γ-Cyclodextrins possessing an azido group and a triisopropylbenzenesulfonyl group as useful synthetic and authentic intermediates for unsymmetrically functionalized derivatives

Article abstract of DOI:10.1016/j.tet.2009.08.061

Seven isomers of cyclomaltooctaose (γ-cyclodextrin) whose C6s were unsymmetrically disubstituted with both an azido group and an arenesulfonyloxy group were prepared and each of them was isolated by reversed phase chromatography. The assignment of the mod

Full text of DOI:10.1016/j.tet.2009.08.061

Tetrahedron 65 (2009) 9474–9480
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g
-Cyclodextrins possessing an azido group and a triisopropylbenzenesulfonyl
group as useful synthetic and authentic intermediates for unsymmetrically
functionalized derivatives
*
Yoshihide Himeno, Atsushi Miyagawa, Masao Kawai, Hatsuo Yamamura
Department of Materials and Science, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Seven isomers of cyclomaltooctaose (g-cyclodextrin) whose C6s were unsymmetrically disubstituted
Received 20 February 2009
Received in revised form 24 August 2009
Accepted 25 August 2009
Available online 29 August 2009
with both an azido group and an arenesulfonyloxy group were prepared and each of them was isolated
by reversed phase chromatography. The assignment of the modified positions in each regioisomers was
unambiguously performed by chemical correlation with the authentic compounds and chemical con-
version to the 3,6-anhydro derivatives followed by high-resolution 2D-1H NMR (COSY, TOCSY, and HO-
HAHA) analyses. The compounds are versatile synthetic and authentic intermediates to prepare
sophisticated derivatives with two different functionalities at desired positions on the molecule for
supramolecular chemistry.
Keywords:
Cyclomaltooctaose
Cyclodextrin
Sulfonate
Ó 2009 Elsevier Ltd. All rights reserved.
Azido
Regioisomer
1. Introduction
unsymmetrically modified
logoub reported a regiospecific tandem reaction on
two regioisomeric (AD and AC) amino alcohol-difunctionalized
derivatives.4 In the case of
-CD, Fujita prepared two (AB and AG)
b
-CDs were prepared.3 Recently, Sol-
-CD to afford
b
Cyclodextrins (CDs) are cyclic oligosaccharides composed of
D-glucoses. The most common species are known as cyclo-
g
maltohexaose
maltooctaose (
(
a
-CD), cyclomaltoheptaose
(
b
-CD), and cyclo-
among seven regioisomers of derivatives whose C6s were bifunc-
g-CD), respectively. The natural CDs are of interest
tionalized by a tosyloxy group and a cysteinyl group.5a Hamada
because of their ability to include a guest molecule into their
cavity. In addition, the CDs serve as scaffolds on which functional
groups can be assembled through chemical modification. Actually,
bifunctionalized CDs have proved to be promising candidates to
perform sophisticated enzyme-like activities1 and an exquisite
guest chirality recognition.2 On view point of expressing a desired
function it must be most important to arrange the two functional
groups systematically on a CD molecule. The CDs composed of six-
to-eight glucose residues possess doughnut-like annular structures
with wide and narrow hydrophilic ends delineated by secondary
2-OH and 3-OH and primary 6-OH groups, respectively. The 6-OHs
exist in every ca. 0.5 nm on the narrow side (ca. 1 nm diameter) of
CD molecule as shown in Figure 1. Arrangement of two different
reported the g-CD derivatives possessing a tosyloxy group and
a dansylamino group on the C6s expressed unique fluorescent
chemo-sensor ability and their sensitivity and selectivity depended
on the substituents positions, although the used CDs were di-
astereomeric mixtures unfortunately.5b There have been no reports
on complete sets of seven
g-CD regioisomers. It seems reasonable
that the seven regioisomeric
g-CDs must enable more sophisti-
cated molecular interaction such as chiral recognition by co-
operation of both the different functional moieties regiospecifically
situated on the CDs. Here we will report a complete set of seven
regioisomers of
g-CD derivatives possessing an azido group and
a sulfonyloxy group on its primary hydroxyl side. The azido group
can be converted to an amino group reductively or to a functional
moiety through a triazine ring formation by click chemistry6 and
the sulfonyloxy group can be easily substituted by a nucleophile.
Therefore, the isomers are expected to be useful as authentic
regioisomers and synthetic intermediates for novel un-
functional groups on the primary hydroxyl side of a-, b-, and g-CD
has five, six, and seven patterns and, therefore, generates five, six,
and seven regioisomers, respectively. Six regioisomers of
symmetrically bifunctional
g-CD derivatives on which the two
substituents are systematically arranged on the nanoplane with
a desired distance.
* Corresponding author. Tel./fax: þ81 52 735 5246.
E-mail address: yamamura.hatsuo@nitech.ac.jp (H. Yamamura).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.061

Y. Himeno et al. / Tetrahedron 65 (2009) 9474–9480
9475
γ-cyclodextrin
HO
OH
OH
primary hydroxyl groups
O
O
O
HO
HO
O
OH
O
HO
OH
HO
O
OH
OH
0.5nm
HO
OH
O
O
O
O
OH
O
HO
HO
HO
O
O
O
OH
OH
O
HO
O
O
O
OH
HO
HO
OH
HO
OH
OH
O
O
secondary hydroxyl groups
HO
HO
OH
Figure 1. Structure of g-cyclodextrin.
2. Results and discussion
triisopropylphenyl groups and the reaction products were analyzed
by RP-HPLC, demonstrating that the last aryl group enabled the
optimal separation (Fig. 2). It should be noted here that a 2,4,6-
Each of CD molecules,
sulfonate by reaction in pyridine with the corresponding arene-
sulfonyl chloride.7 In the case of a
-CD derivative 1 whose 6-OH is
a-, b-, and g-CD, generally affords a 6-O-
triisopropylbezenenesulfonyl (Tips) group was superior to
a
g
mesitylenesulfonyl group that was used in the previous poly-
arenesulfonylated CDs studies.9 In my opinion a bulkier Tips group
may make each of the seven regioisomers form a unique molecular
structure with unique affinity to column stationary phase, enabling
good separation from each other. However the steric hindrance of
the Tips group gave significant disadvantages to the reaction. The
reaction proceeded very slowly and more amounts of the sulfonyl
substituted with an azido group8 additional sulfonylation of its 6-
OH gives seven regioisomers (AB–AH) 2a–2g (Scheme 1). It seems
that the most efficient method to separate the seven isomers is
reversed phase column chromatography.9 Here we can optimize
the separation of the regioisomers by changing the aryl groups as it
was demonstrated in the case of polyarenesulfonylated CDs.9 On
this view point an arenesulfonyloxy group as a leaving group for
nucleophilic substitution seems superior to a halo group because
difference among Cl, Br, and I is too small to cause enough affinity
change to column stationary phase to ensure the separation of the
regioisomers from each other. Therefore, we surveyed by use of RP-
HPLC on the arenesulfonyl groups to find out the one that gave the
chloride (20 times that of
g-CD) and longer reaction time (two
times longer than those by other sulfonyl chloride) were necessary.
In order to overcome the problem we adopted zinc bromide as an
additive to promote the sulfonylation.10 In the presence of zinc
bromide (2.6 times that of g-CD) 6-azido-g-CD 1 was reacted with
Tips chloride (2.5 times) for 40 min to give the desired derivatives
2a–2g. The reaction mixture was applied to low-pressure column
chromatography using an ODS column to get three mixtures of
optimal separation of azido-arenesulfonyl CDs. g-CD was reacted
with sulfonyl chloride possessing mesityl, 1- and 2-naphtyl, 2,4,6-
NaOH
NaN3
view from 6-OH side
4a
4b
4c
2a
3a
3b
3c
AD
AC
AB
AD
AC
AB
AD
AF
2b
2c
1
SO2Cl
AG
AC
2e
2d
AH
AB
N3
4d
3d
2g
2f
OH
OSO2
O
O
O
O
O
O
HO
HO
HO
OH
OH
OH
OH
O
O
O
Scheme 1.

9476
Y. Himeno et al. / Tetrahedron 65 (2009) 9474–9480
Figure 2. RP-HPLC of reaction products of
g
-CD with sulfonyl chloride possessing (a) mesityl, (b) 1- and (c) 2-naphtyl, (d) and (e) 2,3,4-triisopropylphenyl groups. Conditions were
as follows: column:ODS-M80 (250ꢀ4.6 mm, YMC), flow rate: 1.0 mL/min, eluent: (a) 20–50% aq MeCN (30 min); (b)–(d) 10–40% aq MeCN (30 min); (e) 24% aq MeCN. Regioisomers
of azido-Tips- -CDs 2a–2g were shown on (e).
g
seven isomers, namely that of 2a–2c, 2d–2e, and 2f–2g. Each of the
mixtures was applied to preparative ODS-HPLC to isolate each
regioisomer. Total isolated yields of the isomers 2a–2g were 3.9%,
3.8%, 3.9%, 3.7%, 4.0%, 2.2%, and 2.9%, respectively. Each of the iso-
lated isomers gave satisfactory data to demonstrate existence of
observed.11 It demonstrated that the di-sulfonylation on CD was
difficult presumably due to steric hindrance of the bulky Tips
group. However, addition of zinc bromide achieved the desired
di-sulfonylation and low-pressure RP column chromatography
separated four isomers 3a (2.4%), 3b (2.7%), 3c (4.5%), and 3d
(2.0%), respectively, although the yields were relatively low. Each
of the isolated isomers gave satisfactory data to demonstrate
both an azido group and a Tips group on a
NMR, MS, and IR spectra.
g
-CD molecule on its 1H
After separation/isolation, the regioisomers were subjected to
existence of two Tips group on a g
-CD molecule in its 1H NMR and
regioisomeric assignment. The isomers 2a–2g were firstly corre-
lated with two-Tips-group-possessing g-CD derivatives 3a–3d. By
MS spectra. Structure assignment of 3a–3d was done by chemical
conversion of 3a–3d to the known bis(3,6-anhydro) CDs 4a–4d
and subsequent NMR analysis. Each of the four regioisomers of
4a–4d was known to show characteristic proton signals on the 1H
NMR spectrum enough to clarify the relative positions of the two
3,6-anhydroglucose residues on the CD molecule.12 The obtained
4a–4d were correlated with the authentic isomers and accord-
ingly the bis-Tips CDs 3a–3d were assigned as AE, AD, AC, and AB
isomers, respectively (Scheme 1). In order to correlate the bis-Tips
CDs 3a–3d with azido-Tips CDs 2a–2g, one of the Tips group on
each of 3a–3d was substituted with an azido group. The bis-Tips
substituting one of the two Tips groups on 3a–3d with an azido
group, AB isomer 3a gives AB and AH isomers of the azido-Tips-
CDs (Scheme 1). Similarly AC, AD, and AE isomers of the bis-Tips
CDs give (AC and AG), (AD and AF), and AE isomers, respectively.
This provides not only structure correlation between 2a–2g and
3a–3d but also an alternative route to give 2a–2g to the synthesis
from azido-CD 1 described above. So we prepared the bis-Tips
g-
CD 3a–3d. Palin reported that reaction of -CD with Tips chloride
g
gave only a monosulfonate selectively and no disulfonates were
view from 6-OH side
AD
NaOH
AD
5b
2b
OH
N3
OSO2
O
O
O
O
O
O
HO
HO
HO
OH
OH
OH
OH
O
O
O
Scheme 2.

Y. Himeno et al. / Tetrahedron 65 (2009) 9474–9480
9477
in hand, the other diastereomer 2c was determined to be AF isomer.
Similarly all the isomers 2a and 2c–2f were analyzed by the NMR
methods (Fig. 5) and the positions of the azidoglucose and 3,6-
anhydroglucose on each of them were assigned, which did not
contradict the results of conversion of bis-Tips CDs 2a–2d to 1a–1g
described above. Therefore, the structures of all the 2a–2g were
unambiguously established as AE, AD, AF, AC, AG, AB, and AH,
respectively.
Figure 3. 1D-1H NMR spectrum of azido-3,6-anhydro-
g-CD 5b. Protons of the 3,6-
anhydroglucose residue were marked with asterisk.
AE isomer 3a gave only one azido-Tips CD isomer 2a with the
smallest retention time on RP-HPLC, which demonstrated that 2a
was the AE isomer (Scheme 1) The AD isomer 3b was correlated
with 2b and 2c where an azido group existed on A position on the
CD and the Tips group existed on D position or vice versa. Simi-
larly, AC isomer 3c and AB isomer 3d were correlated with 2d and
2e, and (2f and 2g), respectively.
Complete structure assignment of 2a–2g was done by chemical
conversion to their corresponding 3,6-anhydro-CD derivatives fol-
lowed by high-resolution 2D-NMR (COSY, TOCSY, and HOHAHA)
analysis. Compound 2a–2g themselves did not show proton signals
separated enough for the sequence of the eight sugar residues to be
determined. Transformation of a normal glucose (4C1 conforma-
tion) to a 3,6-anhydroglucose (1C4 conformation) on the CD ring
was known to cause drastic changes on the proton signals of not
only the residue itself but also other glucose residues presumably
due to the distortion of CD ring, which facilitated assignment of the
protons and therefore isomer determination.9b,13 Isomer 2b was
converted with alkaline treatment to 5b (Scheme 2) and the
product showed satisfactory data to demonstrate existence of an
azidoglucose and a 3,6-anhydroglucose on a g-CD molecule in its
MS and IR spectra. Similarly other isomers 5a and 5c–5f were
obtained from 2a and 2c–2f. 1H NMR (600 MHz) spectrometric
analyses for 5a–5g firstly allowed the assignment of the H1–H6
protons in each glucose residues with the aid of COSY and TOCSY
experiments, where correlation of the protons started from the
distinctive H1 signals around 5 ppm. Figures 3 and 4a show the 1D
and TOCSY spectra of the isomer 5b. It was easy to discriminate
proton signals of the 3,6-anhydroglucose from those of sulfonylated
and unmodified glucoses in each isomer since the coupling con-
stants and chemical shifts of the 3,6-anhydroglucose residues with
1C4 conformation are unique compared to those other residues with
4C1 conformation.14 The six intact glucoses with 4C1 conformation
in each isomer showed very similar chemical shift patters. How-
ever, the high-resolution NMR experiments (COSY and TOCSY) en-
abled the discrimination and assignment of almost all signals of
sugar residues of each regioisomeric CD (Fig. 4a). It is especially
important to identify the H1 and H4 of all residues. NOEs between
H1 of one residue and H4 of another adjoining residue clarify the
interresidual relationship, that is, the connecting sequence of the
sugar residue. The ROESY spectrum of the isomer 5b displayed
eight distinct interresidual cross peaks between all the eight pairs
of H1s and H4s as shown in Figure 4b, and suggested the existence
of a 3IV,6IV-anhydro-6I-azidomaltotetraose moiety. Therefore, 2b
was unambiguously assigned as the 6A-azido-6D-TipsCD isomer,
which was in consistence with the results of conversion of the AD-
bis-Tips CDs 3b giving 2b and 2c described above. With this result
Figure 4. TOCSY (a) and ROESY (b) spectra of azido-3,6-anhydro-g-CD 5b. Glucose
residues of 5b were named as A–G and protons of the 3,6-anhydroglucose residue (D
residue) were marked with asterisk.

9478
Y. Himeno et al. / Tetrahedron 65 (2009) 9474–9480
5a (AE)
A
1
5
4
2
3
5
5
A
B
C
D
*E
F
G
H
H
F
B
View from
6-OH side
4
3
2
1
1
4
2
G
2
4
3
C
5 3
1
D
5
3
4
2
3
3
1
E
5
5
3 5
2
4
1
2
4
1
N3
4
2
O
1
HO
OH
5.5
5.0
4.5
3.5
4.0
(ppm)
O
5b (AD)
5c (AF)
1
6
2
5 3
3
3
5
3
5
4
4
4
1
1
1
5
2
3
3
3
3 5
2 4
A
B
C
D
E
*F
G
A
B
C
*D
E
F
1
5
2
2
2
4
4
5
3
1
1
5
2
4 2
3
5
3
4
1
5
5
5
4 2
1
1
1
4
2
1
2
6 6
4
3
2
4
5
1
4 2
4
5
1
3
2
2
4
4
3
3 5
G
H
1
1
2
3 5
1
H
3.5
5.5
4.0
(ppm)
5e (AG)
4.5
4.0
5
3.5
4.5
5.0
5.0
5.5
(ppm)
5d (AC)
1
3
3
2
2 4
2 4
5
3
3
3
2
4
2 4
A
B
*C
D
E
F
G
H
A
B
C
D
E
F
5
5
1
1
6
3 5
3
6
53
4
1
1
5
5
2 4
2
4
1
1
4
4
2
2
2
4
3
1
5
5
2
4
3
4
2
1
5
3
5
1
3
1
5
1
3
3 5
2 4
2 4
6
6
4
1
5
3
2
*G
H
1
3 5
4.0
(ppm)
5g (AH)
2
4
1
3.5
4.0
5
6
3
3.5
5.5
5.0
4.5
5.0
1
5.5
4.5
(ppm)
5f (AB)
4 2
2
2
4
5 3
3 5
3
2
2
4
A
B
C
D
E
F
1
A
*B
C
D
E
F
6
1
1
5 3
4
2
5
5
4
5
3
4
1
1
1
5
5
5
1
3
3
3
3
3 5
3
5
3
2 4
2
2
2
4
4
2
1
4
4
2
1
2 4
5
1
1
1
5 3
2
4
2
4
1
1
2
4
G
*H
G
H
3 5
6
6
1
5
3 4
4.0
(ppm)
4.5
3.5
3.5
5.5
5.0
4.0
(ppm)
5.0
4.5
5.5
Figure 5. Proton signals of isomers 5a–5g. The 3,6-anhydroglucoses were marked with asterisk.
3. Conclusion
observe interresidual NOEs. By use of the seven regioisomers of
-CDs possessing an azido group and a sulfonyloxy group on its
primary hydroxyl side as authentic and versatile synthetic in-
termediates sophisticated -CD derivatives with two different
g
In conclusion, a set of seven isomers of unsymmetrically C6
disubstituted -CD were prepared for the first time. Each of isomers
g
g
was isolated using reversed phase chromatographic separation
based on unique affinity of each regioisomer to the stationary
phases. Low yield of AB/AH isomers 2f/2g seemed similar to those
seen in previous disulfonates studies.15 It is presumably due to
steric hindrance of the two sulfonyl groups. Relationship between
elution order of the regioisomers 2a–2g and their corresponding
structures are not clear. We hypothesize that one of the Tips groups
in the corresponding isomer can be self-included in the CD cavity
and therefore each regioisomer forms a unique hydrophobic mo-
lecular structure with unique affinity to column stationary phase.
The assignment of the modified positions in each regioisomers was
unambiguously performed by chemical correlation with the au-
thentic compounds and chemical conversion followed by high-
resolution 2D-1H NMR (COSY, TOCSY, and HOHAHA) analyses to
functionalities at desired positions are now available for supra-
molecular chemistry. Zwitterionic receptor molecules possessing
both an NHþ3 group and a COOꢁ group regiospecifically situated on
g-CD molecule for chiral recognition of amino acids are now being
studied.
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded on a Varian Gemini 300
(300 MHz) or a Bruker Avance 600 (600 MHz). Proton signals were
assigned using COSY, TOCSY (mixing time, 120 ms), and ROESY
(mixing time, 200 ms) experiments. MALDI-TOF mass measurements

Y. Himeno et al. / Tetrahedron 65 (2009) 9474–9480
9479
were performed with a SHIMADZU AXIMA-Resonance, with 2,5-
dihydroxybenzoic acid as the matrix. UV absorbance of fractions on
low-pressure RP column chromatography was recorded on a Shi-
madzu UVmini-1240 instrument. IR spectra were recorded on a Jasco
FT IR 200. TLC wasrun onprecoated silica-gelplates (Art5554, Merck)
using 1-propanol/ethyl acetate/water (7:7:5, v/v/v) as the eluent and
visualizing using UV light and/or staining with 0.1% 1,3-naph-
thalenediol in EtOH/water/H2SO4 [200:157:43 (v/v/v)]. Prepacked
ODS column [Merck, LiChroprep RP-18, size C (37ꢀ440 mm)] was
used for low-pressure RP column chromatography. Analytical RP-
147.6, 150.9, 154.7; MS m/z 1610.5499 (MþNa, 1610.5529 calcd for
C63H101N3NaO41S); IR (KBr) 2104 cmꢁ1. Compound 2d: Rf 0.48; tR
146.9 min [24% MeCN in water; flow rate, 1.0 mL/min]; 1H NMR
(300 MHz, Me2SO-d6)
d
1.18–1.23 [18H, 6ꢀCH3], 2.94 (1H), 3.05–
3.80, 3.80–3.90 (1H), 4.00 (2H), 4.26 (2H), 4.33 (1H), 4.51–4.62(6H),
4.82–4.96 [8H, C(1)H], 5.71–5.93 [16H, C(2)OH and C(3)OH], 7.28
(2H, s, aromatic H); 13C NMR (150 MHz, Me2SO-d6)
d 24.1, 24.2, 24.7,
25.2, 25.3, 25.7, 28.9, 30.0, 34.1, 34.4, 51.8, 60.7, 60.8, 69.3, 70.0, 71.3,
73.0, 73.1, 73.2, 73.4, 73.5, 73.6, 73.7, 73.8, 80.6, 81.4, 81.7, 81.9, 83.4,
101.9, 102.1, 102.3, 102.5, 102.6, 103.0, 103.1, 122.2, 124.6, 130.0,
142.9, 147.6, 148.0, 150.9, 154.6; MS m/z 1610.5540 (MþNa,
1610.5529 calcd for C63H101N3NaO41S); IR (KBr) 2104 cmꢁ1. Com-
pound 2e: Rf 0.48; tR 163.9 min [24% MeCN in water; flow rate,
HPLC was carried out using an YMC J’sphere ODS-M80 column (4 mm;
4.6ꢀ250 mm, YMC Inc.). Preparative HPLC was performed using an
YMC-Pack ODS-M80 column (4
YMC-Guard pack ODS-M80 (5
macia Fine Chemicals Sephadex LH-20 was used for gel permeation
chromatography.
m
m; 20ꢀ250 mm, YMC Inc.) with an
mm; 20ꢀ50 mm, YMC Inc.). A Phar-
1.0 mL/min]; 1H NMR (300 MHz, Me2SO-d6)
d 1.18–1.23 [18H,
6ꢀCH3], 2.94 (1H), 3.08–3.79, 3.82 (1H), 4.01 (2H), 4.27 (2H), 4.38–
4.48 (2H), 4.49–4.65 (5H), 4.80–4.98 [8H, C(1)H], 5.70–6.00 [16H,
C(2)OH and C(3)OH], 7.29 (2H, s, aromatic H); 13C NMR (150 MHz,
4.2. Azido-Tips-CDs 2a–2f
Me2SO-d6) d 24.1, 24.2, 24.7, 25.2, 25.3, 25.7, 28.9, 30.0, 34.1, 34.4,
60.6, 60.7, 60.8, 61.0, 70.0, 71.3, 72.9, 73.0, 73.1, 73.2, 73.3, 73.4, 73.5,
73.6, 73.7, 73.8, 80.2, 81.4, 81.5, 81.7, 81.8, 82.0, 83.5, 101.7, 101.9,
102.4, 102.6, 102.7, 103.1, 122.2, 124.6, 129.9, 147.7, 148.0, 150.9,
154.6; MS m/z 1610.5450(MþNa, 1610.5529 calcd for
C63H101N3NaO41S); IR (KBr) 2105 cmꢁ1. Compound 2f: Rf 0.48; tR
234.7 min [24% MeCN in water; flow rate, 1.0 mL/min]; 1H NMR
6-Azido-g
-CD 18 (576 mg, 0.44 mmol) and zinc bromide
(252 mg, 1.1 mmol) were dissolved in dry pyridine (6 mL) cooled in
an ice water bath and reacted with TipsCl (0.343 g, 1.10 mmol) for
40 min. After addition of water (3 mL), the reaction mixture was
concentrated in vacuo and the residue was added to acetone
(180 mL). The precipitate was collected by centrifugation
(3000 rpm, 10 min) and dissolved in 28% aq MeCN (100 mL). The
solution was subjected to low-pressure RP column chromatography
(size C). After elution with 28% aq MeCN (600 mL) followed by
a gradient elution from 28% aq MeCN (2.7 L) to 31% aq MeCN (2.7 L),
a gradient elution from 31% aq MeCN (2.7 L) to 34% aq MeCN (2.7 L)
gave mixtures of 2a–2c (124 mg), 2d and 2e (65 mg), and 2f and 2g
(53 mg). The mixture of 2a–2c was applied to preparative HPLC
using 24% aq MeCN as an eluent, which gave 2a (26.9 mg, 3.9%), 2b
(26.0 mg, 3.8%), and 2c (27.3 mg, 3.9%). The mixture of 2d and 2e
gave 2d (25.5 mg, 3.7%) and 2e (27.6 mg, 4.0%) using 27% aq MeCN
as an eluent. The isomers 2f (15.2 mg, 2.2%) and 2g (19.8 mg, 2.9%)
were obtained, respectively, from the corresponding mixture using
27% aq MeCN. Compound 2a: Rf 0.48; tR 80.2 min [24% MeCN in
water; flow rate, 1.0 mL/min]; 1H NMR (300 MHz, Me2SO-d6)
(300 MHz, Me2SO-d6)
d
1.19–1.23 [18H, 6ꢀCH3], 2.95 (1H), 3.05–
3.96, 3.82 (1H), 4.00 (2H), 4.18–4.45 (4H), 4.48–4.73 (6H), 4.82–5.03
[8H, C(1)H], 5.65–6.10 [16H, C(2)OH and C(3)OH], 7.30 (2H, s, aro-
matic H); 13C NMR (150 MHz, Me2SO-d6)
d 24.1, 24.2, 24.7, 25.2,
25.3, 25.7, 28.9, 30.0, 30.7, 34.1, 34.4, 60.8, 60.9, 70.1, 71.1, 72.7, 72.9,
73.1, 73.2, 73.3, 73.4, 73.6, 73.7, 73.8, 73.9, 81.3, 81.5, 81.7, 81.9, 82.0,
83.5,102.0,102.2, 102.4,102.5,102.6,102.7,102.8, 103.2,122.2,124.6,
129.7, 147.6, 150.9, 151.1, 154.7; MS m/z 1610.5437 (MþNa,
1610.5529 calcd for C63H101N3NaO41S); IR (KBr) 2104 cmꢁ1. Com-
pound 2g: Rf 0.48; tR 246.3 min [24% MeCN in water; flow rate,
1.0 mL/min]; 1H NMR (300 MHz, Me2SO-d6)
d 1.18–1.23 [18H,
6ꢀCH3], 2.94 (1H), 3.08–3.80, 3.88 (1H), 4.03 (2H), 4.08–4.16 (2H),
4.48–4.61 (6H), 4.66 (1H), 4.83–4.89 [8H, C(1)H], 5.70–5.99 [16H,
C(2)OH and C(3)OH], 7.30 (2H, s, aromatic H); 13C NMR (150 MHz,
Me2SO-d6)
d 24.1, 24.2, 24.7, 25.2, 25.7, 28.9, 30.0, 30.7, 34.1, 34.3,
d
1.02–1.32 [18H, 6ꢀCH3], 2.92 (2H), 3.19–3.80, 3.82 (1H), 3.98 (2H),
60.6, 60.7, 60.8, 60.9, 69.9, 71.0, 72.9, 73.1, 73.3, 73.4, 73.6, 73.9, 81.1,
81.3, 81.6, 81.7, 81.8, 81.9, 82.0, 82.2, 82.6, 101.7, 102.4, 102.5, 102.6,
102.7, 102.8, 103.1, 122.2, 124.7, 129.9, 147.6, 147.9, 151.0, 154.6; MS
m/z 1610.5474 (MþNa, 1610.5529 calcd for C63H101N3NaO41S); IR
4.18–4.31 (3H), 4.43–4.62 (6H), 4.78–4.95 [8H, C(1)H], 5.65–5.94
[16H, C(2)OH and C(3)OH], 7.26 (2H, s, aromatic H); 13C NMR
(150 MHz, Me2SO-d6)
d 24.3, 24.7, 25.2, 25.3, 25.7, 28.9, 30.0, 30.7,
32.5, 34.1, 34.4, 60.0, 60.5, 60.6, 60.7, 61.0, 69.9, 71.2, 72.9, 73.0, 73.1,
73.2, 73.4, 73.5, 73.6, 73.8, 80.8, 81.2, 81.5, 82.0, 83.6, 101.7, 102.0,
102.5, 102.8, 103.0, 122.2, 124.6, 129.9, 147.6, 150.9, 154.6; MS m/z
1610.5434 (MþNa, 1610.5529 calcd for C63H101N3NaO41S); IR (KBr)
2104 cmꢁ1. Compound 2b: Rf 0.48; tR 84.4 min [24% MeCN in water;
(KBr) 2105 cmꢁ1
.
4.3. Di-Tips-CDs 3a–3d
-CD (3.86 g, 3.0 mmol) and zinc bromide (1.70 g, 7.5 mmol)
g
flow rate, 1.0 mL/min]; 1H NMR (300 MHz, Me2SO-d6)
d
1.11–1.23
were dissolved in dry pyridine (50 mL) cooled in an ice water bath
and reacted with TipsCl (2.32 g, 7.43 mmol) for 90 min. After ad-
dition of water (5 mL), the reaction mixture was concentrated in
vacuo and the residue was added to acetone (200 mL). The pre-
cipitate was collected by centrifugation (3000 rpm, 10 min) and
dissolved in 45% aq MeCN (100 mL). The solution was subjected to
low-pressure RP column chromatography (size C). After elution
with 45% aq MeCN (600 mL) followed by a gradient elution from
45% aq MeCN (1.5 L) to 65% aq MeCN (1.5 L), a gradient elution from
65% aq MeCN (750 mL) to 75% aq MeCN (750 mL) gave 3a (130 mg,
2.4%), 3b (145 mg, 2.7%), 3c (244 mg, 4.5%), and 3d (110 mg, 2.0%).
Compound 3a: Rf 0.54; tR 19.9 min [gradient, 30–70% MeCN in
water (40 min); flow rate, 1.0 mL/min]; 1H NMR (300 MHz, Me2SO-
[18H, 6ꢀCH3], 2.94 (1H), 3.05–3.80, 3.82 (1H), 4.00 (2H), 4.19–4.30
(3H), 4.43–4.62 (7H), 4.78–4.95 [8H, C(1)H], 5.67–5.93 [16H,
C(2)OH and C(3)OH], 7.29 (2H, s, aromatic H); 13C NMR (150 MHz,
Me2SO-d6)
d 24.1, 24.3, 24.7, 25.2, 25.3, 25.7, 28.9, 30.0, 30.7, 31.6,
34.1, 34.4, 51.9, 60.1, 60.3, 60.7, 60.8, 70.0, 71.2, 73.0, 73.1, 73.2, 73.4,
73.5, 73.6, 73.7, 80.9, 81.5, 81.6, 81.9, 83.3, 101.7, 102.2, 102.5, 102.7,
103.0, 103.1, 122.2, 124.6, 129.9, 147.6, 147.9, 150.9, 154.6; MS m/z
1610.5397 (MþNa, 161.5529 calcd for 63H101N3NaO41S); IR (KBr)
2104 cmꢁ1. Compound 2c: Rf 0.48; tR 88.4 min [24% MeCN in water;
flow rate, 1.0 mL/min]; 1H NMR (300 MHz, Me2SO-d6)
d 1.08–1.30
[18H, 6ꢀCH3], 2.93 (1H), 3.03–3.80, 3.85 (1H), 4.00 (2H), 4.24 (2H),
4.32 (1H), 4.44 (1H), 4.49–4.61 (4H), 4.67 (1H), 4.80–4.99 [8H,
C(1)H], 5.64–6.01 [16H, C(2)OH and C(3)OH], 7.28 (2H, s, aromatic
d6)
d
0.95–1.30 (36H,12ꢀCH3), 2.92 (2H), 2.95–3.75, 3.80–4.05 (6H),
H); 13C NMR (150 MHz, Me2SO-d6)
d
24.1, 24.3, 24.7, 25.2, 25.3, 25.7,
4.06 (2H), 4.15–4.30 (4H), 4.40–4.70 (5H), 4.85–5.00 [8H, C(1)H],
28.9, 29.9, 30.0, 34.1, 34.4, 51.9, 60.0, 60.5, 60.6, 60.7, 61.0, 61.1, 72.9,
73.1, 73.4, 73.5, 73.6, 73.8, 80.9, 81.0, 81.4, 81.5, 81.6, 81.9, 82.2, 83.5,
101.9, 102.4, 102.5, 102.6, 102.8, 103.0, 103.1, 122.2, 124.5, 129.9,
5.60–6.05 [16H, C(2)OH and C(3)OH], 7.24 (4H, s, aromatic H); 13C
NMR (150 MHz, Me2SO-d6)
d 24.1, 25.1, 25.3, 30.0, 34.3, 60.0, 60.3,
60.5, 69.4, 69.8, 72.8, 73.0, 73.1, 73.4, 73.5, 73.6, 73.9, 80.8, 80.9, 81.2,

9480
Y. Himeno et al. / Tetrahedron 65 (2009) 9474–9480
81.6, 101.7, 102.4, 102.8, 124.5, 129.7, 150.9, 154.5; MS m/z 1851.6800
(MþNa, 1851.6804 calcd for C78H124NaO44S2). Compound 3b: Rf
0.54; tR 21.0 min [gradient, 30–70% MeCN in water (40 min); flow
Compound 5b: Rf 0.20; 1H NMR (600 MHz, D2O): see Figures 3 and
5; MS m/z 1326.4045 (MþNa, 1326.4083 calcd for C48H77N3NaO38),
1299.7 (MþH, calcd for C48H78N3O38); IR (KBr) 2104 cmꢁ1. Com-
pound 5c: Rf 0.20; 1H NMR (600 MHz, D2O): see Figure 5 and
Figure S18; MS m/z 1326.4031 (MþNa, 1326.4083 calcd for
C48H77N3NaO38); IR (KBr) 2103 cmꢁ1. Compound 5d: Rf 0.20; 1H
NMR (600 MHz, D2O): see Figure 5 and Figure S22; MS m/z
1326.4053 (MþNa, 1326.4083 calcd for C48H77N3NaO38); IR (KBr)
2105 cmꢁ1. Compound 5e: Rf 0.20; 1H NMR (600 MHz, D2O): see
Figure 5 and Figure S26; MS m/z 1326.4084 (MþNa, 1326.4083
calcd for C48H77N3NaO38); IR (KBr) 2105 cmꢁ1. Compound 5f: Rf
0.20; 1H NMR (600 MHz, D2O): see Figure 5 and Figure S30; MS m/z
1326.4088 (MþNa, 1326.4083 calcd for C48H77N3NaO38); IR (KBr)
2104 cmꢁ1. Compound 5g: Rf 0.20; 1H NMR (600 MHz, D2O): see
Figure 5 and Figure S34; MS m/z 1326.4088 (MþNa, 1326.4083
rate, 1.0 mL/min]; 1H NMR (300 MHz, Me2SO-d6)
d 1.05–1.30 (36H,
12ꢀCH3), 2.89 (2H), 3.05–3.78, 3.86 (2H), 4.00 (4H), 4.15–4.20 (7H),
4.45–4.65 (4H), 4.80–4.95 [8H, C(1)H], 5.65–6.05 [16H, C(2)OH and
C(3)OH], 7.26 (4H, s, aromatic H); 13C NMR (150 MHz, Me2SO-d6)
d
24.3, 25.1, 25.2, 25.3, 25.6, 30.0, 34.4, 60.0, 60.1, 60.3, 60.5, 60.7,
69.1, 69.9, 72.8, 72.9, 73.0, 73.2, 73.3, 73.5, 73.6, 73.7, 80.6, 81.0, 81.3,
81.4, 81.5, 82.0, 101.8, 102.0, 102.4, 102.5, 103.0, 103.1, 124.5, 129.8,
129.9, 150.9, 154.6; MS m/z 1851.6789 (MþNa, 1851.6804 calcd for
C78H122NaO44S2), 1825.3 (MþH, calcd for C78H123O44S2). Compound
3c: Rf 0.54; tR 24.5 min [gradient, 30–70% MeCN in water (40 min);
flow rate, 1.0 mL/min]; 1H NMR (300 MHz, Me2SO-d6)
d 1.05–1.15
(36H, 12ꢀCH3), 2.93 (2H), 3.05–3.90, 3.90–4.30 (10H), 4.39–4.65
(6H), 4.75–4.95 [8H, C(1)H], 5.65–6.05 [16H, C(2)OH and C(3)OH],
calcd for C48H77N3NaO38); IR (KBr) 2105 cmꢁ1
.
7.28 (4H, s, aromatic H); 13C NMR (150 MHz, Me2SO-d6)
d 24.1, 24.2,
24.7, 25.2, 25.3, 25.7, 34.4, 60.1, 60.6, 60.7, 69.1, 69.3, 70.0, 72.9, 73.0,
73.1, 73.2, 73.3, 73.4, 73.5, 73.6, 73.8, 80.0, 80.7, 81.5, 81.6, 81.7, 81.8,
101.4, 101.9, 102.4, 102.5, 102.9, 124.5, 124.6, 129.8, 130.0, 150.9,
151.0, 154.6, 154.6; MS m/z 1851.6795 (MþNa, 1851.6795 calcd for
C78H122NaO44S2). Compound 3d: Rf 0.54; tR 25.4 min [gradient, 30–
70% MeCN in water (40 min); flow rate, 1.0 mL/min]; 1H NMR
Acknowledgements
We wish to thank Nihon Shokuhin Kako Co. Ltd. for a generous
gift of g-CD and Mr. Shuichi Nakaya of SHIMADZU Corporation for
mass analyses.
(300 MHz, Me2SO-d6)
d
1.00–1.20 (36H, 12ꢀCH3), 2.93 (2H), 3.00–
Supplementary data
3.95, 3.97 (4H), 4.05–4.45 (5H), 4.45–4.65 (5H), 4.70–4.95 [8H,
C(1)H], 5.60–5.90 [16H, C(2)OH and C(3)OH], 7.27 (4H, s, aromatic
RP-HPLC chromatogram of di-Tips-CDs 3a–3d, 13C NMR spectral
data of 2a–2g and 3a–3d, and 1H NMR spectral data of 5a–5g (5a
and 5c–5g; 1D, COSY, TOCSY, ROESY; 5b: COSY) are provided.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.08.061.
H); 13C NMR (150 MHz, Me2SO-d6)
d 24.1, 24.2, 25.1, 25.2, 25.3, 30.0,
34.3, 34.4, 60.5, 60.6, 60.7, 60.8, 68.8, 69.9, 72.7, 73.0, 73.1, 73.2, 73.4,
73.5, 73.7, 73.8, 80.8, 80.9, 81.2, 81.3, 81.4, 81.7, 81.9, 101.6, 102.1,
102.3, 102.4, 102.5, 102.6, 102.9, 124.4, 124.5, 130.1, 130.4, 150.7,
150.8, 154.5, 154.6; MS m/z 1861.6835 (MþNa, 1851.6804 calcd for
C78H122KO44S2).
References and notes
4.4. Conversion of di-Tips-CDs 3a–3d to bis(3,6-anhydro)-CDs
4a–4d
1. (a) Yuan, D. Q.; Dong, S. D.; Breslow, R. Tetrahedron Lett. 1998, 39, 7673–7676;
(b) Fasella, E.; Dong, S. D.; Breslow, R. Bioorg. Med. Chem. 1999, 7, 709–714.
2. (a) Rekharsky, M.; Yamamura, H.; Kawai, M.; Inoue, Y. J. Am. Chem. Soc. 2001,
123, 5360–5361; (b) Yamamura, H.; Rekharsky, M. V.; Ishihara, Y.; Kawai, M.;
Inoue, Y. J. Am. Chem. Soc. 2004, 126, 14224–14233.
3. (a) Fujita, K.; Matsunaga, A.; Imoto, T.; Hirotsu, K.; Kamitori, S.; Higuchi, T. J. Am.
Chem. Soc. 1985, 107, 1790–1791; (b) Fujita, K.; Matsunaga, A.; Ikeda, Y.; Imoto, T.
Tetrahedron Lett. 1985, 26, 6439–6442; (c) Fujita, K.; Yamamura, H.; Imoto, T.
Tetrahedron Lett. 1991, 32, 6737–6740; (d) Fujita, K.; Yamamura, H.; Egashira, Y.;
Imoto, T. Tetrahedron Lett. 1992, 33, 3511–3514; (e) Yuan, D.-Q.; Kitagawa, Y.;
Fukudome, M.; Fujita, K. Org. Lett. 2007, 9, 4591–4594.
Compound 3a (16.7 mg, 9.1ꢀ10ꢁ6 mol) in 1 M aq NaOH (1 mL)
was kept at 60 ꢂC for 2 h. After neutralized by 1 M aq HCl the re-
action mixture was concentrated in vacuo. The residue was dis-
solved in water (0.5 mL) and applied to gel permeation column
chromatography to give a bis(3,6-anhydro) derivative 4a (9.5 mg,
90%). Each of 3b–3d gave the corresponding 4b–4d, respectively
(yield; 4b 76%, 4c 82%, 4d 91%).
4. Guieu, S.; Sollogoub, M. Angew. Chem., Int. Ed. 2008, 47, 7060–7063.
5. (a) Yu, H.; Makino, Y.; Fukudome, M.; Xie, R.-G.; Yuan, D.-Q.; Fujita, K. Tetra-
hedron Lett. 2007, 48, 3267–3271; (b) Narita, M.; Hamada, F. J. Chem. Soc., Perkin
Trans. 2 2000, 823–832.
4.5. Conversion of di-Tips-CDs 3a–3d to azido-Tips-CDs 2a–2g
6. For example: (a) Pe´rez-Balderas, F.; Ortega-Mun˜oz, M.; Morales-Sanfrutos, J.;
´
´
´
Hernandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Asın, J. A.; Isac-Garcıa, J.; San-
toyo-Gonza´lez, F. Org. Lett. 2003, 5, 1951–1954; (b) Srinivasachori, S.; Fichter, K.
M.; Reineke, T. M. J. Am. Chem. Soc. 2008, 130, 4618–4627.
7. Easton, J.; Lincoln, S. F. Modified Cyclodextrins; Scaffolds and Templates for Su-
pramolecular Chemistry; Imperial College: London, 1999.
Compound 3a (3.5 mg, 2.0ꢀ10ꢁ6 mol) in 1 M aq NaOH (1 mL)
reacted with sodium azide (0.14 mg, 2.2ꢀ10ꢁ6 mol) at 60 ꢂC for 1 h.
After the reaction mixture was concentrated in vacuo the residue
was dissolved in 60% aq CH3CN (0.4 mL) and applied to RP-HPLC
analysis. Each of 3b–3d was treated similarly.
8. Hamasaki, K.; Ikeda, H.; Nakamura, A.; Ueno, A.; Toda, F.; Suzuki, I.; Osa, T. J. Am.
Chem. Soc. 1993, 115, 5035–5040.
9. (a) Fujita, K.; Yamamura, H.; Matsunaga, A.; Imoto, T.; Mihashi, K.; Fujioka, T.
J.Am. Chem. Soc. 1986, 108, 4509–4513; (b) Yamamura, H.; Iida, D.; Araki, S.;
Kobayashi, K.; Katakai, R.; Kano, K.; Fujita, K. J. Chem. Soc., Perkin Trans. 1 1999,
3111–3115; (c) Yamamura, H.; Tashiro, H.; Kawasaki, J.; Kawamura, K.; Kawai, M.
Tetrahedron 2007, 63, 2064–2069.
4.6. Conversion of azido-Tips-CDs 2a–2g to azido-3,6-
anhydro-CDs 5a–5g
10. Yamamura, H.; Kawasaki, J.; Saito, H.; Araki, S.; Kawai, M. Chem. Lett. 2001, 706–
708.
11. Palin, R.; Grove, S. J. A.; Prosser, A. B.; Zhang, M.-Q. Tetrahedron Lett. 2001, 42,
8897–8899.
12. Fujita, K.; Yamamura, H.; Imoto, T.; Fujioka, T.; Mihashi, K. J. Org. Chem. 1989, 53,
1943–1947.
13. Yamamura, H.; Nagaoka, H.; Saito, K.; Kawai, M.; Butsugan, Y.; Nakajima, T.;
Fujita, K. J. Org. Chem. 1993, 58, 2936–2937.
14. (a) Fujita, K.; Yamamura, H.; Imoto, T.; Tabushi, I. Chem. Lett. 1988, 543–546;
(b) Fujita, K. Chem. Pharm. Bull. 1991, 39, 2505–2508.
15. (a) Fujita, K.; Matsunaga, A.; Imoto, T. J. Am. Chem. Soc. 1984, 106, 5740–5741;
(b) Fujita, K.; Matsunaga, A.; Imoto, T. Tetrahedron Lett. 1984, 25, 5533–5536.
Compound 2a (16.7 mg, 1.2ꢀ10ꢁ5 mol) in 1 M aq NaOH (1 mL)
was kept at 60 ꢂC for 2 h. After neutralized by 1 M aq HCl the re-
action mixture was concentrated in vacuo. The residue was dis-
solved in water (0.5 mL) and applied to gel permeation column
chromatography (eluent: water) to give a azido-(3,6-anhydro) CD
derivative 5a (9.5 mg, 90%). Each of 2b–2g gave the corresponding
5b–5g, respectively. Compound 5a: Rf 0.20; 1H NMR (600 MHz,
D2O): see Figure 5 and Figure S13; MS m/z 1326.4045 (MþNa,
1326.4085 calcd for C48H77N3NaO38); IR (KBr) 2104 cmꢁ1
.