gel in order to obtain an analytically pure sample in a moderate
36% yield (Scheme 7). Complete assignment of the relative
configuration of compound 17 was possible on the basis of
correlation peaks observed between H-3 and H-5, the protons
at Cα and Cβ of the side chain at C-2 and H-3 and H-5, and
In conclusion, in this work we showed that iminosugars can
be introduced on calix[4]arenes by exploiting a challenging
synthetic strategy that uses a highly regio- and stereoselective
cycloaddition reaction of nitrone 2 to properly di- and tetra-
allylated calixarenes 3−6. Novel enantiopure calix iminosugars
13−16 were synthesized in good yields, and their further
synthetic elaboration to give novel multivalent iminosugars was
studied.
Scheme 7
We therefore think that the nitrone cycloaddition to
polyallylated scaffolds can be used to efficiently and selectively
prepare a rich collection of polyvalent iminosugar ligands
potentially useful in the inhibition of glycosidases.
EXPERIMENTAL SECTION
Commercial reagents were used as received. All reactions were
magnetically stirred and monitored by TLC on 0.25 mm silica gel
■
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plates, and column chromatography was carried out on Silica Gel 60
(32−63 μm). Yields refer to spectroscopically and analytically pure
compounds unless otherwise stated. All the peak assignments reported
in 1H NMR spectra were based on COSY, HMQC, and NOESY
spectra.
methoxy)-25,27-dihydroxy-calix[4]arene (13). A mixture of 3
(132 mg, 0.26 mmol) and nitrone 2 (217 mg, 0.52 mmol) in toluene
(0.52 mL) was stirred at 60 °C for 3 days, and then a TLC control
(petroleum ether/AcOEt 10:1) showed the disappearance of the
starting calixarene (Rf = 0.5). Evaporation of the solvent under
reduced pressure afforded a crude, which was purified by flash column
chromatography using an eluent with increasing polarity (petroleum
ether/AcOEt 4:1 then 3:1) affording pure 13 (180 mg, 0.13 mmol,
52% yield) as a white solid (Rf = 0.4, petroleum ether/AcOEt 3:1): mp
= 65−66 °C; [α]D 25 = −32.1 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ = 7.55 (s, 2H; OH), 7.37−7.29 (m, 30H; Ar−H), 7.10 (d, J
= 7.6 Hz, 4H; Ar−H), 6.88 (m, 4H; Ar−H), 6.74 (t, J = 7.6 Hz, 2H;
Ar−H), 6.72 (t, J = 7.6 Hz, 2H; Ar−H), 4.72−4.66 (m, 2H; 2-H),
4.63−4.52 (m, 12H; OCH2Ar), 4.46 (d, J = 13.2 Hz, 2H; ArCH2Ar),
4.42 (d, J = 13.2 Hz, 2H; ArCH2Ar), 4.18−4.06 (m, 8H; ArOCH2, 4-
H, 5-H), 3.89 (dt, J = 8.8, 4.8 Hz, 2H; 3a-H), 3.72 (dd, J = 9.8, 4.6 Hz,
2H, CH2OBn), 3.65 (dd, J = 9.8, 5.8 Hz, 2H, CH2OBn), 3.46 (q, J =
5.3 Hz, 2H; 6-H), 3.38 (d, J = 13.2 Hz, 2H; ArCH2Ar), 3.36 (d, J =
13.2 Hz, 2H; ArCH2Ar), 2.51−2.43 (m, 2H; 3-H), 2.37−2.31 (m, 2H;
3-H); 13C NMR (50 MHz, CDCl3) δ = 152.9 (s, 2C), 151.4 (s, 2C),
138.1 (s, 2C), 137.8 (s, 2C), 137.6 (s, 2C), 132.8 (s, 4C), 128.8 (d,
4C), 128.6 (d, 4C), 128.1−127.3 (d, 30C), 128.0 (s, 4C), 125.0 (d,
2C), 118.6 (d, 2C), 87.5 (d, 2C), 83.7 (d, 2C), 76.1 (t, 2C), 74.7 (d,
2C), 73.1 (t, 2C), 72.1 (t, 2C), 71.6 (t, 2C), 69.7 (t, 2C), 69.3 (d, 2C),
67.6 (d, 2C), 36.3 (t, 2C), 31.2 (t, 2C), 31.1 (t, 2C); IR (CDCl3):
3369, 3028, 2918, 2863, 1465, 1452, 1089, 1026, 736, 697 cm−1; ESI-
MS calcd for C86H86N2NaO12 (M + Na+) m/z 1361.6. Found m/z
1362.0. Anal. Calcd for C86H86N2O12 (1339.61): C, 77.11; H, 6.47; N,
2.09. Found C, 76.93; H, 6.48; N, 2.08.
Synthesis of 4-Allyl-2,6-dimethylphenyl Methyl Ether (8).
Neat 7 (5 g) was heated at 200 °C for 15 h in a sand bath. TLC
control showed complete conversion of the starting material. Then, a
portion of the obtained red crude oil (512 mg, 3.14 mmol) was
dissolved in dry THF (10 mL), and NaH (150 mg, 6.25 mmol) was
added at 0 °C under nitrogen atmosphere. The mixture was left
stirring at room temperature for 1 h, then CH3I was added (2.2 mg,
15.8 mmol), and the mixture heated at 80 °C for 15 h. Water (20 mL)
was added, and the mixture was extracted with diethyl ether (3 × 10
mL). The organic phase was washed with H2O (3 × 10 mL) and dried
over Na2SO4. Filtration and evaporation of the solvent under reduced
pressure afforded 520 mg (2.95 mmol, 95% yield over two steps) of
pure 8 as a yellow oil: 1H NMR (CDCl3, 200 MHz) δ = 6.86 (s, 2H;
Ar−H), 5.97 (m, 1H; ArCH2CHCH2), 5.20−5.01 (m, 2H;
ArCH2CHCH2), 3.72 (s, 3H; OCH3), 3.31 (d, J = 6.6 Hz, 2H;
ArCH2CHCH2), 2.29 (s, 6H; ArCH3).
(2R,3aR,4R,5R,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
2-[2,6-dimethylphenoxy)methyl]hexahydropyrrolo[1,2-b]-
isoxazole (10). A mixture of nitrone 2 (250 mg, 0.6 mmol) and 7
(194 mg, 1.2 mmol) in toluene (0.6 mL) was stirred at 60 °C for 24 h,
and then a TLC control showed the disappearance of the starting
material. Evaporation of the solvent under reduced pressure afforded a
crude, which was purified by flash column chromatography using an
eluent with increasing polarity (petroleum ether/AcOEt 8:1 then 3:1)
affording pure 10 (182 mg, 0.31 mmol, 52% yield) as a white solid (Rf
= 0.6, petroleum ether/AcOEt 5:1): mp = 77−78 °C; [α]D 23 = −36.2
5,17-Bis({(2S,3aR,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]-hexahydropyrrolo[1,2-b]isoxazol-2-yl}-
methyl)-25,26,27,28-tetrapropoxy-calix[4]arene (14). A mixture
of 4 (106 mg, 0.16 mmol) and nitrone 2 (158 mg, 0.38 mmol) in
toluene (0.38 mL) was stirred at 60 °C for 3 days, and then a TLC
control (petroleum ether/AcOEt 10:1) showed the disappearance of
the starting calixarene 4 (Rf = 0.8). Evaporation of the solvent under
reduced pressure afforded a crude, which was purified by flash column
chromatography (petroleum ether/AcOEt 3:1) affording pure 14 (143
mg, 0.09 mmol, 59% yield) as a white solid (Rf = 0.3, petroleum ether/
1
(c = 0.5, CHCl3); H NMR (CDCl3, 400 MHz) δ = 7.41−7.28 (m,
15H; Ar−H), 7.02 (d, J = 7.2 Hz, 2H; Ar−H), 6.95 (m, 1H; Ar−H),
4.68−4.55 (m, 7H, 2-H; OCH2Ar), 4.14 (dd, J = 5.6, 4.4 Hz, 1H; 5-
H), 4.04 (t, J = 4.0 Hz, 1H; 4-H), 3.95 (dd, J = 10.4, 6.0 Hz, 1H;
ArOCH2); 3.87−3.82 (m, 2H; ArOCH2, 3a-H), 3.80 (dd, J = 10.0, 4.4
Hz, 1H; CH2OBn), 3.72 (dd, J = 9.6, 6.0 Hz, 1H; CH2OBn), 3.45 (q, J
= 5.4 Hz, 1H; 6-H), 2.38 (t, J = 6.8 Hz, 2H; 3-H), 2.31 (s, 6H;
ArCH3); 13C NMR (50 MHz, CDCl3) δ = 155.1 (s), 138.0 (s), 137.7
(s), 137.5 (s), 130.5 (s, 2C), 128.5−127.4 (d, 17C), 123.6 (d), 87.0
(d), 83.4 (d), 75.2 (d), 73.1 (t), 72.1 (t, 2C), 71.6 (t), 69.7 (t), 69.5
(d), 67.7 (d), 36.7 (t), 16.1 (q, 2C); MS (EI) m/z (%) = 579 (M+,
0.2), 458 (6), 400 (7), 105 (14), 91 (100). Anal. Calcd for C37H41NO5
(579.73): C, 76.66; H, 7.13; N, 2.42. Found C, 76.37; H, 7.15; N, 2.24.
(2S,3aR,4R,5R,6R)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
2-(4-methoxy-3,5-dimethylbenzyl)-hexahydropyrrolo[1,2-b]-
isoxazole (11). A mixture of nitrone 2 (250 mg, 0.6 mmol) and 8
(230 mg, 1.3 mmol) in toluene (0.6 mL) was stirred at 60 °C for 3
days, and then a TLC control (petroleum ether/AcOEt 1:4) showed
the disappearance of the starting nitrone 2 (Rf = 0.5). Evaporation of
the solvent under reduced pressure afforded a crude, which was
purified by flash column chromatography using an eluent with
increasing polarity (petroleum ether/AcOEt 5:1 then 3:1) affording
pure 11 (232 mg, 0.31 mmol, 65% yield) as a yellow oil (Rf = 0.33,
25
1
AcOEt 3:1): mp = 54−56 °C; [α]D = −22.9 (c = 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ = 7.40−7.28 (m, 30H; Ar−H), 6.75 (m,
4H; Ar−H), 6.43−6.35 (m, 6H; Ar−H), 4.70−4.54 (m, 12H,
OCH2Ar), 4.42 (d, J = 13.6 Hz, 4H; ArCH2Ar), 4.34 (quint, J = 6.8
Hz, 2H; 2-H), 4.10 (dd, J = 6.2, 4.6 Hz, 2H; 5-H), 3.99−3.93 (m, 6H;
4-H, ArOCH2CH2CH3), 3.82−3.69 (m, 10H; 3a-H, CH2OBn,
ArOCH2CH2CH3), 3.37 (dt, J = 6.3, 5.5 Hz, 2H; 6-H), 3.12 (d, J =
13.6 Hz, 4H; ArCH2Ar), 2.90 (dd, J = 14.0, 5.6 Hz, 2H; ArCH2), 2.64
(dd, J = 14.0, 6.8 Hz, 2H; ArCH2), 2.17−2.12 (m, 4H; 3-H), 2.04−
1.90 (m, 8H; ArOCH2CH2CH3), 1.11 (t, J = 7.6 Hz, 6H;
ArOCH2CH2CH3), 0.99 (t, J = 7.6 Hz, 6H; ArOCH2CH2CH3); 13C
NMR (50 MHz, CDCl3) δ = 155.6 (s, 2C), 155.4 (s, 2C), 138.1 (s,
2C), 137.8 (s, 2C), 137.5 (s, 2C), 135.5 (s, 4C), 133.6 (s, 4C), 130.6
(s, 2C), 129.0 (d, 4C), 128.8 (d, 4C), 128.1−127.1 (d, 30C), 121.7 (d,
2C), 87.4 (d, 2C), 82.6 (d, 2C), 76.9, 76.5 (d, 2C and t, 4C), 73.1 (t,
2C), 72.2 (t, 2C), 71.5 (t, 2C), 69.6 (t, 2C), 68.9 (d, 2C), 67.4 (d,
2C), 39.7 (t, 2C), 38.5 (t, 2C), 30.7 (t, 4C), 23.1 (t, 2C), 22.8 (t, 2C),
10.4 (q, 2C), 9.8 (q, 2C); ESI-MS calcd for C98H110N2NaO12 (M +
Na+) m/z 1529.8. Found m/z 1530.5. Anal. Calcd for C98H110N2O12
(1507.93): C, 78.06; H, 7.35; N, 1.86. Found C, 77.96; H, 7.64; N,
1.68.
23
1
petroleum ether/AcOEt 3:1): [α]D = −29.8 (c = 0.5, CHCl3) H
NMR (400 MHz, CDCl3) δ = 7.36−7.25 (m, 15H; Ar−H), 6.86 (s,
2H; Ar−H), 4.67−4.54 (m, 6H; OCH2Ar), 4.31 (quint, J = 6.6 Hz,
1H; 2-H), 4.07 (t, J = 5.8 Hz, 1H; 5-H), 3.91 (t, J = 4.6 Hz, 1H; 4-H),
3.78−3.66 (m, 3H; 3a-H, CH2OBn), 3.73 (s, 3H; ArOCH3), 3.36−
3.34 (m, 1H; 6-H), 2.94 (dd, J = 14.0, 5.6 Hz, 1H; ArCH2), 2.65 (dd, J
= 14.0, 6.8 Hz, 1H; ArCH2), 2.28 (s, 6H; ArCH3), 2.10 (t, J = 6.8 Hz,
2H; 3-H); 13C NMR (50 MHz, CDCl3) δ = 155.6 (s), 138.4 (s), 138.1
(s), 137.9 (s), 133.3 (s) 130.6 (s, 2C), 129.5 (d, 2C), 128.4−127.5 (d,
15C, C−Ar), 87.6 (d,), 83.0 (d), 77.0 (d), 73.4 (t), 72.5 (t), 71.9 (t),
69.9 (t), 69.4 (d), 67.8 (d), 59.7 (q), 40.0 (t), 38.6 (t), 16.0 (q, 2C);
MS (EI) m/z (%) = 593 (M+, 1), 562 (1), 472 (3), 400 (5), 219 (8),
149 (18), 91 (100). Anal. Calcd for C38H43NO5 (593.75): C, 76.87; H,
7.30; N, 2.36. Found C, 76.52; H, 7.47; N, 2.15.
25,26,27,28-Tetrakis({(2S,3aR,4R,5R,6R)-4,5-bis(benzyloxy)-
6-[(benzyloxy)methyl]hexahydropyrrolo[1,2-b]isoxazol-2-yl}-
methoxy)-calix[4]arene (15). A mixture of 5 (145 mg, 0.25 mmol)
and nitrone 2 (460 mg, 1.1 mmol) in toluene (1.1 mL) was stirred at
60 °C for 3 days, and then a TLC control (petroleum ether/AcOEt
10:1) showed the disappearance of the starting calixarene 5 (Rf = 0.6).
Evaporation of the solvent under reduced pressure afforded a crude,
which was purified by flash column chromatography on alumina
(petroleum ether/AcOEt 5:1) affording pure 15 (277 mg, 0.12 mmol,
49% yield) as a white waxy solid (Rf = 0.4, petroleum ether/AcOEt
26,28-Bis({(2R,3aR,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]-hexahydropyrrolo[1,2-b]isoxazol-2-yl}-
F
dx.doi.org/10.1021/jo301155p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3:1): [α]D 27 = −14.9 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
δ = 7.30−7.23 (m, 60H; Ar−H), 6.67−6.44 (m, 12H; Ar−H), 4.59−
4.42 (m, 32H; 2-H, OCH2Ar, ArCH2Ar), 4.15 (m, 4H; ArOCH2),
4.06−4.03 (m, 8H; 5-H, ArOCH2), 3.98 (m, 4H; 4-H), 3.73−3.71 (m,
8H; 3a-H, CH2OBn), 3.63−3.59 (m, 4H; CH2OBn), 3.35 (m, 4H; 6-
H), 3.15 (d, J = 13.2, 4H; ArCH2Ar), 2.26−2.24 (m, 4H; 3-H), 2.17−
2.13 (m, 4H; 3-H); 13C NMR (50 MHz, CDCl3) δ 155.6 (s, 4C),
138.5 (s, 4C), 138.2 (s, 4C), 137.9 (s, 4C), 135.0 (s, 8C), 128.4−127.4
(d, 68C), 122.3 (d, 4C), 87.8 (d, 4C), 83.4 (d, 4C), 75.0, 74.8 (d, 4C
and t, 4C), 73.3 (t, 4C), 72.2 (t, 4C), 71.7 (t, 4C), 69.9 (t, 4C), 69.1
(d, 4C), 67.5 (d, 4C), 37.5 (t, 4C), 31.3 (t, 4C); ESI-MS calcd for
C144H148N4NaO20 (M + Na+) m/z 2276.1. Found m/z 2276.1. Anal.
Calcd for C144H148N4O20 (2254.73): C, 76.71; H, 6.62; N, 2.48. Found
C, 76.42; H, 6.90; N, 2.56.
temperature for 15 h, and then a TLC control showed disappearance
of 11 (Rf = 0.5, petroleum ether/AcOEt 4:1). After filtration through
Celite, the crude was passed through the ion-exchange resin DOWEX
50WX8, eluting with MeOH (15 mL), H2O (10 mL) and a 10% aq
solution of NH3 (50 mL). Evaporation under reduced pressure
afforded a product that was further purified by flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH (33%) 8:1.5:0.1)
to obtain pure 18 (42 mg, 0.13 mmol, 36% yield) as a white solid: mp
= 110−112 °C; [α]D = +29.4 (c = 0.58, MeOH); H NMR (400
MHz, D2O) δ = 6.83 (s, 2H; Ar−H), 3.86−3.85 (m, 1H;
CH2CHOHCH2), 3.80 (t, J = 7.2 Hz, 1H, 4-H), 3.68−3.56 (m, 6H;
3-H, CH2OH, ArOCH3), 3.17−3.11 (m, 1H; 2-H), 3.07−3.03 (m, 1H,
5-H), 2.63−2.52 (m, 1H; ArCH2), 2.14 (s, 6H; ArCH3), 2.12 (m, 1H;
ArCH2), 1.73−1.66 (m, 2H; ArCH2CHOHCH2); 13C NMR (50
MHz, D2O) δ = 154.3 (s), 134.3 (s), 131.0 (s, 2C), 129.8 (d, 2C), 80.1
(d), 76.4 (d), 69.5 (d), 61.6 (d), 60.8 (t), 59.7 (q), 57.5 (d), 42.4 (t),
38.3 (t), 15.1 (q, 2C); MS (EI) m/z = 325 (M+, 0.9), 276 (12), 176
(22), 149 (18), 132 (100), 86 (17), 60 (35). Anal. Calcd for
C17H27NO5 (325.40): C, 62.75; H, 8.36; N, 4.30. Found C, 62.85; H,
8.46; N, 4.15.
26,28-Bis({3-((2R,3R,4R,5R)-3,4-dibenzyloxy-2-benzyloxy-
methyl-pyrrolidin-5-)-(2R)-2-hydroxypropyl}-25,27-
dihydroxycalix[4]arene (19). A mixture of 13 (100 mg, 0.075
mmol) and Zn dust (245 mg) in CH3COOH/H2O 9:1 (0.9 mL) was
heated at 45 °C for 1.5 h, and then a TLC control (petroleum ether/
AcOEt 1.5:1) showed the disappearance of the starting calixarene 13
(Rf = 0.4). After filtration through cotton, the solution was treated with
a saturated Na2CO3 solution until basic pH was reached. The phase
was extracted with AcOEt (3 × 25 mL), and the combined organic
phases dried over Na2SO4. Filtration and concentration under reduced
pressure afforded a crude, which was purified through flash column
chromatography (petroleum ether/AcOEt 1:1) to obtain pure 19 (67
mg, 0.05 mmol, 66% yield) as a white solid (Rf = 0.1): mp = 95−96
°C; [α]D 25 = −2.0 (c = 1.22, CDCl3); 1H NMR (400 MHz, CDCl3) δ
= 8.67 (s, 2H; OH), 7.33−7.19 (m, 30H; Ar−H), 7.08−7.06 (m, 2H;
Ar−H), 7.03−6.98 (m, 4H; Ar−H), 6.96−6.94 (m, 2H; Ar−H), 6.80
(t, J = 7.6 Hz, 2H; Ar−H), 6.65 (t, J = 7.6 Hz, 2H; Ar−H), 4.58−4.42
(m, 16H; OCH2Ar, CH2CHOHCH2, ArCH2Ar), 4.23 (d, J = 13.2 Hz,
2H; ArCH2Ar), 4.13 (dd, J = 9.2, 2.8 Hz, 2H; ArOCH2), 3.95 (t, J =
3.8 Hz, 2H; 4-H), 3.91−3.86 (m, 4H; 3-H, ArOCH2), 3.68−3.58 (m,
2H; 2-H), 3.54−3.52 (m, 4H; CH2OBn), 3.40−3.34 (m, 6H; 5-H,
ArCH2Ar), 2.10−2.00 (m, 2H; ArOCH2CHOHCH2), 1.92−1.85 (m,
2H; ArOCH2CHOHCH2); 13C NMR (50 MHz, CDCl3) δ = 152.2 (s,
2C), 150.8 (s, 2C), 138.2 (s, 6C), 134.0 (s, 4C), 133.5 (s, 4C), 129.4
(d, 2C), 128.7 (d, 2C), 128.6 (d, 2C), 128.5 (d, 2C), 128.2−127.5 (d,
30C), 125.9 (d, 2C), 119.8 (d, 2C), 89.2 (d, 2C), 86.1 (d, 2C), 80.7 (d
2C), 73.1 (t, 2C), 71.9 (t, 4C), 70.4 (t, 2C), 68.6 (t, 2C), 61.6 (d, 2C),
58.9 (d, 2C), 35.3 (t, 2C), 32.0 (t, 2C), 31.3 (t, 2C); ESI-MS calcd for
C86H90N2NaO12 (M + Na+) m/z 1365.6. Found m/z 1366.1. Anal.
Calcd for C86H90N2O12 (1343.64): C, 76.87; H, 6.75; N, 2.08. Found
C, 76.93; H, 7.18; N, 2.09.
24
1
5,11,17,23-Tetrakis({(2S,3aR,4R,5R,6R)-4,5-bis(benzyloxy)-6-
[(benzyloxy)methyl]-hexahydropyrrolo[1,2-b]isoxazol-2-yl}-
methyl)-25,26,27,28-tetrapropoxy-calix[4]arene (16). A mixture
of 6 (105 mg, 0.14 mmol) and nitrone 2 (257 mg, 0.62 mmol) in
toluene (0.62 mL) was stirred at 60 °C for 3 days, and then a TLC
control (petroleum ether/AcOEt 10:1) showed the disappearance of
the starting calixarene 6 (Rf = 0.6). Evaporation of the solvent under
reduced pressure afforded a crude, which was purified by flash column
chromatography using an eluent with increasing polarity (petroleum
ether/AcOEt 3:1 then 1:1) affording pure 16 (48 mg, 0.02 mmol, 14%
yield) as a white solid (Rf = 0.3, petroleum ether/AcOEt 2:1): mp =
25
1
68−70 °C; [α]D = −30.7 (c = 0.41, CHCl3); H NMR (400 MHz,
CDCl3) δ = 7.36−7.26 (m, 60H; Ar−H), 6.44 (m, 8H; Ar−H), 4.66−
4.50 (m, 24H; OCH2Ar), 4.39 (d, J = 13.0, 4H; ArCH2Ar), 4.17−4.14
(m, 4H; 2-H), 4.06−4.04 (m, 4H; 5-H), 3.89−3.83 (m, 12H, 4-H;
ArOCH2CH2CH3), 3.72−3.65 (m, 12H; 3a-H, CH2OBn), 3.32 (m,
4H; 6-H), 3.06 (d, J = 13.0, 4H; ArCH2Ar), 2.72−2.68 (m, 4H;
ArCH2), 2.46−2.41 (m, 4H; ArCH2), 2.03−1.91 (m, 16H, 3-H;
ArOCH2CH2CH3), 1.04−1.00 (m, 12H; ArOCH2CH2CH3); 13C
NMR (50 MHz, CDCl3) δ 155.1 (s, 4C), 138.4 (s, 4C), 138.1 (s,
4C), 137.8 (s, 4C), 134.5 (s, 8C), 130.8 (s, 4C), 128.8 (d, 4C), 128.5
(d, 4C), 128.3−127.4 (d, 60C), 87.6 (d, 4C), 83.1 (d, 4C), 77.3 (d,
4C), 76.6 (t, 4C), 73.4 (t, 4C), 72.5 (t, 4C), 71.8 (t, 4C), 70.1 (t, 4C),
69.2 (d, 4C), 67.7 (d, 4C), 40.0 (t, 4C), 38.9 (t, 4C), 31.2 (t, 4C), 23.4
(t, 4C), 10.6 (q, 4C); ESI-MS calcd for C156H172N4NaO20 m/z 2444.3.
Found m/z 2444.9. Anal. Calcd for C156H172N4O20 (2423.05): C,
77.33; H, 7.15; N, 2.31. Found C, 77.36; H, 7.25; N, 2.04.
(2R,3R,4R,5R)-2-[(2R)-3-(2,6-Dimethylphenoxy)-2-hydroxy-
propyl]-5-(hydroxymethyl)pyrrolidine-3,4-diol (17). To a sol-
ution of compound 10 (180 mg, 0.31 mmol) in MeOH (25 mL), Pd/
C (20 mg, 11% w) and 10 drops of concentrated HCl were added. The
mixture was left under H2 atmosphere at room temperature for 15 h,
and then a TLC control showed disappearance of 10 (Rf = 0.5,
petroleum ether/AcOEt 5:1). After filtration through Celite, the crude
was passed through the ion-exchange resin DOWEX 50WX8, eluting
with MeOH (15 mL), H2O (10 mL) and a 10% aq solution of NH3
(50 mL). Evaporation under reduced pressure afforded pure 17 (93
25
mg, 0.3 mmol, 97% yield) as a white solid: mp = 95−97 °C; [α]D
=
5,17-Bis({3-((2R,3R,4R,5R)-3,4-dibenzyloxy-2-benzyloxy-
methyl-pyrrolidin-5-)-(2R)-2-hydroxypropyl}-25,26,27,28-tet-
rapropoxy-calix[4]arene (20). A mixture of 14 (50 mg, 0.033
mmol) and Zn dust (108 mg) in CH3COOH/H2O 9:1 (0.4 mL) was
heated at 45 °C for 2 h, and then a TLC control (petroleum ether/
AcOEt 3:1) showed the disappearance of the starting calixarene 14 (Rf
= 0.4). After filtration through cotton, the solution was treated with a
saturated Na2CO3 solution until basic pH was reached. The phase was
extracted with AcOEt (3 × 20 mL), and the combined organic phases
dried over Na2SO4. Filtration and concentration under reduced
pressure afforded a crude, which was purified through flash column
chromatography (CH2Cl2/MeOH/NEt3 30:1:0.1) to obtain pure 20
(42 mg, 0.028 mmol, 86% yield) as a white waxy solid: [α]D 27 = +14.6
+33.6 (c = 0.14, MeOH); 1H NMR (400 MHz, D2O) δ = 7.04 (d, J =
7.0 Hz, 2H; Ar−H), 6.95 (t, J = 7.2 Hz, 1H; Ar−H), 4.13 (ddt, J = 9.6,
6.8, 3.6 Hz, 1H; CH2CHOHCH2), 3.91 (t, J = 7.2 Hz, 1H, 4-H), 3.83
(t, J = 7.2 Hz, 1H, 3-H), 3.79−3.67 (m, 4H; CH2−OH, ArOCH2),
3.35 (td, J = 8.8, 4.4 Hz, 1H; 2-H), 3.27−3.22 (m, 1H; 5-H), 2.19 (s,
6H; ArCH3), 1.97 (ddd,
J = 14.8, 10.0, 4.8 Hz, 1H,
ArOCH2CHOHCH2), 1.84 (ddd, J = 14.8, 8.0, 3.2 Hz, 1H,
ArOCH2CHOHCH2); 13C NMR (50 MHz, D2O) δ = 153.5 (s),
130.4 (s, 2C), 128.0 (d, 2C), 124.0 (d), 78.8 (d), 75.2 (d), 74.9 (t),
66.3 (d), 60.9 (d), 59.2 (t), 56.1 (d), 33.9 (t), 14.4 (q, 2C); MS (EI)
m/z = 311 (M+, 2), 280 (60), 158 (28), 132 (100), 102 (31), 86 (84),
60 (10). Anal. Calcd for C16H25NO5 (311.37): C, 61.72; H, 8.09; N,
4.50. Found C, 61.78; H, 7.86; N, 4.15.
1
(c = 0.25, CHCl3); H NMR (400 MHz, CDCl3) δ = 7.39−7.28 (m,
30H; Ar−H), 6.69 (d, J = 6.4 Hz, 4H; Ar−H), 6.42 (m, 6H; Ar−H),
4.60−4.48 (m, 12H; OCH2Ar), 4.45 (d, J = 13.6 Hz, 2H; ArCH2Ar),
4.44 (d, J = 13.5 Hz, 2H; ArCH2Ar), 4.00−3.95 (m, 4H; 4-H,
CH2CHOHCH2), 3.90−3.85 (m, 6H; 3-H, ArOCH2CH2CH3), 3.78
(t, J = 6.8 Hz, 4H; ArOCH2CH2CH3), 3.60−3.56 (m, 6H; 2-H,
(2R,3R,4R,5R)-2-[(2S)-2-Hydroxy-4-(4-methoxy-3,5-
dimethylphenyl)butyl]5-(hydroxymethyl)pyrrolidine-3,4-diol
(18). To a solution of compound 11 (220 mg, 0.37 mmol) in MeOH
(30 mL), Pd/C (25 mg, 11% w) and 10 drops of concentrated HCl
were added. The mixture was left under H2 atmosphere at room
G
dx.doi.org/10.1021/jo301155p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CH2OBn), 3.40 (q, J = 5.2 Hz, 2H, 5-H), 3.12 (d, J = 13.6 Hz, 2H;
ArCH2Ar), 3.10 (d, J = 13.6 Hz, 2H; ArCH2Ar), 2.71 (dd, J = 13.4, 7.0
Hz, 2H; ArCH2CHOH), 2.58 (dd, J = 13.4, 7.0 Hz, 2H;
ArCH2CHOH), 1.98−1.89 (m, 8H; ArOCH2CH2CH3), 1.88−1.81
(m, 2H; ArCH2CHOHCH2), 1.63−1.56 (m, 2H; ArCH2CHOHCH2),
1.06 (t, J = 7.6 Hz, 6H; ArOCH2CH2CH3), 0.93 (t, J = 7.6 Hz, 6H;
ArOCH2CH2CH3); 13C NMR (50 MHz, CDCl3) δ = 155.7 (s, 2C),
155.6 (s, 2C), 138.0 (s, 2C), 137.9 (s, 4C), 135.6 (s, 4C), 134.1 (s,
4C), 131.6 (s, 2C), 129.2 (d, 4C), 128.3−127.6 (d, 34C), 122 (d, 2C),
88.6 (d, 2C), 85.5 (d, 2C), 76.8 (t, 2C), 76.5 (t, 2C), 73.2 (t, 2C), 72.1
(t, 2C), 71.9 (t, 2C), 71.3 (d, 2C), 69.4 (t, 2C), 61.2 (d, 2C), 59.2 (d,
2C), 43.3 (t, 2C), 36.7 (t, 2C), 31.1 (t, 4C), 23.5 (t, 2C), 23.3 (t, 2C),
10.8 (q, 2C), 10.3 (q, 2C); ESI-MS calcd for C98H114N2NaO12 (M +
Na+) m/z 1533.8. Found m/z 1534.6. Anal. Calcd for C98H114N2O12
(1511.96): C, 77.85; H, 7.60; N, 1.85. Found C, 77.73; H, 7.58; N,
2.11.
Chem. 1999, 7, 1965−1971. (c) Wennekes, T.; van den Berg, R. J. B.
H. N.; Bonger, K. M.; Donker-Koopman, W. E.; Ghisaidoobe, A.; van
der Marel, G. A.; Strijland, A.; Aerts, J. M. F. G.; Overkleeft, H. S.
Tetrahedron: Asymmetry 2009, 20, 836−846.
(7) Diot, J.; García-Moreno, M. I.; Gouin, S. G.; Ortiz Mellet, C.;
Haupt, K.; Kovensky, J. Org. Biomol. Chem. 2009, 7, 357−363.
(8) Compain, P.; Decroocq, C.; Iehl, J.; Holler, M.; Hazelard, D.;
Mena Barragan
Int. Ed. 2010, 122, 5889−5892.
(9) Decroocq, C.; Rodríguez-Lucena, D.; Russo, V.; Mena Barragan
́
, T.; Ortiz Mellet, C.; Nierengarten, J.-F. Angew. Chem.,
́
,
T.; Ortiz Mellet, C.; Compain, P. Chem.Eur. J. 2011, 17, 13825−
13831.
(10) Interestingly, the highest multivalent effect was always found
with jack bean-α-mannosidase.
(11) Compain, P.; Martin, O. R. Iminosugars: from Synthesis to
Therapeutic Applications; Wiley VCH: New York, 2007.
(12) For some recent reports on the synthesis and activity of
ASSOCIATED CONTENT
* Supporting Information
■
́
glycoclusters with calix[4]arenes see: (a) Andre, S.; Grandjean, C.;
S
Gautier, F.-M.; Bernardi, S.; Sansone, F.; Gabius, H.-J.; Ungaro, R.
Chem. Commun. 2011, 47, 6126−6127. (b) Galante, S.; Geraci, C.;
Sciuto, S.; Campo, V. L.; Carvalho, I.; Sesti-Costa, R.; Guedes, P. M.
M.; Silva, J. S.; Hill, L.; Nepogodiev, S. A.; Field, R. A. Tetrahedron
2011, 67, 5902−5912. (c) Moni, L.; Rossetti, S.; Scoponi, M.; Marra,
A.; Dondoni, A. Chem. Commun. 2010, 46, 475−477.
1H NMR spectra of compounds 10−20, 13C NMR spectra of
compounds 9−20, COSY spectra of compounds 9−13 and
15−20, HMQC spectra of compounds 11, 13, and 15−20, 1D
NOESY spectra of compounds 10 and 13, and 2D NOESY
spectra of compounds 14 and 17. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) For some reviews on glycocalixarenes, see: (a) Fulton, D. A.;
Stoddart, F. F. Bioconjugate Chem. 2001, 12, 655−672. (b) Casnati, A.;
Sansone, F.; Ungaro, R. Acc. Chem. Res. 2003, 36, 246−254. (c) Baldini,
L.; Casnati, A.; Sansone, F.; Ungaro, R. Chem. Soc. Rev. 2007, 36, 254−
266. (d) Dondoni, A.; Marra., A. Chem. Rev. 2010, 110, 4949−4977.
(e) Sansone, F.; Baldini, L.; Casnati, A.; Ungaro, R. New J. Chem. 2010,
34, 2715−2728. (f) Dondoni, A. Org. Biomol. Chem. 2010, 8, 3366−
3385. (g) Sansone, F.; Rispoli, G.; Casnati, A.; Ungaro, R. Multivalent
Glycocalixarenes. In Synthesis and Biological Applications of Glyco-
conjugates; Renaudet, O., Spinelli, N., Eds.; Bentham Science
Publishers: Sharjah, United Arab Emirates, 2011; pp 36−63.
(14) (a) Tarbell, D. S.; Kincaid, J. F. J. Am. Chem. Soc. 1940, 62,
728−731. (b) Curtin, D. Y.; Crawford, R. J.; Wilhelm, M. J. Am. Chem.
Soc. 1958, 80, 1391−1397. (c) Hansen, H.-J. Helv. Chim. Acta 1977,
60, 2007−2033.
AUTHOR INFORMATION
Corresponding Author
*E-mail: andrea.goti@unifi.it; casnati@unipr.it.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank MIUR (PRIN 2008 200824M2HX and
200858SA98) and Ente Cassa di Risparmio di Firenze (Ente
CRF) for financial support.
REFERENCES
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1
(16) Compound 9 was obtained >95% pure (from H NMR) with
2005, 3, 1593−1608. (c) Gabius, H.-J.; Andre,
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traces of diastereoisomers and spectroscopically characterized: 1H
NMR (CDCl3, 400 MHz) δ = 7.03−7.01 (m, 3H), 4.69−4.66 (m,
1H), 4.00−3.95 (m, 1H), 3.93−3.89 (m, 1H), 3.86−3.82 (m, 2H),
3.61−3.62 (m, 2H), 2.94 (dd, J = 10.9, 8.8 Hz, 1H), 2.41 (t, J = 7.2 Hz,
2H), 2.32 (s, 6H), 1.24−1.23 (m, 18H); 13C NMR (50 MHz, CDCl3)
δ = 154.7 (s), 130.5 (s, 2C), 128.9 (d, 2C), 124.2 (d), 81.9 (d), 75.9
(d), 74.3 (d), 73.7 (s, 2C), 72.1 (t), 69.7 (d), 59.5 (t), 36.7 (t), 28.5
(q, 3C), 28.4 (q, 3C), 16.1 (q, 2C); MS (EI) m/z (%) = 391 (M+, 26),
334 (48), 57 (100). Anal. Calcd for C23H37NO4 (391.5): C, 70.55; H,
9.52; N, 3.58. Found C, 70.10; H, 9.80; N, 3.57.
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dx.doi.org/10.1021/jo301155p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(21) Compared to the reaction with nitrone 1, the crude reaction
mixture from nitrone 2 appeared cleaner, and essentially only one spot
was detected on TLC.
(22) The reaction carried out at room temperature required
prolonged reaction times (20 days).
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1
(24) Compound 12 was obtained >95% pure (from H NMR) with
traces of diastereoisomers and spectroscopically characterized: 1H
NMR (400 MHz, CDCl3) δ = 7.38 (s, 2H), 7.09 (d, J = 7.6 Hz, 4H),
6.87−6.85 (m, 4H), 6.72 (t, J = 7.6 Hz, 2H), 6.69 (dd, J = 7.6, 7.2 Hz,
2H), 4.82 (m, 2H), 4.42 (d, J = 13.2 Hz, 2H), 4.40 (d, J = 13.2 Hz,
2H), 4.15−4.11 (m, 4H), 3.99 (dt, J = 6.8, 6.0 Hz, 2H), 3.88 (t, J = 5.2
Hz, 2H), 3.66 (m, 2H), 3.55 (dd, J = 10.4, 5.6 Hz, 2H), 3.40 (d, J =
13.6 Hz, 1H), 3.39 (d, J = 13.6 Hz, 1H), 2.96 (t, J = 9.2 Hz, 2H),
2.66−2.59 (m, 2H), 2.51−2.45 (m, 2H), 1.25 (s, 18H), 1.23 (s, 18H);
13C NMR (50 MHz, CDCl3) δ = 153.0 (s, 2C), 151.7 (s, 2C), 132.9
(s, 4C), 128.9 (d, 2C), 128.8 (d, 2C), 128.3 (d, 2C), 128.1 (s, 4C),
125.1 (d, 2C), 118.8 (d, 2C), 81.8 (d, 2C), 76.6 (t, 2C), 76.3 (d, 2C)
75.0 (d, 2C), 74.1 (s, 4C), 69.9 (d, 2C), 59.7 (t, 2C), 37.1 (t, 2C), 31.5
(t, 4C), 29.0 (q, 6C), 28.7 (q, 6C). Anal. Calcd for C58H78N2O10
(963.25): C, 72.32; H, 8.16; N, 2.91. Found C, 72.45; H, 8.27; N, 2.69.
(25) The reaction performed at room temperature showed only the
presence of the starting materials on TLC after 4 days.
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I
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