Synthesis of water-soluble multidentate aminoalcohol β-cyclodextrin derivatives via epoxide opening

Article abstract of DOI:10.1016/j.carres.2011.09.018

New highly soluble β-aminoalcohol β-cyclodextrin (β-CD) derivatives have been synthesized via nucleophilic epoxide opening reactions with mono-6-amino mono-6-deoxy-permethyl-β-CD and mono-6-amino mono-6-deoxy-β-CD. The binding properties of the β-CD were enhanced by linking aminoalcohol subunits which caused its solubility to improve markedly. The reaction conditions were optimised using microwave irradiation giving moderate-to-good yields with a series of epoxides. A regioselective epoxide opening reaction was observed in the reaction with styrene oxide while the stereoselectivity was strictly dependent on substrate structure.

Full text of DOI:10.1016/j.carres.2011.09.018

Carbohydrate Research 346 (2011) 2677–2682
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of water-soluble multidentate aminoalcohol b-cyclodextrin
derivatives via epoxide opening
K. Martina a, M. Caporaso a, S. Tagliapietra a, G. Heropoulos b, O. Rosati c, G. Cravotto a,
⇑
a Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy
b Institute of Organic and Pharmaceutical Chemistry, National Hellenic Res. Found., Vas. Constantinou Av. 48, Athens 116 35, Greece
c Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
New highly soluble b-aminoalcohol b-cyclodextrin (b-CD) derivatives have been synthesized via nucleo-
philic epoxide opening reactions with mono-6-amino mono-6-deoxy-permethyl-b-CD and mono-
6-amino mono-6-deoxy-b-CD. The binding properties of the b-CD were enhanced by linking aminoalcohol
subunits which caused its solubility to improve markedly. The reaction conditions were optimised using
microwave irradiation giving moderate-to-good yields with a series of epoxides. A regioselective epoxide
opening reaction was observed in the reaction with styrene oxide while the stereoselectivity was strictly
dependent on substrate structure.
Received 20 July 2011
Received in revised form 17 September
2011
Accepted 19 September 2011
Available online 22 September 2011
Keywords:
Cyclodextrin
Ó 2011 Elsevier Ltd. All rights reserved.
Epoxides
Selectivity
Microwave activation
Solubilization in water
1. Introduction
hydrogen bond molecular network and dramatically improves
water solubility. This solubilising effect has been observed in the
Cyclodextrins (CDs) possess a well-studied ability to act as
hosts for hydrophobic guests in water.1 Due to their homochirality,
CDs may be used as molecular receptors and constitute examples
of supramolecular chemistry.2 Chromatographic3 and electropho-
retic4 methods as well as stereoselective reactions mediated by
CDs exploit this peculiar property which has been widely explored
by calorimetric, X-ray diffraction, NMR and computational
studies.5
reaction of b-CD with propylene oxide and, as a consequence, 6-
O(2-hydroxypropyl) b-CD showed higher solubility than the 2-O
substituted derivative.9
The ring opening of epoxides by nucleophiles is one of the most
versatile and well established reactions of all ‘click chemistry’ pro-
tocols. This reaction is typically carried out in the presence of a cat-
alyst and a large excess of amines at elevated temperatures. For
this reason, non-conventional techniques, besides the more classi-
cal procedures, have been used to promote the reaction.10 The
reaction of epoxides with amines affords b-aminoalcohols which
are important intermediates for carbohydrate and nucleoside syn-
thesis. When linked to b-CD, the b-aminoalcohol moiety can en-
hance the CD’s binding property and favourably affects its
solubility. These derivatives can efficiently form metal complexes
with b-CD which can then be applied as supramolecular catalysts
in regio- or stereoselective reactions.11 These chemically reactive
subunits interact with the bound guests making a complementary
metal coordination effect. Furthermore, aminoalcohol derivatives
of b-CD may be very attractive as powerful chiral selectors in cap-
illary electrophoresis, as charged b-CDs they are endowed with a
high resolution ability without interfering with the detection of
analytes.12
Because of the regularity of the b-CD ring, the substitution of
one or more hydroxyl groups affects the annular asymmetry,
increasing solubility and influencing its binding properties.
It has been observed that the substituents on the CD’s wider
side, exhibit different host properties than those on the narrower,
primary hydroxyl side. Therefore the synthesis of monosubstituted
CDs has become important over the years and complex procedures
are generally required to obtain regioselectively substituted deriv-
atives.6 Monosubstituted derivatives have been used in the synthe-
sis of dimers and oligomers.7
As has already been reported,8 the solubility of b-CD can be
markedly improved with the attachment of suitable moieties. Even
a
random and low degree of substitution with hydrophilic
hydroxyethyl- or oligo(ethylene glycol)- groups disrupts the
To the best of the authors’ knowledge, there are very few re-
ports on the synthesis of b-CD aminoalcohols and, in these studies,
they are usually obtained by displacement of the tosyl group from
⇑
Corresponding author. Tel.: +39 011 6707684; fax: +39 011 6707687.
E-mail address: giancarlo.cravotto@unito.it (G. Cravotto).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.09.018

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K. Martina et al. / Carbohydrate Research 346 (2011) 2677–2682
Table 1
the 6-monodeoxy-6-mono-(p-tolylsulfonyl)-b-CD with an amino-
alcohol.10,12c The direct etherification of b-CD with epoxides was
reported by Pitha et al.9 and confirmed by Wenz et al.13 They dem-
onstrated that in aqueous alkali and the presence of propylene
oxide, b-CD is alkylated on the primary or the secondary face
which results in a mixture of 2-O, 3-O, 6-O substituted CDs. After
long reaction times, the desired product is isolated in very low
yield. Furthermore native b-CD and derivatives have been used to
initiate the polymerization with ethylene oxide, with the aim to
obtain new biomimetic synthetic pores.14 There are no publica-
tions that refer to the ring opening of epoxides by monoamino
b-CD. In the light of the widespread applications of aminoalcohol
b-CD derivatives, we have systematically studied the nucleophilic
opening of epoxides with monoamino b-CD: a straightforward
way of obtaining a range of multidentate and water-soluble
aminoalcohol b-CD derivatives. In this paper the alkylation of
monoamino b-CD has been achieved with various epoxides and
with the aim of exploring the relationship between structure and
reactivity. Mono-6-amino mono-6-deoxy-permethyl-b-CD was
compared to the mono-6-amino mono-6-deoxy-b-CD in such a
way as to evaluate the reactivity of the hydroxyl group and the
influence of epoxide inclusion. The optimization of these reactions
was studied under microwave (MW) irradiation. The regioselectiv-
ity of the attack was studied when the reaction was performed
with styrene oxide, whereas cyclohexene oxide was chosen as a
symmetrically substituted epoxide which could report on whether
its inclusion into CD yields stereoselective effects.
Assessment of alkylation of mono-6-amino mono-6-deoxy-permethyl-b-CD (1) and
mono-6-amino mono-6-deoxy-b-CD (2) with styrene oxide
Entry
Reagent
Eq. Epoxide
Reaction condition, time
Yielda,b
%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
2
2
5
5
1
1
1
1
1
5
5
5
5
LiBr, DMF, 60 °C, 24 h
LiBr, DMF, 85 °C, 4 h, MW
LiBr, DMF, 60 °C, 24 h
LiBr, DMF, 85 °C, 24 h
LiBr, DMF, 85 °C, 4 h, MW
DMF, 85 °C, 4 h, MW
DMF, 85 °C, 4 h, MW
LiBr, DMF, 85 °C, 19 h
LiBr, DMF, 85 °C, 4 h, MW
DMF, 85 °C, 4 h, MW
H2O, 85 °C, 4 h, MW
18
35
18
38
50
52
—
18
19
32
Traces
10
11
a
All the products were characterized by 1H NMR, 2D NMR (1H–13C HMQC, 1H–1H
COSY), IR spectroscopy and mass spectrometry.
b
Isolated yield obtained after flash chromatography.
effect on the conversion and yield. As already observed in reported
derivatizations of CDs,7a,b,d,15 MW irradiation promotes the reac-
tion cutting down reaction times from 24 to 4 h. As regards the reg-
iochemistry of the ring opening, styrene oxide displays a general
tendency for regioselective attack at the benzylic position when
less nucleophilic aromatic amines are employed. In the presence
of aliphatic amines a lower degree of regioselectivity is observed
and the reaction is controlled by steric factors. The preferential
reaction at the non-benzylic position is achieved only with a
catalyst.16 When permethyl b-CD was reacted with styrene oxide
a single regioisomers was isolated. Using a combination of 1H
NMR and 2D NMR experiments (1H–13C HMQC, 1H–1H COSY), we
were able to discover that the product that resulted from the
nucleophilic attack at the less-hindered epoxide carbon was the
obtained regioisomer. Likewise, the same reaction with mono-6-
amino mono-6-deoxy-b-CD (Table 1, entries 7–10) selectively at-
tacks the b position (5) but differently from the reaction with
permethyl b-CD (1), 5 equiv of epoxide were required to achieve
conversion. Turning to stereochemistry, when styrene oxide was
reacted with 6-monoamino b-CD derivatives 2, TLC showed two
spots with different intensities and Rf values. Reverse phase sepa-
ration yielded an inseparable mixture of the two products (same
molecular weights by MS spectrometry and same 1H NMR spectra).
For this reason, we assume that the mixture was composed of two
epimers with slightly different polarities. The diastereomeric ratio
of product 4 was measured by HPLC and was found to be 9:1 for
the stereoisomeric secondary alcohol. To evaluate the influence
of the solvent on the stereoselectivity, the reaction was repeated
in water but only traces of product were observed by TLC and
HPLC. By HPLC we could not separate the two epimers of products
3, the two spots were evidenced only by bidimensional TLC.
In the second part of this study, cyclohexene oxide was taken as
a symmetrically substituted epoxide and reacted with permethyl
mono-6-amino b-CD in DMF.
Given the fact that most terminal epoxides are inexpensive
and easily available, we also decided to apply this synthetic
approach to the preparation of bifunctional molecules by reacting
monoamino b-CD with diethylene glycol diglycidyl ether and
octadiene dioxide.
2. Results and discussion
Mono-6-amino mono-6-deoxy-permethyl-b-CD was chosen as
a preliminary b-CD substrate and was reacted with styrene oxide
in a series of reactions carried out with the aim of optimising con-
ditions (Scheme 1 and Table 1).
The reactions were performed at 60 °C or 85 °C in DMF under
conventional heating or MW irradiation. The epoxide ratio was
varied from 1 to 5 equiv and in some experiments LiBr was added.
We monitored reaction conversion by TLC and the product was iso-
lated by silica gel column chromatography. The optimised proce-
dure was setup at 85 °C, under MW irradiation with 1 equiv of
styrene oxide, the presence of LiBr points to the catalyst lack of
As with the experiment above, the influence of LiBr catalysis,
the heating conditions and the number of equivalents of epoxides
were compared (Scheme 2 and Table 2). The reaction was moni-
tored by TLC and the hydroxycyclohexylamino b-CD derivative
(5) was isolated by flash chromatography.
Differently to styrene oxide, 4 equiv of cyclohexene oxide were
added to obtain the desired product in satisfactory yields. The reac-
tion required a long reaction time when performed under conven-
tional heating and more than 5 equiv of epoxide did not provide
higher yields (Table 2, entry 4). The reaction was optimised by
heating under MW at 85 °C for 4 h and the final product was ob-
tained in 27% yield.
HO
H2N
HN
O
O
O
O
RO
O
RO
RO
OR
RO
OR
SeeTable 1
OR
O
OR
O
O
O
OR
OR
6
6
1
2
3
4
R= CH3
R = H
R = CH3
R = H
The reaction was repeated on mono-6-amino-mono-6-deoxy-b-
CD. The reaction showed the best results when performed with
Scheme 1. Reaction of mono-6-amino mono-6-deoxy-permethyl-b-CD (1) and
mono-6-amino mono-6-deoxy-b-CD (2) with styrene oxide.

K. Martina et al. / Carbohydrate Research 346 (2011) 2677–2682
2679
Regarding the stereochemistry, nucleophilic ring epoxide open-
ing almost certainly involves an SN2 reaction and occurs with an
inversion in configuration at the point of attack. Bearing this in
mind, it has been assumed that this opening method would give
trans-diaxial rather than trans-diequatorial products. Trans-diaxial
cleavage proceeded via a transition state which is more energeti-
cally favourable than in the trans-diequatorial epoxide opening.17
Assignment of the relative configuration of the b-aminoalcohol
derivative is possible via a comparison of the coupling constants 3J.
When cyclohexene oxide was reacted with 1 neither TLC nor
HPLC revealed stereospecificity. But when we monitored the syn-
thesis of product 6, TLC showed two spots as had been previously
observed with styrene oxide. Reverse phase separation yielded
only the major isomer because the minor was present in a negligi-
ble amount. A 1H NMR spectrum of the isolated compound 6 (see
Fig. 1) was characteristic because the cyclohexyl moiety was found
to be strongly influenced by the presence of CD. All the cylohexanol
diasterotopic methylene groups were seen to split each other.
OH
H2N
HN
O
O
O
RO
O
RO
O
RO
OR
RO
OR
85 °C, DMF
reaction condition
see Table 2
OR
O
OR
O
O
O
OR
OR
6
6
1
2
5
R= CH3
R = H
R = CH3
R = H
6
Scheme 2. Reaction of mono-6-amino-mono-6-deoxy-permethyl-b-CD (1) and
mono-6-amino-mono-6-deoxy-b-CD (2) with cyclohexene oxide.
2D-NMR experiments (1H–13
C
HMQC, 1H–1H COSY) were
Table 2
Assessment of alkylation of mono-6-amino-mono-6-deoxy-permethyl-b-CD (1) and
mono-6-amino-mono-6-deoxy-b-CD (2) with cyclohexene oxide
employed to assign the peaks and remove any doubt. From this
spectrum it was seen that the complexity of CD derivative 6
renders J coupling measurement impossible so that we were un-
able to verify whether the final product had been isolated in the
trans-diaxial or the trans-diequatorial form. The strong interaction
between the CD core and the substituent, as shown in the NMR, has
promoted the hypothesis of a stereoselective ring opening.
The third part of this study focused on the application of the
epoxide ring opening reaction to terminal epoxides.
Monoamino CD derivatives 1 and 2 were reacted with diethyl-
ene glycol diglycidyl ether (7) to give a new highly soluble and
functionalized CD derivative (Scheme 3, Table 3). The reaction re-
quired 10 equiv to obtain satisfactory conversion rates. However,
product 9 was only obtained in a 4% yield and derivative 10 was
isolated in a slightly better 9% yield. As has already been men-
tioned, nucleophilic epoxide opening with CD does not afford com-
plete conversion but, differently from the reactions already
described, diethylene glycol diglycidyl ether gave a mixture of side
products and so the desired products were difficult to isolate.
As expected, product 10 showed higher solubility in water than
the starting material. Therefore, to reach our objective, we evalu-
ated a new epoxide substrate from which the desired b-aminoalco-
hol CD derivative was obtained in a higher yield. 1,7-Octadiene
was epoxidated with MCPBA and isolated in a 95% yield to obtain
1,7-octadiene dioxide (8). The reaction was repeated, with the
same conditions as for diethylene glycol diglycidyl ether, and the
products 11 and 12 were obtained with 30% and 52% yields, respec-
tively Table 3.
Entry
Reagent
Eq. epoxide
Reaction conditiona
Yieldb,c
%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
2
2
1
4
4
7
4
4
1
10
4
10
10
LiBr, 24 h
LiBr, 24 h
LiBr, 48 h
LiBr, 26 h
LiBr, 4 h, MW
4 h, MW
48 h
LiBr, 36 h
4 h, MW
5
12
16.8
15
26
27
Failed
9.2
Failed
30
10
11
4 h, MW
LiBr, 4 h, MW
28
a
The reaction was performed at 85 °C in DMF.
All the products were characterized by 1H NMR, 2D NMR (1H–13C HMQC, 1H–1H
COSY) and mass spectrometry.
b
c
Isolated yield obtained after column chromatography.
R'1
R1
H2N
N
O
O
O
O
O
O
O
O
O
RO
7
O
RO
RO
OR
O
RO
OR
8
85°C, DMF
OR
O
OR
O
O
O
OR
n
OR
n
9-12
1
2
R= CH3
R = H
After NMR and MS analysis we found that the ring opening
reaction with the octadiene dioxide occurred twice so that product
12 is a disubstituted b-CD. When repeated with fewer equivalents
OH
e
d
d
d
O
f
O
d
O
O
R'1
=
9
R = CH3, R1 = H
b
c
d
a
d
OH
e
d
d
O
O
c
O
O
d
R'1
R'1
=
=
10
11
R = H, R1 = H
d
Table 3
b
d
a
f
Results of reaction of mono-6-amino-mono-6-deoxy-b-CD (1) and mono-6-amino-
mono-6-deoxy-permethyl-b-CD (2) with terminal epoxides 7 and 8
OH
h
R = CH3, R1 = H
b
c
f
O
a
g
f
e
d
Entry Reagent Epoxide Reaction condition
Yielda,b
%
OH
h
12 R = H
R1 , R'1 =
a
b
c
O
1
1
7
7 (10 equiv), DMF, 65–85 °C, 4 h,
4
g
e
MW
2
3
2
1
7
8
7 (10 equiv), DMF, 85 °C, 4 h, MW
8 (10 equiv), DMF, 65–85 °C, 4 h,
9
30
Scheme 3. Reaction of mono-6-amino-mono-6-deoxy-b-CD (1) and mono-6-
amino-mono-6-deoxy-permethyl-b-CD (2) with terminal epoxides 7 and 8.
MW
4
2
8
8 (10 equiv), DMF, 65–85 °C, 4 h,
52
MW
10 equiv of cyclohexene oxide under the optimal conditions found
for the permethyl derivatives. The influence of MW in promoting
the reaction was confirmed as had been observed for the permeth-
yl derivative.
All the products were characterized by 1H NMR, 2D NMR (1H–13C HMQC, 1H–1H
COSY) and mass spectrometry.
Isolated yield obtained after column chromatography.
a
b

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K. Martina et al. / Carbohydrate Research 346 (2011) 2677–2682
Figure 1. 1H NMR (300 MHz, DMSO-d6) spectrum of 6-mono(2-hydroxycyclohexylamino)-6-monodeoxy-b-CD (6); on the left, the complete product structure; on the right, a
particular of the bidimensional 1H–13C HSQC spectrum.
of 1,7-octadiene dioxide (8) the reaction with b-CD 2 did not afford
the desired monosubstituted derivative in satisfactory yields.
ppm, coupling constants (J) in Hertz. ESI-mass spectra were per-
formed on a Waters Micromass ZQ spectrometer equipped with
ESI source.
3. Conclusions
4.1. 6-Mono(2-hydroxyl-2-phenyl)ethylamino-6-monodeoxy-
permethyl-b-CD (3)
Overall it can be concluded that nucleophilic epoxide opening
with mono-6-amino mono-6-deoxy-b-CD and mono-6-amino
mono-6-deoxy-permethyl b-CD, promoted by MW, can be consid-
ered a versatile way to obtain b-aminoalcohol derivatives of b-CD
in acceptable yields. The selective formation of the b regioisomer
was observed when the reaction was performed with styrene oxide
and excellent stereoselectivity was achieved in the nucleophilic
epoxide cleavage of styrene and cyclohexene oxides with mono-
6-amino mono-6-deoxy-b-CD. These newly prepared compounds
showed high water solubility and the linked aminoalcohol
subunits enhanced the CD binding properties. Using monoamino
b-CD and terminal diepoxides this protocol afforded new function-
alized b-CD derivatives, versatile intermediates which can be
exploited for further modifications.
The reaction was carried out under magnetic stirring in a
professional MW oven; the temperature was monitored with a
fibre-optic thermometer. Mono-6-amino mono-6-deoxy-permeth-
yl-b-CD (130 mg, 0.09 mmol) was dissolved in anhydrous DMF
(2 mL) and styrene oxide (10.5 lL, 0.09 mmol) was added. The
mixture was irradiated with MW (160 W) at 85 °C for 4 h. The reac-
tion was monitored by TLC (CHCl3/MeOH 9:1) and spots were visu-
alized with
a phosphomolybdic acid stain. The solvent was
partially evaporated and the reacted mixture was diluted with
CH2Cl2, washed with water and finally dried (Na2SO4). The crude
residue was purified by CC (CH2Cl2/CH3OH) to yield 73 mg (52%
yield) of the desired product.
Compound 3 is a white powder; Rf = 0.61 (CHCl3/CH3OH 9:1); 1H
NMR (300 MHz, CDCl3) d = 7.36–7.27 (m, 5H, H-Ar), 5.12 (m, 7H, H-
1), 4.75 (m, 1H, Ph-CH(OH)), 3.84–3.81 (m, 14H, H-5, H-6A), 3.64–
3.502 (m, 63H, 3-OCH3, 2-OCH3, H-4,H-6B, H-3), 3.302 (m, 18H, 6-
OCH3), 3.29 (m, 7H, H-2), 2.95 (m, 1H, CH2–NH), 2.78 (m, 1H,
CH2–NH) ppm; 13C NMR (75 MHz, CDCl3): d = 142.6 (Cipso), 128.72–
4. Experimental
Commercially available reagents and solvents were used
without further purification. Native CDs were kindly provided by
Wacker Chemie. 6-Amino-mono-6-deoxy-b-CD (1) and mono-
6-amino-mono-6-deoxy-permethyl-b-CD (2) were prepared in
accordance with the well established procedure.18,19 Diethylene
glycol diglycidyl ether was purified from a commercially available
50% pure solution (column chromatography DCM/MeOH). Reac-
tions were monitored by TLC on Merck 60 F254 (0.25 mm) plates.
Spot detection was carried out by staining with 5% H2SO4 in etha-
nol or with phosphomolybdic acid stain. IR spectra were recorded
with a Shimadzu FT-IR 8001 spectrophotometer. NMR spectra
were recorded with a Bruker 300 Avance (300 MHz and 75 MHz
for 1H and 13C, respectively) at 25 °C; chemical shifts are calibrated
to the residual proton and carbon resonances of the solvent:
DMSO-d6 (dH = 2.54, dC = 39.5). Chemical shifts (d) are given in
126.2 (Cortho, Cmeta, Cpara), 99.3 (C1), 82.4–82.06 (C2, C3)
80.81–80.51 (C4), 71.75–71.47 (C6, PhCHOH), 71.31–71.17 (C5),
61.86–61.76 (3-OCH3), 59.27–59.24 (2-OCH3), 59.01–58.69
(6-OCH3), 57.84 (CH2NH) ppm; MS (ESI): m/z calcd for C70H119NO35
[M+H]+ 1535.7 found 1535.87, C70H119NO35 [M+H+Na]2+ 779.35
found 779.25.
4.2. 6-Mono(2-hydroxyl-2-phenyl)ethylamino-6-monodeoxy-b-
CD (4)
The reaction was carried out under magnetic stirring in a
professional MW oven, the temperature was monitored with a

K. Martina et al. / Carbohydrate Research 346 (2011) 2677–2682
2681
fibre-optic thermometer. Mono-6-amino-mono-6-deoxy-b-CD
(100 mg, 0.09 mmol) was dissolved in anhydrous DMF (2 mL)
ppm; 13C NMR (DMSO, 75 MHz): d = 102.84 (C1), 82.5 (C4), 73.87
(C3), 73.32 (C-b), 73.27 (C2), 72.90 (C5), 63.16 (C-a), 60.7 (C-6),
46.23 (C-60), 34.54 (C-c), 30.03 (C-f), 24.86 (C-d, C-e) ppm; MS
(ESI): m/z calcd for C48H81NO35 [M+H]+ 1232.46 found 1233.14.
and styrene oxide (50.2
was irradiated with MW (160 W) at 85 °C for 4 h. It was partially
evaporated, dissolved with 800 L of water then precipitated with
lL, 0.44 mmol) was added. The mixture
l
cold acetone. The precipitate was purified by reverse phase column
chromatography (H2O/CH3OH gradient from 97:3 to methanol
100%) to yield 36 mg (32% yield) of the desired product.
4.5. 1,7-Octadiene dioxide (8)
Octadiene (1.37 mL, 9.07 mmol) was dissolved in 25 mL of DCM
and stirred at 0 °C. MCPBA (4.68 g, 18.08 mmol) dissolved in 45 mL
of DCM was added dropwise. The solution was left at 0 °C under
stirring overnight. The reaction was monitored by TLC (PE/EtOAc
8:2) and spots were visualized with a phosphomolybdic acid stain.
The solution was washed three times with water and finally dried
(Na2SO4). 1.39 g (95% yield) of the desired product was recovered
and employed without further purifications. Analytical data were
in accordance with reported values.20
Compound 5 is a white powder; Rf = 0.45 (iPrOH/H2O/EtOAc/
NH4OH = 5:3:1:1); 1H NMR (300 MHz, DMSO-d6) d = 7.37–7.27
(m, 5H, H-Ar), 5.82–5.71 (m, 14H, O(2)H, O(3)H), 4.88 (br s 7H,
H-1), 4.66 (m, 1H, PhCH(OH)), 4.53 (m, 6H, O(6)H), 3.7–3.6 (m,
28H, H-6, H-3), 3.5–3.2 (m, overlaid with water, H-2, H-4, H-5),
2.61 (m, 2H, CH2–NH) ppm; 13C NMR (75 MHz, DMSO) d = 145.47
(Cipso), 128.76 (Cmeta), 126.72 (Cortho, Cpara), 102.84 (C1), 82.4 (C4),
73.3 (C3), 73.28 (C2), 72.88 (C5), 70.48 (PhCH(OH)), 57.5 (C6),
57.35 (CH2NH) 49.64 (C60) ppm; MS (ESI): m/z calcd for
C
50H79NO35 [M+H]+ 1254.4 found 1255.45.
4.6. 6-Mono(2-hydroxy-3-(2-(2-(oxiran-2-
ylmethoxy)ethoxy)ethoxy) propylamino)-6-monodeoxy-
permethyl-b-CD (9)
4.3. 6-Mono(2-hydroxycyclohexyl)amino-6-monodeoxy-
permethyl-b-CD (5)
The reaction was carried out under magnetic stirring in a
professional MW oven, the temperature being monitored with a
fibre-optic thermometer. Mono-6-amino mono-6-deoxy-permeth-
yl-b-CD (300 mg, 0.212 mmol) was dissolved in anhydrous DMF
The reaction was carried out under magnetic stirring in a
professional MW oven, the temperature was monitored with a
fibre-optic thermometer. Mono-6-amino mono-6-deoxy-permeth-
yl-b-CD (150 mg, 0.11 mmol) was dissolved in anhydrous DMF
(2 mL) and diethylene glycol diglycidyl ether (292 lL, 2.12 mmol)
(1 mL) and cyclohexene oxide (43
mixture was irradiated with MW (160 W) at 85 °C for 4 h. The reac-
tion was monitored by TLC (CHCl3/MeOH 9:1) and spots were visu-
l
L, 0.42 mmol) was added. The
was added. The mixture was irradiated with MW (160 W) at
65 °C for 1 h then 85 °C for 3 h. The reaction was monitored by
TLC (CHCl3/MeOH 95:5) and spots were visualized with phospho-
molybdic acid stain. The solvent was partially evaporated and the
reacted mixture was diluted with CH2Cl2, washed with brine and
finally dried (Na2SO4). The crude residue was purified by column
chromatography (CH2Cl2/CH3OH) to yield 14 mg (4% yield) of the
desired product.
alized with
a phosphomolybdic acid stain. The solvent was
partially evaporated and the reacted mixture was diluted with
CH2Cl2, washed with water and finally dried (Na2SO4). The crude
residue was purified by CC (CH2Cl2/CH3OH) to yield 50 mg (27%
yield) of the desired product.
Compound 6 is a white powder; Rf = 0.54 (CHCl3/CH3OH 9:1);
Compound 10 is white powder; Rf = 0.54 (CHCl3/CH3OH 9:1); 1H
NMR (CDCl3, 300 MHz) d = 5.14 (br s 7H, H-1), 4.01 (m, 1H, H-6A0),
3.86–3.81 (m, 14H, H-5, H-6A), 3.65–3.51 (m, 64H, 3-OCH3,2-OCH3,
1H NMR (CDCl3, 300 MHz) d = 5.18–5.03 (m, 7H, H-1), 4.05–3.98
A
0
A
(m, 1H, H-6 ), 3.87–3.82 (m, 14H, H-5, H-6 ), 3.64–3.52 (m, 64H,
3-OCH3,2-OCH3, H-4,H-6B, H-3, H-a), 3.40 (m, 19H, 6-OCH3, H-
B
B
0
H-4,H-6 , H-3, CH–NH), 3.41 (m, 18H, 6-OCH3, H-6 ), 3.21–3.18
(m, 23H, H-2, H-e, H-a, H-b, H-c, H-d), 2.81 (m, 1H, H-f), 2.63 (m,
1H, H-f), ppm; 13C NMR (CDCl3, 75 MHz): d = 98.9 (C-1), 80.04
(C-2), 81.67 (C-3), 80.50 (C-4), 71.45, 71.47 (C-c, C-d), 71.83,
71.51, 71.22 (C-5, C-6), 61.28 (3-OCH3), 58.92 (2-OCH3), 58.41
(6-OCH3), 59.3 (CH2NH), 52.17 (C-e), 47.35 (C-f); MS (ESI): m/z
calcd for C72H129NO39 [M+H]+ 1632.81 found 1633.36.
B
0
6 ), 3.22–3.18 (m, 7H, H-2), 1.27 (m, 4H, H-c, H-f), 0.081 (m, 4H,
H-d, H-e) ppm; 13C NMR (CDCl3, 75 MHz): d = 98.7 (C-1), 82.15,
81.87, 81.66 (C-2, C-3), 80.70, 80.30, 80.14 (C-4), 72.42, 71.64,
71.3 (C-5, C-6), 62.9, 61.84, 61.62 (3-OCH3), 58.73 (2-OCH3),
57.73 (6-OCH3), 42.9 (C-60), 30.01 (C-c), 23.6 (C-f), 21.7, 21.2
(C-d, C-e) ppm; MS (ESI): m/z calcd for C68H121NO35 [M+H]+
1511.77, found 1512.03.
4.7. 6-Mono(2-hydroxy-3-(2-(2-(oxiran-2-
4.4. 6-Mono(2-hydroxycyclohexylamino)-6-monodeoxy-b-CD
ylmethoxy)ethoxy)ethoxy) propylamino)-6-monodeoxy-b-CD
(6)
(10)
The reaction was carried out under magnetic stirring in a pro-
fessional MW oven, the temperature was monitored with a fibre-
optic thermometer. Mono-6-amino mono-6-deoxy-b-CD (100 mg,
0.09 mmol) was dissolved in anhydrous DMF (2 mL) and cyclohex-
The reaction was carried out under magnetic stirring in a profes-
sional MW oven, the temperature being monitored with a fibre-
optic thermometer. Mono-6-amino mono-6-deoxy-b-CD (300 mg,
0.26 mmol) was dissolved in anhydrous DMF (2 mL) and diethylene
ene oxide (100
ated with MW (160 W) at 85 °C for 4 h. It was partially evaporated,
dissolved with 800 L of water then precipitated with cold ace-
l
L, 0.88 mmol) was added. The mixture was irradi-
glycol diglycidyl ether (363
was irradiated with MW (160 W) at 85 °C for 4 h. It was partially
evaporated, dissolved with 800 L of water then precipitated with
lL, 2.64 mmol) was added. The mixture
l
l
tone. The precipitate was purified by reverse phase column chro-
matography (H2O/CH3OH gradient from 97:3 to methanol 100%)
to yield 33 mg (30% yield) of the desired product.
cold acetone. The precipitate was purified by reverse phase column
chromatography (H2O/CH3OH gradient from 97:3 to methanol
100%) to yield 26 mg (9% yield) of the desired product.
Compound 7 is a white powder; Rf = 0.41 (iPrOH/H2O/EtOAc/
NH4OH = 5:3:1:1); 1H NMR (DMSO-d6, 300 MHz) d = 5.72 (m,
14H, O(2)H, O(3)H), 4.83 (m, 7H, H-1), 4.62–4.45 (m, 6H, O(6)H),
3.63–3.48 (m, 28H, H-6, H-3), 3.40–3.2 (m, overlaid with water,
Compound 11 is a white powder; Rf = 0.49 (iPrOH/H2O/EtOAc/
NH4OH = 5:3:1:1); 1H NMR (DMSO-d6, 300 MHz) d = 5.87–5.68
(m, 14H, O(2)H, O(3)H), 4.83 (m, 7H, H-1), 4.48–4.46 (m, 6H,
O(6)H), 3.77–3.25 (m, 28H), 3.35–3.31 (m, overlaid with water,
H-2, H-4, H-5, H-6, H-3, H-b, H-c. H-d), 2.92 (m, 1H, H-e), 2.75
(m, 1H, H-f), 2.47 (m, 2H, H-f, H-a) 2.35 (m, 1H, H-a), ppm; 13C
NMR (DMSO-d6, 75 MHz): d = 102.8 (C1), 82.38 (C4), 73.88 (C3),
A
0
H-2, H-4, H-5), 3.04–2.98 (m, 2H, H-b, H-6 ), 2.64 (d, J = 11.4 Hz,
B
0
H-6 ), 2.11 (m, 1H, H-a), 1.91 (d, 1H, H-f), 1.77 (m, 1H, H-c), 1.56
(m, 2H, H-e, H-d), 1.17 (m, 3H, H-c, H-d, H-e), 0.85 (m, 1H, H-f)

2682
K. Martina et al. / Carbohydrate Research 346 (2011) 2677–2682
73.27 (C2), 72.89 (C5), 70.15, 70.77(C-c, C-d), 66.27 (C-b) 62.42
Acknowledgements
(C-a), 60.76 (C6), 52.42 (C-e), 47.85 (C-f) ppm; MS (ESI): m/z calcd
for
C
52H89NO39 [M+H]+ 1352.50 found 1353.03, [M+Na+H]2+
Financial support from Regione Piemonte (NanoIGT, Converging
Technologies 2007) and MIUR (PRIN 2008—A Green Approach to
Process Intensification in Organic Synthesis) is gratefully
acknowledged.
688.24 found 688.10.
4.8. 6-Mono(2-hydroxy-6-(oxyran2-yl)hexylamino)-6-
monodeoxy-permethyl-b-CD (11)
Supplementary data
The reaction was carried out under magnetic stirring in a
professional MW oven, the temperature was monitored with a
fibre-optic thermometer. Mono-6-amino mono-6-deoxy-permeth-
yl-b-CD (150 mg, 0.11 mmol) was dissolved in anhydrous DMF
(1.5 mL) and 1,7-octadiene dioxide (150 mg, 1.06 mmol) was
added. The mixture was irradiated with MW (160 W) at 85 °C for
4 h. The reaction was monitored by TLC (CHCl3/MeOH 9:1) and
spots were visualized with a phosphomolybdic acid stain. The sol-
vent was partially evaporated and the reacted mixture was diluted
with CH2Cl2, washed with water and finally dried (Na2SO4). The
crude residue was purified by column chromatography (CH2Cl2/
CH3OH) to yield 47 mg (30% yield) of the desired product.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.09.018.
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3.99 (m, 1H, H-6 ), 3.87 (m, 14H, H-5, H-6 ), 3.62–3.49 (m, 64H,
3-OCH3,2-OCH3, H-4,H-6B, H-3, CH–NH), 3.45 (m, 18H, 6-OCH3),
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4.9. 6-Mono(di-2-hydroxy-6-(oxyran2-yl) hexylamino)-6-
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acetone. The precipitate was purified by reverse phase column
chromatography (H2O/CH3OH gradient from 97:3 to methanol
100%) to yield 234 mg (52% yield) of the desired product.
Compound 13 is a white powder; Rf = 0.46 (iPrOH/H2O/EtOAc/
NH4OH = 5:3:1:1); 1H NMR (DMSO-d6, 300 MHz) d = 5.87–5.68
(m, 14H, O(2)H, O(3)H), 4.86 (m, 7H, H-1), 4.64–4.51 (m, 6H,
O(6)H), 3.66–3.21 (m, overlaid with water, H-2, H-4, H-5, H-6, H-
3, H-b), 2.87 (m, 1H, H-g), 2.72 (m, 1H, H-h), 2.44 (m, 2H, H-h,
H-a) 2.32 (m, 1H, H-a) 1.5–1.15 (m, 16H, H-c, H-d, H-e, H-f)
ppm; 13C NMR (DMSO-d6, 75 MHz): d = 103.04 (C1), 82.49 (C4),
74.03 (C3), 73.05 (C2), 72.85 (C5), 66.58 (C-b) 62.16 (C-a), 60.31
(C6), 52.43 (C-g), 47.13 (C-h), 31.9 (C-c, C-f), 26.82, 26.38, 26.47,
25.82 (C-d, C-e) ppm; MS (ESI): m/z calcd for C58H99NO38 [M+H]+
1418.58 found, [M+Na+H]2+ 721.29 found 721.12.
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