Novel amphiphilic cyclodextrins: Per[6-deoxy-6-(4,5-dicarboxy-1,2,3-triazol-1-yl)-2,3-di-0-methyl] derivatives

Article abstract of DOI:10.1135/cccc19980534

Per[6-deoxy-6-(4,5-dicarboxy-1,2,3-triazol-1-yl)-2,3-di-0-methyl] substituted α- and β-cyclodextrins 6a and 6b were prepared by 1,3-dipolar cycloaddition reaction of the corresponding per(6-azido-6-deoxy-2,3-di-0-methyl)cyclodextrins 4a and 4b with dimethyl acetylenedicarboxylate.

Full text of DOI:10.1135/cccc19980534

534
Kraus, Budesinsky, Zavada:
NOVEL AMPHIPHILIC CYCLODEXTRINS: PER[6-DEOXY-6-(4,5-DICARBOXY-
1,2,3-TRIAZOL-1-YL)-2,3-DI-O-METHYL] DERIVATIVES
1
2
3,
Tomas KRAUS , Milos BUDESINSKY and Jiri ZAVADA *
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
166 10 Prague 6, Czech Republic; e-mail: 1 kraus@uochb.cas.cz, 2 budesinsky@uochb.cas.cz,
3 zavada@uochb.cas.cz
Received February 10, 1998
Accepted March 20, 1998
Dedicated to the memory of Professor Vlado Prelog.
Per[6-deoxy-6-(4,5-dicarboxy-1,2,3-triazol-1-yl)-2,3-di-O-methyl] substituted α- and β-cyclodextrins
6a and 6b were prepared by 1,3-dipolar cycloaddition reaction of the corresponding per(6-azido-6-
deoxy-2,3-di-O-methyl)cyclodextrins 4a and 4b with dimethyl acetylenedicarboxylate.
Key words: α-Cyclodextrin; β-Cyclodextrin; Per-carboxy cyclodextrins; 1,3-Dipolar cycloaddition;
1,2,3-Triazoles.
Cyclodetrins (CD) are a class of cyclic oligosaccharides composed of glucopyranose
units. They possess a truncated cone geometry involving a hydrophobic cavity lined by
two hydrophilic faces of primary (upper rim) and secondary (lower rim) hydroxyl
groups (Fig. 1, A), which allows inclusion and/or transport of a variety of organic
substrates in aqueous solution. This property1–3 has led to a widespread application of
cyclodextrins in separation processes as well as in food, cosmetic and pharmaceutical
industries2.
There has been a growing interest in a selective chemical modification of cyclodex-
trins aimed at transformation of the hydrophilic exterior into an amphiphilic one4–6
.
This should extend the applicability of cyclodextrins to non-aqueous solutions and
allow, moreover, formation of a wide range of organized assemblies, either alone or in
the presence of other amphiphilic or guest molecules, which might be useful in trans-
port of biologically active compounds or in construction of biosensors.
We are interested in the self-assembly of amphiphilic cyclodextrins, organized by
electrostatic interactions and/or ionic hydrogen bonds. As possible tectons for such
* The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Novel Amphiphilic Cyclodextrins
535
self-assembly, we have chosen cyclodextrins persubstituted with carboxyl groups at the
upper and with alkoxy groups at the lower rim, enhancing thus, simultaneously, the
hydrophilicity of the former and lipophilicity of the latter face. Towards these ends, we
have recently developed a novel synthetic procedure7 allowing preparation of the
hitherto inaccessible hexakis(6-O-carboxymethyl-2,3-di-O-methyl)-α-cyclodextrin and
heptakis(6-O-carboxymethyl-2,3-di-O-methyl)-β-cyclodextrin (Fig. 1, B). In this com-
munication we report another approach towards analogous amphiphilic compounds
possessing, however, twice as many of carboxyl groups at the upper rim (Fig. 1, C).
RESULTS
Synthesis of the target amphiphilic cyclodetrins has been performed following Scheme 1.
In the first two steps the parent cyclodextrins 1a, 1b were converted – via the corre-
sponding 6-deoxy-6-iodo derivatives 2a, 2b – into per(6-azido-6-deoxy)cyclodetrins
3a, 3b by modification of known procedures8. In the next step the azides 3a, 3b were
permethylated by treatment with sodium hydride and methyl iodide, giving rise to the
pure crystalline per(6-azido-6-deoxy-2,3-di-O-methyl)cyclodextrins 4a, 4b. In the key
step, the permethylated azides 4a, 4b were heated with an excess of dimethyl
acetylenedicarboxylate. Dipolar cycloaddition9 involving the acetylene and azide
grouping yielded, after chromatography, pure per{6-deoxy-6-[4,5-bis(methoxycarbo-
nyl)-1,2,3-triazol-1-yl]-2,3-di-O-methyl}cyclodetrins 5a, 5b. The methyl esters were
quantitatively hydrolyzed with potassium hydroxide in aqueous methanol at ambient
temperature, yielding, after ion exchange, the desired free acids 6a, 6b.
The structure of the novel compounds 5a, 5b and 6a, 6b was confirmed by 1H NMR,
13C NMR and FAB MS spectra. The NMR spectra showed a line broadening effect
which was partly reduced at higher temperature (60 °C), 2D-COSY spectra were used
X
n
X
O
RO
OR
O
(OR)
(OR)
n
n
n
n = 6, 7
HOOC
C: X =
COOH
, R = Me
A: X = OH, R = H
B: X = OCH COOH, R = Me
2
N
N
N
FIG. 1
Persubstituted cyclodextrins
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

536
Kraus, Budesinsky, Zavada:
for structural assignment of protons. Carbon signals were assigned using heteronuclear
1H–13C 2D-HMQC spectra (Table I).
In this way, an easy access to a new family of amphiphilic polycarboxycyclodetrins,
which exhibit solubility in organic solvents (e.g. alcohols, acetone) as well as in water,
has become available. It is assumed that the proposed synthesis will be applicable also
for the homologues with longer (more lipophilic) alkoxy residues. On the other hand,
CH N
2
3
CH OH
2
CH I
2
i)
ii)
O
O
O
HO
HO
HO
OH
OH
OH
O
O
O
n
n
n
2a, 2b
1a, 1b
3a, 3b
iii)
COOH
N
COOMe
N
HOOC
MeOOC
MeO
N
N
N
N
CH N
2
3
O
O
iv)
v)
O
MeO
MeO
OMe
OMe
OMe
O
O
O
n
n
n
6a, 6b
5a, 5b
i) Ph P/I /DMF; ii) NaN /DMF; iii) MeI/NaH/DMF;
4a, 4b
1a-6a: n = 6
1b-6b: n = 7
3
2
3
+
iv) MeOOC
COOMe, toluene; v) 1. KOH/MeOH/H O, 2. Dowex 50X2, H
2
SCHEME 1
the cycloaddition methodology may also be employed for the preparation of “super-
hydrophilic” cyclodextrin derivatives lacking the amphiphilic (lipophilic) properties. In
the β-cyclodextrin series, a pertinent synthesis of the unalkylated analogue of 6b, hep-
takis[6-deoxy-(4,5-dicarboxy-1,2,3-triazol-1-yl]-β-cyclodextrin has been concurrently
reported11.
EXPERIMENTAL
1H NMR and 13C NMR spectra were measured on FT NMR spectrometer Varian UNITY-500 (1H at
500 MHz; 13C at 125.7 MHz) at +60 °C in hexadeuteriodimethyl sulfoxide. Chemical shifts are referenced
to the signal of solvent (δ (1H) 2.50 and δ (13C) 39.7).
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Novel Amphiphilic Cyclodextrins
537
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

538
Kraus, Budesinsky, Zavada:
FAB MS spectra were recorded with a ZAB-EQ VG analytical intrument using a diethyl disulfide
matrix. Specific optical rotations were measured on a Perkin–Elmer 241 polarimeter at 23 °C. Thin-
layer chromatography (TLC) was performed with precoated Silica Gel 60F-254 plates (Merck) which
were developed by spraying with 5% sulfuric acid in ethanol and heating. Compound 2b was pre-
pared using the procedure described by Stoddart et al.6. Cyclodetrins (Fluka) were dried at 100 °C
for 20 h prior to use. Solvents were dried by common methods.
Hexakis(6-deoxy-6-iodo)-α-cyclodetrin (2a)
The reaction conditions for the preparation of 2a are analogous to those described in literature12
.
Thus, triphenylphosphine (21 g, 80 mmol) was dissolved in dry DMF (80 ml) and iodine (20.25 g,
80 mmol) was slowly added. The mixture was stirred for 15 min and 1a (5.8 g, 5.96 mmol) was
added. The mixture was stirred for 18 h at 80 °C. The resulting dark brown solution was concentrated
to about a half and cooled down to room temperature. Sodium methoxide (3 mol l–1, 30 ml, 90 mmol)
was added dropwise with stirring and efficient cooling, keeping the temperature below 10 °C. The
mixture was further stirred for 30 min and poured into methanol (400 ml). The precipitate was
washed with methanol, dried at room temperature, dissolved in DMF (100 ml) and reprecipitated by
methanol (400 ml). This partially purified product was Soxhlet-extracted with methanol for 48 h to
give 7.8 g (80.2%) of a fine powder, m.p. 249–250 °C (dec.), (ref.12 227 °C dec.). 13C NMR spec-
trum was in accord with the reported one12.
Hexakis(6-azido-6-deoxy)-α-cyclodextrin (3a)
To a solution of 2a (1.3 g, 0.79 mmol) in DMF (25 ml), sodium azide (0.62 g, 9.6 mmol) was added.
The mixture was stirred at 60 °C for 20 h and then poured into water (200 ml). The fine precipitate
was decanted and resuspended in a new portion of warm water (200 ml). The suspension was stirred
at 60 °C for 30 min, allowed to cool down to room temperature, partially decanted to reduce the total
volume to about one half and filtered on fine sintered glass. Compound 3a (0.85 g, 95.8%) was re-
1
covered as a white powder after drying over phosphorus pentoxide in vacuo. H NMR and 13C NMR
spectra were in accord with the reported ones13
.
Heptakis(6-azido-6-deoxy)-β-cyclodextrin (3b)
This compound was prepared starting from 2b (17 g, 8.93 mmol) and sodium azide (6.1 g, 93.8 mmol)
1
using the same procedure as for 3a. The product (11.5 g, 98%) was obtained as a white powder. H NMR
and 13C NMR spectra were in accord with the reported ones6.
Hexakis(6-azido-6-deoxy-2,3-di-O-methyl)-α-cyclodextrin (4a)
Compound 3a (5.3 g, 4.72 mmol) was added to a stirred suspension of oil-free sodium hydride (2.58 g,
133 mmol) in dry DMF (200 ml). The mixture, which tended to solidify, was stirred vigorously for
15 min and methyl iodide (7.04 ml, 113.2 mmol) was added dropwise within 3 h under cooling,
keeping the temperature of the reaction mixture below 20 °C. The mixture was stirred for 15 h at
room temperature and the excess of sodium hydride was decomposed by dropwise addition of methanol
(30 ml) under stirring and cooling. The solution was poured into an ice-water mixture, the resulting
precipitate was collected, washed with water and dried in vacuo. The product was purified by column
chromatography (silica gel, gradient elution chloroform–chloroform/methanol 98 : 2) followed by
crystallization from heptane to give 4a (5.55 g, 91%) after extensive drying in vacuo, m.p. (ref.14)
1
144–146 °C. H NMR and 13C NMR spectra were in accord with the reported ones13.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Novel Amphiphilic Cyclodextrins
539
Heptakis(6-azido-6-deoxy-2,3-O-methyl)-β-cyclodetrin (4b)
Compound 3b (10.9 g, 8.32 mmol) was dissolved in dry DMF (300 ml) containing oil-free sodium
hydride (5.59 g, 0.233 mol) and the solution was vigorously stirred for 30 min. Methyl iodide (14.5 ml,
233 mmol) was added portionwise during 3 h under intensive cooling. The mixture was further
stirred for 15 h at room temperature and worked up as described for 4a. Column chromatography
followed by recrystallization from heptane afforded 4b (11 g, 87.7%), m.p. (ref.14) 85–93 °C.
Hexakis{6-deoxy-6-[4,5-bis(methoxycarbonyl)-1,2,3-triazol-1-yl]-2,3-di-O-methyl}-α-cyclodextrin (5a)
Compound 4a (0.516 g, 0.4 mmol) was dissolved in toluene (8 ml) and dimethyl acetylenedicarbox-
ylate (0.590 ml, 4.8 mmol) was added. The solution was heated at 100 °C for 15 h, and the solvent
was evaporated. Subsequent flash chromatography (silica gel, gradient elution chloroform–chloro-
form/methanol 25 : 1) gave 5a (0.690 g, 80.4%) as a white foam; [α]D +112.6° (c 0.13, CHCl3). For
1H NMR and 13C NMR data see Table I. FAB MS, m/z: 2 145 [M + H]+, 2 167 [M + Na]+. For
C84H114N18O48 (2 143.7) calculated: 47.04% C, 5.36% H, 11.76% N; found: 46.70% C, 5.28% H,
11.73% N.
Heptakis{6-deoxy-6-[4,5-bis(methoxycarbonyl)-1,2,3-triazol-1-yl]-2,3-di-O-methyl}-β-cyclodextrin (5b)
Prepared from 4a (0.516 g, 0.343 mmol) and dimethyl acetylenedicarboxylate (0.590 ml, 4.8 mmol)
in toluene (8 ml) as described for 5a. The yield was 0.775 g (90.5%) of a white foam; [α]D +100.9°
(c 0.13, CHCl3). For 1H NMR and 13C NMR data see Table I. FAB MS, m/z: 2 502 [M + H]+. For
C98H133N21O56 (2 501.2) calculated: 47.04% C, 5.36% H, 11.76% N; found: 46.65% C, 5.30% H,
11.48% N.
Hexakis[6-deoxy-6-(4,5-dicarboxy-1,2,3-triazol-1-yl)-2,3-di-O-methyl]-α-cyclodextrin (6a)
Compound 5a (0.0858g, 0.04 mmol) was dissolved in MeOH (1.2 ml), potassium hydroxide (1.44 ml
of 1 M aqueous solution, 1.44 mmol) was added and the reaction mixture was stirred for 24 h at room
temperature. The solvents were partially evaporated, water (2 ml) was added and the solution was
applied onto a column of Dowex 50X8 H+ (3 ml). The column was eluted with water to neutral re-
action of the eluate. Evaporation of the eluate gave 3b (0.08 g, 97%) as a white foam after drying
1
over P2O5 in high vacuum; [α]D +22.6° (c 0.13, H2O). For H NMR and 13C NMR data see Table I.
FAB MS, m/z: 1 976 [M + H]+. For C72H90N18O48 (1 975.6) calculated: 43.77% C, 4.59% H, 12.76% N;
found: 43.38% C, 4.79% H, 12.36% N.
Heptakis[6-deoxy-6-(4,5-dicarboxy-1,2,3-triazol-1-yl)-2,3-di-O-methyl]-β-cyclodextrin (6b)
Hydrolysis of 5b (0.08 g, 0.032 mmol) under analogous conditions as described for preparation of 6a
gave 6b (0.072 g, 97%); [α]D +13.8° (c 0.12, H2O). For 1H NMR and 13C NMR data see Table I.
FAB MS, m/z: 2 306 [M + H]+. For C84H105N21O56 (2 304.9) calculated: 43.77% C, 4.59% H,
12.76% N; found: 43.42% C, 4.71% H, 12.41% N.
We are grateful for the financial support from the Grant Agency of the Czech Republic (grant No.
203/97/0025).
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

540
Kraus, Budesinsky, Zavada:
REFERENCES AND NOTES
1. Jicsinski L., Hashimoto H., Fenyvesi E., Ueno A. in: Cyclodextrin Derivatives. Comprehensive
Supramolecular Chemistry (J. Szejtli and T. Osa, Eds), Vol. 3. Elsevier, London 1996.
2. Duchene D., Ed.: Cyclodextrins and Their Industrial Uses. Editions de la Sante, Paris 1987.
3. Wenz G.: Angew. Chem., Int. Ed. Engl. 1994, 33, 803.
4. Coleman A. W., Kasselouri A.: Supramol. Chem. 1993, 1, 155.
5. Parrot-Lopez H., Chang-Chun Ling, Ping-Zhang, Baszkin A., Albrecht G., deRango C., Coleman A. W.:
J. Am. Chem. Soc. 1992, 114, 479.
6. Ashton P. R., Koniger R., Stoddart J. F., Alker D., Harding V. D.: J. Org. Chem. 1996, 61, 903.
7. Kraus T., Budesinsky M., Zavada J.: Carbohydr. Res. 1997, 304, 81.
8. The procedure described by Ashton and coworkers (ref.6) for the derivatives 2b and 3b has been
now modified for the preparation of the lower homologues 2a and 3a.
9. Only a few applications of the dipolar cycloaddition may be found in saccharide chemistry; see
refs10,11
.
10. Norris P., Horton P., Levine B. R.: Heterocycles 1996, 43, 2643.
11. Roehri-Stoeckel C., Dangles O., Brouillard R.: Tetrahedron Lett. 1997, 38, 1551.
12. Baer H. H., Berenguel A. V., Shu Y. Y., Defaye J., Gadelle A., Gonzales F. S.: Carbohydr. Res.
1992, 228, 307.
13. Boger J., Corcoran R. I., Lehn J.-M.: Helv. Chim. Acta 1978, 61, 2190.
14. According to 1H NMR spectra, the obtained crystals strongly held heptane despite the extensive
drying in high vacuum.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)