An improved and alternative method for the preparation of per(6-bromo-6-deoxy)cyclodextrins

Article abstract of DOI:10.1055/s-0030-1260241

A practical and efficient approach to the regioselective synthesis of per(6-bromo-6-deoxy)cyclodextrins is described. The method utilizes the easily accessible (chloro(phenylthio)methylene)dimethylammonium chloride (CPMA), circumventing disadvantages of earlier protocols. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260241

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612
SHORT PAPER
An Improved and Alternative Method for the Preparation of
Per(6-bromo-6-deoxy)cyclodextrins
a
b
I
W
mprove
d
Synthesis of
P
e
er(6-brom
o
i
-6-deo
h
xy)cyclodext
u
r
ins a Xue,* Lifen Zhang
a
School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8915686; E-mail: xuewh@lzu.edu.cn
b
School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. of China
Received 12 August 2011; revised 31 August 2011
Dedicated to Professor Biao Yu, Shanghai Institute of Organic Chemistry, on the occasion of his 45 birthday and in recognition of his
brilliant contributions to glycochemistry
th
strong base, such as sodium methoxide, in the workup.
Abstract: A practical and efficient approach to the regioselective
The use of triphenylphosphine is associated closely with
the inconvenience of generating stoichiometric triphe-
synthesis of per(6-bromo-6-deoxy)cyclodextrins is described. The
method utilizes the easily accessible (chloro(phenylthio)methyl-
nylphosphine oxide as byproduct. To circumvent these
problems and to establish the regioselective substitution at
the C-6 position of the glucose repeat units as a general
methodology, a facile, robust, and mild alternative to
per(6-bromo-6-deoxy)cyclodextrins is required.
ene)dimethylammonium chloride (CPMA), circumventing disad-
vantages of earlier protocols.
Key words: regioselective bromination, cyclodextrins, CPMA
a-Cyclodextrin, b-cyclodextrin, and g-cyclodextrin are A recent methodology revealed that (chloro(phenyl-
natural oligomers consisting of six, seven, and eight D- thio)methylene)dimethylammonium chloride (CPMA), a
glucopyranose residues, respectively, linked by a-1,4-gly- readily accessible reagent, can mildly and selectively ha-
cosidic bonds into a macrocycle. Currently, there is in- logenate primary hydroxy groups in the presence of un-
creasing interest in modified cyclodextrins for protected secondary hydroxy groups.10 The protocol led
applications in the areas of supramolecular chemistry and us to envisage that the reactions of free carbohydrate de-
materials science. Through modification, cyclodextrins rivatives such as cyclodextrins with the reagent may pro-
become effective templates for the generation of a wide duce 6-deoxyhalocyclodextrins. Here, we report a mild
1
range of molecular hosts. Per(6-bromo-6-deoxy)cyclo- and regioselective procedure for the efficient conversion
dextrins, in particular, have emerged as a typical class of of cyclodextrins into per-6-brominated derivatives.
fascinating modifiers and significant precursors suitable
In our study, bis(trichloromethyl) carbonate (BTC), in-
for further synthetic transformations. Other derivatives of
stead of phosgene, was adopted due to its higher safety in
cyclodextrins, in which all primary hydroxy groups are re-
the preparation of CPMA. CPMA, which was easily pre-
2
placed by such important functionalities as azido, ami-
pared on large scale, was further demonstrated to be a sta-
3
2b
no, and thiol groups, may be efficiently synthesized
from the perbrominated cyclodextrins. All of these mono-
facially substituted analogues function not only as scaf-
folds of diverse multivalent systems of biologically active
ble solid reagent. We observed that the halogenating
reagent (2.0 equiv per glucose unit) reacted with b-cyclo-
dextrin (1, n = 7) in the presence of tetrabutylammonium
bromide (2.0 equiv per glucose unit) in anhydrous N,N-
dimethylformamide to afford per(6-bromo-6-deoxy)-b-
cyclodextrin (2, n = 7) in a good yield. This protocol also
4
5
compounds, but also as supramolecular building blocks
6
and drug delivery systems.
A common approach for perbromination on the primary led to efficient and total bromination at the C-6 position
side is the treatment of cyclodextrins with traditional bro- when applied to a- or g-cyclodextrin (Scheme 1). The re-
7
minating reagents such as MeSO Br, the Vilsmeier– actions smoothly proceeded at room temperature without
2
2
b,8
9
1
Haack reagent, and Ph P–NBS in N,N-dimethylform- heating. No undesired byproducts could be detected by H
3
amide under prolonged heating. These reagents, however, and 13C NMR spectroscopy. Tetrabutylammonium bro-
suffer from many practical drawbacks. MeSO Br is usual- mide and the resulting thiocarbamate in the reactions are
2
ly inaccessible due to its high price and strong toxicity. highly soluble in acetone so that they can be conveniently
The Vilsmeier salt is quite sensitive to moisture and com- washed out. During the workup of products, no base such
paratively difficult to handle; in particular, its relatively as sodium methoxide was required. The pure products can
poor shelf life necessitates the prompt, fresh preparation be isolated from the reaction mixture by evaporation of
prior to use. Furthermore, the removal of excess Vilsmeier the solvent and subsequent simple filtration and washing.
salt from the reaction system requires a large amount of a No chromatography or crystallization is necessary, thus
this protocol is potentially applicable to the wholesale
preparation of per(6-bromo-6-deoxy)cyclodextrins.
SYNTHESIS 2011, No. 22, pp 3612–3614
x
x.
x
x
.
2
0
1
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In conclusion, a novel method based on an accessible,
shelf stable, and efficient reagent for selectively perbro-
Advanced online publication: 26.09.2011
DOI: 10.1055/s-0030-1260241; Art ID: H80011SS
Georg Thieme Verlag Stuttgart · New York
©

SHORT PAPER
Improved Synthesis of Per(6-bromo-6-deoxy)cyclodextrins
3613
1
H NMR (DMSO-d ): d = 3.34 (d, J = 10.0 Hz, 14 H, H-6), 3.59–
6
OH
Br
3
.66 (m, 14 H, H-2, H-4), 3.86 (t, J = 8.4 Hz, 7 H, H-3), 3.99 (d,
O
O
J = 10.0 Hz, 7 H, H-5), 4.95 (s, 7 H, H-l), 5.88 (s, 7 H, OH-3), 5.98
HO
HO
(
d, J = 8.0 Hz, 7 H, OH-2).
OH O
OH O
n
n
13
C NMR (DMSO-d ): d = 102.58 (C1), 85.10 (C4), 72.75 (C3),
6
7
2.52 (C2), 71.47 (C5), 34.91 (C6).
1
2
n = 6, 7 or 8
+
HRMS (ESI): m/z [M + Na] calcd for C H O NaBr : 1590.7687;
4
2
63 28
7
found: 1590.7724.
Scheme 1 Reagents and conditions: CPMA, TBAB, DMF, r.t.,
90%.
>
Octakis(6-bromo-6-deoxy)-g-cyclodextrin (2, n = 8)
Yield: 6.8 g (95%).
minating the primary face of cyclodextrins has been de-
scribed. The practicable protocol allows for the
production of large amounts of the title compounds,
which are versatile building blocks in cyclodextrin chem-
istry.
2
0
[
1
a]D +113.6 (c 1.0, DMF); R = 0.60.
f
H NMR (DMSO-d ): d = 3.35 (s, 16 H, H-6), 3.61–3.62 (m, 16 H,
H-2, H-4), 3.79 (s, 8 H, H-3), 3.96 (d, J = 10.0 Hz, 8 H, H-5), 4.94
s, 8 H, H-1), 5.85 (s, 8 H, OH-3), 5.97 (d, J = 5.6 Hz, 8 H, OH-2).
6
(
1
3
C NMR (DMSO-d ): d = 102.60 (C1), 85.12 (C4), 72.79 (C3),
2.55 (C2), 71.52 (C5), 34.88 (C6).
6
7
The a-, b-, and g-cyclodextrins were recrystallized from water and
+
HRMS (ESI): m/z [M + Na] calcd for C H O NaBr : 1814.7371;
found: 1814.7428.
4
8
72 32
8
dried over P O under reduced pressure in a drying pistol at 110 °C
2
5
prior to use. All the reagents and solvents were commercial prod-
ucts and used as received, unless otherwise noted. DMF was dis-
tilled over CaH prior to use. TLC was performed on precoated
plates of silica gel 60 F254 using EtOAc–i-PrOH–concd aq NH3–
H O (1:5:3:1) as eluent; visualization of spots was effected by char-
2
2
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
ring with 20% (v/v) H SO in EtOH. Optical rotations were mea-
2
4
sured with a JASCO DIP-370 digital polarimeter, using a sodium Acknowledgment
1
13
lamp (l = 589 nm) at 20 °C. The H and C NMR spectra were re-
This work was financially supported by the Fundamental Research
Funds for Lanzhou University (lzujbky-2009-27 and lzujbky-2011-
corded on a Varian Mercury Plus 400 spectrometer at 400 MHz in
DMSO-d with references at d = 2.49 ppm and 39.50 ppm (DMSO),
6
1
36).
or in CDCl with references at 7.26 ppm (CHCl ) and 77.0 ppm
3
3
(
CDCl ), respectively. High-resolution mass spectra (HRMS) were
3
recorded on a Bruker APEX II mass spectrometer using electro-
spray ionization (ESI).
References
(
1) Easton, C. J.; Lincoln, S. F. Modified Cyclodextrin; Imperial
Per(6-bromo-6-deoxy)cyclodextrins 2; General Procedure
To a soln of CPMA (2 equiv per glucose unit) in anhyd DMF (100
mL) was added freshly dried a-, b-, or g-cyclodextrin (1, n = 6, 7,
or 8; 4 mmol) and anhyd TBAB (2 equiv per glucose unit) with stir-
ring at r.t. After the reaction was complete, as monitored by TLC,
DMF was removed under reduced pressure and the resulting residue
was poured into sat. Na CO soln (100 mL); the reaction mixture
College Press: London, 1999, 1.
(2) (a) Parrot-Lopez, H.; Ling, C.-C.; Zhang, P.; Baszkin, A.;
Abrecht, G.; Rango, C. D.; Coleman, A. W. J. Am. Chem.
Soc. 1992, 114, 5479. (b) Gorin, B. I.; Riopelle, R. J.;
Thatcher, G. R. J. Tetrahedron Lett. 1996, 37, 4647.
(c) David, L.; Abdoulaye, G.; Vincent, M.; Serge, P.;
Florence, D. Carbohydr. Res. 2005, 340, 1225.
2
3
was allowed to stir for another 1 h. Addition of cold acetone (200
mL) gave a precipitate which was collected by filtration and ex-
(3) Vizitiu, D.; Walkinshaw, C. S.; Gorin, B. I.; Thatcher, G. R.
J. J. Org. Chem. 1997, 62, 8760.
haustively washed with H O and acetone to yield 2 as a white solid.
(4) (a) Ortiz-Mellet, C.; Benito, J. M.; Fernández, G.; Law, H.;
Chmurski, K.; Defaye, J.; O’Sullivan, M. L.; Caro, H. N.
Chem. Eur. J. 1998, 4, 2523. (b) Gómez-García, M.;
Benito, J. M.; Rodríguez-Lucena, D.; Yu, J.-X.; Chmurski,
K.; Mellet, C. O.; Gallego, R. G.; Maestre, A.; Defaye, J.;
Fernández, J. M. G. J. Am. Chem. Soc. 2005, 127, 7970.
2
Hexakis(6-bromo-6-deoxy)-a-cyclodextrin (2, n = 6)
Yield: 5.2 g (96%).
20
[
a]D +97.4 (c 1.0, DMF); R = 0.53.
f
1
H NMR (DMSO-d ): d = 3.34 (d, J = 8.8 Hz, 12 H, H-6), 3.59–
6
(
c) Song, Y.; Kohlmeir, E. K.; Meade, T. J. J. Am. Chem.
3
.67 (m, 12 H, H-2, H-4), 3.80 (t, J = 8.4 Hz, 6 H, H-3), 3.99 (d,
Soc. 2008, 130, 6662. (d) Ravoo, B. J.; Darcy, R. Angew.
Chem. Int. Ed. 2000, 39, 4324.
J = 10.0 Hz, 6 H, H-5), 4.95 (s, 6 H, H-1), 5.86 (s, 6 H, OH-3), 5.98
(
d, J = 8.0 Hz, 6 H, OH-2).
(
5) (a) Clarke, R. J.; Coates, J. H.; Lincoln, S. F. Adv.
Carbohydr. Chem. Biochem. 1988, 46, 205. (b) Brown, S.
E.; Coates, J. H.; Easton, C. J.; van Eyk, S. J.; Lincoln, S. F.;
May, B. L.; Style, M. A.; Whalland, C. B.; Williams, M. L.
J. Chem. Soc., Chem. Commun. 1994, 47. (c) Brown, S. E.;
Coates, J. H.; Easton, C. J.; Lincoln, S. F. J. Chem. Soc.,
Faraday Trans. 1994, 90, 739. (d) Brown, S. E.; Haskard,
C. A.; Easton, C. J.; Lincoln, S. F. J. Chem. Soc., Faraday
Trans. 1995, 91, 1013. (e) Majewska, U. E.; Chmurski, K.;
Biesiada, K.; Olszyna, A. R.; Bilewicz, R. Electroanalysis
1
3
C NMR (DMSO-d ): d = 102.59 (C1), 85.10 (C4), 72.76 (C3),
6
7
2.53 (C2), 71.49 (C5), 34.88 (C6).
+
HRMS (ESI): m/z [M + Na] calcd for C H O NaBr : 1366.8003;
3
6
54 24
6
found: 1366.8049.
Heptakis(6-bromo-6-deoxy)-b-cyclodextrin (2, n = 7)
Yield: 5.8 g (92%).
[
a]D20 +91.2 (c 1.0, DMF); R = 0.71.
f
2006, 18, 1463.
Synthesis 2011, No. 22, 3612–3614 © Thieme Stuttgart · New York

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614
W. Xue, L. Zhang
SHORT PAPER
(
6) (a) Ortega-Caballero, F.; Mellet, C. O.; Gourriérec, L. L.;
Guilloteau, N.; Giorgio, C. D.; Vierling, P.; Defaye, J.;
Fernández, J. E. M. Org. Lett. 2008, 10, 5143.
187, 203. (b) Gadelle, A.; Defaye, J. Angew. Chem., Int. Ed.
Engl. 1991, 30, 78. (c) Khan, A. R.; D’Souza, V. T. J. Org.
Chem. 1994, 59, 7492. (d) Chmurski, K.; Defaye, J.
Tetrahedron Lett. 1997, 38, 7365. (e) Chmurski, K.;
Defaye, J. Pol. J. Chem. 1999, 73, 967.
(
b) Srinivasachari, S.; Fichter, K. M.; Reineke, T. M. J. Am.
Chem. Soc. 2008, 130, 4618.
(
(
7) Takeo, K.; Sumimoto, T.; Kuge, T. Starch/Stärke 1974, 26,
(9) Chmurski, K.; Defaye, J. Supramol. Chem. 2000, 12, 221.
(10) Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C.
Tetrahedron Lett. 2000, 41, 6049.
111.
8) (a) Takeo, K.; Mitoh, H.; Uemura, K. Carbohydr. Res. 1989,
Synthesis 2011, No. 22, 3612–3614 © Thieme Stuttgart · New York