Smart regioselectivity towards mono 6-hydroxyl α-cyclodextrin amphiphilic derivatives

Article abstract of DOI:10.1039/d0ra00299b

Following the trend of eco-friendly development, a smart regioselective modification is described herein, for mono 6-hydroxyl and penta-alkyl coexistence on the primary face of α-cyclodextrins with no additional catalysis or no enzyme process, just via the adjustment of the ratio of alkali to alkylation agent, with good yields. The novel procedure minimized the tedious protection, deprotection steps and provided useful intermediates for further cutting edge research. Thus, the scope of green and economical access is extended from penta-pentenyl substitution to C₄-C₆ alkyl group substitution. It was speculated that the mechanism might be controlled by the concentration of alkali in the system and the steric effects of the electrophilic reagent RBr.

Full text of DOI:10.1039/d0ra00299b

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PAPER
Smart regioselectivity towards mono 6-hydroxyl a-
cyclodextrin amphiphilic derivatives†
Cite this: RSC Adv., 2020, 10, 10695
ab
ad
Yangyi Mao,c Jianwei Maoe and Yongmin Zhang
*
*
Yanli Cui,
Following the trend of eco-friendly development, a smart regioselective modification is described herein,
for mono 6-hydroxyl and penta-alkyl coexistence on the primary face of a-cyclodextrins with no
additional catalysis or no enzyme process, just via the adjustment of the ratio of alkali to alkylation agent,
with good yields. The novel procedure minimized the tedious protection, deprotection steps and
provided useful intermediates for further cutting edge research. Thus, the scope of green and
economical access is extended from penta-pentenyl substitution to C4–C6 alkyl group substitution. It
was speculated that the mechanism might be controlled by the concentration of alkali in the system and
the steric effects of the electrophilic reagent RBr.
Received 11th January 2020
Accepted 10th February 2020
DOI: 10.1039/d0ra00299b
rsc.li/rsc-advances
a low overall yield. In 1998, D'Souza reviewed strategies for
selective modication of CDs, including regioselective mono-
1. Introduction
modications, but nevertheless, the methods used were
traditional.9 Traditionally the most popular method for mon-
omodications at the 6-position of CDs is via nucleophilic
attack from a reagent containing the appropriate group on
a mono-6-sulfonylcyclodextrin. These monosulfonates are
prepared by reacting 1 equiv. of p-toluenesulfonyl chloride
with CD in pyridine. However, monotosylation of CD is oen
a nonselective process and produces a mixture of primary as
well as secondary side tosylated products together with di- or
tri-tosylated derivatives.9 Alternatively, from the opposite
point of view, an approach has been developed over the years,
which involves the deprotection of the protected CDs. The
methodology uses diisobutylaluminium hydride (DIBAL-H) as
a dealkylating reagent and has been successfully applied to
benzylated CDs,15 allowing access to polyhetero-functionalized
CDs containing two, three or even six different functional-
ities.16 For example, when perbenzylated a-CD was treated
with excess DIBAL-H at room temperature, the mono-
debenzylated product was formed in 64% yield, the hydroxyl
group being on the primary face.15 The mono-demethylation
could also occur on the primary face of hexakis(2,3-di-O-
benzyl)-6-hexa-O-methyl-a-CD, but with a low yield (30%).17
Recently Ghosh et al. applied this methodology to per-6-O-tert-
butyldimethylsilylated CDs to produce mono- and di-O-desi-
lylated CDs,18 for example, the mono-O-desilylated-a-CD
product was isolated in 71% yield.
Cyclodextrins (CDs) are a family of cyclic oligosaccharides
derived from starch enzymolysis that possess molecule cavities
with topological structures. CDs and their cyclodextrin deriva-
tives (CDDs) have attracted widespread attention for their
increasingly expanding applications from traditional to cutting
edge research in elds such as: cosmetics, food additives, drug
carriers, analysis and catalysis technologies, and recently in
stimuli-responsive carriers, cyclodextrin–graphene, supramo-
lecular systems and other CD-based biomolecules.1–7 The
monosubstituted CDs are synthesized by introducing a desired
functional group or biomolecule to the single hydroxyl, or the
mono hydroxyl on cyclodextrins connected with another bio-
logical macromolecule or polymer. Monosubstituted derivatives
were also utilized in the synthesis of dened CD dimers and
oligomers, which exhibit stronger binding constants towards
guest molecules than the corresponding monomers due to the
cooperative inclusion.8
The CD molecule has numerous hydroxyl groups in three
different positions that make tiny differences to its reaction
activity. The selective derivatization is oen a tough task,
involving elaborate multistep protection-deprotections, with
a
´
´
Sorbonne Universite, CNRS, Institut Parisien de Chimie Moleculaire, UMR 8232, 4
Place Jussieu, 75005 Paris, France. E-mail: yongmin.zhang@upmc.fr; Tel: +33
144276153
bDepartment of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou 310027,
Herein a one-pot approach is reported for the preparation
of a novel series of mono 6-hydroxyl a-CDs with a variety of
alkyl groups on the primary face using no additional catalysis
or no enzyme process. However, the efficient method and
unique structure of the substrates have not been reported as
far as is known. Among the linkages (e.g., sulde,10,11 amine,12
China. E-mail: cuiyl@zju.edu.cn; Tel: +86 13858036095
cHangzhou Yanqing Biotechnology Co., Ltd, Hangzhou 310052, China
dInstitute for Interdisciplinary Research, Jianghan University, Wuhan Economic and
Technological Development Zone, Wuhan 430056, China
eZhejiang University of Science and Technology, Hangzhou 310013, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra00299b
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2.3. 6I–O-Hydroxyl-6II–VI-penta-O-pentylenyl-(per-2,3-di-O-
benzyl)-a-cyclodextrin (5e) and per-6-O-(pentylenyl-1)-per-2,3-
di-O-benzyl-a-cyclodextrin (6e)
ester,13 ether,14 etc.) available for the attachment of functional
groups to CDs, ether bonds are the most desirable, because
they are less susceptible to degradation by oxidation or
hydrolysis and obtained by a single nucleophilic reaction of
a hydroxyl group of the CDs with an appropriate electrophile.
The CD ethers either serve as amphiphilic sections, ene-end
CDDs for further functionalization, or act as reaction inter-
mediates of click reactions, or are converted into articial
enzymes, and others. In other words, the published
substrates can provide versatile variation for fast CD-based
research.
To a solution of 4 (51 mg, 0.02485 mmol) in 7 mL of dry DMF,
was added 60% NaH (13.90 mg, 0.3479 mmol) under argon at
room temperature, then 5-bromo-1-pentene (88.91 mg, 0.5964
mmol) was added. The mixture was stirred at room tempera-
ture until the starting product 4 had disappeared, and was
then hydrolyzed by MeOH (7 mL) and evaporated. The residue
was dissolved in dichloromethane. The organic phrase was
washed with saturated NaCl and water, dried over anhydrous
magnesium sulfate, ltered, and then concentrated. The
residue was puried by silica gel chromatography (cyclo-
hexane : ethyl acetate, 5 : 1) to give the title compounds 5e
(39.1 mg, 65.81%) and 6e (19.50 mg, 31.94%) as white
powders.
2. Materials and methods
2.1. General methods
Analytical grade chemicals were used for all reactions and all
solvents were dried over standard drying agents and freshly
distilled prior to use. Optical rotations were measured at 20 ꢀ
5e. The Rf ¼ 0.18 (cyclohexane/ethyl acetate, 5 : 1); [a]D
¼
1
+27.6 (c 1, CHCl3); H-NMR (400 MHz, CDCl3) d 7.40–7.10 (m,
60H, Ph), 5.92–5.76 (m, 5H, 5 ꢂ CH]CH2), 5.71 (d, 1H, J1,2
¼
ꢁ
2 C with a PerkinElmer model 241 digital polarimeter, using
0
3.86 Hz, H1), 5.67 (d, 1H, J1,2 ¼ 3.76 Hz, H1 ), 5.53, 5.47 (dd, 2H,
J ¼ 10.5 Hz, CH2Ph), 5.25 (dd, 2H, J ¼ 10.7 Hz, CH2Ph), 5.16 (d,
J1,2 ¼ 3.48 Hz, H1), 5.08–4.97 (m, 2H, CH]CH2), 4.57, 4.50 (dd,
2H, J ¼ 12.6 Hz, CH2Ph), 4.22–4.16 (m, 1H, H5), 4.09–4.00 (m,
a 10 cm, 1 mL cell. Electrospray ionization (ESI)-time-of-ight
mass spectra were obtained with a Micromass (UK) LCT ESI-
TOF spectrometer. The NMR spectra (1H, 13C) were recorded
on a Bruker DRX-400, DMX-500 instrument (Karlsruhe, Ger-
many) at ambient temperature with tetramethylsilane as an
internal standard and the coupling constants are represented
in Hz. Assignments were aided by carrying out correlated
spectroscopy (COSY) experiments. The reactions were moni-
tored by thin-layer chromatography (TCL) on a precoated plate
of Merck silica gel 60 F254 (layer thickness: 0.2 mm, Darmstadt,
Germany) and detection by charring with sulfuric acid. Flash
column chromatography was performed on Merck silica gel 60
(230–400 mesh).
2H, H4, H6a), 3.98–3.92 (m, 1H, H3), 3.60–3.50 (m, 3H, H2, H6b
,
H–(O–CH2)), 3.43–3.36 ðm; 1H; H ꢃ ðO ꢃ CH0 ÞÞ; 2.20–2.01 (m,
2
10H, CH2–CH]CH2), 1.78–1.63 (m, 10H, CH2CH2–CH]CH2).
13C-NMR (100 MHz, CDCl3) d 139.41, 139.33, 139.29, 139.25,
139.16, 138.63, 138.49, 138.44, 138.22, 138.10, 137.96, (C, Ph),
138.16, 138.02, 137.93, 137.89 (CH]CH2), 128.16–126.34 (CH,
Ph), 114.88, 114.87, 114.84, 114.78, 114.71 (CH]CH2), 98.87,
98.20, 98.14, 98.10, 98.09, 97.73 (C1), 81.60, 81.49, 81.37, 81.19,
81.11, 80.89, 80.84, 80.68, 80.50, 80.20, 79.79, 79.60, 79.17,
79.05, 78.15, 77.69, 75.49, 74.28, 71.94, 71.83, 71.74, 71.41,
71.34, 71.10 (C2, C3, C4, C5), 76.32, 76.17, 76.00, 75.98, 74.15,
74.10, 73.31, 73.22, 73.12, 72.94, 72.35, 72.30, 71.56, 71.21,
71.01, 70.98, 61.05, 61.00 (CH2Ph, O–CH2, C6). 30.28, 30.23,
30.19, 30.18, 30.16 (CH2–CH]CH2), 29.01, 28.84, 28.81, 28.60,
28.58 (CH2CH2–CH]CH2). HRMS (MALDI-TOF, M + Na+) m/z
calcd for C145H172O30Na 2416.1826, found 2416.1944.
2.2. Per-2,3-di-O-benzyl-a-cyclodextrin (4)
A solution of 3 (100 mg, 0.04335 mmol) in 5 mL of 0.05 M
NaOMe (dry dichloromethane and dry methanol, 1 : 1) was
stirred under argon for 24 h at room temperature. The Amber-
lite IR 120/H+ resin was then added, and this mixture was stir-
red until the pH became neutral. The mixture was ltered, and
the resin was washed with a mixture of dichloromethane and
methanol (1 : 1). The ltrate was then concentrated. The
residue was puried by silica gel chromatography (dichlor-
omethane : methanol, 15 : 1) to provide the title compound 4
(88.01 mg, 99.00%) as a white powder. The Rf ¼ 0.43 (dichlor-
6e. The Rf ¼ 0.43 (cyclohexane : ethyl acetate, 5 : 1); [a]D ¼ +25
(c 1, CHCl3); 1H-NMR (400 MHz, CDCl3) d 7.30–7.20 (m, 10H, Ph),
5.89–5.78 (m, 1H, CH]CH2), 5.24, 4.92 (dd, 2H, J ¼ 11.01 Hz,
CH2Ph), 5.16 (d, 1H, J1,2 ¼ 3.48 Hz, H1), 5.08–4.97 (m, 2H, CH]
CH2), 4.57, 4.50 (2d, 2H, J ¼ 12.60 Hz, CH2Ph), 4.19 (dd, 1H, J2,3
¼
9.59 Hz, J3,4 ¼ 8.34 Hz, H3), 4.09–4.00 (m, 2H, H4, H6a), 3.97–3.92
(m, 1H, H5), 3.60–3.50 (m, 3H, H2, H6b, one of O–CH2), 3.43–3.36
(m, 1H, one of O–CH2), 2.19–2.03 (m, 2H, CH2–CH]CH2), 1.73–
1.66 (m, 2H, CH2CH2–CH]CH2). 13C-NMR (100 MHz, CDCl3)
d 139.38 (C, Ph), 138.37 (C, Ph), 138.01 (CH]CH2), 128.13 (CH,
Ph), 127.96 (CH, Ph), 127.74 (CH, Ph), 127.40 (CH, Ph), 127.24
(CH, Ph), 126.89 (CH, Ph), 114.79 (CH]CH2), 98.60 (C1), 81.09
(C3), 79.18 (C4), 78.99 (C2), 75.52 (CH2Ph), 72.77 (CH2Ph), 71.39
(C5), 71.08 (O–CH2), 69.56 (C6), 30.25 (CH2–CH]CH2), 28.86
(CH2CH2–CH]CH2). HRMS (FAB+, M + Na+) m/z calcd for
1
omethane : methanol, 15 : 1); [a]D ¼ +50 (c 1, CHCl3); H-NMR
(400 MHz, CDCl3) d 7.20–7.30 (m, 10H, Ph), 5.16, 4.88 (dd, 2H,
J ¼ 11.6 Hz, CH2Ph), 5.08 (d, 1H, J1,2 ¼ 3.52 Hz, H1), 4.88 (1H,
OH), 4.65, 4.49 (dd, 2H, J ¼ 12.27 Hz, CH2Ph), 4.17–4.07 (m, 2H,
H3, H6a), 3.96–3.90 (m, 1H, H5), 3.78–3.67 (m, 2H, H2, H6b), 3.54
(dd, 1H, J1,2 ¼ 3.52 Hz, J2,3 ¼ 9.81 Hz, H2). 13C-NMR (100 MHz,
CDCl3) d 139.12 (C, Ph), 138.21 (C, Ph), 128.17 (CH, Ph), 127.98
(CH, Ph), 127.68 (CH, Ph), 127.46 (CH, Ph), 127.29 (CH, Ph),
126.95 (CH, Ph), 98.00 (C1), 80.80 (C3), 79.56 (C4), 78.93 (C2),
75.39 (CH2Ph), 73.20 (C5), 73.01 (CH2Ph), 63.00 (C6).
C
150H180O30Na 2484.2457, found 2484.2475.
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2.4. 6I–O-Hydroxyl-6II–VI-penta-O-pentyl-a-cyclodextrin (7e)
and per-6-O-pentyl-a-cyclodextrin (8e)
(CH, Ph), 127.35 (CH, Ph), 127.12 (CH, Ph), 126.79 (CH, Ph),
98.97 (C1), 80.99 (C3), 79.80, 78.98 (C2, C4), 75.45 (CH2Ph), 72.76
(CH2Ph), 71.16 (O–CH2), 69.34 (C5), 66.56 (C6), 15.13 (CH3).
HRMS (MALDI/TOF, M + Na+) m/z calcd for C132H156O30Na
2244.0561, found 2244.0574.
To a solution of 5e (61.01 mg, 0.02476 mmol) in a mixture of
methanol/AcOH (1 : 1, 12 mL) was added Pd–C (10%, 42.10 mg),
and the resulting mixture was then was stirred under an
atmosphere of H2 for 12 h at room temperature. The results of
the TLC (cyclohexane : ethyl acetate, 5 : 1) indicated that the
starting product had disappeared. The catalyst was removed by
ltration and was washed with a mixture of dichloromethane
and methanol (1 : 1). The ltrate was then concentrated. The
residue was puried by silica gel chromatography (dichlor-
omethane : methanol, 8 : 1) to give the title compound 7e
(27.61 mg, 80.02%) as a white powder. The Rf ¼ 0.54 (dichlor-
omethane : methanol, 6 : 1); [a]D ¼ +66.7 (c 1, CHCl3/MeOH,
2.6. Per-6-O-allyl-per-2,3-di-O-benzyl-a-cyclodextrin (6b)
A similar method to that described for obtaining 6e, was per-
formed to give the title compound 6b (81.70%) as a white
powder. The Rf ¼ 0.27 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼
1
+36.6 (c 1, CHCl3); H-NMR (500 MHz, CDCl3) d 7.42–7.05 (m,
10H, Ph), 5.97–5.77 (m, 1H, CH]CH2), 5.20, 4.88 (dd, 2H, J ¼
11.08 Hz, CH2Ph), 5.03 (d, 1H, J1,2 ¼ 2.92 Hz, H1), 5.13–5.11 (m,
2H, CH]CH2), 4.47, 4.41 (2d, 2H, J ¼ 10.95 Hz, CH2Ph), 4.17–
3.43 (8H, H3, H4, H6a, H5, H6b, O–CH2, H2), 1.26–0.82 (m, 2H,
CH2–CH]CH2). 13C-NMR (125 MHz, CDCl3) d 139.44 (C, Ph),
138.37 (C, Ph), 134.87 (CH]CH2), 128.10 (CH, Ph), 127.92 (CH,
Ph), 127.83 (CH, Ph), 127.39 (CH, Ph), 127.16 (CH, Ph), 126.84
(CH, Ph), 117.85 (CH]CH2), 99.00 (C1), 80.91 (C3), 79.75 (C4),
78.91 (C2), 75.49 (CH2Ph), 72.74 (CH2Ph), 72.30 (O–CH2), 71.29
(C5), 69.05 (C6). HRMS (MALDI/DHB, M + Na+) m/z calcd for
7 : 3); 1H-NMR (400 MHz, pyridine-d5) d 5.55 (d, 1H, J1,2
¼
3.1 Hz, H1), 5.49 (d, 1H, J1,2 ¼ 3.1 Hz, H1), 5.48–5.43 (m, 4H, 4 ꢂ
H1), 4.74–4.62 (m, 6H, 6 ꢂ H3), 4.52–4.29 (m, 10H, H2, H4, 6 ꢂ
H5, H6a), 4.23–3.91 (m, 21H, 5 ꢂ H2, 5 ꢂ H6a, 6 ꢂ H6b, 5 ꢂ H4),
3.73–3.58 (m, 10H, 5 ꢂ OCH2), 1.75–1.58 (m, 10H, 5 ꢂ CH2-
CH2CH2CH3), 1.43–1.23 (m, 10H, 5 ꢂ CH2CH3, 5 ꢂ CH2CH2-
CH3), 0.90–0.82 (m, 15H, 5 ꢂ CH3). 13C-NMR (100 MHz,
pyridine-d5) d 104.46, 104.28, 104.18 (C1), 83.07, 83.92, 83.83,
83.69 (C2), 75.59, 75.55 (C3), 74.70, 74.62, 74.40, 74.51 (C4),
73.09, 73.03 (C5), 72.47, 72.44, 72.42, 72.37 (O–CH2), 70.91,
70.86, 70.77, 70.74, 70.59, 62.04 (C6), 30.57, 30.56 (CH2CH2-
CH2CH3), 29.35, 29.31 (CH2CH2CH3), 3.44 (CH2CH3), 14.86
(CH3). HRMS (ESI-TOF, M ꢃ Hꢃ) m/z calcd for C61H109O30
1321.7004, found 1321.6957.
A similar method to that described for obtaining 7e, was
performed to give the title compound 8e (81.10%) as a white
powder. The Rf ¼ 0.48 (dichloromethane : methanol, 8 : 1); [a]D
¼ +81.5 (c 0.7, CHCl3 : methanol, 7 : 3); 1H-NMR (400 MHz,
pyridine-d5) d 5.46 (d, 1H, J1,2 ¼ 3.1 Hz, H1), 5.18–5.02 (br, 2H, 2
ꢂ OH), 4.65 (t, 1H, J ¼ 9.14 Hz, H3), 4.44–4.38 (m, 1H, H5), 4.19–
4.13 (m, 2H, H4, H6a), 4.11 (dd, 1H, J1,2 ¼ 3.10 Hz, J2,3 ¼ 9.70 Hz,
H2), 4.04–3.99 (m, 1H, H6b), 3.72–3.66 (m, 2H, O–CH2), 1.75–
1.61 (m, 2H, CH2CH2CH2CH3), 1.44–1.27 (m, 4H, CH2CH3,
CH2CH2CH3), 0.87 (t, 1H, J ¼ 7.2 Hz, CH3). 13C-NMR (100 MHz,
pyridine-d5) d 104.26 (C1), 83.90 (C4), 75.52 (C3), 74.55 (C2), 73.01
(C5), 72.43 (O–CH2), 70.79 (C6), 30.55 (CH2CH2CH2CH3), 29.34
(CH2CH2CH3), 23.42 (CH2CH3), 14.85 (CH3). HRMS (ESI, M +
Na+) m/z calcd for C66H120O30Na 1415.7762, found: 1415.7760;
HRMS (ESI, M + K+) m/z calcd for C66H120O30K 1431.7502, found
1431.7544; HRMS (ESI, M + 2Na+) m/z calcd for C66H119O30Na2
1437.7582, found 1437.7544.
C
138H156O30Na 2316.0574, found 2316.0574.
2.7. 6I–O-Hydroxyl-6II–VI-penta-O-propyl-(per-2,3-di-O-
benzyl)-a-cyclodextrin (5c) and per-6-O-propyl-2,3-di-O-benzyl-
a-cyclodextrin (6c)
A similar method to that described for obtaining 5e was per-
formed to give the title compound 5c (60.40%) as a white
powder. The Rf ¼ 0.15 (cyclohexane : ethyl acetate, 5 : 1); [a]D
1
¼ +21.2 (c 1, CHCl3); H-NMR (400 MHz, CDCl3): d 7.37–7.05
0
(m, 60H, Ph), 5.64 (m 1H, H1), 5.67 (m 1H, H1 ), 5.48, 5.42 (dd,
2H, J ¼ 9.71 Hz, CH2Ph), 5.23, 5.18 (dd, 2H, J ¼ 11.05 Hz,
CH2Ph), 4.95–4.70, 4.58–4.30, 4.28–3.24 (m, 70H, H1, CH2Ph,
H5, H4, H6a, H3, H2, H6b, O–CH2), 1.60–1.26 (m, 10H, –CH2–),
0.96–0.81 (m, 15H, –CH3). 13C-NMR (100 MHz, CDCl3)
d 139.47, 139.38, 139.36, 139.34, 139.29, 139.21, 138.71,
138.54, 138.50, 138.25, 138.16, 137.99 (C, Ph), 128.33–126.34
(CH, Ph), 98.97, 98.27, 98.16, 98.11, 98.06, 97.73 (C1), 81.70,
81.51, 81.33, 81.20, 80.95, 80.90, 80.71, 80.64, 80.22, 79.85,
79.67, 79.18, 79.02, 78.15, 77.72, 77.20, 76.35, 76.18, 76.02,
76.00, 75.67, 74.07, 74.04, 73.86, 73.39, 73.32, 73.23, 73.18,
73.11, 72.92, 72.34, 72.29, 71.94, 71.89, 71.75, 71.39, 70.99,
70.49, 69.99, 69.60, 69.43, 60.73 (C2, C3, C4, C5, CH2Ph, O–CH2,
C6), 22.96, 22.85, 22.76, 22.65, 22.56 (–OCH2CH3), 10.64–10.38
(–CH3). HRMS (MALDI/DHB,
135H162O30Na 2286.1045, found 2286.1043.
A similar method as that described for obtaining 6e, was
M +
Na+) m/z calcd for
C
2.5. Per-6-O-ethyl-2,3-di-O-benzyl-a-cyclodextrin (6a)
A similar method to that described for obtaining 6e, was per- performed to give the title compound 6c (33.73%) as a white
formed to give the title compound 6a (80.50%) as a white powder. The Rf ¼ 0.44 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼
1
powder. The Rf ¼ 0.32 (cyclohexane/ethyl acetate, 5 : 1.5); [a]D ¼ +18.3 (c 1, CHCl3); H-NMR (500 MHz, CDCl3) d 7.36–7.06 (m,
1
+20.1 (c 1, CHCl3); H-NMR (500 MHz, CDCl3) d 7.40–7.04 (m, 10H, Ph), 5.19, 4.87 (dd, 2H, J ¼ 10.00 Hz, CH2Ph), 5.10 (d, 1H,
60H, Ph), 5.20, 4.89 (dd, 12H, J ¼ 10.00 Hz, CH2Ph), 5.04 (d, 6H, J1,2 ¼ 3.15 Hz, H1), 4.47, 4.44 (dd, 2H, J ¼ 10.00 Hz, CH2Ph), 4.14
J1,2 < 1 Hz, H1), 4.50, 4.42 (2d, 12H, J ¼ 10.00 Hz, CH2Ph), 4.13 (dd, 1H, J2,3 ¼ 10.10 Hz, J3,4 ¼ 8.56 Hz, H3), 4.03–3.88 (m, 3H,
(dd, 6H, H3), 3.63–3.56, 3.55–3.38 (m, 42H, H6a, H5, H4, H6b, H2, H4, H5 H6a), 3.61–3.27 (m, 4H, H6b, H2, O–CH2), 1.33–1.19 (m,
O–CH2), 1.14 (s, 18H, CH3). 13C-NMR (125 MHz, CDCl3) d 139.46 2H, CH2), 0.92–0.81 (m, 3H, CH3). 13C-NMR (125 MHz, CDCl3)
(C, Ph), 138.41 (C, Ph), 128.06 (CH, Ph), 127.89 (CH, Ph), 127.79 d 139.43 (C, Ph), 138.38 (C, Ph), 128.06 (CH, Ph), 127.90 (CH,
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Ph), 127.72 (CH, Ph), 127.32 (CH, Ph), 127.19 (CH, Ph), 126.81 1.20 (m, 30H, –CH2CH2–), 0.95–0.82 (m, 15H, –CH3). 13C-NMR
(CH, Ph), 98.75 (C1), 81.05 (C3), 79.49, 79.02 (C4, C2), 75.46 (125 MHz, CDCl3) d 139.40, 139.36, 139.26, 139.16, 138.64,
(CH2Ph), 73.21 (CH2Ph), 72.72 (O–CH2), 71.40 (C5), 69.48 (C6), 138.49, 138.44, 138.22, 138.11, 137.36 (C, Ph), 128.62–126.29
29.63, (OCH2–CH2), 10.54 (CH3). HRMS (MALDI/DHB, M + Na+) (CH, Ph) 98.75, 98.03, 98.01, 97.96, 97.71, 97.66 (C1), 81.56,
m/z calcd for C138H168O30Na 2328.1473, found 2328.1513.
81.42, 81.20, 81.10, 81.06, 80.88, 80.67, 80.47, 80.42, 80.07,
79.92, 79.86, 79.66, 79.15, 79.10, 79.02, 78.94, 78.12, 77.68,
76.32, 76.17, 76.03, 75.97, 75.14, 74.05, 73.99, 73.29, 73.19,
73.07, 72.86, 72.32, 72.21, 71.92, 71.88, 71.82, 71.66, 71.51,
71.37, 71.28, 70.97, 70.48, 69.78, 69.58, 69.43, 60.84 (C2, C3, C4,
C5, CH2Ph, O–CH2, C6), 29.63, 28.13, 22.47 (–OCH2–CH2–CH2–
CH2), 14.00 (–CH3). HRMS (MALDI/DHB, M + Na+) m/z calcd for
2.8. 6I–O-Hydroxyl-6II–VI-penta-O-butyl-(per-2,3-di-O-benzyl)-
a-cyclodextrin (5d) and per-6-O-butyl-2,3-di-O-benzyl-a-
cyclodextrin (6d)
A similar method as that described for obtaining 5e, was per-
formed to give the title compound 5d (51.88%) as a white
C
145H182O30Na 2426.2603, found 2426.2608.
powder. The Rf ¼ 0.29 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼
A similar method to that described for obtaining 6e, was
1
+19.5 (c 1, CHCl3); H-NMR (400 MHz, CDCl3): d 7.46–6.98 (m,
60H, Ph), 5.66 (d, 1H, J1,2 3.36 Hz, H1), 5.62 (d, 1H, J1,2 ¼ 3.36 Hz,
performed to give the title compound 6f (24.32%) as a white
powder. The Rf ¼ 0.56 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼
0
H1 ), 5.47, 5.41 (dd, 2H, J ¼ 9.86 Hz, CH2Ph), 5.21, 5.17 (dd, 2H, J
1
+16.0 (c 1, CHCl3); H-NMR (400 MHz, CDCl3) d 7.25–7.10 (m,
10H, Ph), 5.17, 4.86 (dd, 2H, J ¼ 11.01 Hz, CH2Ph), 5.13 (d, 1H,
J1,2 ¼ 3.22 Hz, H1), 4.52, 4.45 (2d, 2H, J ¼ 12.17 Hz, CH2Ph),
4.18–4.09 (m, 1H, H3), 4.04–3.97 (m, 2H, H6a, H4), 3.92–3.87 (m,
1H, H5), 3.56–3.43 (m, 3H, H6b, H2, one of O–CH2), 3.37–3.30 (m,
1H, one of O–CH2), 1.60–1.50 (m, 2H, OCH2–CH2), 1.36–1.19 (m,
4H, –CH2–CH2), 0.90–0.84 (m, 3H, CH3). 13C-NMR (100 MHz,
CDCl3) d 139.38 (C, Ph), 138.39 (C, Ph), 128.10 (CH, Ph), 127.93
(CH, Ph), 127.70 (CH, Ph), 127.35 (CH, Ph), 127.25 (CH, Ph),
126.86 (CH, Ph), 98.35 (C1), 81.13 (C3), 79.05, 78.99 (C4, C2),
75.48 (CH2Ph), 72.73 (CH2Ph), 71.79 (O–CH2), 71.34 (C5), 69.50
(C6), 29.37, 28.22, 22.50 (CH2–CH2–CH2), 14.00 (CH3). HRMS
(MALDI/DHB, M + Na+) m/z calcd for C150H192O30Na 2496.3388,
found 2496.3391.
¼ 10.05 Hz, CH2Ph), 4.94–4.64, 4.59–4.27, 4.25–3.32 (m, 70H,
H1, CH2Ph, H5, H4, H6a, H3, H2, H6b, O–CH2), 1.65–1.20 (m, 20H,
–CH2CH2–), 0.95–0.83 (m, 15H, –CH3). 13C-NMR (100 MHz,
CDCl3) d 139.48, 139.40, 139.36, 139.33, 139.23, 138.69, 138.55,
138.51, 138.28, 138.18, 138.03 (C, Ph), 128.31–126.36 (CH, Ph),
98.90, 98.86, 98.20, 98.10, 97.83, 97.77 (C1), 81.65, 81.55, 81.47,
81.22, 81.11, 80.95, 80.92, 80.75, 80.56, 80.17, 79.88, 79.71,
79.24, 79.12, 78.23, 77.80, 76.29, 76.14, 76.01, 75.96, 75.69,
75.64, 74.35, 74.13, 74.07, 73.30, 73.22, 73.10, 72.90, 72.36,
72.28, 71.95, 71.88, 71.78, 71.61, 71.45, 71.37, 71.33, 71.19,
71.08, 70.54, 69.92, 69.67, 69.50, 69.46, 60.94 (C2, C3, C4, C5,
CH2Ph, O–CH2, C6), 31.92–31.49, 29.67, 19.39–19.15 (–OCH2-
CH2CH2–), 14.03–13.84 (–CH3). HRMS (MALDI/DHB, M + Na+)
m/z calcd for C140H172O30Na 2356.1793, found: 2356.1826.
A similar method to that described for obtaining 6e, was
performed to give the title compound 6d (35.37%) as a white
2.10. 6I–O-Hydroxyl-6II–VI-penta-O-hexyl-(per-2,3-di-O-
benzyl)-a-cyclodextrin (5g) and per-6-O-butyl-2,3-di-O-benzyl-
a-cyclodextrin (6g)
powder. The Rf ¼ 0.52 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼
1
+21.6 (c 1, CHCl3); H-NMR (500 MHz, CDCl3) d 7.24–7.11 (m,
10H, Ph), 5.18, 4.87 (dd, 2H, J ¼ 10.97 Hz, CH2Ph), 5.12 (d, 1H,
J1,2 ¼ 3.15 Hz, H1), 4.52, 4.45 (2d, 2H, J ¼ 8.93 Hz, CH2Ph), 4.16–
4.10 (m, 1H, H3), 4.02–3.97, 3.92–3.88, 3.56–3.44, 3.39–3.32 (m,
7H, H4, H5, H2, H6a, H6b, O–CH2), 1.34–1.18 (m, 4H, CH2–CH2),
0.96–0.78 (m, 3H, CH3). 13C-NMR (125 MHz, CDCl3) d 139.43 (C,
Ph), 138.38 (C, Ph), 128.06 (CH, Ph), 127.90 (CH, Ph), 127.72
(CH, Ph), 127.32 (CH, Ph), 127.19 (CH, Ph), 126.81 (CH, Ph),
98.83 (C1), 81.05 (C3), 79.49, 79.02 (C4, C2), 75.46 (CH2Ph), 73.21
(CH2Ph), 72.72 (O–CH2), 71.40 (C5), 69.48 (C6), 29.63, 22.80
(CH2–CH2), 10.51 (CH3). HRMS (MALDI/DHB, M + Na+) m/z
calcd for C144H180O30Na 2412.2493, found: 2412.2452.
A similar method to that described for obtaining 5e, was per-
formed to give the title compound 5g (45.68%) as a white
powder. The Rf ¼ 0.35 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼ +22.2 (c 1, CHCl3); 1H-NMR (400 MHz, CDCl3) d 7.40–6.97
(m, 60H, Ph), 5.67 (d, 1H, J1,2 ¼ 4.00 Hz, H1), 5.64 (d, 1H, J1,2
¼
0
4.00 Hz, H1 ), 5.48, 5.41 (dd, 2H, J ¼ 12 Hz, J ¼ 8 Hz, CH2Ph),
5.21, 5.17 (dd, 2H, J ¼ 12.00 Hz, CH2Ph), 4.95–4.70, 4.59–4.30,
4.25–3.28 (m, 70H, H1, CH2Ph, H5, H4, H6a, H3, H2, H6b, O–
CH2), 1.63–1.47, 1.36–1.20 (m, 40H, –CH2CH2CH2CH2–), 0.92–
0.82 (m, 15H, –CH3). 13C-NMR (100 MHz, CDCl3) d 139.41,
139.30, 139.27, 139.17, 138.64, 138.49, 138.43, 138.22, 138.11,
137.96 (C, Ph), 128.27–126.29 (CH, Ph), 98.74, 98.04–97.96,
97.64 (C1), 81.60, 81.55, 81.41, 81.19, 81.06, 80.88, 80.67, 80.42,
80.06, 79.90, 79.68, 79.14, 79.10, 78.13, 77.70, 77.18, 76.28,
76.16, 76.01, 75.93, 75.16, 74.05, 74.00, 73.29, 73.19, 73.06,
2.9. 6I–O-Hydroxyl-6II–VI-penta-O-pentyl-(per-2,3-di-O-
benzyl)-a-cyclodextrin (5f) and per-6-O-pentyl-2,3-di-O-benzyl-
a-cyclodextrin (6f)
A similar method to that described for obtaining 5e, was per- 72.86, 72.37, 72.29, 72.22, 71.93, 71.88, 71.91, 71.70, 71.36,
formed to give the title compound 5f (71.68%) as a white 71.30, 70.97, 70.49, 69.81, 69.60, 69.42, 60.84 (C2, C3, C4, C5,
powder. The Rf ¼ 0.32 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼
CH2Ph, O–CH2, C6), 31.84–31.56, 29.81–29.31, 25.75–25.63,
1
+18.2 (c 1, CHCl3); H-NMR (500 MHz, CDCl3) d 7.51–6.86 (m, 22.56 (–CH2CH2CH2CH2CH2–), 14.00 (–CH3). HRMS (MALDI/
60H, Ph), 5.67 (d, 1H, J1,2 ¼ 2.58 Hz, H1), 5.64 (d, 1H, J1,2
¼
DHB, M + Na+) m/z calcd for C150H192O30Na 2496.3432, found
0
3.86 Hz, H1 ), 5.48, 5.41 (dd, 2H, J ¼ 12.44 Hz, CH2Ph), 5.21, 5.17 2496.3391.
(dd, 2H, J ¼ 10.72 Hz, CH2Ph), 4.94–4.64, 4.59–4.27, 4.25–3.32
A similar method to that described for obtaining 6e, was
00
(m, 70H, H1 , CH2Ph, H5, H4, H6a, H3, H2, H6b, O–CH2), 1.60– performed to give the title compound 6g (34.32%) as a white
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Table 1 Optimization of regioselective substitution for compound 4 Table 2 Yields of regioselective 6-substituted a-CDs (compound 4
with 5-bromo-1-pentene
with diverse RBra)
Reaction ratio (mol)
Yield (%)
Yield (%)
Entry
RBr
5
6
Entry
4 : NaH : 5-bromo-1-pentene
5e
6e
1
2
3
4
5
6
7
–CH2CH3
0
0
6a 80.50
6b 81.70
6c 33.73
6d 35.37
6e 31.94
6f 24.32
6g 34.32
1
2
3
4
5
6
7
8
9
10
1 : 12 : 10
1 : 12 : 12
1 : 12 : 14
1 : 12 : 16
1 : 12 : 18
1 : 12 : 20
1 : 12 : 30
1 : 14 : 24
1 : 14 : 18
1 : 16 : 12
6.08
7.00
91.28
90.00
73.80
61.30
56.78
40.90
47.05
31.94
30.07
91.00
–CH2CH]CH2
–CH2CH2CH3
–(CH2)3CH3
–(CH2)3CH]CH2
–(CH2)4CH3
5c 60.40
5d 51.88
5e 65.81
5f 71.68
5g 45.68
20.00
32.00
40.00
56.28
50.24
65.81
62.93
5.00
–(CH2)5CH3
a
Reaction ratio (mol): 4 : NaH : RBr ¼ 1 : 14 : 24.
3. Results and discussion
powder. The Rf ¼ 0.64 (cyclohexane : ethyl acetate, 5 : 1); [a]D
¼
This involved phenomenon caught in our previous research on
cyclodextrins.8,20 This study was performed by using compound
4, which was synthesized from native a-CD according to
a method the literature, as the starting material (Scheme 3).14 In
1
+30.2 (c 1, CHCl3); H-NMR (400 MHz, CDCl3) d 7.27–7.07 (m,
10H, Ph), 5.17, 4.86 (dd, 2H, J ¼ 12.61 Hz, CH2Ph), 5.15 (d, 1H,
J1,2 ¼ 3.34 Hz, H1), 4.48 (2d, 2H, J ¼ 12.61 Hz, CH2Ph), 4.13 (t,
1H, J ¼ 9.00 Hz, H3), 4.04–3.95 (m, 2H, H4, H6a), 3.93–3.86 (m,
1H, H5), 3.56–3.41 (m, 3H, H6b, H2, one of O–CH2), 3.37–3.28 (m,
1H, one of O–CH2), 1.58–1.49 (m, 2H, OCH2–CH2), 1.36–1.20 (m,
6H, –CH2–CH2–CH2), 0.89–0.85 (m, 3H, CH3). 13C (100 MHz,
CDCl3) d 139.40 (C, Ph), 138.41 (C, Ph), 128.10 (CH, Ph), 127.94
(CH, Ph), 127.70 (CH, Ph), 127.35 (CH, Ph), 127.25 (CH, Ph),
126.86 (CH, Ph), 98.42 (C1), 81.15 (C3), 79.07, 78.98 (C4, C2),
75.48 (CH2Ph), 72.74 (CH2Ph), 71.85 (O–CH2), 71.34 (C5), 69.52
(C6), 31.73, 29.68, 25.79, 22.61 (OCH2–CH2–CH2–CH2–CH2),
14.05 (CH3). HRMS (MALDI/DHB, M + Na+) m/z calcd for
C
156H204O30Na 2580.4328, found 2580.4330.
Scheme 1 Diverse RBr induced outcomes of 6-substituted a-CDs.
Scheme 2 Reaction of pentenyl a-CD derivatives.
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(6%, Table 1, entry 1). When the amounts of 5-bromo-1-pentene
were increased, the yield of mono hydroxyl a-CD derivative 5e
increased up to 66% (Table 1, entry 8) whereas the complete
alkylation of a-CD 6e decreased. However, only the amount of
NaH was increased singly, that not leading to the yield of 5e
improved (Table 1, entries 2 and 10). It seemed that a balance
between the amount of NaH and 5-bromo-1-pentene existing.
The ratio (4 :NaH : RBr ¼ 1 : 14 : 24) was found from the
experiments to be benecial for obtaining 5e.
Aer accidentally discovering this phenomenon, we were
very curious about whether other alkyl bromides caused the
same selections. Next a variety of alkyl bromides were used,
instead of 5-bromo-1-pentene, to perform a similar alkylation
on the primary face of a-CD derivative 4 (Scheme 1).
Scheme 3 Synthesis of a-CD derivative 4.
When bromoethane or 3-bromopropene were used, only the
complete alkylation of a-CDs 6a, 6b were found even under the
conditions of 4 : NaH : RBr ¼ 1 : 14 : 24 (Table 2, entries 1 and 2).
In the other reactions involved, similar phenomena were observed
as when 5-bromo-1-pentene was used. In particular when the ratio
of 4 : NaH : RBr was 1 : 14 : 24, some mono hydroxyl a-CD deriv-
atives could be obtained as major compounds, the highest yield
(72%) being obtained for 5f (Table 2, entry 6).
The pentenyl a-CD derivatives 5e and 6e were hydrogenated
with hydrogen catalyzed by Pd–C (10%) at 14 kPa to give 7e and
8e for further amphiphilic study (Scheme 2). The hydroxyl group
existing in 5e and 7e could also be modied for use in CD
applications.
this nucleophilic substitution, NaH promoted the deprotona-
tion of CD hydroxyl groups for nucleophilic agent formation, or
reacts with the bromine ion of RBr. The RBr forms carbon
cations for use as electrophiles.
Firstly, 5-bromo-1-pentene was chosen for alkylation on the
primary face of a-CD derivative 4 because pentenyl has terminal
double bond, which can then form cyclodextrin dimers and
oligomers or perform click reactions, or be converted into other
groups (Scheme 2). When compound 4 was treated with 5-
bromo-1-pentene in the presence of NaH at a ratio of
4 : NaH : 5-bromo-1-pentene ¼ 1 : 12 : 10, 6-hexa-O-pentenyl a-
CD 6e was obtained as the major product (91%), and 6-hydroxyl-
6-penta-O-pentenyl a-CD 5e was isolated as a minor product
Fig. 1 The heteronuclear multiple quantum interference coherence (HMQC) of compound 5f.
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Fig. 2 The HMQC of compound 6f.
All the new synthetic compounds 5c, 5d, 5f, 5g, 6a, 6b, 6c,
6d, 6f, 6g and 5e, 6e, 7e, 8e were characterized by 1H-NMR and
13C-NMR, as well as HRMS (see ESI†). It can be seen from the
NMR spectra that the hydroxyl on the CDDs (5c, 5d, 5e, 5f, 5g,
7e) made the molecules asymmetric (Fig. 1), from their 13C-
NMR 6 anomeric carbons were found, whereas the 6-per
alkyl CDDs (6a, 6b, 6c, 6d, 6e, 6f, 6g, 8e) were symmetric
because the NMR spectra look like those of monosaccharides
(Fig. 2). In a paper from 1991, Angibeaud and Utille19, assigned
4. Conclusion
In summary, we have achieved 6-hydroxyl and penta-alkyl on
primary face of a-cyclodextrin in one pot. It seems that the
mono 6-hydroxyl a-cyclodextrin derivatives would be difficult to
obtain directly through a traditional thought. Even though the
exact mechanism is still unclear, the regioselective modica-
tions described previously minimized the reagents required, the
labor, the time, and facilitated the availability of a variety of
selectively modied a-CDs on the primary face which will be
useful for cross-disciplinary researchers. The novel molecule 5e
has two reactive points, hydroxyl and pentenyl groups, which
can be further used for research in supramolecular chemistry,
biological materials, drug delivery, and so on. In our unpub-
lished data, we are exploring the derivatization on two reactive
points for further applications.
1
79.00 to C4, 80.80 to C2. In fact, the H–13C correlation spec-
trum indicated that C2 should be at 79.00, and C4 80.80 (in this
case C2 at 78.93 and C4 at 79.56). Moreover, C3 was not
assigned at all in ref. 19.
For the mechanism, it was speculated that there were two
interfering factors, the concentration of alkali in the system and
the steric effects of the electrophilic reagent RBr. When the RBr
amount increased, the NaH concentration decreased and the
ratio of the 4 : NaH : RBr arrived at a certain value, fewer NaH in
the system would lose deprotonation capacity to one of the
hydroxyl groups of compound 4 leading to weakening of its
nucleophilic attack. Therefore, the regioselective products
accounted for a certain yield. The steric hindrance also affected
the regioselective reaction. It can be seen from the short chain
RBr bromoethane or 3-bromopropene that even if the ratio of
4 : NaH : RBr was adjusted no regioselective product was
obtained.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The nancial support from the National Natural Science
Foundation of China under Grant No. 30870553, the Ministry of
Science and Technology of the People's Republic of China under
Grant No.2010DFA34370, the Science and Technology
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Department of Zhejiang Province under Grant No. 2013C14012, 11 G. Nelles, M. Weisser, R. Back, P. Wohlfart, G. Wenz and
the Natural Science Foundation of Zhejiang under Grant No.
LQY18B060002 and the Zhejiang Cultural Relic Protection
Science and Technology Project under Grant No. 2020011 for
this work is greatly appreciated.
S. Mittler-Neher, Controlled orientation of cyclodextrin
derivatives immobilized on gold surfaces, J. Am. Chem.
Soc., 1996, 118(21), 5039–5046.
12 R. Petter, J. Salek, C. Sikorski, G. Kumaravel and F. Lin,
Cooperative binding by aggregated mono-6-(alkylamino)-
beta-cyclodextrins, J. Am. Chem. Soc., 1990, 112(10), 3860–
3868.
References
1 J. Zhang and P. Ma, Cyclodextrin-based supramolecular
systems for drug delivery: recent progress and future
perspective, Adv. Drug Delivery Rev., 2013, 65(9), 1215–1233.
2 W. Tang and S. Ng, Monosubstituted positively charged
cyclodextrins: synthesis and applications in chiral
separation, J. Sep. Sci., 2008, 31(18), 3246–3256.
3 J. Lenik, Cyclodextrins based electrochemical sensors for
biomedical and pharmaceutical analysis, Curr. Med. Chem.,
2017, 24(22), 2359–2391.
4 R. Liao, P. Lv, Q. Wang, J. Zheng, B. Feng and B. Yang,
Cyclodextrin-based biological stimuli-responsive carriers
for smart and precision medicine, Biomater. Sci., 2017,
5(9), 1736–1745.
5 N. Erdogar, G. Varan and E. Bilensoy, Amphiphilic
cyclodextrin derivatives for targeted drug delivery to
Tumors, Curr. Top. Med. Chem., 2017, 17(13), 1521–1528.
6 L. Fan, C. Luo, M. Sun and H. Qiu, Synthesis of graphene
oxide decorated with magnetic cyclodextrin for fast
chromium removal, J. Mater. Chem., 2012, 22(47), 24577–
24583.
13 A. Cro and R. Bartsch, Synthesis of chemically modied
cyclodextrins, Tetrahedron, 1983, 39(9), 1417–1474.
14 S. Tian, H. Zhu, P. Forgo and V. D'Souza, Selectively
monomodied cyclodextrins: synthetic strategies, J. Org.
Chem., 2000, 65(9), 2624–2630.
¨
15 A. Pearce and P. Sinay, Diisobutylaluminium-promoted
regioselective de-O-benzylation of perbenzylated
cyclodextrins: a powerful new strategy for the preparation
of selectively modied cyclodextrins, Angew. Chem. Int. Ed.,
2010, 39(20), 3610–3612.
16 B. Wang, E. Zaborova, S. Guieu, M. Petrillo, M. Guitet,
´
´
Y. Bleriot, M. Menand, Y. Zhang and M. Sollogoub, Site-
selective hexa-hetero-functionalization of a-cyclodextrin an
archetypical C6-symmetric concave cycle, Nat. Commun.,
2014, 5, 5354.
¨
17 W. Wang, A. Pearce, Y. Zhang and P. Sinay,
Diisobutylaluminium-promoted regioselective de-O-
methylation of cyclodextrins: an expeditious entry to
selectively modied cyclodextrins, Tetrahedron: Asymmetry,
2001, 12(3), 517–523.
7 G. Varan, C. Varan, N. Erdogar and E. Bilensoy, Amphiphilic
cyclodextrin nanoparticles, Int. J. Pharm., 2017, 531(2), 457–
469.
8 D. Dong, D. Baigl, Y. Cui, P. Sinay, M. Sollogoub and
Y. Zhang, Amphiphilic bipolar duplex a-cyclodextrin
forming vesicles, Tetrahedron, 2007, 63, 2973–2977.
9 A. Khan, P. Forgo, K. Stine and V. D'Souza, Methods for
selective modications of cyclodextrins, Chem. Rev., 1998,
98(5), 1977–1996.
10 F. Sallas, P. Leroy, A. Marsura and A. Nicolas, First selective
synthesis of thio-b-cyclodextrin derivatives by a direct
Mitsunobu reaction on free b-cyclodextrin, Tetrahedron
Lett., 1994, 35(33), 6079–6082.
18 R. Ghosh, P. Zhang, A. Wang and C. Ling,
Diisobutylaluminum hydride mediated regioselective
desilylations: access to multisubstituted cyclodextrins,
Angew. Chem. Int. Ed., 2012, 51(7), 1548–1552.
19 P. Angibeaud and J. Utille, Cyclodextrin chemistry; part I,
application of a regioselective acetolysis method for benzyl
ethers, Synthesis, 1991, 9, 737–738.
20 Y. Cui, S. Xu and J. Mao, One-pot synthesis of hexias (6-O-
acryl) cyclodextrin derivatives at room temperature, J.
Inclusion Phenom. Macrocyclic Chem., 2015, 83, 187–191.
10702 | RSC Adv., 2020, 10, 10695–10702
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