Efficient synthesis of pure monotosylated beta-cyclodextrin and its dimers

Article abstract of DOI:10.1016/j.carres.2013.08.018

6-O-Monotosyl-β-cyclodextrin (mono-Ts-βCD) is one of the most important intermediates in the production of substituted βCD. So far, performing the monotosylation reaction and, in particular, the purification steps was challenging, relied on toxic solvents

Full text of DOI:10.1016/j.carres.2013.08.018

Carbohydrate Research 381 (2013) 59–63
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Efficient synthesis of pure monotosylated beta-cyclodextrin
and its dimers
⇑
Giuseppe Tripodo , Christian Wischke, Axel T. Neffe, Andreas Lendlein
Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Kantstrasse 55, 14513 Teltow, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2013
Received in revised form 16 August 2013
Accepted 17 August 2013
Available online 25 August 2013
6-O-Monotosyl-b-cyclodextrin (mono-Ts-bCD) is one of the most important intermediates in the produc-
tion of substituted bCD. So far, performing the monotosylation reaction and, in particular, the purification
steps was challenging, relied on toxic solvents, and resulted in long and expensive procedures at, impor-
tantly, low yields. Here, the reaction of cyclodextrin with p-toluenesulfonyl chloride in aqueous environ-
ment is described to obtain a highly pure mono-Ts-bCD, for which a single-step purification with a cation
exchange resin was applied. With this synthetic route and purification, yields could be increased from
typically <10–15% to 35%, and organic solvents could be avoided. As characterized by FTIR, mass spec-
trometry, elemental analysis, and NMR, mono-Ts-bCD was obtained with a molar purity of >98 mol %.
From mono-Ts-bCD, b-cyclodextrin dimers linked by ethylenediamine (bis-Et-bCD) were successfully
prepared (yield 93%, purity 96 mol %) in a one-step approach using an anion exchange resin to trap leav-
ing groups that typically interfere in the reaction. This synthesis procedure with a direct collection of
Keywords:
b-Cyclodextrin
Monotosyl b-cyclodextrin
b-Cyclodextrin dimer
Ion exchange resin
side-products may be
cyclodextrins.
a
general strategy applicable for nucleophilic substitution of tosylated
Ó 2013 Elsevier Ltd. All rights reserved.
Establishing synthetic approaches for mono tosylation of
b-cyclodextrin (bCD) was a milestone in cyclodextrin derivatiza-
tion, since it allowed subsequent derivatization or coupling of
bCD at its primary hydroxyl group.1–7 While different methods to
selectively functionalize one single primary hydroxyl group of
cyclodextrins were reported, several by-products may be formed
requiring extensive subsequent purification procedures. The most
common synthetic strategies exploit either organic or aqueous sol-
vent/base systems. In some cases, pyridine served as both solvent
and organic base,8–10 but generally should be avoided because of
difficulties to remove residual toxic pyridine and of the massively
formed by-products. One approach for selective monotosylation at
position 2 of bCD employs a dimethylformamide/carbonate buffer
medium, but also requires extensive purification based on large
quantities of organic solvents.10,11
monofunctionalization of the primary hydroxyl groups, while the
secondary hydroxyl groups of cyclodextrin are complexed with
copper.13 Alternatively, a selective monotosylation of O-2 second-
ary hydroxyl groups is possible by 1-(p-tolylsulfonyl)-(1H)-1,2,4-
triazole.14 Still, the required subsequent purification step remains
critical due to the presence of a large amount of impurities includ-
ing (i) inorganic salts, (ii) p-toluenesulfonic acid or its chloride salt
either free or complexed by bCD, and (iii) multi-tosylated bCD.15–17
Additionally, it should be noted that molar ratios of tosyl chlo-
ride to bCD up to 23.8 were employed,18 which represents an inef-
ficient reaction and could lead to extensive purification
procedures. By performing the synthesis with a molar excess of
tosyl chloride in the range 1.8–6.0,6,15,17 yields of 10–48% were re-
ported. Still, the purification by crystallization is critical and often
results only in lower yields of <10–15% of the isolated pure
product.
One of the first strategies to avoid organic solvents in mono-
tosylation reaction of
a
CD and bCD has been reported by Iwakura
However, the availability of pure mono-Ts-bCD at suitable
quantities is required as a key substance for subsequent nucleo-
philic substitution, for example with ethylenediamine to obtain
monoamine-bCD or bis-Et-bCD, which are of interest for instance
as enzyme-like models or to create host-guest inclusion com-
plexes.19,20 Bis-Et-bCD is typically prepared in a two-step synthe-
sis, in which first monoamine-bCD is formed, purified, and
isolated, and subsequently reacted with mono-Ts-bCD to give the
bis-Et-bCD.19–21 An alternative one-step synthesis relies on DMF
as an undesired solvent.22 All these methods showed low, variable
yields of this reaction.
et al., who used an aqueous solution of pH 1112 and enabled a pref-
erential monotosylation at the primary hydroxyl groups as
desired.11 Subsequently, reactions in water/NaOH have been
widely employed to obtain mono-Ts-bCD, for example, using cop-
per complexes to direct the reaction toward a more regioselective
⇑
Corresponding author. Tel.: +49 3328 352 450; fax: +49 3328 352 452.
E-mail address: andreas.lendlein@hzg.de (A. Lendlein).
Present address: Department of Drug Sciences, University of Pavia, Viale
Taramelli 12, 27100 Pavia, Italy.
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.08.018

60
G. Tripodo et al. / Carbohydrate Research 381 (2013) 59–63
Here, methods should be provided to obtain pure mono-Ts-bCD
(ꢀ1.85 g/100 mL), the non-reacted bCD as well as the water-solu-
ble p-toluenesulfonic acid were efficiently removed by thrice
washing the precipitate with water. Importantly, several grams
of sodium cations, which may reduce an effective crystallization
of the product, could also be eliminated by using the cation ex-
change resin, which subsequently was easily removed by filtration.
The functionalization of bCD with p-toluenesulfonyl groups was
confirmed by FTIR based on the peaks at 1230 cmꢁ1 (Ph-SO2-R) and
815 cmꢁ1 (Ph-SO2-O-R), which both were not present in bCD or p-
toluenesulfonyl chloride and could be attributed to alkyl substi-
tuted tosyl groups. Additionally, the 1H NMR spectrum (Fig. 1A)
showed the characteristic peaks of aromatic protons at 7.77 and
7.43 ppm. A molar amount of >98% of tosyl groups in the mono-
Ts-bCD was detected by comparing the integral of the anomeric
protons (H1) at 4.85–4.77 ppm with that of Ph-CH3 at 2.44 ppm,
which stresses the high purity of the obtained product. Further-
more, based on the integral ratios of the anomeric proton and
the multiplet at 4.51–4.45 ppm (OH-6), which were calculated to
be 7:6, it was confirmed that only one of the seven primary hydro-
xyl groups of bCD was tosylated. Unshielding effects of the tosyl
substituent resulted in a downfield peak shift at 4.35 for the two
protons of the derivatized C60 and at 4.20 ppm for the adjacent
C50 proton, respectively, which proved binding of the tosyl group
to the C60 carbon.
by facile and reproducible chemistry that does not employ organic
solvents. Furthermore, a one-step synthesis procedure for bis-Et-
bCD with direct collection of side products should be developed,
which results in higher yields and avoids DMF as a solvent. For
both synthetic steps, ion exchange resins as easily removable sub-
stances were proposed to overcome the existing limitations by (i)
enabling an efficient isolation of mono-Ts-bCD with high yields
and purity, and (ii) supporting the one-step preparation of bis-Et-
bCD by capturing leaving groups that compete with the progress
of the reaction.
The monotosylation reaction of bCD was performed in aqueous
NaOH at pH 11 for 1 h as generally established in the literature.
However, the reported subsequent purification by crystallization
or precipitation in organic solvents did not result in pure product
at reasonable yields (often ꢀ10%).17 Therefore, it was proposed
that suspending a cation exchange resin in the H+ form in the crude
product may efficiently induce the precipitation of the product.
This precipitation should occur due to the fast lowering of the
pH from pH 11 to acidic conditions by exchange of H+ from the re-
sin with sodium cations from NaOH solution causing a reduction of
mono-Ts-bCD solubility. The precipitation of mono-Ts-bCD was
observed as hypothesized. Since the aqueous solubility of mono-
Ts-bCD is much lower (<0.04 g/100 mL)11 than that of bCD
Figure 1. NMR spectra of mono-Ts-bCD as obtained from the purification procedure with the cation exchange resin. (A) 1H NMR. (B) 13C NMR.

G. Tripodo et al. / Carbohydrate Research 381 (2013) 59–63
61
In the 13C NMR spectrum (Fig. 1B), peak shifts could be detected
due to the functionalization of one (C60) out of a total of seven C6
carbons of bCD, namely, (i) a downfield shift of C60 to 69.67 ppm,
(ii) an upfield shift of adjacent C50 to 68.87 ppm, and (iii) upfield
shifts of C40 (80.73 ppm) and C10 (101.25 ppm). These values are
in accordance with the theory of Breslow, according to which the
tosylation of a hydroxyl group leads to a downfield shift of the car-
formed as impurity due to the employed high molar excess of eth-
ylenediamine, and (v) a low yield due to the two step reaction with
intermediate purification.
It was proposed that at least some of these issues could be over-
come, if the release of p-toluenesulfonic acid from the reactant as a
leaving group during the nucleophilic attack of ethylenediamine
(pKb1 = 4.11 0.10) to the mono-Ts-bCD may be compensated.
Since p-toluenesulfonic acid will be in its anionic form in the pres-
ence of a base such as ethylenediamine, an anion exchange resin
(DowexÒ 1 ꢂ 8 200–00 mesh [2 meq, exchange capacity 1.0 meq/
mL] either with Clꢁ or OHꢁ counter-ions) was directly added to
the reaction mixture. In this way, p-toluenesulfonic acid as a leav-
ing group that can cause side reactions could be collected in situ,
while the easy filtration of the resin facilitated its removal from
the reaction mixture (Fig. 2).
In contrast to the cyclodextrin monotosylation performed in
water, the formation of bis-Et-bCD requires the use of an organic
polar-aprotic solvent to reduce the possible hydrolysis of mono-
Ts-bCD during the reaction at relatively high temperatures. In con-
trol experiments studying solvent effects, mono-Ts-bCD in DMF
was subjected to the reaction conditions without any resin or eth-
ylenediamine. This resulted in a 40 mol % reduction of the peaks of
the tosyl group and the appearance of a multiplet at 7.99 ppm cor-
responding to the formamide proton of DMF as observed in 1H
NMR (data not shown). It can be expected that DMF may have at-
tacked mono-Ts-bCD as a nucleophile, thereby reducing the avail-
able amount of mono-Ts-bCD for subsequent reactions and
forming undesired side products.23,24 When the same experiment
was performed with 1-methyl-2-pyrrolidone (NMP) as solvent,
no alterations of the starting mono-Ts-bCD were detected. Despite
the failure in the mentioned control experiments, DMF was in-
cluded as solvent candidate in order to evaluate, whether the pres-
ence of the resin can improve the reaction in this solvent. In
particular, the anion exchange resin was used with two different
counter-ions, namely, hydroxyl (OHꢁ form) or chloride (Clꢁ form).
The OHꢁ form resin led to products with a similar derivatization
degree of ꢀ90 mol % for both solvents, which were lower than
bon carrying the hydroxyl (the
a
carbon), a small upfield shift of
car-
the b carbon as well as an even smaller upfield shift of the
c
bon.11 All 13C NMR peaks of non-functionalized carbon atoms
showed the same chemical shift as the starting bCD supporting
that a mono-functionalized product was obtained.
Mass spectrometry (MS) revealed a molecular weight of the
molecular ion [M+H]+ of 1289.377 g molꢁ1, which perfectly agreed
with the calculated value for mono-functionalized bCD. Impor-
tantly, compared to previous approaches to obtain mono-Ts-bCD,
the entire process, that was scaled up to 60 g batches being puri-
fied by treatment with 546 mL of pre-swollen cation exchange re-
sin (see Section 1), required not more than 5 h. Furthermore, this
procedure allowed to use lower amounts of p-toluenesulfonyl
chloride (molar ratio p-toluenesulfonyl chloride/cyclodex-
trin = 1.5) compared to some of the previously reported ap-
proaches in NaOH/water environment.10,13,16 The average yield
for several prepared mono-Ts-bCD batches was reproducible at
35 3% with a remarkable purity.
In the next step of this work, an efficient synthesis of bis-Et-bCD
is introduced, which enabled high yields and avoided DMF as a sol-
vent. While being frequently suggested as an effective complexing
agent,19–21 the synthesis of bis-Et-bCD from mono-Ts-bCD by
reaction with ethylenediamine as reported in the literature was
associated with the following challenges: (i) the presence of free
p-toluenesulfonic acid produced from the nucleophilic attack of
ethylenediamine on mono-Ts-bCD apparently reduced the reactiv-
ity of the ethylenediamine by forming ion pairs, (ii) cross-reactions
between mono-Ts-bCD and the reaction medium occur when DMF
is used as solvent, (iii) toxicological concerns impede the use of
DMF in biomedical applications, (iv) monoamine-bCD is often
Figure 2. Formation of bis-Et-bCD in the presence of the anion exchange resin.

62
G. Tripodo et al. / Carbohydrate Research 381 (2013) 59–63
for the Clꢁ form (96 mol %) of the resin. This may be explained by
the hydrolysis of the tosyl group of mono-Ts-bCD in the presence
of OHꢁ anions at reaction conditions of 80 °C for 24 h. Another
explanation for the higher degree of derivatization with the Clꢁ
form resin might be a higher binding affinity of p-toluenesulfonic
acid due to the acid–base reaction occurring between the anion ex-
change resin and p-toluenesulfonic acid. This may lead to the re-
lease of the stronger acid HCl that ultimately shifts the chemical
equilibrium toward the desired products (Fig. 2). Considering (i)
the higher degree of functionalization obtained by using the resin
in the Clꢁ form, (ii) the reasonable yield of 93%, and (iii) that NMP,
differently from DMF, did not take part in the reactions, these reac-
tion conditions have been considered the first choice and were fur-
ther applied. Furthermore, differently from DMF that is generally
considered toxic even at low concentrations, NMP can be used also
for injection in humans.25
47.26 ppm, which correspond to the upfield shifted C60 bonded
to ethylenediamine as well as the CD-bonded ethylene carbons of
ethylenediamine. Peaks of carbons of non-reacted ethylenedia-
mine at around 40.2 ppm were not observed in the product. MS
studies also confirmed the formation of the bis-Et-bCD by the
molecular ion at m/z 2315.991 [M+Na]+.
Overall, the established synthetic procedure with integrated
purification based on a reusable cation exchange resin finally re-
moved by filtration allowed the preparation of pure mono-Ts-
bCD in a new, fast, ecologic, and selective method, which may be
of interest also for an industrial process. Furthermore, a single-step
procedure to improve the nucleophilic substitution to tosyl-cyclo-
dextrin by amines such as ethylenediamine has been introduced
using an anion exchange resin. In this way, bis-Et-bCD could be ob-
tained in high molar yield using only
ethylendiamine.
a slight excess of
1H NMR (DMSO-d6) showed an almost complete disappearance
of the peaks of the tosyl groups (7.77, 7.43, and 2.44 ppm), the
presence of a new multiplet at 2.51–3.02 ppm corresponding to –
CH2CH2– of ethylenediamine, and an upfield shift of derivatized
C60 protons (Fig. 3A). A small amount of p-toluenesulfonic acid
(<2 mol %) as impurity and mono-Ts-bCD (<2 mol %) were found
in the product without additional purification, as could also be
visualized by TLC. 13C NMR (DMSO-d6) spectra (Fig. 3B) also
showed bis-Et-bCD formation by the peaks at 48.46 and
1. Experimental
1.1. Materials
b-CD, p-toluenesulfonyl chloride, ethylenediamine (99.5%), cat-
ion exchange resin 50 W ꢂ 4 20–50 mesh in hydrogen form (Dow-
exÒ), anion exchange resin 1 ꢂ 8 200–400 mesh in Clꢁ form
(DowexÒ), 1-methyl-2-pyrrolidinone (NMP; anhydrous, 99.5%),
Figure 3. NMR spectra of bis-Et-bCD as obtained from the reaction procedure in the presence of the anion exchange resin. (A) 1H NMR. (B) 13C NMR.

G. Tripodo et al. / Carbohydrate Research 381 (2013) 59–63
63
N,N-dimethylformamide (DMF; anhydrous, 99.8%), and acetone
(99.5%) were from Sigma–Aldrich (Taufkirchen, Germany).
on paper to remove the resin. The product was precipitated in ace-
tone (20-fold excess v/v), collected by centrifugation, and washed 5
times in acetone. The pellet was dried under reduced pressure,
1.2. Equipment
subsequently solubilized in 70 mL water, filtered (0.45
filter), and freeze dried.
lm syringe
Melting points were determined on a melting point apparatus
B-540 (Büchi, Essen, Germany). ESI-MS spectrometry was per-
formed on APCI-Q-TOFmicro (Waters GmbH, Eschborn, Germany).
FT-IR spectra were acquired on an 8400S spectrometer (Shimadzu,
Duisburg, Germany). NMR spectroscopy was carried out on a
Bruker Avance 500 MHz (Bruker Biospin GmbH, Rheinstetten,
Germany). Elemental analysis was performed with a Flash EA
1112 CHNS/O automatic elemental analyzer (Thermo scientific,
Braunschweig, Germany).
Thin layer chromatography (TLC) was performed on precoated-
silica gel 60 plates (Merck, Darmstadt, Germany) with n-buta-
nol:methanol:water:30 wt.% ammonia in water (4:3:2:3) as eluent
with subsequent staining (p-anisaldehyde/methanol/acetic acid/
sulfuric acid solution 1:200:20:10) and heating.19
Yield: 93% with respect to starting mono-Ts-bCD for the system
of NMP/Clꢁ form resin.
TLC: Rf = 0.29 and two small spots at Rf = 0.12 (monoamine) and
Rf = 0.40 (monotosyl).
1H NMR (DMSO-d6): d = 6.18–5.31 (m, 28H), 5.04–4.73 (m,
14H), 4.72–4.21 (m, 12H), 3.95–3.82 (m, 4H), 3.80–3.20 (m, 80H),
3.02–2.51 (m, 8H –CH2NHCH2CH2NHCH2–) ppm.
1.3. Synthesis of 6-O-Monotosyl-b-cyclodextrin (mono-Ts-bCD)
A solution of bCD was prepared by slowly adding 35.2 mL
(88 mmol) of aqueous 2.5 N NaOH to 10 g (8.8 mmol) of bCD being
suspended in 90 mL water. After 5 min, 2.52 g (13.22 mmol) of p-
toluenesulfonyl chloride was added in five portions and the formed
suspension was continuously stirred for 1 h at 25 °C (400 rpm,
magnetic stirrer). After filtration and washing of the residue
(2 ꢂ 10 mL water), a total of 91 mL of pre-swollen cation exchange
resin 50 W ꢂ 4 20–50 mesh in the H+ form (100 meq, exchange
capacity 1.1 meq/mL) was added to the filtered solution. After
20 min, the mixture was first filtered through a Büchner funnel
provided with glass wool to collect the exchange resin. Second,
the precipitated white product was collected on filter paper. After
washing with 3 ꢂ 30 mL water, the product was lyophilized.
Yield: 35% (based on starting b-cyclodextrin).
Derivatization Degree (DD) for this sample: 96 mol % (for the
system NMP/Clꢁ form resin).
13C NMR (DMSO-d6): d = 101.90 (C1); 81.49 (C4); 73.01, 72.38,
72.01 (C3, C5, C2); 70.32 (C50); 59.88 (C6); 48.47 (C60); 47.26
(–NH-CH2-CH2-NH–) ppm.
m/z (ESI): calculated 2292; found 2315 [M+Na]+.
References
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Melting point: 160–162 °C.
FTIR: 1600 cmꢁ1 (Ph-SO2–), 1230 cmꢁ1 (Ph-SO2-R), 815 cmꢁ1
(Ph-SO2-O-R), 665 cmꢁ1 (Ph-SO2–).
1H NMR (DMSO-d6): d = 7.77 (mc, 2H Ph), 7.43 (mc, 2H Ph),
5.83–5.63 (m, 14H, OH1 and OH3 Cyd), 4.85–4.77 (m, 7H, H1
Cyd), 4.51–4.45 (m, 6H, OH6 CyD), 4.35 (mc, 2H, H60 CyD), 4.20
(mc, 1H, H50 CyD), 3.75–3.40 (m, 25H, H3, H5 and H6 CyD), 3.40–
3.15 (m, H2, H4 overlap with water), 2.44 (s, 3H, Ph-CH3) ppm.
Derivatization Degree (DD): >98 mol %.
13C NMR (DMSO-d6): d = 144.77 (C Ts); 132.846 (C Ts); 129.98
(C Ts); 127.55 (C Ts); 101.89 (C1); 98.14 (C10); 81.47(C4); 81.15
(C40); 73.02, 72.40, 72.00 (C2, C3, C5); 69.67 (C50); 68.87 (C60);
59.88 (C6); 21.17 (CH3 Ts) ppm.
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m/z (ESI): calculated 1289.1970, found 1289.3770 [M+H]+.
Elemental analysis: calculated—C: 45.65; H: 5.94; S: 2.49; de-
tected—C: 45.71; H: 6.29; S: 2.84.
1.4. Synthesis of N,N0-bis-6-(6-deoxy-b-
cyclodextrin)ethylenediamine (bis-Et-bCD)
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After complete solubilization of 1 g (0.77 mmol) of mono-Ts-
bCD in 15 mL NMP (standard procedure) or DMF, a total volume
of 2 mL of pre-swollen anion exchange resin 1 ꢂ 8 200–400 mesh
(2 meq, exchange capacity 1.0 meq/mL) either with Clꢁ or OHꢁ
counter-ions were added followed by 77.8 lL (1.16 mmol) of ethy-
lenediamine. The OHꢁ form was obtained from the Clꢁ form by
flushing with 1.5 N NaOH, washing with water, and finally swelling
in NMP or DMF. The reaction mixture was incubated at 80 °C under
argon atmosphere for 24 h. Then, the reaction solution was filtered
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