Control of the regioselectivity for new fluorinated amphiphilic cyclodextrins: Synthesis of di- and tetra(6-deoxy-6-alkylthio)- and 6-(perfluoroalkypropanethio)-α-cyclodextrin derivatives

Article abstract of DOI:10.1021/jo801111b

(Figure Presented) Twelve new di- and tetraderivatized α-cyclodextrin molecules having either alkylthio and perfluoroalkylpropanethio functions at the primary face have been synthesized by using the procedure of Sinay for di-O-debenzylation of perbenzylated α-cyclodextrins. A new strategy of protection/deprotection has been developed for introducing the lipophilic chains. The coupling reaction involves the reaction between the appropriate α-cyclodextin derivative, regioselectively modified at C-6 positions by a good leaving group (O-mesityl for disubstituted or iodine for tetrasubstituted derivatives), with the thioalkyl or the thioperfluoroakylpropane chains. These nucleophilic reagents are obtained from the in situ basic hydrolysis of the alkylisothiouronium bromides or perfluoalkylropropane and the isothiouronium iodides. These multistep reactions give the desired amphiphilic α-cyclodextrins in good overall yields of 33% to 58%.

Full text of DOI:10.1021/jo801111b

Control of the Regioselectivity for New Fluorinated Amphiphilic
Cyclodextrins: Synthesis of Di- and Tetra(6-deoxy-6-alkylthio)- and
6-(Perfluoroalkypropanethio)-r-cyclodextrin Derivatives
Bernard Bertino-Ghera,† Florent Perret,*,† Bernard Fenet,‡ and He´le`ne Parrot-Lopez*,†
UniVersite´ de Lyon, Lyon, F-69003, France, UniVersite´ Lyon 1, ICBMS UMR CNRS 5246, LCO2,
Baˆtiment Raulin, 43, bd du 11 noVembre 1918, Villeurbanne, and Centre de Re´sonnance Magne´tique
Nucle´aire Liquide, Baˆtiment Curien, 3, rue Victor Grignard, 69622 Villeurbanne F-69622, France
florent.perret@uniV-lyon1.fr
ReceiVed June 18, 2008
Twelve new di- and tetraderivatized R-cyclodextrin molecules having either alkylthio and perfluoro-
alkylpropanethio functions at the primary face have been synthesized by using the procedure of Sinay¨
for di-O-debenzylation of perbenzylated R-cyclodextrins. A new strategy of protection/deprotection has
been developed for introducing the lipophilic chains. The coupling reaction involves the reaction between
the appropriate R-cyclodextin derivative, regioselectively modified at C-6 positions by a good leaving
group (O-mesityl for disubstituted or iodine for tetrasubstituted derivatives), with the thioalkyl or the
thioperfluoroakylpropane chains. These nucleophilic reagents are obtained from the in situ basic hydrolysis
of the alkylisothiouronium bromides or perfluoalkylropropane and the isothiouronium iodides. These
multistep reactions give the desired amphiphilic R-cyclodextrins in good overall yields of 33% to 58%.
Introduction
allowed the preparation of various self-assembled structures
including vesicles,4 nanospheres,5 nanocapsules,6 solid-lipid
nanoparticles,7 and liquid crystals.8 Their self-organizational
properties depend on the nature, the number, and the length of
hydrophobic chains at the different faces. Due to their potential
Modified cyclodextrins (CDs) with pendant lipophilic groups
at the primary1 or at the secondary faces2 are of considerable
interest in supramolecular chemistry, especially for pharmaceuti-
cal applications.3 Their capacity for self-organization in water
(4) 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.
(5) Skiba, M.; Wouessidjewe, D.;. Coleman, A.;. Fessi, H.; Devissaguet, J. P.;.
Duchene, D.;. Puisieux, F. PCT Int. Appl. WO 9325195, 1993.
(6) Skiba, M.; Skiba-Lahiani, M.; Arnaud, P. J. Inclusion Phenom. Macro-
cyclic Chem. 2003, 44, 151–154.
(7) Dubes, A.; Parrot-Lopez, H.; Abdelwahed, W.; Degobert, G.; Fessi, H.;
Shahgaldian, P.; Coleman, A. W. Eur. J. Pharm. Biopharm. 2003, 55, 279–282.
(8) Ling, C. C.; Darcy, R.; Risse, W. J. Chem. Soc., Chem. Commun. 1993,
43840.
* Corresponding author.
† ICBMS UMR CNRS 5246.
‡ Centre de Re´sonnance Magne´tique Nucle´aire Liquide.
(1) Peroche, S.; Degobert, G.; Puteaux, J.-L.; Blanchin, M.-G.; Fessi, H.;
Parrot-Lopez, H. Eur. J. Pharm. Biopharm. 2005, 60, 123–131.
(2) Dubes, A.; Parrot-Lopez, H.; Shahgaldian, P.; Coleman, A. W. J. Colloid
Interface Sci. 2003, 259, 203–211.
(3) Duchene, D.; Ponchel, G.; Wouessidjewe, D. AdV. Drug DeliVery ReV.
1999, 36, 29–40.
10.1021/jo801111b CCC: $40.75
Published on Web 08/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7317–7326 7317

Bertino-Ghera et al.
activity in biomedical research, fluorine-containing organic
compounds have attracted scientific attention.9 Furthermore, it
has been demonstrated that vesicles and nanocapsules made
from fluorinated surfactants are usually more stable and less
permeable than those made from nonfluorinated surfactants.10
For example, Skiba et al.6 described the synthesis of nanocap-
sules made from the 2,3-di-O-decafluorooctanoyl-ꢀ-cyclodextrin,
suitable vehicles for oxygen solubilization.
then used by Breslow et al.19 to functionalize two adjacent
D-glucose units at the C-6 position of ꢀ-CD.
Coleman et al.20 showed that use of the well-known sterically
hindered methodology via use of the trityl group leads to tri
-and tetrafunctionalized R-CDs, depending on the stoichiometry
of the reagents. The complete separation of the different
regioisomers was achieved by chromatography column after per-
methylation of the secondary face. Methylated analogues were
then obtained in 15-30% yield. More recently, Poorters et al.21
used the supertrityl protecting group (sTrCl ) tris(4-tert-
butylphenyl)methyl chloride) for the selective tetrafunctional-
ization of R-CD, leading to the tetraprotected R-CD in position
6A,6B,6D,6E in 47% yield.
In our research group, ꢀ-cyclodextrin derivatives, selectively
substituted at the C-6 position by one, two, or seven perfluoro-
hexylpropanethio chains, have been synthesized and studied.11
These novel derivatives were obtained by thioalkylation of ꢀ-CD
derivatives having tosyl or iodo groups at the C-6 position.
Nevertheless, for ꢀ-cyclodextrin derivatives, the lipophilic-hy-
drophilic balance is very strongly shifted to lipophilicity and may
reflect the noncompatibility of the 7-fold symmetry of these
heptamers toward water12 and also toward chain organization in
the assemblies. We thus moved our attention to the use of
R-cyclodextrin derivatives so as to favor both the interactions with
water and the organization of the molecular assemblies.13
Recently, per-alkylthio and per-perfluoroalkylpropanethio-
R-cyclodextrin derivatives and their O-2, O-3 methylated
analogues have been synthesized.14 Unfortunately, the nonm-
ethylated molecules are highly insoluble in aqueous, organic,
or fluorous solvents. The O-2, O-3 methylated analogues have
shown higher solubilities in organic solvents and their interfacial
properties could be studied. The assembly properties of the
molecules at the air-water interface show a clear difference
between alkylthio and perfluoroalkylpropanethio derivatives,
with higher molecular areas and collapse pressures observed
for the later.14
A far more elegant alternative approach is the regioselective
deprotection of perfunctionalized cyclodextrins, thus combining
the advantageous aspects of the first two methods mentioned
above.
Sinay¨ et al.22 have demonstrated that DIBAL-promoted de-
O-benzylation of perbenzylated cyclodextrins occurs with
remarkably high regioselectivity, giving access to either mono-
6-O-debenzylated or 6A,6D-di-O-debenzylated derivatives.
We have used this strategy to synthesize di- and tetradeben-
zylated R-cyclodextrins in view of their further modification
for the synthesis of new amphiphilic derivatives.
Here we describe the multistep syntheses of di- and tetra(6-
deoxy-6-alkylthio)-R-cyclodextrins and di- and tetra(6-deoxy-
6-perfluoroalkylpropanethio)-R-cyclodextrins. We also present
the preparation of di- or tetrasubstituted R-cyclodextrins modi-
fied at the primary face by good leaving groups, through an
easy synthetic route with high yield and controlled regioselec-
tivity.
Due to the low solubility of the derivatives persubstituted at
the primary face and nonmodified at the secondary face in
common solvents, another strategy has been used to lead to more
soluble R-cyclodextrin derivatives, with the introduction of only
two or four hydrophobic chains at the primary face.
Results and Discussion
Perbenzylation of R-CD (1) was achieved by using the
method described by Lecourt et al.23 Perbenzylated R-CD 2 was
prepared by direct benzylation of R-CD in DMSO with benzyl
chloride and NaH during 12 h at room temperature. Compound
2 was then obtained in 90% yield after column purification
(EtOAc in cyclohexane gradient) (Scheme 1).
To selectively synthesize di- and tetrasubstituted derivatives,
many strategies have been developed in the past for differentiat-
ing the primary hydroxyl groups of cyclodextrins. Only two
recent methods present high yield along with a controlled
regioselectivity: Fujita et al.15 have synthesized 6A-6B, 6A-6C,
and 6A-6D disubstituted R-CDs derivatives using mesitylsulfonyl
chloride in pyridine, and these compounds have been separated
by using reversed phase chromatography, leading to yields
ranging from 7% to 14%. In the same way with an excess of
sulfonyl reagent, tetrasubstituted R-CDs were obtained with less
than 4% yield. An elegant method is to use bridging reactants
to introduce sulfonyl groups at the primary face. Tabushi et al.
used geometrically well-defined disulfonyl arenes to control the
regioselectivity of the difunctionalization.16-18 This strategy was
The procedure described by Pearce et al.22 has been followed
for the selective deprotection of the perbenzylated intermediate.
The mechanism of this remarkable reaction was determined in
2004, according to numerous results obtained by the same
group.23 The supposed mechanism implies two sequential
reactions of O-debenzylation. Selectivity for the primary face
has been explained by the high density of benzyl groups on the
secondary face. The first debenzylation takes place on only one
glucosidic unit. Because of the steric hindrance caused by the
aluminum alkoxide, the second DIBAL pair is forced to interact
with the most distant glucosidic unit. The authors claimed that
the steric hindrance is strengthened by the presence of the benzyl
groups. A single debenzylation is usually obtained with 30 equiv
of DIBAL per R-CD while in the case of di-O-debenzylation,
(9) Krafft, M. P. AdV. Drug DeliVery ReV. 2001, 47, 209.
(10) Gadras, C.; Santaella, C.; Vierling, P. J. Controlled Release 1999, 57,
29.
(11) Peroche, S.; Parrot-Lopez, H. Tetrahedron Lett. 2002, 44, 241–245.
(12) Schalchli, A.; Benattar, J. J.; Tchoreloff, P.; Zhang, P.; Coleman, A. W.
Langmuir 1993, 9, 1968.
(13) Tchoreloff, P.; Boissonade, M. M.; Coleman, A. W.; Baszkin, A.
Langmuir 1995, 11, 191.
(14) Bertino Ghera, B.; Perret, F.; Baudouin, A.; Coleman, A. W.; Parrot-
Lopez, H. New J. Chem. 2007, 31, 1899–1906.
(15) Fujita, K.; Yamamura, H.; Matsunaga, A.; Imoto, T.; Mihashi, K.;
Fijioka, T. J. Am. Chem. Soc. 1986, 112, 5212–5219.
(16) Tabushi, I.; Kuroda, Y.; Yokota, K.; Yuan, L. C. J. Am. Chem. Soc.
1981, 103, 711–12.
(17) Tabushi, I.; Yamamura, K.; Nabeshima, T. J. Am. Chem. Soc. 1984,
106, 5267–70.
(18) Tabushi, I.; Yuan, L. C.; Shimokawa, K.; Yokota, K.; Mizutani, T.;
Kuroda, Y. Tetrahedron Lett. 1981, 22, 2273–6.
(19) Breslow, R.; Canary, J. W.; Varney, M.; Waddell, S. T.; Yang, D. J. Am.
Chem. Soc. 1990, 112, 5212–19.
(20) Ling, C. C.; Coleman, A. W.; Miocque, M. Carbohydr. Res. 1992, 223,
287–91.
(21) Poorters, L.; Armspach, D.; Matt, D. Eur. J. Org. Chem. 2003, 1377–
1381.
(22) Pearce, A. J.; Sinay, P. Angew. Chem., Int. Ed. 2000, 39, 3610–3612.
(23) Lecourt, T.; Herault, A.; Pearce, A. J.; Sollogoub, M.; Sinay, P. Chem.-
Eur. J. 2004, 10, 2960–2971.
7318 J. Org. Chem. Vol. 73, No. 18, 2008

New Di- and TetraderiVatized R-Cyclodextrin Molecules
SCHEME 1. Synthesis of the Tetrabenzylated r-Cyclodextrin 3
SCHEME 2. Synthesis of Disubstituted Amphiphilic r-Cyclodextrins 6 and 7
120 equiv are needed, indicating the steric hindrance at the
primary face after the formation of the first intermediate.22
For these reasons, in was decided to introduce sulfonyl groups,
as iodide or bromide moieties would be cleaved under catalytic
hydrogenation conditions. Use of the p-toluenesulfonyl group
led to a mixture of derivativessmonotosylated, ditosylated, and
even monochlorotosylated compoundssand thus use of tosyl-
chloride has been excluded. Activation of hydroxyl groups with
methanesulfonyl chloride in anhydrous pyridine led to the
desired compound 4 in quantitative yield (Scheme 2).
Treatment of 2 with excess diisobutylaluminium (120 equiv
DIBAL) in anhydrous toluene at 50 °C during 2 h gave the
desired di-O-debenzylated compound 3 in 91% yield. This
compound was characterized by 13C and 1H NMR and by
positive mode electrospray mass spectroscopy and the obtained
data are consistent with those given in the literature.23
To synthesize difunctionalized R-cyclodextrins, it is necessary
to adopt a strategy of protection, activation, and deprotection
of the hydroxyl groups:
Synthesis of 4 has already been described24 under different
conditions (CH2Cl2, Et3N) but the product was neither isolated
1
nor characterized. H NMR characterization of this compound
shows the disappearance of the peak at 3.19 ppm, corresponding
In view of further deprotection of the benzyl groups by
hydrogenation, the chosen leaving groups should be stable with
regard to these conditions and also activate hydroxyl groups.
(24) Bistri, O.; Sinay, P.; Sollogoub, M. Tetrahedron Lett. 2005, 46, 7757–
7760.
J. Org. Chem. Vol. 73, No. 18, 2008 7319

Bertino-Ghera et al.
TABLE 1. Yields of the Coupling Reaction between
Isothiouronium Salts and Compound 5
found in the form of three doublets for H-1 and three triplets
for H-3 and H-4, respectively. On the other hand, H-2 and H-5
protons are grouped together and are found under the shape of
widened singlets.
Concerning the 13C NMR, the chemical shift at 34.2 ppm,
corresponding to C-6A and C-6D, is characteristic of the success
of the perfluorobutylpropanethio chain coupling. Furthermore,
the presence of 3 different signals for all the cyclodextrin core
carbons indicates a 2-fold symmetry of the CD. Mass spec-
trometry of 7a confirms the presence of only [M + H]+ at
1547.4 and [M + K]+ at 1563.4.
All compounds in the series 6 and 7 have been characterized
in this way. Further details are given in the Experimental
Section.
Concerning tetrasubstituted R-cyclodextrins, they have been
synthesized from 6A,6B,6D,6E-tetra-O-benzylper-2,3-di-O-benzyl-
R-cyclodextrin 3 in four steps, as described in Scheme 3.
The protecting group we have to introduce on free hydroxyl
groups of compound 3 has to present many characteristics. It
should be stable against benzylic ether cleavage conditions in
the presence of Pd/C, against dehydration conditions (100 °C
under vacuum during 12 h at least) necessary for iodine
substitution of the four hydroxyl groups, and against iodination
reaction in the presence of PPh3/I2, warming at 80 °C during
15 h. Furthermore, this protecting group has to be easily cleaved
in not too basic conditions to avoid intramolecular nucleophilic
substitution of iodine atoms by hydroxyl groups in the O-3
position, which would lead to the formation of a 3,6-anhydro-
R-CD derivative.
R
compd
yield (%)
C4H9
C6H13
C8H17
C4F9
C6F13
C8F17
6a
6b
6c
7a
7b
7c
56
53
77
52
54
56
to the alcohol functionality, and the appearance of a singlet at
2.60 ppm, corresponding to the methanesulfonyl protons. In the
13C NMR, the carbon of the methanesulfonyl group appears at
37.6 ppm and those of the glucosidic unit bearing these groups
at 70.4 ppm. Introduction of two methanesulfonyl groups is
confirmed by positive mode electrospray mass spectroscopy,
which shows the presence of monocharged ion at m/z ratio
2571.2 ([M + H]+) and 2592.7 ([M + Na]+), corresponding to
the desired compound.
After the introduction of the activating groups, deprotection
of all benzyl groups was undertaken via catalytic hydrogenation
in an AcOEt:MeOH 1:1 mixture, using stoichiometric quantities
of Pd/C under H2 at 10 bar pressure; the catalytic proportions
described by Sinay¨ et al.22 were not effective here. Compound
1
5 is obtained in 92% yield. H NMR shows the disappearance
of all the benzyl protons, the anomeric protons appear as three
doublets at 4.80, 4.87, and 4.90 ppm, two triplets corresponding
to the primary alcohol functions appear at 4.57 and 4.63 ppm.
13C NMR shows the disappearance of both aromatic and
benzylic carbon atoms and the conservation of the carbon of
the methylsulfonate group at 37.5 ppm. Mass spectroscopy
shows only one peak for m/z 1129.3 ([M + H]+). 6A,6D-Di-O-
methylsulfonyl-R-cyclodextrin 5 is thus obtained with controlled
regioselectivity in 75% yield starting from native R-cyclodextrin
1. This intermediate compound 5 is the precursor for the
syntheses of all the disubstituted amphiphilic derivatives.
For the introduction of perfluoroalkyl chains, we have
developed a new strategy using a polar reaction between a
perfluoroalkylpropanethiol and a cyclodextrin bearing a suitable
leaving group.14 The traditional radical reaction method using
Hein and Meintchen’s procedure25 led to mixtures of substituted
cyclodextrins.26 The use of a precursor to generate this thiol in
situ is preferred because of the facile oxidative dimerization of
the perfluoropropanethiol.
Introduction of silyl or acetyl protecting groups on compound
3 failed because of the nonselective deprotection of the benzyl
groups in the following step: unfortunately both silyl and acetyl
groups are cleaved under debenzylation conditions. For this
reason, we chose to introduce methyl groups at the free hydroxyl
groups in compound 3. In the presence of sodium hydride and
methyl iodide in DMF, compound 8 is obtained in 98% yield.
Hydrogenolysis of the benzyl ether groups is then realized by
using 0.5 equiv of Pd/C, under 1 atm of H2 in an AcOEt/MeOH
1/1 mixture. Compound 9 is obtained in 98% yield and
characterized by NMR and mass spectroscopy. Because of the
selectivity of iodination for the primary face, we have chosen
to introduce iodine atoms in the presence of PPh3/I2 for
activating these positions. Solid/liquid extraction was used for
purification of compound 10, which was obtained in 64% yield.
(6A,6B,6C,6D-tetradeoxy-6A,6B,6C,6D-tetraiodo)-(6C,6F-di-O-methyl)-
R-cyclodextrin 10 has been characterized by use of HSQC-
TOCSY, HSQC, and HMBC (see the SI).
Using the procedures of Garcia-Lopez et al.,27 compound 5
reacts with hydrocarbonated isothiouronium salts or their
perfluoroalkylpropane analogues12 in the presence of cesium
carbonate in DMF to give 6 and 7 with good yields (Table 1),
after 4 days at 60 °C.
1
In the H NMR, the anomeric protons are found as three
2-Dimensional NMR spectroscopy (HSQC, HMBC, and
TOCSY-HSQC) has allowed the complete assignment of all
proton and carbon signals (see the Supporting Information). The
success of the coupling reaction in this series was confirmed
distinct doublets at 5.41, 5.48, and 5.50 ppm for respectively
H-1B and H-1E, H-1C and H-1F, and H-1A and H-1D. The
presence of a signal due to the methyl protons as a singlet at
3.50 ppm demonstrates the retention of these functions during
the iodination reaction. 13C NMR shows that each type of
carbon atom is present as three different peaks, showing the
2-fold symmetry of the molecule and thus the success of the
tetraiodination. In the 13C NMR spectra, each type of carbon
of the CD skeleton is observed as three separate peaks,
indicating a 2-fold symmetry for compound 10, consistent
with tetraiodination. The four different C6 species, each
linked to an iodine, are observed at 9.0 and 10.9 ppm
respectively for (C-6A, C-6D) and (C-6B, C-6E), characteristic
of the chemical shifts of a methylenic carbon bearing an
by 13C NMR spectroscopy. For 7a, for example, the H NMR
1
shows singlets for H-6aA, H-6bA, H-6aD, and H-6bD at 3.23 ppm.
Signals of the propyl chain grafted on sulfur atom are found at
1.92 ppm for CH2CH2CF2, 2.28 ppm for CH2CF2, and 2.61 ppm
for SCH2. It is worth noting that H-1, H-3, and H-4 signals are
(25) Hein, M.; Mientchen, T. Tetrahedron Lett. 1998, 39, 6679.
(26) Peroche, S. , Ph.D. Thesis, No. 254 2003, Universite′ Claude Bernard,
Lyon 1, 2003.
(27) Garcia-lopez, J.; Hernandez-Mateo, F.; Isac-Garcia, J.; Kim, J.; Roy,
R.; Santoyo-Gonzalez, F.; Vergas-Berengeul, A. J. Org. Chem. 1999, 64, 522–
531.
7320 J. Org. Chem. Vol. 73, No. 18, 2008

New Di- and TetraderiVatized R-Cyclodextrin Molecules
SCHEME 3. Synthesis of Tetrasubstituted Amphiphilic r-Cyclodextrins xs 211 and 12
of the propyl spacer and C6A,B,D,E are found between 20.4
and 32.2 ppm: 20.4 ppm for CH2-CH2-CF2 and 29.2 - 32.2
ppm for CH2-CF2, CH2-S, and C6A,B,D,E. The O-methyl
carbons are found at 58.5 ppm. Carbons of the perfluoro-
alkylated chain are found at 110.3 and 118.6 ppm, in two
distinct multiplets (Figure 1).
TABLE 2. Yields of the Coupling Reaction between
Isothiouronium Salts and Compound 10
R
compd
yield (%)
C4H9
C6H13
C8H17
C4F9
C6F13
C8F17
11a
11b
11c
12a
12b
12c
86
81
65
85
93
86
The 19F solid state NMR spectrum remains unchanged,
indicating that the perfluorooctyl chain has not been cleaved.
Mass spectroscopy experiments have been performed to prove
that there are no less substituted products. For example, for the
compound 12b, only monomolecular ions at 1072.1 [M + K +
H]2+, 2505.0 [M + H]+, and 2526.8 [M + Na]+ have been
observed indicating the presence of only tetrasubstituted R-cy-
clodextrin. Similar spectra were observed for all tetraderivatives.
iodine atom. Finally, it is worth noting that there is a quite
important difference of chemical shifts between C-3, C-4,
C-5, and C-6 of glucosidic units bearing iodine and those
bearing a methyl group. ESI MS experiments in negative
mode show only one peak for [M + Cl]- at 1474.9 supporting
the absence of mono-, di-, or triiodinated side products. The
tetraiodo derivative 10 has been synthesized in 50% yield
starting from native R-CD and is a good general candidate
for tetrafunctionalization of R-CD. Coupling of perfluoro-
alkylpropane or hydrocarbonated chains to 10, via the
isothiourionium salts, was undertaken in anhydrous DMF,
as previously described for compounds 6 and 7, and affords
compounds 11a-c and 12a-c in good yields (Table 2).
These tetrafunctionalized derivatives 11 and 12 are insoluble
in most common organic solvents and were thus characterized
by solid NMR spectroscopy, as previously described for O-6-
alkylthio- and perfluoroalkylpropanethio-R-cyclodextrins.14Thus
success of the coupling to yield 12c is observed in CPMAS
13C NMR by the disappearance of the signals at 9.0 and 10.9
ppm, corresponding to the C-6 carbons of glucosidic units
bearing iodine atoms. The peaks arising from carbon atoms
The hydrocarbonated analogues have been characterized in
a similar manner. For 11c, the solid state NMR CPMAS 13C
spectrum allowed observation of the analogous signals for the
carbon atoms of the CD core (Figure 2). The carbon atoms of
the undecanoyl chain are observed at 14.2 and 23.0 ppm and a
set of peaks centered at 31.2 ppm is observed, corresponding
to the CH3, CH2CH3, and CH2 carbon atoms, respectively. As
previously noted, success of the coupling reaction is demon-
strated by the disappearance of the signals corresponding to
those carbon atoms linked to iodine atoms, at 9.0 and 10.9 ppm.
Finally, the electrospray mass spectrum confirms the presence
of the tetrathioalkylated derivatives and the absence of under-
substituted derivatives. For 11c, only monomolecular ions at
1570.5 [M + H]+ and 1592.2 [M + Na]+ are observed.
J. Org. Chem. Vol. 73, No. 18, 2008 7321

Bertino-Ghera et al.
FIGURE 1. 13C solid state NMR (CPMAS, 125 MHz) of compound 12c.
FIGURE 2. 13C solid state NMR (CPMAS, 125 MHz) of compound 11c.
Conclusion
Experimental Section
Syntheses: 6A,6D-Di-O-methylsulfonyl-6B,6C,6E,6F-tetra-O-ben-
zyl(per-2,3-di-O-benzyl)-r-cyclodextrine (4). To a solution of 322
(3.50 g, 1.45 mmol) in anhydrous pyridine (50 mL) under argon at
0 °C was added dropwise methylsulfonyl chloride (900 µL, 11.6
mmol, 8 equiv). The reaction mixture was stirred during 3 h at
room temperature under argon and the reaction monitored by TLC
(cyclohexane/EtOAc: 6/2). The reaction was quenched by adding
saturated NaHCO3 solution (50 mL). The organic phase was
extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were washed with brine (100 mL) and dried over Na2SO4. The
solvent was evaporated and the resulting solution containing
pyridine was coevaporated three times with toluene to afford 4 with
quantitative yield. Mp 56 °C dec. IR ν (cm-1) 3030 (C-H Ar),
We have developed two new synthetic routes allowing access
to di- and tetrasubstituted R-cyclodextrins bearing methane-
sulfonyl or iodo groups. The two synthetic intermediates have
been obtained in excellent yields, with perfectly controlled
regioselectivities, and are key products for further di- or
tetrafunctionalizations of R-CD. Di- and tetrasubstituted am-
phiphilic R-cyclodextrins bearing perfluoroalkylpropanethio and
alkylthio chains have finally been synthesized in good yields,
39-58%, in 5 steps for the disubstituted amphiphilic R-cyclo-
dextrin derivatives, and 33-47% in 6 steps for the tetrasubsti-
tuted derivatives. Whereas tetrafunctionalised derivatives are
not soluble in most common solvents, disubstituted compounds
have comparable solubilities as native R-cyclodextrin (DMF,
DMSO, and pyridine), except in water.
2925 (C-H), 1354 (C-SO2-C), 1092 (C-O-C). [R]22 +31 (c
D
1.0 in CHCl3). 1H NMR (CDCl3, 300 MHz, 25 °C, assignments by
COSY, DEPT, HSQC, and HMBC) δ (ppm) 2.60 (s, 6H, CH3
mesyl), 3.35 (dd, 2H, 2 × H-2, J ) 3.2 and 9.8 Hz), 3.41 (dd, 2H,
2 × H-2, J ) 3.2 Hz and 9.8 Hz), 3.47-3.52 (m, 4H, H-2A, H-2D,
2 × H-6b), 3,60 (t, 2H, H-4A, H-4D, J ) 9,0 Hz), 3.72 (d, 2H, 2 ×
H-6b, J ) 10.5 Hz), 3.90-4.26 (m, 22H, H-3A, H-3B, H-3C, H-3D,
H-3E, H-3F, H-4B, H-4C, H-4E, H-4F, H-5A, H-5B, H-5C, H-5D, H-5E,
H-5F, H-6aA, H-6aB, H-6aC, H-6aD H-6aE, H-6aF), 4.29-4.57 (m,
20H, H benz., H-6bA, H-6bD), 4.81-4.95 (m, 12H, H-1B, H-1C,
H-1E, H-1F, H benz.), 5.02 (d, 2H, H benz., J ) 11.4 Hz), 5.11 (d,
2H, H-1A and H-1D, J ) 3,6 Hz), 5.17 (d, 2H, H benz., J ) 10,8
A series of amphiphilic cyclodextrins having potentially
various values of hydrophobic/hydrophilic balance, depending
of the number (2, 4, or 612), the length (C4, C6, or C8), and the
nature (fluorinated or hydrocarbonated) of these grafted chains,
is then available for studying their behavior in aqueous medium,
their self-organization at the air/water interface, and in aqueous
medium in the form of nanoparticles to transport biologically
active compounds.
7322 J. Org. Chem. Vol. 73, No. 18, 2008

New Di- and TetraderiVatized R-Cyclodextrin Molecules
Hz), 5.34 (d, 2H, H benz., J ) 11.1 Hz), 7.09-7.29 (m, 80H, HAr).
13C NMR (CDCl3, 75 MHz assignments by DEPT, HSQC, and
HMBC) δ (ppm) 37.6 (CH3 mesyl), 69.3, 69.6 (C-6B, C-6C, C-6E,
C-6F), 70.0 (C-5A, C-5D), 70.4 (C-6A, C-6D), 71.9, 72.4 (C-5B, C-5C,
C-5E, C-5F), 72.8, 73.1, 73.4, 73.8, 73.9, 75.4, 76.3, 76.5 (C benz.),
78.5 (C-2A, C-2D), 79.4, 79.6 (C-2B, C-2C, C-2E, C-2F), 80.3 (C-
4A, C-4D), 80.9, 81.1, 81.9 (C-3A, C-3B, C-3C, C-3D, C-3E, C-3F,
C-4B, C-4C, C-4E, C-4F), 98.9, 100.4 (C-1B, C-1C, C-1E, C-1F), 100.7
(C-1A, C-1D), 127.1-128.7 (CHar), 138.6-139.9 (CAr). MS (ESI)
m/z 1308.2 [(M + 2Na)/2]2+, 2571.2 [M + H]+, 2592.7 [M + Na]+.
HRMS calcd for C122H136O34S2Na 2291.8252, found 2291.8238.
6A,6D-Di-O-methylsulfonyl-r-cyclodextrin (5). To a solution of
4 (0.258 g, 100 µmol) in a 1:1 EtOAc/MeOH mixture (20 mL)
was added 10% Pd/C (0.106 g, 100 µmol, 1 equiv). The reaction
mixture was stirred during 24 h at room temperature under 10 bar
H2 atmosphere. The reaction was monitored by TLC (n-BuOH/
ethanol/water: 5/4/3). The mixture was then filtered (Celite) into a
separating funnel, washing thoroughly with MeOH. The solvent is
then evaporated under vacuum to afford 5 as a white powder, in
Hz), 6.38 (t, 2H, OH-6B, OH-6E, J ) 5.5 Hz), 6.46 (t, 2H, OH-6C,
OH-6F, J ) 5.0 Hz), 7.38-7.45 (m, 6H, OH-3), 7.65 (br s, 2H,
OH-C2B, OH-C2E), 7.76 (br s, 2H, OH-C2C, OH-C2F). 13C NMR
(pyridine-d5, 125 MHz, assignments by TOCSY, HMBC, and
HSQC) δ (ppm) 14.4 (CH3), 23.1 (CH2-CH3), 28.8 (CH2-
CH2-CH2-S), 29.3 (CH2-CH2-CH2-CH2-S), 30.0 (CH2-
CH2-S), 32.1 (CH2-CH2-CH3), 33.7 (CH2-S), 34.6 (C-6A, C-6D),
61.3 (C-6B, C-6C, C-6E, C-6F), 72.7 (C-5A, C-5D), 73.9-74.0 (C-
5B, C-5C, C-5E, C-5F, C-2A, C-2B, C-2C, C-2D, C-2E, C-2F), 74.7
(C-3A, C-3D), 74.8 (C-3C, C-3F), 74.9 (C-3B, C-3E), 83.1 (C-4B, C-4C,
C-4E, C-4F), 86.2 (C-4A, C-4D), 103.4 (C-1A, C-1D), 103.8 (C-1B,
C-1E), 103.9 (C-1C, C-1F). MS (ESI) m/z 1201.5 [M + H]+, 1218.5
[M + NH4]+. HRMS calcd for C50H88O28S2Na 1223.4801, found
1223.4812.
6A,6D-Dideoxy-6A,6D-dinonanethio-r-cyclodextrine (6b). The meth-
anolic filtrate was evaporated under vacuum to afford 6b as a white
powder. Yield 77%. Mp 213 °C dec. IR ν (cm-1) 3317 (O-H),
1
2923 and 2850 (C-H), 1072 (CH-OH). H NMR (pyridine-d5,
300 MHz, assignment by TOCSY, HMBC, and HSQC) δ (ppm)
0.85 (m, 6H, CH3), 1.31-1.34 (m, 20H, CH2-CH2-
CH2-CH2-CH2-CH3), 1.42-1.50 (m, 4H, CH2-CH2-CH2-S),
1.66-1.76 (m, 4H, CH2-CH2-S), 2.77-2.87 (m, 4H, CH2-S),
3.22 (dd, 2H, H-6aA, H-6aD, J ) 6.2 and 13.5 Hz), 3.41 (d, 2H,
H-6bA, H-6bD, J ) 13.5 Hz), 4.12 (m, 8H, H-2A, H-2B, H-2C, H-2D,
H-2E, H-2F, H-4A, H-4D), 4.38 (t, 2H, H-4C, H-4F, J ) 9.3 Hz),
4.41 (t, 2H, H-4B, H-4E, J ) 9.2 Hz), 4.48 (d, 4H, H-6bB, H-6bC,
H-6bE, H-6bF, J ) 3.2 Hz), 4.54-4.64 (m, 10H, H-5A, H-5B, H-5C,
H-5D, H-5E, H-5F, H-6aB, H-6aC, H-6aE, H-6aF), 4.74 (t, 2H, H-3A,
H-3D, J ) 9.2 Hz), 4.77 (t, 2H, H-3C, H-3F, J ) 9,3 Hz), 4.80 (t,
2H, H-3B, H-3E, J ) 9.2 Hz), 5.57 (br s, 4H, H-1A, H-1C, H-1D,
H-1F), 5.64 (d, 2H, H-1B, H-1E, J ) 2.0 Hz), 6.50 (t, 2H, OH-6B,
OH-6E, J ) 5.2 Hz), 6.58 (t, 2H, OH-6C, OH-6F, J ) 5.2 Hz),
7.38-7.45 (m, 6H, OH-3), 7.65 (br s, 2H, OH-C2B, OH-C2E), 7.76
(br s, 2H, OH-C2C, OH-C2F). 13C NMR (pyridine-d5, 75 MHz,
assignments by TOCSY, HMBC, and HSQC) δ (ppm) 14.5 (CH3),
23.2 (CH2-CH3), 29.0 (CH2-CH2-CH2-S), 29.7, 29.9, 30.1 (CH2-
-CH2-CH2-CH2-CH2-CH2-S), 30.1 (CH2-CH2-S), 32.5
(CH2-CH2-CH3), 33.9 (CH2-S), 34.8 (C-6A, C-6D), 61.5 (C-6B,
C-6C, C-6E, C-6F), 72.7 (C-5A, C-5D), 74.0-74.3 (C-5B, C-5C, C-5E,
C-5F, C-2A, C-2B, C-2C, C-2D, C-2E, C-2F), 74.9 (C-3A, C-3D), 75.0
(C-3C, C-3F), 75.1 (C-3B, C-3E), 83.3 (C-4B, C-4C, C-4E, C-4F), 86.4
(C-4A, C-4D), 103.6 (C-1A, C-1D), 103.9 (C-1B, C-1E), 104.0 (C-
1C, C-1F). MS (ESI) m/z 648.6 [M + K + H]2+, 1257.6 [M + H]+,
1274.5 [M + Na]+, 1295.4 [M + K]+. HRMS calcd for
C54H96O28S2Na 1279.5427, found 1279.5429.
92% yield. Mp 156 °C dec. IR ν (cm-1) 3310 (O-H), 2931 (C-H),
22
1332 (C-SO2-C), 1075 (CH-OH). [R]22
+145 (c 1.0 in
D
1
DMSO). H NMR (DMSO-d6, 300 MHz, 25 °C, assignments by
COSY, DEPT, HSQC) δ (ppm) 3.19 (s, 6H, CH3 mesyl), 3.30-3.48
(m, 12H, H-2A, H-2B, H-2C, H-2D, H-2E, H-2F, H-4A, H-4B, H-4C,
H-4D, H-4E, H-4F), 3.52-3.81 (m, 18H, H-3A, H-3B, H-3C, H-3D,
H-3E, H-3F, H-5B, H-5C, H-5E, H-5F, H-6aB, H-6aC, H-6aE, H-6aF,
H-6bB, H-6bC, H-6bE, H-6bF), 3.91-3.93 (m, 2H, H-5A, H-5D), 4.31
(d, 2H, H-6bA, H-6bD, J ) 9.6 Hz), 4.52 (dd, 2H, H-6aA, H-6aD, J
) 3.8 and 10.7 Hz), 4.57 (t, 2H, OH-6, J ) 6.3 Hz), 4.63 (t, 2H,
OH-6, J ) 5.3 Hz), 4,80 (d, 2H, H-1A, H-1D, J ) 3.0 Hz), 4,87 (d,
2H, 2 × H-1, J ) 3.0 Hz), 4.90 (d, 2H, 2H-1, J ) 3.0 Hz),
5.45-5.63 (m, 12H, OH-2, OH-3).13C NMR (DMSO-d6, 75 MHz
assignments by DEPT and HSQC) δ (ppm) 37.5 (CH3 mesyl), 60.7,
61.3 (C-6B, C-6C, C-6E, C-6F), 69.6 (C-5A, C-5D), 70.3 (C-6A, C-6D),
72.6, 72.9, 73.1 (C-2A, C-2B, C-2C, C-2D, C-2E, C-2F, C-5B, C-5C,
C-5E, C-5F), 73.9 (C-3A, C-3D), 74.0 (C-3B, C-3C, C-3E, C-3F), 82.6,
83.0, 83.4 (C-4A, C-4B, C-4C, C-4D, C-4E, C-4F), 102.5 (C-1A, C-1D),
102.7(C-1B, C-1C, C-1E, C-1F). MS (ESI) m/z 1129.3 [M + H]+,
1146.3 [M + NH4]+, 1151.3 [M + Na]+, 1167.3 [M + K]+, 1219.3
[M + Na - H]+. HRMS calcd for C38H64O34S2Na 1151.2618, found
1151.2609.
General Procedure for the Preparation of 6A,6D-Dideoxy-6A,6D-
dialkylthio-r-cyclodextrins (6a-c). Dry Cs2CO3 (1.73 g 5.31
mmol, 12 equiv) was added to a solution of alkylisothiouronium
bromide14 (4 equiv) in anhydrous DMF (10 mL) and the mixture
was stirred for 2 h at room temperature under argon. A solution
of 5 (0.500 g, 1equiv) in anhydrous DMF (10 mL) was then
added dropwise to the suspension during 1 h. The reaction
mixture was stirred for 4 days at 60 °C under argon and the
reaction monitored by TLC (n-BuOH/ethanol/water: 5/4/3). The
product was then precipitated from cold acetone (500 mL). The
precipitated was filtered off, then washed with acetone, water,
then MeOH.
6A,6D-Dideoxy-6A,6D-diundecanethio-r-cyclodextrin (6c). The
precipitate was reprecipitated in warm EtOH (10 mL), filtered, and
dried under vacuum to afford 6c as a white powder. Yield 62%. Mp
213 °C dec. IR ν (cm-1) 3325 (O-H), 2922 and 2853 (C-H), 1073
(CH-OH). 1H NMR (DMSO-d6, 500 MHz, assignment by TOCSY,
HMBC, HSQC) δ (ppm) 0.87 (t, 6H, CH3, J ) 7.0 Hz), 1.26 (br s,
28H, 14 CH2), 1.34-1.35 (m, 2H, CH2-CH2-CH2-S), 1.42-1.48
(m, 4H, CH2-CH2-S), 2.50 (s, 4H, CH2-S), 2.67 (dd, 2H, H-6aA,
H-6aD, J ) 8.3 and 13.8 Hz), 2.93 (d, 2H, H-6bA, H-6bD, J ) 8.3
Hz), 3.28-3.35 (m, 8H, H-2A, H-2B, H-2C, H-2D, H-2E, H-2F, H-4A,
H-4D), 3.44 (t, 2H, 2 × H-4, J ) 9.3 Hz), 3.46 (t, 2H, 2 × H-4, J )
9.5 Hz), 3.54 (d, 4H, H-6bB, H-6bC, H-6bE, H-6bF, J ) 9.4 Hz),
3.62-3.66 (m, 4H, H-5B, H-5C, H-5E, H-5F), 3.71-3.77 (m, 8H, H-3A,
H-3B, H-3C, H-3D, H-3E, H-3F, 2 × H-6a), 3.81 (t, 2H, H-5A, H-5D, J
) 8.5 Hz), 3.90 (d, 2H, 2 × H-6a, J ) 10.8 Hz), 4.80 (br s, 4H, H-1A,
H-1B, H-1D, H-1E), 4.84 (br s, 2H, H-1C, H-1F), 4.45 (br s, 2H, 2 ×
OH-6), 4.55 (br s, 2H, 2 × OH-6), 5.62 (br s, 6H, OH IIary), 5.78 (br
s, 2H, OH IIary). 13C NMR (DMSO-d6, 125 MHz, assignment by
TOCSY, HMBC, HSQC) δ (ppm) 15.0 (CH3), 23.1 (CH2-CH3), 28.3
(CH2-CH2-CH2-S), 29.3, 29.9, 29.9, 30.1, 30.3 (CH2), 29.5
(CH2-CH2-S), 32.4 (CH2-CH2-CH3), 33.2 (CH2-S), 34.3 (C-6A,
C-6D), 60.3 (C-6B, C-6C, C-6E, C-6F), 72.0 (C-5A, C-5D), 72.8-72.9
(C-5B, C-5C, C-5E, C-5F, C-2A, C-2B, C-2C, C-2D, C-2E, C-2F), 74.0
(C-3A, C-3B, C-3C, C-3D, C-3E, C-3F), 82.7 (C-4B, C-4C, C-4E, C-4F),
6A,6D-Dideoxy-6A,6D-diheptanethio-r-cyclodextrin (6a). The meth-
anolic filtrate was evaporated under vacuum to afford 6a as a white
powder. Yield 53%. Mp 209 °C dec. IR ν (cm-1) 3313 (O-H),
2925 et 2850 (C-H), 1075 (CH-OH). 1H NMR (pyridine-d5, 500
MHz, assignements by TOCSY, HMBC, and HSQC) δ (ppm) 0.86
(m, 6H, CH3), 1.30 (br s, 12H, CH2-CH2-CH2-CH3), 1.38-1.49
(m, 4H, CH2-CH2-CH2-S), 1.62-1.72 (m, 4H, CH2-CH2-S),
2.74-2.84 (m, 4H, CH2-S), 3.19 (dd, 2H, H-6aA, H-6aD, J ) 6.2
and 13.4 Hz), 3.37 (d, 2H, H-6bA, H-6bD, J ) 13.4 Hz), 4.10 (m,
8H, H-2A, H-2B, H-2C, H-2D, H-2E, H-2F, H-4A, H-4D), 4.38 (t, 2H,
H-4C, H-4F, J ) 9.0 Hz), 4.42 (t, 2H, H-4B, H-4E, J ) 9.2 Hz),
4.47 (d, 4H, H-6bB, H-6bC, H-6bE, H-6bF, J ) 9.4 Hz), 4.51-4.59
(m, 10H, H-5A, H-5B, H-5C, H-5D, H-5E, H-5F, H-6aB, H-6aC, H-6aE,
H-6aF), 4.69 (t, 2H, H-3A, H-3D, J ) 8.9 Hz), 4.71 (t, 2H, H-3C,
H-3F, J ) 8.6 Hz), 4.76 (t, 2H, H-3B, H-3E, J ) 8.2 Hz), 5.54 (br
s, 4H, H-1A, H-1C, H-1D, H-1F), 5.61 (d, 2H, H-1B, H-1E, J ) 2.9
J. Org. Chem. Vol. 73, No. 18, 2008 7323

Bertino-Ghera et al.
86.6 (C-4A, C-4D), 102.5, 102.9 (C-1A, C-1B, C-1D, C-1E), 103.1 (C-
1C, C-1F). MS (Maldi) m/z 1335.8 [M + Na]+, 1351.7 [M + K]+.
HRMS calcd for C58H104O28S2Na 1335.6053, found 1335.6047.
General Procedure for the Preparation of 6A,6D-Dideoxy-6A,6D-
di(3-perfluoroalkylpropanethio)-r-cyclodextrins (7a-c). Dry
Cs2CO3 (1.84 g 5.65 mmol, 7.5 equiv) was added to a solution
of 3-perfluoroalkylpropane isothiouronium iodide14 (3.76 mmol,
5 equiv) in anhydrous DMF (20 mL) and the mixture was stirred
for 1 h at room temperature under argon. A solution of 5 (0.850
g, 0.75 mmol, 1 equiv) in anhydrous DMF (15 mL) was then
added dropwise to the suspension during 40 min. The reaction
mixture was stirred for 4 days at 80 °C under argon and the
reaction monitored by TLC (n-BuOH/ethanol/water: 5/4/3). After
cooling, the product was precipitated from cold acetone (500
mL). The precipitated was filtered off, thenwashed with acetone,
water (10 mL), and then MeOH (50 mL).
4B, C-4E), 82.2 (C-4C, C-4F), 84.7 (C-4A, C-4D), 101.6 (C-1A, C-1D),
101.9 (C-1B, C-1E), 102.1 (C-1C, C-1F). 19F NMR (DMSO-d6, 280
MHz, CFCl3) δ (ppm) -81.2 (t, 3F, CF3, J ) 9.8 Hz), -114.0-114.2
(m, 2F, CH2-CF2), -122.6 (m, 2F, CF2), -123.5 (m, 2F, CF2),
-123.6 (m, 2F, CF2), -123.9 (m, 2F, CF2), -126.7 (m, 2F,
CF2-CF3). MS (Maldi) m/z 1747.3 [M + Na]+, 1763.2 [M + K]+.
HRMS calcd for C54H70F26O28S2Na 1747.2978, found 1747.2973.
6A,6D-Dideoxy-6A,6D-di(3-perfluorooctylpropanethio)-r-cyclo-
dextrin (7c). The precipitate was reprecipitated in warm EtOH (10
mL), filtered, and dried under vacuum to afford 7c as a cream powder
in 56% yield. Mp 245 °C dec. IR ν (cm-1) 3325 (O-H), 2925 (C-H),
1236-1147 (C-F), 1078 (C-O-C). 1H NMR (DMSO-d6, 500 MHz)
δ (ppm) 1.74 (m, 4H, CH2-CH2-S), 2.27 (tt, 4H, CH2-CF2, J )
7.9 and 18.6 Hz), 2.64 (t, 4H, CH2-S, J ) 6.2 Hz), 2.77 (dd, 2H,
H-6aA, H-6aD, J ) 6.2 and 13.0 Hz), 2.99 (d, 2H, H-6bA, H-6bD, J )
13.0 Hz), 3.26 (dd, 2 × H-2, J ) 2.7 and 9.1 Hz), 3.28 (dd, 2 × H-2,
J ) 2.7 and 7.8 Hz), 3.30 (dd, 2 × H-2, J ) 2.7 and 9.9 Hz),
3.33-3.42 (m, 4H, 4 × H-4), 3.44 (t, 2H, 2 × H-4, J ) 9.2 Hz),
3.58-3.60 (m, 10H, H-5A, H-5B, H-5C, H-5D, H-5E, H-5F, H-6bB,
H-6bC, H-6bE, H-6bF), 3.73-3.84 (m, 8H, H-3A, H-3B, H-3C, H-3D,
H-3E, H-3F, H-6aB, H-6aC, H-6aE, H-6aF), 4.52 (br s, 2H, OH-6), 4.56
(br s, 2H, OH-6), 4.78 (d, 4H, H-1A, H-1B, H-1D, H-1E, J ) 2.7 Hz),
6A,6D-Dideoxy-6A,6D-di(3-perfluorobutylpropanethio)-r-cyclo-
dextrine (7a). The methanolic filtrate was evaporated under vacuum
to afford compound 7a as a white powder in 52% yield. Mp 235
°C dec. IR ν (cm-1) 3368 (O-H), 2930 (C-H), 1231-1151 (C-F),
1
1080 (C-O-C). H NMR (pyridine-d5, 500 MHz, assignment by
TOCSY, HMBC, HSQC) δ (ppm) 1.92 (qi, 4H, CH2-CH2-S, J
) 7.2 Hz), 2.28 (tt, 4H, CH2-CF2, J ) 8.5 and 19.1 Hz), 2.61-2.90
(m, 4H, CH2-S), 3.23 (br s, 4H, H-6aA, H-6aD, H-6bA, H-6bD),
4.08-4.14 (m, 6H, H-2A, H-2B, H-2C, H-2D, H-2E, H-2F), 4.18 (t,
2H, H-4A, H-4D, J ) 8.8 Hz), 4.25 (t, 2H, H-4C, H-4F, J ) 8.8
Hz), 4.34 (t, 2H, H-4B, H-4E, J ) 9.2 Hz), 4.35-4.44 (m, 6H,
H-6aB, H-6aE, H-6bB, H-6bC, H-6bE, H-6bF), 4.50-4.52 (m, 8H,
H-5A, H-5B, H-5C, H-5D, H-5E, H-5F, H-6aC, H-6aF), 4.68 (t, 2H,
H-3A, H-3D, J ) 8.8 Hz), 4.71 (t, 2H, H-3C, H-3F, J ) 8.9 Hz),
4.73 (t, 2H, H-3B, H-3E, J ) 9.2 Hz), 5.51(d, 2H, H-1A, H-1D, J )
3.2 Hz), 5.53 (d, 2H, H-1C, H-1F, J ) 3.1 Hz), 5.58 (d, 2H, H-1B,
H-1E, J ) 2.9 Hz), 6.43 (t, 2H, OH-6B, OH-6E, J ) 6.0 Hz), 6.52
(t, 2H, OH-6C, OH-6F, J ) 5.6 Hz), 7.40-7.49 (m, 6H, OH-3),
7.61 (br s, 2H, OH-C2B, OH-C2E), 7.61 (br s, 2H, OH-C2C, OH-
C2F). 13C NMR (pyridine-d5, 125 MHz, assigment by TOCSY,
HMBC, HSQC) δ (ppm) 20.9 (CH2-CH2-S), 29.7 (CH2-CF2, J
) 21.8 Hz), 32.7 (CH2-S), 34.2 (C-6A, C-6D), 61.3 (C-6B, C-6E),
61.7 (C-6C, C-6F), 72.5 (C-5A, C-5D), 73.86 (C-5B, C-5E), 73.94
(C-2A, C-2C, C-2D, C-2F), 74.1 (C-2B, C-2E), 74.2 (C-5C, C-5F),
74.8 (C-3A, C-3D), 74.9 (C-3C, C-3F), 75.0 (C-3B, C-3E), 83.1 (C-
4B, C-4E), 83.4 (C-4C, C-4F), 85.6 (C-4A, C-4D), 103.4 (C-1A, C-1D),
103.7 (C-1B, C-1E), 103.8 (C-1C, C-1F). 19F NMR (pyridine-d5, 280
MHz, CFCl3) δ (ppm) -82.3 (t, 3F, CF3, J ) 9.1 Hz), -113.1 (m,
2F, CH2-CF2), -123.4 (m, 2F, CF2), -125.1 (m, 2F, CF2-CF3).
MS (Maldi) m/z 1547.4 [M + Na]+, 1563.4 [M + K]+. HRMS
calcd for C50F18H70O28S2Na 1547.3105, found 1547.3104.
4.83 (d, 2H, H-1C, H-1F, J ) 2.7 Hz), 5.61 (br s, 12H, OH IIary). 13
C
NMR (DMSO-d6, 75 MHz) δ (ppm) 19.8 (CH2-CH2-S), 28.5
(CH2-CF2, J ) 21.7 Hz), 30.8 (CH2-S), 32.7 (C-6A, C-6D), 59.6
(C-6B, C-6E), 59.8 (C-6C, C-6F), 70.7 (C-5A, C-5D), 71.6-72.1 (C-5B,
C-5C, C-5E, C-5F, C-2A, C-2B, C-2C, C-2D, C-2E, C-2F), 72.9 (C-3A,
C-3B, C-3C, C-3D, C-3E, C-3F), 81.4 (C-4B, C-4E), 81.9 (C-4C, C-4F),
84.9 (C-4A, C-4D), 101.3 (C-1A, C-1D), 101.7 (C-1B, C-1E), 102.0 (C-
1C, C-1F). MS (Maldi) m/z 1947.5 [M + Na]+, 1963.4 [M + K]+.
HRMS calcd for C58F34H70O28S2Na 1947.2860, found 1947.2858.
6A,6D-Di-O-methyl-6B,6C,6E,6F-tetra-O-benzyl(per-2,3-di-O-ben-
zyl)-r-cyclodextrin (8). To a solution of 322 (10.00 g, 4,14 mmol)
in anhydrous DMF (40 mL) under argon was added at 0 °C NaH
(95%, 0.628 g, 24.85 mmol, 6 equiv). The reaction mixture was
stirred during 1 h at room temperature under argon. Methyl iodide
(1.55 mL, 24.85 mmol, 6 equiv) was then added dropwise in 5
min. The mixture was stirred at room temperature for 3 h and the
reaction was monitored by TLC (cyclohexane/AcOEt: 6/2). The
reaction was quenched by adding MeOH (10 mL), then water (100
mL). The organic layer was extracted with diethyl ether (3 × 50
mL) and organic layers were combined, washed with brine (100
mL), dried on Na2SO4, and then evaporated under vacuum. The
crude product was purified by flash chromatography (SiO2, eluent
gradient 0-20% EtOAc in cyclohexane) to afford compound 8 as
a white foam. Yield 98%. IR ν (cm-1) 3030 (C-H ar), 2926 (C-H),
1091 (C-O-C). 1H NMR (CDCl3, 300 MHz, assignment by
COSY, DEPT, HSQC) δ (ppm) 3.13 (s, 6H, CH3), 3.36 (d, 2H,
H-6aA, H-6aD, J ) 10.5 Hz), 3.41-3.60 (m, 10H, H-2A, H-2B, H-2C,
H-2D, H-2E, H-2F, H-6aB, H-6aC, H-6aE, H-6aF), 3.74 (d, 2H, H-6bA,
H-6bD, J ) 10.2 Hz), 3.85-4.15 (m, 22H, H-3A, H-3B, H-3C, H-3D,
H-3E, H-3F, H-4A, H-4B, H-4C, H-4D, H-4E, H-4F, H-5A, H-5B, H-5C,
H-5D, H-5E, H-5F, H-6bB, H-6bC H-6bE, H-6bF), 4.34-4.55 (m, 20H,
H benz.), 4.83-4.89 (m, 6H, H benz.), 5.00 (d, 2H, 2 × H-1, J )
3.3 Hz), 5.04 (d, 2H, 2 × H-1, J ) 3.6 Hz), 5.06 (d, 2H, 2 × H-1,
J ) 3.6 Hz), 5.13-5.23 (m, 6H, H benz.), 7.07-7.30 (m, 80H,
HAr). 13C NMR (CDCl3, 75 MHz, assigment by COSY, DEPT,
HSQC) δ (ppm) 59.5 (CH3), 69.6 (C-6B, C-6C, C-6E, C-6F), 71.5
(C-5B, C-5C, C-5E, C-5F), 71.9 (C-6A, C-6D), 72.0 (C-5A, C-5D),
73.2, 73.5, 73.8, 75.8, 76.0, 76.7 (C benz.), 79.3, 79.5, 79.5, 79.7,
79.8 (C-2A, C-2B, C-2C, C-2D, C-2E, C-2F, C-4B, C-4C, C-4E, C-4F),
80.4 (C-4A, C-4D), 81.4 (C-3A, C-3B, C-3C, C-3D, C-3E, C-3F), 99.2,
99.4 (C-1A, C-1B, C-1C, C-1D, C-1E, C-1F), 127.4-128.8 (CHar),
138.7-139.89 (CAr). MS (ESI) m/z 1222.2 [(M + 2H)/2]2+, 1244.2
[(M + 2Na)/2]2+, 2442.9 [M + H]+, 2465.0 [M + Na]+. HRMS
calcd for C150H160O30Na 2464.0892, found 2464.0894.
6A,6D-Dideoxy-6A,6D-di(3-perfluorohexylpropanethio)-r-cyclo-
dextrin (7b). The precipitate was reprecipitated in warm EtOH (10
mL), filtered, and dried under vacuum to afford 7b as a cream
powder in 54% yield. Mp 238 °C dec. IR ν (cm-1) 3324 (O-H),
2924 (C-H), 1233-1144 (C-F), 1077 (C-O-C). 1H NMR
(DMSO-d6, 500 MHz) δ (ppm) 1.76 (qi, 4H, CH2-CH2-S, J )
7.3 Hz), 2.29 (tt, 4H, CH2-CF2, J ) 7.3 and 19.2 Hz), 2.66 (t, 4H,
CH2-S, J ) 7.3 Hz), 2.83 (dd, 2H, H-6aA, H-6aD, J ) 5.8 and
12.9 Hz), 2.99 (d, 2H, H-6bA, H-6bD, J ) 12.9 Hz), 3.28-3.32
(m, 6H, H-2A, H-2B, H-2C, H-2D, H-2E, H-2F), 3.35 (t, 2H, H-4A,
H-4D, J ) 8.8 Hz), 3.42 (t, 2H, 2*H-4, J ) 8.9 Hz), 3.43 (t, 2H,
2 × H-4, J ) 8.9 Hz), 3.62-3.66 (m, 10H, H-5A, H-5B, H-5C,
H-5D, H-5E, H-5F, H-6bB, H-6bC, H-6bE, H-6bF), 3.74-3.77 (m,
8H, H-3A, H-3B, H-3C, H-3D, H-3E, H-3F, 2 × H-6a), 3.85 (br s,
2H, 2 × H-6a), 4.48 (br s, 2H, OH-6), 4.53 (br s, 2H, OH-6), 4.78
(d, 4H, H-1A, H-1B, H-1D, H-1E, J ) 1.6 Hz), 4.83 (d, 2H, H-1C,
H-1F, J ) 3.1 Hz), 5.54-5.59 (br s, 6H, OH IIary), 5.63-5.66 (br
s, 2H, OH IIary). 13C NMR (DMSO-d6, 75 MHz) δ (ppm) 20.1
(CH2-CH2-S), 29.0 (CH2-CF2, J ) 20.3 Hz), 31.2 (CH2-S), 33.0
(C-6A, C-6D), 59.8 (C-6B, C-6E), 60.0 (C-6C, C-6F), 70.8 (C-5A,
C-5D), 72.0-72.3 (C-5B, C-5C, C-5E, C-5F, C-2A, C-2B, C-2C, C-2D,
C-2E, C-2F), 73.1 (C-3A, C-3B, C-3C, C-3D, C-3E, C-3F), 81.8 (C-
6A,6D-Di-O-methyl-r-cyclodextrin (9). To a solution of 8 (9.48
g, 3.88 mmol) in a 1:1 EtOAc/MeOH mixture (100 mL) was added
10% Pd/C (2.05 g, 100 mmol, 0.5 equiv). The reaction mixture
7324 J. Org. Chem. Vol. 73, No. 18, 2008

New Di- and TetraderiVatized R-Cyclodextrin Molecules
was stirred during 46 h at room temperature under 1 bar H2
atmosphere. The reaction achievement was monitored by TLC (n-
BuOH/EtOH/H2O: 5/4/3). The mixture was then filtered off on
Celite, which was washed with water. After evaporation under vacuum,
compound 9 was obtained as a white powder: Yield: 98%. Mp 227
precipitated from cold acetone (500 mL), then the precipitate was
filtered off, washed with acetone (100 mL) and water (50 mL),
and then reprecipitated from warm EtOH (10 mL) to afford the
desired compound as a white powder.
6A,6B,6D,6E-Tetradeoxy-6A,6B,6D,6E-tetraheptanethiodi(6C,6F-O-
methyl)-r-cyclodextrin (11a). Yield 86%. Mp 188 °C dec. IR ν
(cm-1) 3325 (O-H), 2923 and 2854 (C-H), 1232-1148 (C-F),
1083 (CH-OH). 13C NMR (125 MHz, CP, HP Dec, MAS 10 kHz,
RD ) 4 s) δ (ppm) 14.2 (CH3), 23.0 (CH2-CH3), 29.3-33.8 (CH2,
C-6), 58.6 (OCH3), 73.3 (C-2, C-3, C-5), 81.4-85.5 (C-4), 102.9
(C-1). MS (ESI) m/z 1457.4 [M + H]+, 1479.7 [M + Na]+. HRMS
calcd for C66H120O26S4Na 1479.6848, found 1479.6853.
°C dec. IR ν (cm-1) 3330 (O-H), 2919 (C-H), 1076 (CH-OH).
1
[R]22 +141 (c 1.03 in H2O). H NMR (D2O, 300 MHz, assigment
D
by COSY, DEPT, HSQC) δ (ppm) 3.39 (s, 6H, CH3), 3.54-3.65 (m,
12H, H-2A, H-2B, H-2C, H-2D, H-2E, H-2F, H-4A, H-4B, H-4C, H-4D,
H-4E, H-4F), 3.77-4.01 (m, 24H, H-3A, H-3B, H-3C, H-3D, H-3E, H-3F,
H-5A, H-5B, H-5C, H-5D, H-5E, H-5F, H-6aA, H-6aB, H-6aC, H-6aD,
H-6aE, H-6aF, H-6bA, H-6bB, H-6bC, H-6bD, H-6bE, H-6bF), 4.78-4.85
(d, 6H, H-1A, H-1B, H-1C, H-1D, H-1E, H-1F, J ) 2.4 Hz). 13C NMR
(D2O, 75 MHz, assignment by DEPT, HSQC) δ (ppm) 58.9 (CH3),
60.8 (C-6B, C-6C, C-6E, C-6F), 71.0 (C-5A, C-5D), 71.1 (C-6A, C-6D),
72.0 (C-2A, C-2B, C-2C, C-2D, C-2E, C-2F), 72.5 (C-5B, C-5C, C-5E,
C-5F), 73.8 (C-3A, C-3B, C-3C, C-3D, C-3E, C-3F), 82.0 (C-4B, C-4C,
C-4E, C-4F), 82.1 (C-4A, C-4D), 102.0 (C-1B, C-1C, C-1E, C-1F), 102.2
(C-1A, C-1D). MS (ESI) m/z 520.1 [(M + H + K)/2]2+, 1001.4 [M +
H]+, 1018.4 [M + NH4]+, 1023.2 [M + Na]+. HRMS calcd for
C38H64O30Na 1023.3380, found 1023.3378.
6A,6B,6D,6E-Tetradeoxy-6A,6B,6D,6E-tetranonanethiodi(6C,6F-O-
methyl)-r-cyclodextrin (11b). Yield 81%. Mp 198 °C dec. IR ν
(cm-1) 3315 (O-H), 2922 and 2853 (C-H), 1230-1149 (C-F),
1085 (CH-OH). 13C NMR (125 MHz, CP, HP Dec, MAS 10 kHz,
RD ) 4 s) δ (ppm) 14,2 (CH3), 23.0 (CH2-CH3), 29.7-32.2 (CH2,
C-6), 58.5 (OCH3), 72.2 (C-2, C-3, C-5), 83.1-85.5 (C-4), 102.6
(C-1). MS (ESI) m/z 1570.5 [M + H]+, 1592.2 [M + Na]+. HRMS
calcd for C74H136O26S4Na 1591.8100, found 1591.8105.
6A,6B,6D,6E-Tetradeoxy-6A,6B,6D,6E-tetraundecanethiodi(6C,6F-O-
methyl)-r-cyclodextrin (11c). Yield 65%. Mp 203 °C dec. IR ν
(cm-1) 3321 (O-H), 2921 and 2852 (C-H), 1228-1148 (C-F),
1085 (CH-OH). 13C NMR (125 MHz, CP, HP Dec, MAS 10 kHz,
RD ) 4 s) δ (ppm) 14.2 (CH3), 23.0 (CH2-CH3), 29.7-34.2 (CH2,
C-6), 59.0 (OCH3), 73.1 (C-2, C-3, C-5), 83.5-85.5 (C-4), 103.0
(C-1). MS (ESI) m/z 868.9 [M + K + NH4]2+, 1682.8 [M + H]+,
1704.9 [M + Na]+. HRMS calcd for C82H152O26S4Na 1703.9352,
found 1703.9360.
(6A,6B,6D,6E-Tetradeoxy-6A,6B,6D,6E-tetraiodo)di(6C,6F-O-meth-
yl)-r-cyclodextrin (10). Compound 9 was dried under vacuum at
100 °C during 15 h before use. To a solution of triphenylphosphine
(13.21 g, 50.00 mmol, 16 equiv) in anhydrous DMF (60 mL) under
argon was added iodine (12.78 g, 50.00 mmol, 16 equiv). After 10
min of stirring at room temperature, a solution of 9 (3.15 g, 3.15
mmol) in anhydrous DMF (30 mL) was added dropwise. The
reaction mixture was then stirred at 80 °C during 23 h under argon
and the reaction achievement monitored by TLC (n-BuOH/EtOH/
H2O: 5/4/3). The solution was then concentrated under vacuum to
remove 50 mL of DMF. A 3 M sodium methanolate solution (19
mL) was then added at 0 °C and the reaction mixture was stirred
at room temperature for 1 h. Iced ethanol (800 mL) was then poured
into the solution to precipitate the compound, which was then
filtered off and washed with EtOH. The brown solid was extracted
with EtOH overnight with a Soxhlet apparatus to afford 10 as a
General Procedure for the Preparation of 6A,6B,6D,6E-Tet-
radeoxy-6A,6B,6D,6E-tetra(3-perfluoroalkylpropanethio)di(6C,6F-O-
methyl)-r-cyclodextrin (12a-c). Dry Cs2CO3 (1.63 g, 5.00 mmol,
24 equiv) was added to a solution of 3-perfluoroalkylpropane
isothiouronium iodide14 (16 equiv) in anhydrous DMF (20 mL)
and the mixture was stirred for 1 h at room temperature under argon.
A solution of 10 (0.300 g, 0.18 mmol, 1 equiv) in anhydrous DMF
(10 mL) was then added dropwise to the suspension during 20 min.
The solution was stirred at 80 °C for 90 h under argon. After
cooling, the product was precipitated from cold acetone (500 mL),
then the precipitate was filtered off, washed with acetone (100 mL)
and water (50 mL), and then reprecipitated from warm EtOH (10
mL) to afford the desired compound as a white powder.
powder. Yield 64%. Mp 208 °C dec. IR ν (cm-1) 3343 (O-H),
1
2916 (C-H), 1079 (CH-OH). [R]22 +85 (c 0.53 in DMF). H
D
NMR (pyridine-d5, 500 MHz, assigment by TOCSY, HMBC,
HSQC) δ (ppm) 3.50 (s, 6H, CH3), 3.80 (dd, 2H, H-6bB, H-6bE, J
) 6.7 and 11.0 Hz), 3.85 (t, 2H, H-4B, H-4E J ) 9.2 Hz), 3.87-3.90
(m, 2H, H-6bC, H-6bF), 3.93-3.95 (m, 8H, H-4C, H-4F, H-5C, H-5F,
H-6aA, H-6aD, H-6aC, H-6aF), 3,99 (dd, 2H, H-6bA, H-6bD, J )
4.6 and 10.8 Hz), 4.03-4.06 (m, 4H, H-5B, H-5E, H-6aB, H-6aE),
4.08-4.11 (m, 8H, H-2A, H-2B, H-2C, H-2D, H-2E, H-2F, H-4A,
H-4D), 4.43 (dd, 2H, H-5A, H-5D, J ) 4.6 and 9.5 Hz), 4.63 (t, 2H,
H-3A, H-3D, J ) 9.6 Hz), 4.67 (t, 2H, H-3B, H-3E, J ) 9.2 Hz),
4.70 (t, 2H, H-3C, H-3F, J ) 8.2 Hz), 5.41 (d, 2H, H-1C, H-1F, J )
2.9 Hz), 5.48 (d, 2H, H-1A, H-1D, J ) 3.1 Hz), 5.50 (d, 2H, H-1B,
H-1E, J ) 2.9 Hz), 7.08 (br s, 14H, OH-2, OH-3). 13C NMR
(pyridine-d5, 125 MHz, assigment by HMBC, HSQC) δ (ppm) 9.0
(C-6B, C-6E), 10.9 (C-6C, C-6F), 59.3 (O-CH3), 70.4 (C-5C, C-5F),
71.3 (C-5B, C-5E), 71.9 (C-6A, C-6D), 72.1 (C-5A, C-5D), 73.6 (C-
2B, C-2E), 73.66 (C-2A, C-2D), 73.7 (C-2C, C-2F), 74.09 (C-3B, C-3E),
74.11 (C-3C, C-3F), 73.8 (C-3A, C-3D), 83.2 (C-4A, C-4D), 87.5 (C-
4B, C-4E), 87.6 (C-4C, C-4F), 103.4 (C-1C, C-1F), 103.45 (C-1A,
C-1D), 103.5 (C-1B, C-1E). MS (ESI) m/z 732.1 [(M + H + Na)/
2]2+, 740.2 [(M + H + K)/2]2+, 1463.0 [M +Na]+. HRMS calcd
for C38H60O26I4Na 1462.9450, found 1462.9446.
6A,6B,6D,6E-Tetradeoxy-6A,6B,6D,6E-tetra(3-perfluorobutylpro-
panethio)di(6C,6F-O-methyl)-r-cyclodextrin (12a). Yield 85%. Mp
213 °C dec. IR ν (cm-1) 3339 (O-H), 2929 (C-H), 1238-1145
(C-F), 1088 (C-O-C). 13C NMR (125 MHz, CP, HP Dec, MAS
10 kHz, RD ) 4 s) δ (ppm) 19.9 (CH2-CH2-S), 29.3-32.3
(CH2-CF2, CH2-S, C-6), 58.1 (OCH3), 67.4-73.6 (C-2, C-3, C-5),
82.0-84.4 (C-4), 102.1 (C-1), 106.5-120.2 (CF2 and CF3). 19F
NMR (470 MHz, MAS 10 and 12 kHz, RD ) 4 s, PhCF3) δ (ppm)
-81.3 (m, 3F, CF3), -113.3 (m, 2F, CH2-CF2), -123.7 (m, 2F,
CF2), -125.5 (m, 2F, CF2-CF3). MS (ESI) m/z 1072.1 [M + K +
H]2+, 2105.2 [M + H]+, 2127.5 [M + Na]+. HRMS calcd for
C66H84F36O26S4Na 2127.3457, found 2127.3465.
6A,6B,6D,6E-Tetradeoxy-6A,6B,6D,6E-tetra(3-perfluorohexylpro-
panethio)di(6C,6F-O-methyl)-r-cyclodextrin (12b). Yield 93%. Mp
231 °C dec. IR ν (cm-1) 3337 (O-H), 2924 (C-H), 1235-1143
(C-F), 1086 (C-O-C). 13C NMR (125 MHz, CP, HP Dec, MAS
10 kHz, RD ) 4 s) δ (ppm) 20.4 (CH2-CH2-S), 29.2-32.1
(CH2-CF2, CH2-S, C-6), 58.1 (OCH3), 73.1 (C-2, C-3, C-5),
82.0-83.6 (C-4), 103.1 (C-1), 108.9-118.1 (CF2 and CF3). 19F
NMR (470 MHz, MAS 10 and 12 kHz, RD ) 4 s, PhCF3) δ (ppm)
-81.4 (m, 3F, CF3), -113.7 (m, 2F, CH2-CF2), -121.5 to -122.7
(m, 6F, CF2), -126.2 (m, 2F, CF2-CF3). MS (ESI) m/z 1072.1
[M + K + H]2+, 2505.0 [M + H]+, 2526.8 [M + Na]+. HRMS
calcd for C74H84F52O26S4Na 2527.3201, found 2527.3212.
6A,6B,6D,6E-Tetradeoxy-6A,6B,6D,6E-tetra(3-perfluorooctylpro-
panethio)di(6C,6F-O-methyl)-r-cyclodextrin (12c). Yield 86%. Mp
245 °C dec. IR ν (cm-1) 3326 (O-H), 2922 (C-H), 1238-1145
General Procedure for the Preparation of 6A,6B,6D,6E-Tet-
radeoxy-6A,6B,6D,6E-tetraalkylthiodi(6C,6F-O-methyl)-r-cyclodex-
trin (11a-c). Dry Cs2CO3 (1.900 g, 5.83 mmol, 24 equiv) was
added to a solution of alkylisothiouronium bromide14 (16 equiv)
in anhydrous DMF (20 mL) and the mixture was stirred for 2 h at
room temperature under argon. A solution of 10 (0.350 g, 0.24
mmol, 1 equiv) in anhydrous DMF (15 mL) was then added
dropwise to the suspension during 20 min. The solution was stirred
at 80 °C for 90 h under argon. After cooling, the product was
J. Org. Chem. Vol. 73, No. 18, 2008 7325

Bertino-Ghera et al.
(C-F), 1089 (C-O-C). 13C NMR (125 MHz, CP, HP Dec, MAS
10 kHz, RD ) 4 s) δ (ppm) 20.4 (CH2-CH2-S), 29.2-32.2
(CH2-CF2, CH2-S, C-6), 58.5 (OCH3), 73.6 (C-2, C-3, C-5),
81.5-84.0 (C-4), 102.9 (C-1), 110.3-118.6 (CF2 and CF3). 19F
NMR (470 MHz, MAS 10 and 12 kHz, RD ) 4 s, PhCF3) δ (ppm)
-81.4 (m, 3F, CF3), -113.1 (m, 2F, CH2-CF2), -1212 tp -122.2
(m, 10F, CF2), -126.0 (m, 2F, CF2-CF3). MS (ESI) m/z 2906.4
[M + H]+, 2928.2 [M + Na]+, 2943.2 [M + K]+. HRMS calcd
for C82H84F68O26S4Na 2927.2946, found 2927.2952.
Baudoin (Laboratoire de Chimie Organome´tallique de Surface,
LCOMS, CNRS UMR 9986, CPE Lyon) for solid state NMR,
and Natali Henriques and Christian Duchamp for mass spec-
troscopy analysis (Centre Commun de Spectrome´trie de Masse,
UMR5246, Universite´ Claude Bernard Lyon1).
Supporting Information Available: General experimental
1
procedures, spectral/analytical data, and copies of H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Ph.D. fellowship from the
French National Ministry of Education and Research, Dr. Anne
JO801111B
7326 J. Org. Chem. Vol. 73, No. 18, 2008