β-Cyclodextrin-glycerol dimers: Synthesis and NMR conformational analysis

Article abstract of DOI:10.1002/ejoc.201201716

The synthesis of new β-cyclodextrin dimers linked through their primary faces by different glycerol-like moieties by click chemistry is described. The unusual behaviour of these cyclodextrin-glycerol dimers in aqueous solution has been studied by NMR spec

Full text of DOI:10.1002/ejoc.201201716

FULL PAPER
DOI: 10.1002/ejoc.201201716
β-Cyclodextrin–Glycerol Dimers: Synthesis and NMR Conformational Analysis
[a]
[b]
[b]
[c]
Vanessa Legros, Cécile Vanhaverbeke, Florence Souard, Christophe Len, and
Jérôme Désiré*[
a]
Keywords: Cyclodextrins / Glycerol / Click chemistry / Conformation analysis
The synthesis of new β-cyclodextrin dimers linked through
their primary faces by different glycerol-like moieties by
click chemistry is described. The unusual behaviour of these
cyclodextrin–glycerol dimers in aqueous solution has been
studied by NMR spectroscopy. We show that, depending on
the length of the linking arm between the two cyclodextrins,
the dimers could adopt very different conformations in water:
symmetrical or pseudo[1]rotaxane-like structures through
one D-glucopyranose unit tumbling in one β-cyclodextrin.
Introduction
CD derivatives consisting of two CD units linked by
tethers of different nature have received much attention be-
cause of their improved binding abilities and molecular
selectivity compared with those of native CDs. In compari-
son with CD monomers, bridged bis(β-CD) derivatives
clearly allow two hydrophobic cavities to be in close vicinity,
which is an improvement; moreover, the presence of func-
tional linkers between the two CDs can supply a well-orga-
nized pseudo-cavity that may afford supplementary binding
Cyclodextrins (CDs) are versatile macrocyclic malto-
oligosaccharides composed of α-(1Ǟ4)-linked d-glucopyr-
anose units in the C chair conformation. The most com-
4
1
mon CDs have six, seven or eight d-glucopyranose units
and are referred to as α-, β- and γ-CD, respectively. As a
consequence of the structure, CDs are hydrophilic entities
that feature a hydrophobic conical cavity. Due to their
unique cup-like structures, CDs are known to form in-
clusion complexes in aqueous solution with a large variety
of organic targets with a hydrophobic nature and a suitable
size and geometry, and are involved in many supramo-
lecular applications.[ Because of such an ability to behave
as hosts, CDs and their chemically modified derivatives find
a wide range of applications that include the areas of drug
[11,12]
properties.
Since early work on the synthesis and cooperative bind-
[13]
[14]
ing of CD dimers by the groups of Breslow, Tabushi,
[15]
[16]
Harada
and Fujita,
much effort has been devoted to
making CD dimers with a variety of functional tethers.
Recently, click chemistry has proved its efficiency to access
1,2]
[11]
[17]
such dimeric structures in a straightforward manner. Re-
[
2–4]
[5]
[6]
delivery,
analytical chemistry,
artificial enzymes,
cent conformational analysis of bridged bis(β-CD) deriva-
tives has highlighted that some CD dimers were able to
adopt unusual conformations and behave as pseudo[1]-
[7]
[8]
[9]
photochemical sensors, food technology, catalysis and
nanostructured functional materials.[ However, the rela-
tively low values for the binding constants of native CDs
or simply modified CD monomers with model substrates
appeared to be a limitation in some of their applications.
10]
rotaxanes in water solution through tumbling of the pyr-
[18]
anose units of CDs.
This inversion phenomenon results
in limited accessibility to the CD cavities and is of major
importance for understanding and controlling CD applica-
tions.
Herein, we report our contribution regarding the synthe-
sis of β-CD dimers with glycerol-like structures as linking
arms. Such compounds were obtained by click chemistry
coupling reactions. To access CD dimers with different
physical properties, (i) the length of the linking arm be-
tween the two CDs has been modified; (ii) an allyl group
has been introduced on the secondary hydroxy group of the
glycerol moiety, which should allow further modifications
of the CD dimers by thiol–ene click reactions; and (iii) the
[
a] Université de Poitiers, CNRS UMR 7285, Institut de Chimie
des Milieux et Matériaux de Poitiers,
4
Rue Michel Brunet, 86022 Poitiers, France
Fax: +33-3-44971591
E-mail: jerome.desire@univ-poitiers.fr
[
[
b] Université de Grenoble I/CNRS, UMR 5063, Département de
Pharmacochimie Moléculaire, ICMG FR 2607,
4
70 rue de la Chimie, BP 53, 38041 Grenoble, France
c] Université de Technologie de Compiègne, Ecole Supérieure de
Chimie Organique et Minérale, EA 4297 UTC/ESCOM, Centre behaviour of native and permethylated CDs in solution has
de Recherches Royallieu,
been studied by NMR spectroscopy. As already observed
BP 20529, 60205 Compiègne cedex, France
[
18]
in the literature for very few examples, one of these CD
dimers showed unusual conformations in aqueous solution.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201716.
Eur. J. Org. Chem. 2013, 2583–2590
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Legros, C. Vanhaverbeke, F. Souard, C. Len, J. Désiré
FULL PAPER
Results and Discussion
Synthesis
cleophilic substitutions starting from mono-6-amino-β-
[
20]
CD.
formed in two steps from β-CD by following a standard
The synthesis of mono-6-azido-β-CD 5 was per-
[
21]
literature procedure.
of CH I in DMF was achieved as previously detailed to
Permethylation of 5 with an excess
To access β-CD dimers in which CD moieties are linked
by spacers of variable lengths, which could also allow fur-
ther easy modifications, we turned our attention to glycerol-
like moieties. Starting from 1,3-dichloro-2-propanol (1), we
obtained the dipropargylated glycerol derivative 3 in 34%
yield in one step by treatment with propargyl alcohol in
sodium hydroxide at reflux.[ Similarly, from epichlorhyd-
rin (2) and butynol in the presence of aqueous sodium
hydroxide and tetrabutylammonium bromide in petroleum
3
[
21]
give mono-6-azido-2,3,6-per-O-methyl-β-CD 6.
Bis-
propargylated glycerol arm 3 (1.2 equiv.) was then subjected
to CuAAC with 5 or 6 (2 equiv.) and a mixture of
CuSO ·5H O (2 equiv.)/sodium ascorbate (NaAsc; 4 equiv.)
4
2
in DMSO at 85 °C to give CD dimers 7 and 8 in 18 and
1% yield, respectively, after semi-preparative HPLC purifi-
cation for 7 and classical silica gel column purification for
(Scheme 2). In a similar manner (Scheme 2), CuAAC re-
19]
5
8
ether, dialkyne
Scheme 1).
4 was obtained in moderate yield
actions were performed starting from azido-CDs 5 or 6 and
alkynyl glycerol arm 4 to give β-CD dimers 9 and 10 in 42
(
1
and 64% yield, respectively. These new CD dimers gave H
and 13C NMR spectroscopy and mass spectrometry data
consistent with their structures.
To introduce modifications of biological interest (pen-
etrating or targeting agents) directly onto the linker moiety
of the β-CD dimer, we synthesized linking arm 11 in 67%
yield by direct alkylation of compound 3 using allyl brom-
ide in the presence of sodium hydride in DMF (Scheme 3).
Because thiol–ene reactions have emerged recently in the
Scheme 1. Synthesis of glycerol-type linking arms 3 and 4. Reagents
[22]
family of click reactions, linker 11 was designed to allow
and conditions: (a) NaOH (aq.), reflux, 3 h, 34%; (b) NaOH (aq.),
orthogonal click reactions: first the CuAAC reaction, as de-
scribed previously for the synthesis of dimers 7–10, then a
thiol–ene click reaction to introduce various modifications.
4
Bu NBr, petroleum ether, room temp., 18 h, 38%.
With these linkers in hand, the β-CD dimers could be Few examples of this click–click strategy have been reported
I
[23]
obtained directly by using the Cu -catalysed azide–alkyne in the literature,
and none on CD derivatives. CuAAC
cycloaddition reaction (CuAAC). Indeed, this click chemis- reactions between dialkyne 11 and native or permethylated
try reaction has been extensively used as an efficient tool to monoazido-β-CD derivatives 5 and 6 were performed as de-
[
17]
build mono-, di- and tritopic CDs from azido-CDs.
In scribed for the synthesis of other dimers in the presence of
our group, during the synthesis of CD–nucleobase deriva- a mixture of CuSO ·5H O/sodium ascorbate in DMSO at
4
2
tives, we also found that click reactions using mono-6- 85 °C (Scheme 3). Dimers 12 and 13 were obtained in 14
azido-β-CD were more efficient than the corresponding nu- and 53% yield, respectively, from 5 and 6.
4 2
Scheme 2. Synthesis of β-CD dimers 7–10 with glycerol-type linkers. Reagents and conditions: (a) 3, CuSO ·5H O, NaAsc (aq.), DMSO,
85 °C. (b) 4, CuSO
4 2
·5H O, NaAsc (aq.), DMSO, 85 °C.
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β-Cyclodextrin–Glycerol Dimers
Scheme 3. Synthesis of β-CD dimers 12 and 13 with a functionalized glycerol linker. Reagents and conditions: (a) NaH, DMF, room
temp., o/n, 67%; (b) 5 or 6,CuSO ·5H O, NaAsc (aq.), DMSO, 85 °C.
4 2
Six new β-CD dimers were obtained: three with native
CDs (7, 9, 12) and three that were permethylated (8, 10,
13). CDs 7 and 8 differed from 9 and 10 by the spacer
length; CDs 12 and 13 possessed a functionalized glycerol
linker. During characterization of these six new β-CD di-
mers by NMR spectroscopy, unexpected observations
prompted us to undertake a detailed NMR spectroscopy
study in solution.
Solution NMR Spectroscopy Conformational Analysis
1H NMR spectra of the synthesized dimers 7, 9 and 12 in
[
D ]DMSO and 8, 10 and 13 in CDCl (see the Supporting
6 3
Information) revealed only one singlet for the triazole pro-
tons H8-X and H8-Y (Figure 1), which was indicative of a
symmetrical conformation.
1
Figure 2. H NMR spectra of β-CD dimer 9 (13 mm, 298 K) in [D
6
]-
DMSO (A) and D O at 298 (B) and 318 K (C). AA relates to the
2
symmetrical conformation, BC and DE to the unsymmetrical
forms.
1
To clarify this phenomenon, H NMR spectroscopy ex-
periment was performed at 318 K (Figure 2, C). At this
temperature, five separated signals are clearly observed (δ =
Figure 1. β-CD dimer 9.
7
.84, 7.89, 8.07, 8.11 and 8.12 ppm). Three species can be
1
H NMR spectra of dimer 9 in D O or [D ]DMSO are deduced from integral values: one symmetrical form, AA,
2
6
not similar, in contrast with NMR spectra of dimers 7, 8, with only one singlet at δ = 8.11 ppm and two unsymmetri-
0, 12 and 13: whereas only one singlet was observed for cal forms, a major one, BC, and a minor one, DE (Figure 2,
H8 in [D ]DMSO, the spectrum in D O revealed intriguing C), with a distinct signal for both H8-X and H8-Y triazole
1
6
2
signals. Effectively, at 298 K in the dissociating solvent [D6]- protons (δ = 7.84 and 8.12 ppm for BC and δ = 7.89 and
DMSO, both H8-X and H8-Y protons appear as a singlet 8.07 ppm for DE). The H8 protons chemical shifts of un-
1
at δ = 7.81 ppm (Figure 2, A), whereas the H NMR spec- symmetrical forms BC and DE are close, which suggest two
trum in D O (Figure 2, B) is more complicated with two neighbouring structures. Considering the very close down-
2
broad singlets at δ = 7.58 and 7.64 ppm and a large signal field chemical shifts of H8 protons (δ = 8.07, 8.11 and
at δ = 7.90 ppm.
8.12 ppm) of the three forms, the assumption can be made
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V. Legros, C. Vanhaverbeke, F. Souard, C. Len, J. Désiré
FULL PAPER
that all forms have one side with very similar chemical envi- H6-C of the CD (see Figure 3 and the Supporting Infor-
ronments. Therefore, each unsymmetrical form BC and DE mation). This clearly demonstrates that BC folds as a hair-
should have one AA-like side.
pin because of the H10-B/H8-C correlation. We can also
It has been reported that increasing the temperature has conclude that the triazole moiety linked to B-CD is in-
[
24]
a detrimental effect on the CD-inclusion phenomenon;
cluded into the CD on the other side (C-CD) because H10-
the free form used to be favoured. The solution equilibrium B correlates with internal protons of C-CD. For the minor
of the AA/BC/DE forms in D O is modified upon increas- DE form, the lack of resolution allows fewer correlations
2
1
ing the temperature from 298 to 318 K, as observed in H to be observed (see the Supporting Information). Neverthe-
NMR spectra of dimer 9 at those temperatures. The ratios less, interesting correlations can be distinguished that are
of symmetrical/unsymmetrical AA/BC/DE forms vary from different from those of the BC form. Indeed, a long-range
30:45:25 to 40:38:22 (Table 1). At 318 K, an increase in the correlation between H6-D of the CD and H13-D indicates
integral value for the symmetrical free form is observed, as different folding of the linker: the bend of the hairpin is
described before.
shifted from the middle of the dimer in the case of the BC
form to C11-D in the case of the DE form.
Table 1. Ratio of the three forms observed by 1H NMR spec-
2
troscopy in D O, depending on the temperature, for dimer 9.
T [K]
AA form[a]
BC form[a]
DE form[a]
2
3
98
18
30
40
45
38
25
22
[
a] Percentage calculated from integrals of H8 signals in the 1
NMR spectrum.
H
Although rarely evidenced, tumbling of a pyranose unit
of CDs has been recently highlighted. Liu et al. described
the synthesis of tetrakis(permethyl-β-CD)-modified zinc(II)
porphyrin and showed that some CDs included the por-
phyrin by rotating 360° around the pivot d-glucopyranose
unit in the methylated CD when dissolved in water.[
18a]
Har-
ada et al. reported the formation of a pseudo[1]rotaxane
dimer from an altro-α-CD dimer by using tumbling of an
[
18b,18c]
altropyranose unit.
They demonstrated that alkyl
CD dimers with long and flexible chains formed the self-
inclusion complex easily in aqueous solution. Monflier et
al. also described an unusual inversion phenomenon of β-
Figure 3. 2D-NOESY NMR spectrum enlargement (H10 region)
at 298 K for dimer 9, and the proposed structure of BC in water.
CD dimers in water.[
18d]
Through a detailed NMR confor-
mational analysis, they clearly showed that one of the CD
d-glucopyranose units underwent 360° rotation in water, so
that the CD linker was included into one of the CD cavities.
The BC and DE conformations are similar, but distinct.
They concluded that tumbling strongly depended on the na- NMR spectroscopy results suggest strong interactions of
ture of the spacer. the linker, either the triazole part for BC or the glycerol
Based on these data, we suppose that dimer 9 could be- part for DE (see Figure 3 and the Supporting Information)
have as a pseudo-rotaxane through tumbling of one CD with one of the two CD cavities. Tables summarising
glucopyranose unit, as described previously. Regarding the exhaustive NOE correlations for each unsymmetrical form
two upfield H8 proton chemical shifts (δ = 7.84 and are given in the Supporting Information. The inclusion of
7.89 ppm), it can be assumed that these signals attest to a these hydrophobic moieties could explain the temperature
chemical environment that is different from the AA-like stability of the three conformations in D O (Figure 2).
2
side. Unsymmetrical forms BC and DE may have structures Moreover, DE appears to be an intermediate form between
in which a part of the spacer is included in the cavity of the AA and BC: the CD of the E side is partially blocked on
opposite CD. This might be possible only by a 360° rotation the glycerol part of the linker thanks to the presence of a
of one of the substituted d-glucopyranose units of the β- hydroxy group.
CD dimer. To confirm this hypothesis, we performed 2D-
NOE correlations have been used as constraints in Sybyl
NOESY NMR spectroscopy experiments to observe long- software to build, after molecular dynamic calculations, the
range correlations between the triazole and/or spacer with illustrative 3D models outlined in Figure 4. In the case of
the CD moiety (Figure 3). In the AA form, no long-range the AA form, no constraints have been set. For the BC
correlations have been observed. On the contrary, in the form, after iterative assays, four distance constraints are
case of BC and DE, long-range dipolar couplings have been sufficient to obtain a structure that complies with every ob-
observed. For the BC form, proton H10-B correlates with served NOE. For the DE form, the lack of NOEs makes
proton H8-C of the linker and protons H3-C, H5-C and the 3D structure built with four constraints uncertain. Nev-
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β-Cyclodextrin–Glycerol Dimers
Figure 4. Top: Proposed structures of CD dimer 9 in water at 298 K from NMR spectroscopic data. Bottom: Corresponding models of
the three conformations.
ertheless, in the DE conformation, the linking arm clearly enon is not observed when dimers are composed of per-
appears to be less deeply included into the cavity of the CD methylated β-CDs, probably due to a lack of space in the
than that of the BC form.
cavity. For dimers composed of native β-CDs, the only one
able to give rise to tumbling of one glucopyranose unit is
the one with the more flexible linking arm, as expected.
Compared with the previously described CD dimers in
which inversion processes underwent the formation of only
two species in water solution (one symmetrical and one un-
Conformational Equilibrium Study and the Inversion
Process
From our NMR spectroscopic data, we demonstrated symmetrical),[18] for the first time, a third form can be de-
that, amongst six new CD dimers linked by glycerol-type scribed, probably due to the polar nature of the linker. The
arms of two different lengths, only one showed three dif- free hydroxy group of the glycerol moiety behaves as a tem-
ferent conformations in water: β-CD dimer 9. The phenom- porary stopper during the pseudo-rotaxanation process.
2
Scheme 4. Proposed click chemistry in DMSO and inversion processes in D O.
Eur. J. Org. Chem. 2013, 2583–2590
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V. Legros, C. Vanhaverbeke, F. Souard, C. Len, J. Désiré
FULL PAPER
As already mentioned in the literature by Monflier et NMR spectroscopy experiments showed that, depending on
al.,[
18d]
the inversion process occurs from the symmetrical the length of the linker between the two CDs, as well as the
conformation once the synthesis of the dimer has been nature of the substituent borne by the β-CDs, these dimers
achieved. Indeed, the synthesis was performed in DMSO, a could adopt very different conformations in water. Five
known dissociating solvent, which does not allow any in- compounds have only one linear and symmetrical confor-
clusion of the linking arm in the cavity of a monoazido-β- mation. Interestingly, the sixth could adopt either symmet-
CD unit after the first click reaction occurred (Scheme 4).
rical or pseudo[1]rotaxane-like structures. In this case,
Monoazido-β-CD 5 was added in two different ways, giv- native CDs are linked by the more flexible arm and three
ing similar results: either 2 equiv. were directly added at the different conformations are present in water solution. Com-
beginning of the reaction or 5 was added portionwise pared with the previously described CD dimers, in which
1
(
equivalent by equivalent). A H NMR spectrum of the ob- tumbling afforded two species, for the first time, a third
tained dimer 9 in [D ]DMSO revealed a singlet for H8 tri- form could be observed. These results suggest that one of
6
azole protons. After evaporation of [D ]DMSO and di- the d-glucopyranose units undergoes 360° rotation to in-
6
1
lution in D O, the H NMR spectrum again showed signals duce more or less deep inclusion of the linker into the CD
2
in the triazole region as described before. Thus, the inver- cavity. This behaviour in water might impact the physical
sion process happens only once the dimer is diluted in water properties of such dimers; our work in this direction will be
and not during the synthesis and gives rise to three dimers reported soon.
(Scheme 4).
To confirm this hypothesis for the inversion process,
complementary NMR spectroscopy experiments were per- Experimental Section
1
formed. Starting from H NMR spectroscopic analysis in
General: All reagents were used as purchased from commercial sup-
D O, gradual additions of [D ]DMSO were performed
2
6
pliers without further purification. Solvents (DMF, THF) were dis-
tilled under anhydrous conditions. TLC plates (Macherey–Nagel,
ALUGRAM SIL G/UV254, 0.2 mm silica gel 60 Å) were visualized
(
Figure 5) with increasing [D ]DMSO/D O ratios. From an
6 2
initial spectrum showing the three forms for dimer 9 (lane
0), we observed that, by adding small amounts of [D6]- under 254 nm UV light and/or by dipping the TLC plate into a
DMSO, initial upfield signals gradually disappeared. We solution of phosphomolybdic acid (3 g) in ethanol (100 mL) fol-
lowed by heating with a heat gun. Purifications by column
chromatography were performed using Macherey–Nagel silica gel
observed that, once the [D ]DMSO/D O ratio reached 0.68,
6
2
1
the resulting H NMR spectrum of the dimer showed one
singlet at δ = 8.12 ppm for triazole H8 protons. Only one
symmetrical conformation remains present in solution; thus
demonstrating the reversibility of the inversion process.
60 (15–40 μm). Semi-preparative HPLC purifications were per-
formed by using a C18 reversed-phase column and a water/acetoni-
trile system as the eluent. NMR spectroscopy experiments were
recorded with a Bruker Avance 400 spectrometer at 400 MHz for
1
13
H nuclei and at 100 MHz for C nuclei. The chemical shifts are
expressed in ppm relative to tetramethylsilane (TMS; δ = 0 ppm)
and the coupling constant, J, in Hz. NMR multiplicities are re-
ported by using the following abbreviations: br = broad, s = singlet,
d = doublet, t = triplet, q = quadruplet and m = multiplet. Micro-
wave irradiations were performed with a CEM Discover apparatus.
HRMS were obtained from the Mass Spectrometry Service,
CRMPO, at the University of Rennes I, France, using a MICRO-
MASS ZABSPEC-TOF spectrometer and a VARIAN MAT311
spectrometer.
Synthesis
1
(
,3-Bis(prop-2-ynyloxy)propan-2-ol (3): 1,3-Dichloropropan-2-ol
0.37 mL, 3.88 mmol) was added dropwise to a mixture of propar-
gyl alcohol (0.90 mL, 15.47 mmol, 4 equiv.) and sodium hydroxide
0.68 g, 17.10 mmol, 4.4 equiv.) in water (5 mL). The mixture was
(
then heated at reflux for 3 h, cooled and neutralized with 2 m HCl.
After extraction with dichloromethane (3ϫ 20 mL), the organic
layers were dried and concentrated under vacuum. The residue was
Figure 5. 1H NMR spectra (magnification of the H8 region) of
dimer
9
in
D
2
O
(lane 0) with gradual addition of [D
O ratio from 0.02 to 0.68).
6
]-
DMSO ([D
6
]DMSO/D
2
2 2
purified by silica-gel column chromatography (CH Cl ) to give 3
as a clear yellow oil (0.22 g, 34%). Physical data are in accordance
with the literature.[
00 MHz): δ = 4.17 (s, H1Ј, 4 H), 3.87 (s, H
, H
, 4 H), 2.44 (s, H3Ј, 2 H) ppm. 13C NMR (CDCl
3
19]
R
f
= 0.18 (CH
Cl
). H NMR (CDCl
, 1 H), 3.63–3.52 (m,
, 100 MHz):
, 2 C), 69.3 (C , 1
1
2
2
3
,
4
H
2
Conclusions
1
3
Six new β-CD dimers linked by glycerol-type arms have δ = 79.4 (C2Ј, 2 C), 74.9 (C3Ј, 2 C), 70.9 (C
been synthesized by click chemistry in a very straightfor- C), 58.6 (C1Ј, 2 C) ppm.
1
, C
3
2
ward manner. One linker was designed so that a thiol–ene
1,3-Bis(but-3-ynyloxy)propan-2-ol
(4):
3-Butynol
(610 mg,
click reaction could be performed directly on the obtained 8.64 mmol, 4 equiv.) and tetrabutylammonium bromide (690 mg,
triazole-containing CD-dimers: this work is in progress. 2.16 mmol) were added to a solution of sodium hydroxide (860 mg,
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β-Cyclodextrin–Glycerol Dimers
B–G
B
C–G
2
.16 mmol) in water (1.5 mL). Petroleum ether (10 mL) was then
added to the mixture, and finally 1-chloro-2,3-epoxypropane
200 mg, 21.6 mmol) was added dropwise. The mixture was stirred
H
H
(C
5
CD, H
6
CD, H11, H13, H14, 83 H), 3.08–2.84 (m, H10,
13
6
CD, 8 H) ppm. C NMR ([D
6
]DMSO, 100 MHz): δ = 143.7
(
9
, 2 C), 123.7 (C
8
, 2 C), 102.2 (C1CD, 14 C), 82.0–71.9 (C2CD,
B–G
A
overnight at room temperature, diluted with water (20 mL) then
extracted with dichloromethane (3ϫ 20 mL). The combined or-
ganic layers were washed with saturated aq. NaCl (20 mL), water
C
3CD, C4CD, C
C), 68.6 (C14, 1 C), 59.9 (C
5
CD, 54 C), 70.0 (C
5
CD, 2 C), 69.7 (C11, C13, 4
CD, 10 C), 58.9 (C B
CD, 2 C), 50.3
6
C–G
6
A
+
(C
6
CD, 2 C), 25.8 (C10, 2 C) ppm. ES-HRMS [M + Na] : calcd.
71Na: 2537.8510; found 2537.8517.
(
20 mL), dried and the solvents evaporated to dryness. The residue
was purified by silica-gel column chromatography [petroleum ether
PE)/EtOAc, 90:10 to 60:40] to give 4 as a colourless oil (0.16 g,
for C95H N O
154 6
Per-O-methylated CD Dimer (10): From 4 (20 mg, 0.11 mmol) and
6 (270 mg, 0.19 mmol), dimer 10 was obtained as a white powder
180 mg, 64%). R
CDCl , 400 MHz): δ = 7.47 (s, H
H), 4.87–4.67 (m, H CD, 4 H), 4.04 (H CD, 2 H), 3.93–2.93 (H10,
6 5
11, H13, H14, H2CD, H3CD, H4CD, H
211 H) ppm. C NMR (CDCl
24.0 (C , 2 C); 99.2–98.8 (C1CD, 14 C); 82.7–58.5 (C10, C11, C13,
8
(
1
3
8%). R
f
= 0.23 (80:20 PE/EtOAc). H NMR (CDCl
, 1 H), 3.62–3.47 (m, H , H , H1Ј, 8 H), 2.66
br. s, OH, 1 H), 2.47–2.43 (m, H2Ј, 4 H), 1.97 (t, J = 2.8 Hz, H4Ј
3
, 400 MHz):
1
(
(
f
= 0.45 (CH
2
Cl
2
/MeOH: 94:6). H NMR
δ = 3.97–3.92 (m, H
(
2
1
3
3
8
, 2 H), 5.28–5.08 (m, H1CD, 14
,
A
A
H) ppm. 13C NMR (CDCl
2
6
3
, 100 MHz): δ = 81.2 (C3Ј, 2 C), 71.9–
, C1Ј, C4Ј, 7 C), 19.8 (C2Ј, 2 C) ppm. ES-HRMS
Na: 219.0998; found 219.0997.
B–G
B–G
H
5
CD, H
6
CD, OCH3CD
,
1 2 3
9.3 (C , C , C
1
3
+
3
, 100 MHz): δ = 144.3 (C
9
, 2 C);
[
M + Na] : calcd. for C11
H
16
O
3
1
C
Typical Procedures for CuAAC Reactions Between Mono-6-azido-β-
CD 5 or 6 and Alkyne Derivatives 3, 4 or 11: Mono-6-azido-β-CD
B–G
14, C2CD, C3CD, C4CD, C5CD, C
6
CD, OCH3CD, 115 C), 51.1
A
Na]+: calcd. for
(
C
6
CD
,
2
C) ppm. ES-HRMS [M
N O71Na: 3098.4800; found 3098.4782.
+
(150 mg, 0.13 mmol, 2 equiv.), the alkyne derivative (100 mg,
C
135
H
234
6
0
0
.08 mmol, 1.2 equiv.) and copper sulfate pentahydrate (30 mg,
.13 mmol, 2 equiv.) were dissolved in DMSO (4 mL). A solution
3-[1,3-Bis(prop-2-ynyloxy)propan-2-yloxy]prop-1-ene (11): Sodium
hydride (40 g, 1.78 mmol, 3 equiv.) was added to a solution of com-
pound 3 (100 mg, 0.59 mmol.) in anhydrous DMF (5 mL) at 0 °C.
After 10 min allyl bromide (220 mg, 1.78 mmol, 3 equiv.) was
added dropwise then the mixture was stirred overnight at room
temperature. A few drops of methanol were added then the mixture
was concentrated and the residue purified by silica-gel column
of sodium ascorbate (51 mg, 0.26 mmol, 4 equiv.) in water (1 mL)
was added dropwise to this solution for 15 min, then the mixture
was stirred at 85 °C for 24 h (for 8, 9 and 13), or at 85 °C for 80 min
under microwave (MW) activation (for 7, 10 and 12). For the hy-
droxy CDs, acetone (20 mL) was added and the precipitate was
filtered off. The crude was then purified by semi-preparative HPLC
(
gradient elution with H
2
O/CH
3
CN from 98:2 to 70:30 in 20 min
chromatography (CH
67%). R = 0.61 (CH
5.85 (m, CH-allyl, 1 H), 5.28–5.12 (m, CH
4 H), 4.13–4.11 (m, O-CH -allyl, 2 H), 3.69–3.57 (m, H
5 H), 2.42 (s, H3Ј, 2 H) ppm. C NMR (CDCl
35.0 (CH-allyl, 1 C), 117.1 (CH -allyl, 1 C), 79.7 (C2Ј, 2 C), 76.8
, 1 C), 74.6 (C3Ј, 2 C), 71.3 (O-CH -allyl, 1 C), 69.8 (C , C , 2
C), 58.7 (C1Ј, 2 C) ppm. ES-HRMS [M + Na] : calcd. for
Na: 231.0999; found 231.0997.
2
Cl
2
) to give 11 as a colourless oil (80 mg,
1
for 7 and 12, and from 15:95 to 50:50 in 20 min for 9). For the
per-O-methylated CDs, the crude mixture was concentrated then
purified by silica-gel column chromatography (CH
f
2
Cl
2
). H NMR (CDCl
-allyl, 2 H), 4.16 (s, H1Ј
, H , H
3
, 400 MHz): δ = 5.95–
2
,
,
2
Cl
2
/MeOH,
2
1
2
3
1
3
1
00:0 to 94:6). Yields are given after freeze-drying of the samples.
3
, 100 MHz): δ =
1
2
CD Dimer (7): From 3 (10 mg, 0.08 mmol) and 5 (150 mg,
.13 mmol), dimer 7 was obtained as a white powder (30 mg, 18%).
= 0.42 (40:60 H O/CH CN, 1% NH ]-
OH). 1H NMR ([D
DMSO, 400 MHz): δ = 8.01 (s, H , 2 H), 5.88–5.65 (m, OH2CD
OH3CD, 28 H), 4.89–4.77 (m, H1CD, H
(
C
2
2
1
3
0
R
+
f
2
3
4
6
12 16 3
C H O
8
,
A
6
CD, 16 H), 4.62–4.47 (m,
CD Dimer (12): From 11 (17 mg, 0.083 mmol) and 5 (200 mg,
B–G
A
A
OH
6
CD, H10, 16 H), 4.29 (m, H6Ј CD, 2 H), 3.97 (m, H
5
CD, 2
0
1
.14 mmol), dimer 12 was obtained as a white powder (30 mg,
B–G
C–GCD, H12, H13
H), 3.63–3.06 (m, H2CD, H3CD, H4CD, H
5
CD, H
6
,
1
4%). R
O, 400 MHz): δ = 8.03 (s, H
H), 5.30–5.15 (m, CH -allyl, 2 H), 5.04–4.95 (m, H1CD, H
f
= 0.42 (40:60 H
2
O/CH
3 4
CN, 1% NH OH). H NMR
B
13
7
1
1
6
9 H), 3.08–2.84 (m, H
00 MHz): δ = 143.9 (C
4 C), 83.0–63.3 (C10, C12, C13, C2CD, C3CD, C4CD, C5CD, 61 C),
6
CD, 4 H) ppm. C NMR ([D
6
]DMSO,
(
D
2
8
, 2 H), 5.91–5.84 (m, CH-allyl, 1
, 2 C), 126.6 (C , 2 C), 101.9–101.4 (C1CD
8
,
A
9
CD, 16
CD, 2 H, J =
-allyl, 2 H, J = 6 Hz), 3.95–3.46 (m, H2CD
2
6
A
A
H), 4.66–4.58 (m, H6Ј CD, H10, 6 H), 4.14 (t, H
Hz), 4.08 (d, O-CH
5
C–G
B
A
0.3 (C
6
CD, 10 C), 59.1 (C
6
CD, 2 C), 51.1 (C
6
CD, 2 C) ppm.
9
H
2
,
+
ES-HRMS [M + Na] : calcd. for C93
found 2509.8209.
H
150
N
6
O71Na: 2509.8264;
B–G
C–G
3CD, H4CD, H
B
5
CD, H
6
CD, H12, H13, 79 H), 3.16–2.79 (m,
O, 100 MHz): δ = 134.1 (CH-
-allyl, 1 C), 102.0–101.4
-allyl, C2CD, C3CD, C4CD
13
H
allyl, C
6
CD, 4 H) ppm. C NMR (D
2
9 2
, 3 C), 126.4 (C8, 2 C), 118.2 (CH
1CD, 14 C), 83.0–70.7 (C13, O-CH
Per-O-methylated CD Dimer (8): From 3 (60 mg, 0.35 mmol) and
(1.0 g, 0.70 mmol), dimer 8 was obtained as a white powder
(
C
2
,
6
(
C–G
1
C5CD, 58 C), 69.3 (C , 2 C), 63.4 (C , 2 C), 60.1 (C
5
CD
, 10 C),
540 mg, 51%). R
f
= 0.21 (CH
2
Cl
2
/MeOH 95/5). H NMR (CDCl
3
,
12
10
6
9.0 (C B
A
+
6
6
CD, 2 C), 51.1 (C CD, 2 C) ppm. ES-HRMS [M + Na] :
4
4
3
00 MHz): δ = 7.64 (s, H
8
, 2 H), 5.32–5.12 (m, H1CD, 14 H), 4.93–
A
A
96 154 6 71
calcd. for C H N O Na: 2549.8500; found 2549.8522.
.79 (m, H
6
CD, 4 H), 4.68 (m, H10, 4 H), 4.09 (m, H
5
CD, 2 H),
B–GCD, H
B–G
.97–3.05 (m, H12, H13, H2CD, H3CD, H4CD, H
5
6
CD
,
Per-O-methylated CD Dimer (13): From 11 (10 mg, 0.06 mmol) and
(150 mg, 0.10 mmol), dimer 13 was obtained as a white powder
OCH3CD, 203 H) ppm. 13C NMR (CDCl
, 100 MHz): δ = 144.3
3
6
(
C
C
9
, 2C), 124.9 (C
8
, 2C), 99.2–98.3 (m, C1CD, 14C), 82.6–58.4 (C10
,
1
(
80 mg, 53%). R
f
= 0.32 (CH
00 MHz): δ = 7.61 (s, H , 2 H), 5.90–5.80 (m, CH-allyl, 1 H),
.31–5.27 (m, CH -allyl, 2 H), 5.14–5.09 (m, H1CD, 14 H), 4.88–
CD, 4 H), 4.63 (s, H10, 4 H), 4.20–4.06 (m, O-CH
CD, 4 H), 3.95–3.02 (m, H12, H13, H2CD,
2 2 3
Cl /MeOH: 93:7). H NMR (CDCl ,
B–G
12, C13, C2CD, C3CD, C4CD, C5CD, C
6
CD, OCH3CD, 113 C), 51.2
4
5
4
8
A
2 C) ppm. ES-HRMS [M +
Na]+: calcd. for
N O71Na: 3070.4463; found 3070.4469.
6
(C
6
CD,
230
2
C
133
H
A
.75 (m, H
6
2
-
A
CD Dimer (9): From 4 (30 mg, 0.13 mmol) and 5 (150 mg,
0
4
allyl, H
5
H
3CD, H4CD
,
B–GCD, H
B–G
CD, OCH3CD, 203 H) ppm. C NMR (CDCl
100 MHz): δ = 144.6 (C , 2 C), 135.1 (CH-allyl, 1 C), 125.0 (C
-allyl, 1 C), 99.3–98.4 (C1CD, 14 C), 82.7–58.5 (C12
13
,
.13 mmol), dimer 9 was obtained as a white powder (110 mg,
2%). R = 0.48 (40:60 H O/CH CN, 1% NH
OH). 1H NMR
]DMSO, 400 MHz): δ = 7.81 (s, H , 2 H), 5.90–5.64 (m, C), 117.0 (CH
OH2CD, OH3CD, 28 H), 5.03–4.76 (m, H1CD, H
H
5
6
3
f
2
3
4
9
8
, 2
([D
6
8
2
,
A
B–G
6
CD, 16 H), 4.59–
C
13, O-CH
2
-allyl, C2CD, C3CD, C4CD, C5CD, C
A
6
CD, OCH3CD, 114
C–G
A
B
+
4
8
.48 (m, OH
6
CD, H6Ј CD, 12 H), 4.31 (t, OH
6
CD, 2 H, J =
C), 51.3 (C CD, 2 C). ES-HRMS [M + Na] : calcd. for
6
A
Hz), 3.97 (m, H
5
CD, 2 H), 3.63–3.06 (m, H2CD, H3CD, H4CD
,
C
136
H
234
N
6
O71Na: 3110.4764; found 3110.4782.
Eur. J. Org. Chem. 2013, 2583–2590
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2589

V. Legros, C. Vanhaverbeke, F. Souard, C. Len, J. Désiré
FULL PAPER
NMR Spectroscopy Measurements: NMR spectroscopy experi-
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[
[
Acknowledgments
The authors thank the Ministère de l’Enseignement Supérieur et de
la Recherche, and the Centre National de la Recherche Scientifique
(CNRS) for their constant supports. Roquette Frères (Lestrem,
France) is gratefully acknowledged for generous gifts of β-CD. C. V.
thanks Prof. Julian Garcia for helpful participation.
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Received: December 20, 2012
Published Online: March 13, 2013
2590
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2583–2590