Novel fluorinated amphiphilic cyclodextrin derivatives: Synthesis of mono-, di- and heptakis-(6-deoxy-6-perfluoroalkylthio)-β-cyclodextrins

Article abstract of DOI:10.1016/S0040-4039(02)02539-X

A new series of fluorinated amphiphilic β-cyclodextrin derivatives has been synthesized. The strategy is based on the modification of the C-6 position of the mono-6-deoxy-6^A-para-tolylsulfonyl, di-6^A, 6^D-deoxy-6^A, 6^D-(para-tolylsulfonyl) and heptakis-(6-deoxy-6-iodo)-β-cyclodextrin precursors. The synthesis lead to mono-perfluoroalkylthio-, di-perfluoroalkylthio- and heptakis-perfluoroalkylthio-β-cyclodextrin in excellent yields (90-99%).

Full text of DOI:10.1016/S0040-4039(02)02539-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 241–245
Novel fluorinated amphiphilic cyclodextrin derivatives:
synthesis of mono-, di- and
heptakis-(6-deoxy-6-perfluoroalkylthio)-b-cyclodextrins
Sandrine Peroche and H e´ l e` ne Parrot-Lopez*
Synth e` se, Reconnaissance et Organisation Mol e´ culaire et Biomol e´ culaire-UMR CNRS 5078, Universit e´ Claude Bernard-Lyon I,
Domaine Scientifique de la Doua, B aˆ t. J. Raulin, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne cedex, France
Received 11 September 2002; revised 12 November 2002; accepted 13 November 2002
Abstract—A new series of fluorinated amphiphilic b-cyclodextrin derivatives has been synthesized. The strategy is based on the
A
A
D
A
D
modification of the C-6 position of the mono-6-deoxy-6 -para-tolylsulfonyl, di-6 , 6 -deoxy-6 , 6 -(para-tolylsulfonyl) and
heptakis-(6-deoxy-6-iodo)-b-cyclodextrin precursors. The synthesis lead to mono-perfluoroalkylthio-, di-perfluoroalkylthio- and
heptakis-perfluoroalkylthio-b-cyclodextrin in excellent yields (90–99%). © 2002 Elsevier Science Ltd. All rights reserved.
Cyclodextrins or cyclomaltoheptaoses (CDs) have sig-
nificant potential as drug carriers arising from their
ability to form inclusion complexes. The potential
double-chain amphiphiles and phospholipids in
aqueous solution; these fluorinated liposomes showed
lower drug permeation across the liposomal bilayer,
and the results of the toxicology studies were satisfac-
tory. Thus, the combination of inclusion properties of
the CDs and the useful amphiphilic properties of
fluorocarbon chains should lead to molecules possess-
ing novel physical, chemical and biological properties,
and with higher hydrophobicity compared to their
1
utility of such inclusion phenomena includes solubiliza-
2
3
tion, encapsulation, and transport of biologically
4
active molecules. Amphiphilic b-cyclodextrin deriva-
tives are of considerable interest for pharmaceutical
applications in view of their capacity for self-organiza-
tion in water. With the aim of providing versatile
carrier and delivery systems for hydrophilic and
7
12
hydrocarbon analogs.
5
6
lipophilic drugs, liposomes, nanoparticles, vesicles
8
and micellar aggregates have been prepared from
amphiphilic cyclodextrins.
In previous studies, amphiphilic cyclodextrins were
obtained by the introduction of lipophilic groups at the
13
upper and/or lower rims. The substitution of the
upper rim is more efficient and does not require protec-
tion and deprotection steps. The self-organization
depends essentially on the number and the length of the
hydrophobic chains; in view of the above, we have
synthesized mono-, di- and heptakis-b-cyclodextrin
derivatives substituted at C-6 by a perfluorohexyl-
propanethiol chain.
In recent years, in view of their unique hydrophobic
and colloidal self-assembly properties, highly fluori-
9
nated surfactants have been increasingly studied. Riess
1
0
et al. synthesized several surfactants with one or more
perfluoroalkylated hydrophobic for possible application
in the biomedical field. Films and fluorinated vesicles
made from fluorinated surfactants are usually, more
stable and less permeable than those made from stan-
1
1
dard surfactants. Vierling et al. synthesized fluori-
nated liposomes by dispersion of fluorinated
The hydrofluorocarbon thiol 3 is obtained from the
3-perfluorohexylpropan-1-ol 1 in two steps (Scheme 1)
Scheme 1. Synthesis of the 3-perfluorohexylpropanethiol, 3. Reagents and conditions: (i) P O (6 equiv.), H PO (85%, 6 mL), KI
2
5
3
4
(
2.6 equiv.), 120°C, 4 h; (ii) thiourea (2 equiv.), THF/H O (20:1) (42 mL), 80°C, 3 h followed by NH OH at 20°C.
2 4
*
Corresponding author. E-mail: h.parrot@cdlyon.univ-lyon1.fr
040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
0
PII: S0040-4039(02)02539-X

2
42
S. Peroche, H. Parrot-Lopez / Tetrahedron Letters 44 (2003) 241–245
1
4
1,
available via a literature method, gives 2 (88%
stitution at C-6 leads to a diminution in the molecular
symmetry giving two doublets for the H-1 anomeric
protons; a doublet at 5.60 ppm integrating for one
proton was characteristic of the substituted glucopyran-
ose and the doublet at 5.69 ppm integrating for 6
protons corresponds to the unsubstituted glucopyran-
ose unities. The positive mode electrospray mass spec-
trum of 8 plus one sodium ion shows m/z ratio of
1533.5.
15
yield) in an elimination–addition reaction in the pres-
ence of phosphoric acid and potassium iodide. In the
second step, according to Pucci’s method 2 reacts with
thiourea, to give after hydrolysis with NH OH the thiol
1
6
4
1
7
derivative 3.
Fluorinated amphiphilic b-cyclodextrin derivatives 8
and 10 were synthesized from b-cyclodextrin 4 in two
steps (Scheme 2). b-Cyclodextrin 4 was monotosylated
18
at O-6 in pyridine at a temperature lower than 5°C or
Similar experiments were carried out with heptakis
1
9
fully substituted by iodide with iodine in presence of
(6-deoxy-6-iodo)-b-cyclodextrin
7
(250 mg, 0.13
1
9
triphenylphosphine in DMF at 70°C to yield 5 (30%)
and 7 (89%), respectively. The thio-ether linkage is
realized via nucleophilic displacement of the tosyl or
iodide groups in presence of the 3-perfluorohexyl-
propanethiol 3. For 8, to a solution of 3 (490 mg, 0.38
mmol) in methanol (2 mL) is added a solution of
MeONa in MeOH (1 M, 0.9 mL, 0.91 mmol). The
mixture was stirred during 2 h at rt. The solvent is
removed and anhydrous DMF (3 mL) is added to the
residue under a nitrogen atmosphere. To this solution is
mmol) and 3 (14 equiv., 1.84 mmol). The fluorinated
amphiphilic cyclodextrin 10 was isolated in the 99%
yield. MALDI mass spectrometry clearly demon-
strates that 10 was heptasubstituted (m/z 3789 [10+Na] )
and that under-substituted derivatives are absent.
21
+
1
9
F
NMR shows the presence of perfluoroalkyl chains and
the symmetrical nature of 10 is confirmed by the pres-
1
ence in the H NMR of only a doublet (J=3.2 Hz) at
5.56 ppm for the H-1 b-cyclodextrin anomeric protons
(Fig. 1).
added
cyclodextrin 5 (300 mg, 0.76 mmol) in anhydrous DMF
2 mL) drop wise. The reaction mixture was stirred for
4 h at 70°C and the reaction stopped by addition of
a
solution of mono-6-para-tolylsulfonyl-b-
The preparation of selectively modified cyclodextrins is
a major synthetic challenge. The difficulty lies not only
in the control of the number of O-alkylated sites but
also in the reproducibility of the reaction. Recently,
(
2
acetone (20 mL). The precipitate was recovered by
filtration, washed with acetone and purified by precipi-
tation from ethanol. The product 8 was obtained in
22
Sina y¨ et al. described an elegant approach that con-
sists of the regioselective deprotection of perbenzylated
2
0
1
13
23
9
4% yield. The H and C NMR spectra were
cyclodextrins 11 (Scheme 3). The regioselective di-O-
A
D
recorded in pyridine and were assigned by comparison
with the corresponding spectra of 5, the signals of the
methyl and aromatic protons are absent. The monosub-
debenzylation at O-6 , O-6 is efficiently achieved in
the presence of excess (140 equiv.) diisobutylaluminum
hydride (DIBALH) (1.5 M) in toluene at 30°C for 2 h
Scheme 2. Synthesis of fluorinated amphiphilic b-cyclodextrins. Reagents and conditions: (i) para-tolylsulfonyl chloride (1 equiv.,
dry pyridine, 5°C); (ii) conditions in Scheme 3; (iii) PPh (15 equiv.), DMF, I (15.5 equiv.), 70°C, 18 h; (iv) 3-perfluorohexyl-
3
2
propanethiol 3 (2 equiv. for 8, 4 equiv. for 9 and 14 equiv. for 10), MeONa/MeOH (1 M), dry DMF, 70°C, 24 h.

S. Peroche, H. Parrot-Lopez / Tetrahedron Letters 44 (2003) 241–245
243
1
Figure 1. H NMR spectrum in pyridine-d of compound persubstitued at C-6, 10.
5
Scheme 3. Synthesis of the AD regioisomers. Reagents and conditions: (i) benzyl chloride (27.5 equiv.), dry DMSO, 20°C, 7 h; (ii)
DIBAL (140 equiv.), anhydrous toluene, 30°C, 2 h; (iii) para-tolylsulfonyl chloride (28 equiv.), dry pyridine, 20°C, 36 h; (iv) Pd/C
10%, Pd black, MeOH/formic acid (8:2), 20°C, 2 days.
A
D
A
D
(
95% yield). The AD regioisomer 12 was identified by
6 , 6 -Deoxy-6 , 6 -di-perfluorohexylpropanethiol-b-
cyclodextrin 9 was accessible from the key intermediate
6 (120 mg, 0.08 mmol) in anhydrous DMF (2 mL) by
nucleophilic displacement of the di-tosyl groups by the
1
13
H, C NMR and electrospray mass spectrometry
which are in agreement with literature values. The two
free hydroxyl groups in the AD positions were activated
by coupling of para-tolylsulfonyl groups. A mixture of
2
6
hydrofluorocarbon chain 3 (131 mg, 0.33 mmol). Sub-
stitutions by two perfluoroalkylchains were confirmed
1
2 (2.20 g, 0.773 mmol) and para-tolylsulfonyl chloride
19
1
13
(
4.13 g, 21.66 mmol) in dry pyridine (100 mL) was
by F, H and C NMR spectroscopy. The chemical
A,D A,D
stirred under nitrogen atmosphere at 25°C for 36 h.
Chloroform was added and the mixture extracted.
Organic layers were evaporated and the residue recrys-
tallized in ethanol to give the novel b-cyclodextrin
intermediate 13 in 99% yield. The complete debenzyl-
ation (13, 800 mg, 0.25 mmol) in ethyl acetate (10 mL)
in presence of Pd/C 10% (3 g, 2.8 mmol) in methanol/
formic acid (8:2) (100 mL) gave the AD regioisomer 6
in 44% yield after 2 days. In the previous work of
Hamada, the ditosylated regioisomers AB, AC and
AD were prepared directly from b-cyclodextrin in the
presence of excess of para-tolylsulfonyl chloride in pyr-
idine at rt. The AD regioisomer was separated from the
reaction mixture by reversed-phase column (LiChro-
shifts (pyridine-d ) of H-6
and H-6%
at 3.36 and
5
3.59–3.66 ppm, respectively, indicated that the substitu-
tions occurs at C-6A and C-6D position. The MALDI
mass spectrum of 9 showed monocationic species corre-
sponding to [9+Na] : (m/z 1909) and [9+K] : (m/z
1925).
2
4
+
+
In conclusion, we have synthesized a series of novel
perfluoroalkylated amphiphilic cyclodextrins in which
the upper rim is mono, di and hepta functionalized with
perfluorohexylpropanethiol chains. The thiolate chain
was an excellent nucleophile and we have not observed
competitive bridging reactions between O-3 and C-6 as
2
5
2
7
was previously described by Stoddart et al. The
regioselective introduction of two chains in AD posi-
prep RP 18, MeOH/H O, 1:1) with a yield of <3%.
2

2
44
S. Peroche, H. Parrot-Lopez / Tetrahedron Letters 44 (2003) 241–245
tions or hepta chains gives the new cyclodextrin in
excellent yield. Studies on the aqueous self-organization
properties of the molecules are currently being
undertaken.
16. Barth e´ l e´ my, P.; Ameduri, B.; Chabaud, E.; Popot, J. L.;
Pucci, B. Org. Lett. 1999, 1, 1689–1692.
17. 3-Perfluorohexylpropanethiol 3: Yield: 70%;. H NMR
1
(CDCl ) l (ppm): 1.41 (t, 1H, SH, J=8.2 Hz), 1.89–2.01
3
(
(
2
m, 2H, CH -CF ), 2.14–2.35 (m, 2H, CH ), 2.59–2.70
2 2 2
13
m, 2H, CH -SH); C NMR (CDCl ) l (ppm): 24.7 (C ),
2 3 3
Acknowledgements
19
5.0 (C ), 29.7 (C );. F NMR (CDCl , CFCl ) l (ppm):
2
1
3
3
−
81.2 (m, 3F, CF ), −114.3 (m, 2F, CF -CH ), −122.3 (m,
3
2
2
2
−
F, CF ), −123.2 (m, 2F, CF ), −123.8 (m, 2F, CF ),
126.5 (m, 2F, CF -CF ). MS ES m/z: [M+Na] 417.
2 3
2 2 2
+
We are grateful to the MRET for financial support.
1
1
8. Khan, A. R.; Forgo, P.; Stine, K.; D’Souza, V. T. Chem.
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A
A
2
20. 6 -Deoxy, 6 -(3-perfluorohexylpropanethio)-cyclomalto-
−
1
heptaose 8: yield 94%. Mp 230°C; IR w (cm ) 3306 (OH
1
free); 2926 (CꢀH stretch); 1237–1153 (CꢀF stretch);
H
3
4
NMR (pyridine-d , 500 MHz) l (ppm) 1.85–1.96 (m, 2H,
5
CH -CH -SH), 2.18–2.39 (m, 2H, CH -SH), 2.89 (t, 2H,
2
2
2
A
CH -CF , J=6.7 Hz), 3.33–3.44 (dd, 1H, H-6 , J=6.7
2
2
%
A
5
and 13.0 Hz), 3.59–3.68 (m, 1H, H-6 ), 4.28–5.52 (m,
30H, H-2, H-3, H-4, H-5, H-6), 5.60 (d, 1H, H-1 ,
A
J=3.2 Hz), 5.69 (d, 6H, H-1, J=3.2 Hz), 6.46 (s, 6H,
13
OH-6), 7.65 (m, 7H, OH-2), 7.86 (m, 7H, OH-3);
C
NMR (pyridine-d ) l (ppm) 106.2 (C ), 85.5 (C ), 77.5,
5
1
4
A
6
7
8
9
. Perrier, E.; Terry, N.; Rival, D.; Coleman, A. W. Jpn.
Kokai Tokkyo Koho 2001, Jp 2001323002.
77.3, 77.0 (C , C , C ), 64 (C ), 36.5 (C ), 35.4 (CH -S-),
2 3 5 6 6 2
33.6 (CH -CF ), 20.7 (CH -CH -S); F (pyridine-d5,
1
9
2
2
2
2
. Ravoo, B. J.; Darcy, R. Angew. Chem., Int. Ed. 2000, 39,
CFCl ) l (ppm) −80.2 (m, 3F, CF ), −112.9 (m, 2F,
CF -CH ), −121.1 (m, 2F, CF ), −122.1 (m, 2F, CF ),
2 2 2 2
3
3
4
324–4326.
. Mazzaglia, A.; Ravoo, B. J.; Darcy, R.; Gambadauro, P.;
Mallamace, F. Langmuir 2002, 18, 1945–1948.
. (a) Riess, J. G.; Greiner, J. Carbohydr. Res. 2000, 327,
−122.6 (m, 2F, CF ), −125.4 (m, 2F, CF -CF ). ES MS
2 2 3
+
(+) m/z: [M+Na] 1533.5.
21. Heptakis-[6-deoxy-6-(3-perfluorohexylpropanethio)]-cyclo-
−
1
1
4
47–168; (b) Riess, J. G. Tetrahedron 2002, 58, 4113–
131; (c) Riess, J. G. J. Drug Targeting 1994, 2, 455–468.
maltoheptaose 10: yield 99%; mp 210°C; IR w (cm ) 3306
(OH free); 2926 (CꢀH stretch); 1237–1153 (CꢀF strech);
1
1
1
0. (a) Krafft, M. P.; Riess, J. G. Biochimie 1998, 80, 489–
H NMR (pyridine-d , 500 MHz) l (ppm): 2.14–2.21 (m,
5
5
2
14; (b) Krafft, M. P. Adv. Drug Deliv. Rev. 2001, 47,
09–228.
2H, CH -CH -S), 2.38–2.60 (m, 2H, CH -S-), 2.70 (m,
2
2
2
2H, CH -CF ), 3.27 (dd, 1H, H-6, J=7.6 and 14.0 Hz),
2
2
1. (a) Gadras, C.; Santaella, C.; Vierling, P. J. Control. Rel.
999, 57, 29–34; (b) Guittard, F.; Geribaldi, S. J. Fluorine
3.70 (m, 1H, H-6%), 4.06 (t, 1H, H-5, J=9.0 Hz), 4.21 (m,
1H, H-4), 4.49–4.71 (m, 2H, H-2, H-3), 5.56 (d, 1H, H-1,
J=3.2 Hz), 7.60 (d, 1H, OH-3, J=2.0 Hz), 8.15 (d, 1H,
1
Chem. 2001, 107, 363–374.
13
1
1
2. Ling, C. C.; Darcy, R.; Risse, W. J. Chem. Soc., Chem.
OH-2, J=6.0 Hz); C NMR (pyridine-d ) l (ppm): 105.7
5
Commun. 1993, 438–440.
(C ), 88.4 (C ), 76.7, 76.3, 75.8 (C , C , C ), 36.0 (C ),
1
4
2
3
5
6
1
9
3. (a) Tanaka, M.; Azumi, R.; Tachibana, H.; Nakamura,
T.; Kawabata, Y.; Matsumoto, M.; Miyasaka, T.;
Tagaki, W.; Nakahara, H.; Fukufa, K. Thin Solid Films
34.7 (CH -S-), 31.9 (CH -CF ), 22.8 (CH -CH -S);
F
2
2
2
2
2
NMR (pyridine-d , CFCl ) l (ppm): −80.8 (m, 3F, CF ),
5
3
3
−113.5 (m, 2F, CF -CH ), −121.5 (m, 2F, CF ), −122.5
2
2
2
1
994, 244, 832–835; (b) Greenhall, M. H.; Lukes, P.;
(m, 2F, CF ), −122.8 (m, 2F, CF ), −125.9 (m, 2F,
CF -CF ); Maldi MS m/z: [M+Na] 3789.
2 3
2 2
+
Kataky, R.; Agbor, N. E.; Badyal, J. P.; Yarwood, J.;
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2
A
D
B
C
E
F
G
Parrot-Lopez, H. Langmuir 1995, 11, 13–15.
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Fluorine Chem. 1994, 68, 49–56.
24. 6 ,
6 -para-Tolylsulfonyl-6 ,6 ,6 ,6 ,6 -benzyl-2,3-O-
1
1
perbenzyl-cyclomaltoheptaose 13: Yield: 99%; mp 64°C;
R =0.4 (ethyl acetate/cyclohexane, 1:4); IR w (cm ):
f
−
1
5. 1-Iodo-3-perfluorohexylpropane 2: Yield: 88%; R =0.8
3078–3001 (CꢀH), 1597–1438 (CꢀH arom.), 1375 (O-
f
−
1
1
(
cyclohexane/ethyl acetate 55:5); IR w (cm ): 2660 (CꢀH
SO ). H NMR (CDCl ) l (ppm): 2.13 and 2.14 (s, 6H,
2
3
1
stretch), 1233–1120 (CꢀF stretch); H NMR (CDCl ) l
CH ), 3.19–3.30 (m, 4H), 3.39–5.42 (m, 82H), 5.61 (d,
3
3
A
D
(ppm): 2.12–2.35 (m, 4H, H-2, H-3), 3.27 (t, 2H, H-1,
2H, H-1 and H1 ; J=3.8 Hz), 6.91–7.40 (m, 95H, CH
arom), 7.66 (m. 4H, CH arom tosyl). C NMR (CDCl3)
l (ppm): 22.11 (CH ), 66.3 (C , C6 ), 69.8 (C ), 73.8
(C , C , C , CH ), 79.6 (C , C4 ), 81.6 (C4
1
3
13
J=6.4 Hz); C NMR (CDCl ) l (ppm): 4.2 (C ), 24.7
(
3
1
19
A
D
3 6 6
C ), 32.3 (C ); F NMR (CDCl , CFCl ) l (ppm): −81.3
2
3
3
3
A
4
D
B,C,E,F,G
(
m, 3F, CF ), −114.1 (m, 2F, CF -CH ), −122.3 (m, 2F,
), 99.2
3
2
2
2
3
5
2
CF ), −123.3 (m, 2F, CF ), −123.9 (m, 2F, CF ), −126.5
(C ), 1127.4–128.8 (CH-benzyl), 130.4 (CH-tosyl), 128.7–
140.0 (C-arom). ES.MS (+) m/z: 1600.6 [M+2Na] /2.
2
2
2
1
+
++
(
m, 2F, CF -CF ). MS ES m/z: [M+Na] 511.
2
3

S. Peroche, H. Parrot-Lopez / Tetrahedron Letters 44 (2003) 241–245
245
1
3
2
2
5. Narita, M.; Hamada, F.; Suzuki, I.; Osa, T. J. Chem.
Soc., Perkin Trans. 2 1998, 2751–2758.
OH-2), 7.89 (m, 7H, OH-3); C NMR (pyridine-d ) l
5
(ppm): 104.7 and 104.2 (C ), 86.5 (C ), 77.9–74.1 (C , C ,
1
4
2
3
A
D
A
D
A
5 6 6 7 9 8
6. 6 , 6 -Deoxy-6 , 6 -di-(3-perfluorohexylpropanethio)-
C ), 61.7 (C ), 34.4 (C ), 32.7 (C ), 30.3 (C ), 21.0 (C );
−
1
19
cyclomaltoheptaose 9: yield 90%; mp 230°C; IR w (cm )
306 (OH), 2926 (CꢀH stretch), 1237–1153 (CꢀF stretch);
F NMR (pyridine-d
5
, CFCl
), −114.0 (m, 2F, CF -CH
), −123.7 (m, 2F, CF
2
3
) l (ppm): −81.3 (m, 3F,
), −122.3 (m, 2F, CF ),
), −126.6 (m,
3
CF
3
2
2
2
1
H NMR (pyridine-d , 500 MHz) l (ppm): 1.82–2.01 (m,
−123.3 (m, 2F, CF
2
5
+
+
4
2
2
H, CH -CH -SH), 2.10–2.42 (m, 4H, CH -SH), 2.89 (t,
2F, CF -CF ); Maldi MS m/z: [M+Na] 1909, [M+K]
2 3
2
2
2
A,D
H, CH -CF , J=6.7 Hz), 3.36 (m, 2H, H-6 ), 3.66 (m,
1925.
2
2
A,D
H, H-6% ), 4.02–5.75 (m, 30H, H-2, H-3, H-4, H-5,
27. Ashton, P. R.; Ellwood, P.; Staton, I.; Stoddart, J. F.
H-6), 5.69 (m, 7H, H-1), 6.51 (s, 5H, OH-6), 7.65 (m, 7H,
Angew. Chem., Int. Ed. Engl. 1991, 30, 80–81.