Cyclodextrin ketones as oxidation catalysts: Investigation of bridged derivatives

Article abstract of DOI:10.1039/b814245a

A series of α-cyclodextrin derivatives containing a 3, 4 or 5 membered ether-linked bridge between the 6A and 6D oxygen atoms, with and without a ketone, were prepared. The synthesis used perbenzylated α-cyclodextrin A,D-diol as a starting material upon which O-alkylation and further modifications led to the di-O-(buta-1,4-diyl), the di-O-(penta-1,5- diyl) and the di-O-(buta-2-on-1,4-diyl) derivatives, which were debenzylated, and compared with the previously reported di-O-(propa-2-on-1,3-diyl) derivative. Permethylated derivatives of the di-O-(propa-2-on-1,3-diyl) and the buta-1,4-diyl derivatives were also made. The 6A,6D-di-O-(propa-2-on-1,3-diyl)- 6C,6F-di-O-methyl and di-O-pivaloyl derivatives were also prepared. The new compounds were analysed for catalysis of the oxidation of amines and alcohols.

Full text of DOI:10.1039/b814245a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Cyclodextrin ketones as oxidation catalysts: Investigation of
bridged derivatives†
Thomas Hauch Fenger, Lavinia G. Marinescu and Mikael Bols*
Received 15th August 2008, Accepted 23rd October 2008
First published as an Advance Article on the web 21st January 2009
DOI: 10.1039/b814245a
A series of a-cyclodextrin derivatives containing a 3, 4 or 5 membered ether-linked bridge between the
6
A and 6D oxygen atoms, with and without a ketone, were prepared. The synthesis used perbenzylated
a-cyclodextrin A,D-diol as a starting material upon which O-alkylation and further modifications led to
the di-O-(buta-1,4-diyl), the di-O-(penta-1,5-diyl) and the di-O-(buta-2-on-1,4-diyl) derivatives, which
were debenzylated, and compared with the previously reported di-O-(propa-2-on-1,3-diyl) derivative.
Permethylated derivatives of the di-O-(propa-2-on-1,3-diyl) and the buta-1,4-diyl derivatives were also
made. The 6A,6D-di-O-(propa-2-on-1,3-diyl)-6C,6F-di-O-methyl and di-O-pivaloyl derivatives were
also prepared. The new compounds were analysed for catalysis of the oxidation of amines and alcohols.
Introduction
and eventually forms 2-amino-phenoxazine-3-one in a process that
requires oxidation by two molecules of H
In this mechanism formation of the hydroperoxide adduct is
a crucial step which should be favored if the ketone is electron
poor such as in 1 and 6. Nevertheless variation in hydrogen
peroxide concentration did not affect the rate. Some of the steps
2
2
O .
Supramolecular chemistry is a science that attempts to understand
and use chemistry beyond the molecule. A fascinating research
area is aimed at using supramolecular chemistry to achieve
catalysis thereby creating what are de facto artificial enzymes.
Cyclodextrins are very attractive supramolecular hosts to be
included as artificial enzymes due to their good binding properties
in water and their water solubility.
Our group has recently reported that cyclodextrin ketones catal-
yse various oxidation reactions such as epoxidation,
and alcohol oxidation. Particularly the two latter reactions occur
1
2
–26
(
b)-(d) in the oxidation to the nitro derivative and formation of 2-
amino-phenoxazin-3-one from hydroxylamine may occur outside
the cyclodextrin cavity, but the rate-determining step must occur
inside.
In order to gain more insight into the function of the ketone it
was decided to prepare and study ketones related to structure
4,9
2
7,28
29
amine
30
quite effectively with catalyst 1 and hydrogen peroxide in buffer
1. In this paper we present synthesis and oxidation catalysis
(
Fig. 1): Oxidation of the amine 2 to nitro derivative 3 occurs with
experiments with a number of new ketones. Herein is also included
a rate acceleration of 680, while alcohol 4 is oxidised to aldehyde 5
with a rate acceleration up to 63 000. The trifluoroketone 6 has also
the study of the ether linked analogue 7 already prepared and
27
earlier investigated for epoxidation catalysis. This compound has
31
been investigated for these reactions, but is less efficient. Though
contains a potentially more reactive ketone the rate acceleration
an intrinsically less reactive ketone than 1, but essentially identical
structure.
6
is only about 100 for both type of substrates. Native cyclodextrins
or simple ketones (acetone etc.) do not give rate acceleration for
Results and discussion
29,30
these reactions.
Thus the bridged ketone appears essential, and
the mechanism outlined in Fig. 1 (framed box) has been proposed
for the amine oxidation: (a) Hydrogen peroxide initially reacts
with the ketone forming a hydroperoxide adduct, (b) the amine,
bound in the cyclodextrin cavity, is oxidised to hydroxylamine,
while the ketone is regenerated and a molecule of water is
formed, (c) the hydroxylamine is oxidised to nitroso by another
hydroperoxide adduct (formed from ketone as in (a)) and the
ketone is regenerated with two molecules of water being formed,
It was suggested that the bridge in the capped cyclodextrin
might itself play some function in the catalysis. Albeit native
cyclodextrins do not catalyse the oxidation, the bridging of the
upper rim might change the cavity structure and its binding
properties to make the substrate more reactive when included.
Therefore bridged cyclodextrins containing no catalytic groups
were desired. We carried out the transformation 8–11 described
32
previously by Pearce and Sina y¨ (Scheme 1), to obtain the
(
d) another hydroperoxide adduct oxidises nitroso to nitro (e) while
cyclodextrin derivative 11 that has butan-1,4-diyl group linked
the ketone is regenerated and a molecule of water is formed. o-
Aminophenols step out of this mechanism at the hydroxylamine
stage as it in that case rearranges readily to the quinone imine
A
D
to the 6 and 6 . The intermediate 10, the Grubbs product, was
subjected to hydroboration/oxidation with 9-BBN and H
2
2
O ,
which gave the expected product 13 in 25% yield, but also the
by-product 14 in a surprisingly high yield (54%). The formation
of diol 14 is somewhat of a mystery. An isomerisation during the
olefin metathesis to form 19 (Scheme 2) appears to explain the
formation; there are indeed reports of such olefin isomerisations
during the Grubbs reaction, as it has been shown that after
extended reaction times due to the decomposition products from
(
Fig. 1, bottom). The quinone imine reacts with 2-aminophenol
Department of Chemistry, University of Aarhus, DK-8000, Denmark.
E-mail: mb@chem.au.dk
1
13
†
Electronic supplementary information (ESI) available: H and C NMR
spectra. See DOI: 10.1039/b814245a
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 933–943 | 933

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Fig. 1 Artificial enzymes containing ketones 1, 6 and 7, substrates 2 and 4 and products 3 and 5. The framed box shows the mechanism proposed for
amine oxidation. Below is shown the transformation of o-(N-hydroxylamino)phenol to quinone imine and dimerisation and oxidation of the quinone
imine to 2-amino-phenoxazin-3-one.
3
3
the ruthenium catalyst a migration of the double bond can occur.
MeI/NaH and additional acidic hydrolysis, the monool 27 was
obtained in 34% yield. Finally, this compound was oxidised with
Dess–Martin periodinane to give the permethylated ether-ketone
28 in 63% yield.
However there is no indication that a significant impurity of 19
is present in the olefin metathesis product, which appears to be
only the symmetrical compound 10. Secondly, the hydroboration
of 19 would indeed form the alcohols 13 and 20 and the latter can
ring-open to aldehyde 21 (Scheme 2). However since 21 is formed
during the oxidative leg of the hydroboration, borane should not
be present to reduce it to 14. Therefore we believe the ring opening
must occur during the reductive leg of the hydroboration. The
following would account for the formation of 14: Coordination
of the borane to the oxygen in 10 and a reductive cleavage with
allylic rearrangement of the double bond would give 3-butenyl
ether 22 (Scheme 2). Subsequent hydroboration of 22 gives 14.
The monool 13 could be separated from 14 by chromatography,
and it was isolated in 25% yield. Oxidation of 13 with Dess–Martin
periodinane gave the ketone 15 in 84%, which was deprotected by
hydrogenolysis to the final ketone 16 (Scheme 1).
It has been shown that benzylated cyclodextrins, such as 10, with
a bridge between A and D residues upon further treatment with
DIBAL undergoes a selective bis-debenzylation at the primary
34
benzylated alcohols from the B‡ and E sugars. Thus reaction
27
35
of 29 with DIBAL gives the diol 30 (Scheme 4), which have
the B and E residues deprotected. Compound 30 was further
modified as outlined in Scheme 5: Methylation with MeI and
NaH gave the derivative 31 in 98% yield. The bridged alkene 31
was dihydroxylated with OsO
4
and cleaved with NaIO to give the
4
ketone 32 in 74% yield. Removal of the benzyl groups gave the
di-O-methyl ether-ketone 33 in excellent yield.
Alternatively 30 was treated with pivaloyl chloride and triethyl
amine to form diester 34 in 89% yield. Further OsO
4
catalysed
Another bridged cyclodextrin without reactive groups was made
dihydroxylation and NaIO cleavage gave the ketone 35 in
82% yield. Hydrogenolysis afforded the unprotected cyclodextrin
derivative 36 in quantitative yield.
The unprotected and methylated cyclodextrins were tested as
catalysts for oxidation of various amines and alcohol substrates
in water at neutral pH with a low concentration (64 mM) of
4
34
by reaction of diol 8 with 1,5-dichloropentane in the presence of
NaH. The product 17 was obtained in modest yield and the final
A
D
deprotection gave 6 ,6 -pentanediyl ether 18.
A methylated analogue of the bridge ether ketone 7 was
prepared as outlined in Scheme 3. Simple methylation of 7 is
not possible due to a-methylation and lability of the ketone. The
H
2
2
O present. The existence of catalysis was determined by
protected form of 7, alias 23, was reduced with NaBH to give
4
the monool 24 in 93% yield. The compound was converted to the
corresponding tetrahydropyranyl ether 25, using 3,4-dihydropyran
and camphor sulfonic acid, which afforded 25 in 96% yield.
Debenzylation gave derivative 26 in 95%. After methylation with
‡
There is some inconsistency in the literature as to the direction of
numbering of the cyclodextrin residues with the letter nomenclature. Here
we number in the direction from aglycon to glycon or from 4 to 1 position,
which appears to be most accepted.
9
34 | Org. Biomol. Chem., 2009, 7, 933–943
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Scheme 1 Synthesis of bridged ketones 11, 12, 16 and 18.
Scheme 2 Proposed steps for formation of cyclodextrin diol 14.
comparing the change in UV-absorption of identical samples
with and without a small concentration of catalyst (~1 mM). If
catalysis was observed, the experiment was performed at different
concentrations of substrate to determine a series of initial reaction
rates. These were plotted into a Hanes plot to see if Michaelis-
Menten kinetics was followed. If so, kinetic parameters, kcat and
These results are shown in Table 1. kuncat was determined from the
series of experiments where the substrate was oxidised with H
without catalyst and used to determine kcat/kuncat
2
O
2
.
Almost all the ketones displayed enzymatic catalysis for amine
oxidation, while almost none displayed catalysis for alcohol
oxidation (Table 1). The acetone-bridged a-cyclodextrin 7, which
27
K
m
, were obtained by using non-linear regression curve fitting.
previously has been shown to catalyse epoxidation, catalysed
This journal is © The Royal Society of Chemistry 2009
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Scheme 3 Synthesis of the methylated cyclodextrin ketone 28.
Scheme 4 The structure of the starting materials 29 and 30.
Scheme 5 Synthesis of tetrasubstituted cyclodextrin ketones 33 and 36.
the reaction of several aromatic amines with rate-accelerations of
24–225 times. This is significant, but nevertheless lower than the
activity displayed by 1 for which the rate-accelerations were up to
cavity. The K values between 7 and the two substrates, 2- and
d
1
4-aminophenol, were therefore determined by NMR-titration,
which gave the values 0.15 and 37 mM, respectively. This confirms
the significant difference in binding between the two substrates
and 7, albeit the binding of 2-aminophenol by NMR-studies
29
1
068 times. The most plausible explanation for this lower activity
is that the ketone functionality in 7 is less reactive than in 1 because
the oxy-groups are less electron-withdrawing. The K values were
interesting: for 4-aminophenol they were much higher than for
the 2-aminophenols. Since the K is equal to (kcat+k-1)/k it is
considered, for a catalyst where kcat is much smaller than diffusion,
essentially to be identical to the dissociation constant K ; thus
m
appeared to be somewhat stronger than reflected in the K value.
m
An explanation for the poor binding of 4-aminophenol could be a
poorer fit of this longer substrate in the cavity because it is capped.
The complete lack of catalysis by 7 of alcohol oxidation is
surprising since compound 1 proved to be a good catalyst for
these substrates. Obviously the reactivity of the ketone is crucial
for the alcohol oxidation.
m
1
d
binding of 4-aminophenol should rather surprisingly be much
smaller than that of 2-aminophenol in the narrow a-cyclodextrin
9
36 | Org. Biomol. Chem., 2009, 7, 933–943
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◦
Table 1 Kinetic parameters for the enzymatic oxidation of various substrates by H
cyclodextrin catalyst. — means no catalysis
2
O
2
in phosphate buffer at pH 7.0 and 25 C in the presence of the
6
-1
Catalyst
Substrate
kcat/kuncat
k
cat (10 s )
m
K (mM)
a
b
7
1
2-aminophenol
225
124
136
—
1541 ± 54
273 ± 55
1507 ± 247
—
4.45 ± 0.26
43.0 ± 1.3
10.3 ± 1.0
—
4
2
-aminophenol
c
-amino-4-methylphenol
d
benzyl alcohol
a
b
1
6
2-aminophenol
-aminophenol
161
—
101
—
1063 ± 103
—
4.4 ± 0.8
—
—
14.0 ± 0.6
—
19.9 ± 4.8
—
—
4
1
2
4
e
-phenylethanol
-hydroxylbenzyl alcohol
-methoxybenzyl alcohol
f
g
—
a
1
2-aminophenol
392
—
—
—
15
2589 ± 568
—
—
—
19.5 ± 1.0
—
—
—
b
4
1
2
4
-aminophenol
e
-phenylethanol
-hydroxylbenzyl alcohol
-methoxybenzyl alcohol
f
g
0.63 ± 0.12
2.77 ± 0.92
a
1
8
2-aminophenol
30
—
—
—
—
196 ± 23
6.8 ± 0.6
b
4
1
2
4
-aminophenol
—
—
—
—
—
—
—
—
e
-phenylethanol
-hydroxylbenzyl alcohol
-methoxybenzyl alcohol
f
g
a
1
2
2
8
2-aminophenol
—
—
—
a
b
2-aminophenol
-aminophenol
35
89
—
—
—
229 ± 8
89 ± 8
—
—
—
3.3 ± 0.2
4
1
2
4
23.3 ± 0.6
e
-phenylethanol
-hydroxylbenzyl alcohol
-methoxybenzyl alcohol
—
—
—
f
g
a
3
3
3
6
2-aminophenol
178
—
—
1174 ± 26
28.4 ± 0.2
b
4
-aminophenol
—
—
—
—
d
benzyl alcohol
a
b
2-aminophenol
-aminophenol
386
45
150
—
750 ± 19
80 ± 42
1658
36 ± 0.2
35.7 ± 3.0
10.3 ± 1.1
—
4
2
c
-amino-4-methylphenol
d
benzyl alcohol
—
a
b
c
d
e
Oxidised to 2-aminophenoxazin-3-one. Oxidised to 4-nitrophenol. Oxidised to 2-nitro-4-methylphenol. Oxidised to benzaldehyde. Oxidised to
f
g
acetophenone. Oxidised to 2-hydroxybenzaldehyde. Oxidised to 4-methoxybenzaldehyde.
This journal is © The Royal Society of Chemistry 2009
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The substituted analogues of 7, 33 and 36, catalysed the amine
oxidation similarly to 7 (Table 1). The dipivaloyl derivative 36
was very similar to 7 in terms of rate acceleration, but the K
values were all high. The K values for binding of 2- and 4-
m
d
aminophenol were determined also by NMR-titration to be 34
and 33 mM, respectively, confirming poor binding of the substrates
into the cyclodextrin cavity (Fig. 2). The dimethyl analogue 33 was
interestingly less effective than 36. It is not easy to find a reason,
how the change of substituent from 33 to 36 favors catalysis; one
possibility being that the bulky tert-butyl in 36 forces the C and
F substituents into a conformation that is less bulky around the
ketone than a simple methyl group.
Fig. 3 Putative mechanism for the catalysis of oxidation of 2-aminophe-
nol by 11.
Conclusion
It has been found that the electrophilicity of the ketone is an
advantage for the efficiency of A,D bridged ketone cyclodextrin
derivatives as artificial oxidases. This is in agreement with earlier
findings in epoxidation reactions. Permethylation of the cyclodex-
trin is possible; the compound retains its catalytic activity, but
there is an impeding effect. Remarkably, A,D bridged cyclodextrin
derivatives without a ketone can catalyse some oxidations; some-
thing that unsubstituted cyclodextrins cannot do. These molecules
can presumably bind hydrogen peroxide at the primary rim. More
substitution at the primary rim of bridged cyclodextrins results
in a decrease of binding efficiency, however the catalysts are still
active for oxidation of certain substrates.
Fig. 2 NMR-titration curve for calculation of the binding constant
between 36 and 2-aminophenol.
Experimental
Another interesting analogue of 7 is the permethylated analogue
8. Comparison of these two compounds allows an evaluation
General
2
of the influence of permethylation on catalysis by a cyclodextrin
derivative; something that to our knowledge hitherto has not
been done. The disturbance in the hydrogen bonding of the
secondary rim should have an influence on the inner structure of
the cyclodextrin cavity and should influence the catalysis efficiency.
Thus, the methylated ketone 28 has a lower rate acceleration than
Solvents were distilled under anhydrous conditions. All reagents
were used as purchased without further purification. Evaporation
was carried out in a rotatory evaporator. Glassware used for
◦
water-free reactions was dried for 2 h at 130 C before use.
Columns were packed with silica gel 60 (230–400 mesh) as the
stationary phase. TLC plates (Merck, 60, F254) were visualised by
spraying with cerium sulfate (1%) and molybdic acid (1.5%) in
7
, but the same binding profile with a high K for 4-aminophenol.
m
Hence the main effect of methylation appears to be an impediment,
perhaps caused by steric effects, of the catalytic reaction at the
secondary rim.
The butanoic ketone 16 was not a good catalyst except for 2-
aminophenol. It is undoubtedly crucial here that the ketone is
even less electrophilic than that of 7. A low degree of catalysis was
observed for 16 on the oxidation of 4-methoxybenzyl alcohol.
Bridged cyclodextrins without a ketone (11, 12, and 18) could
in fact catalyse some of the reactions (Table 1), though catalysis
was typically poor or nonexistent. Nevertheless the catalysis by
1
13
10% H
2
SO and heating until coloured spots appeared. H-, C-
4
NMR and COSY experiments were carried out with a Varian
Mercury 400 instrument. Monoisotopic mass spectra (MALDI-
TOF MS) were obtained on a Bruker Daltonics mass spectrometer
using a a-cyanohydroxycinnamic acid (a-CHCA) matrix. Spectra
were calibrated using a peptide calibration standard solution.
28 31
27
Compounds 1, 6 and 7 were prepared as previously described.
A
D
A-F
A-F
Synthesis of 6 ,6 -di-O-allyl-2 , 3
6
,
B,C,E,F
-hexadecakis-O-benzyl-a-cyclodextrin (9)
11 is remarkable given that unmodified cyclodextrin provides
no catalysis of these reactions. Since the function of the ketone
mainly is to bind hydrogen peroxide in the vicinity of the amine,
it appears that in 11 hydrogen peroxide is bound by other means.
The most likely binders are the hydroxyl groups on the primary
rim, and this is supported by the observation that permethylated
To a solution of hexadecabenzylated a-CD diol (8, 3.19 g,
1.32 mmol) in 160 ml dry DMF, under N , rt, NaH was added,
and left stirring in 30 min. Allylbromide was added dropwise and
stirred for 3.5 h, afterwards 300 ml water and 200 ml EtOAc were
added, and extracted with EtOAc (4 ¥ 75 ml) prior to drying
2
12 gave absolutely no catalysis. A possible mode of binding could
with MgSO
4
and evaporation. The residue was purified by flash
be hydrogen bonding to two vicinal 6-OH groups (Fig. 3). In
unmodified cyclodextrins these OH’s are occupied by internal
hydrogen bonding explaining why no catalysis is observed.
chromatography, EtOAc:pentane, 1:4 to give 2.98 g of diallylated
1
compound 9 (90% yield) as a colourless foam. H-NMR (CDCl
3
,
400 MHz) d
H
: 5.77 (m, 2H, allyl), 5.21 (t, J = 11,3, 6H), 5.15–
9
38 | Org. Biomol. Chem., 2009, 7, 933–943
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5
3
1
.06 (m, 8H), 4.91 (m, 6H), 4.54–4.37 (m, 20H), 4.18–4.16 (m,
NaOH and 10 ml H
2
O
2
(35%) were added, the mixture was stirred
1
3
H), 4.10–3.78 (m, 25H), 3.62–3.43 (m, 14H). C-NMR (CDCl
3
,
overnight at rt. 150 ml CH
extracted with CH Cl (3 ¥ 10 ml), the combined organic phases
were washed with sat. NH Cl (3 ¥ 50 ml) and brine 50 ml. The
residue was purified by flash chromatography, EtOAc:pentane, 1:4.
The desired product 13 appeared at R
= 0.28, in 25% yield (0.65 g),
and the diol 14 R 0.12, 54% yield (1.42 g), (TLC: EtOAc:pentane,
1:3) as colourless foams. 13: H-NMR (CDCl
2
Cl
2
was added and the water phase was
00 MHz) d : 139.4, 139.3, 138.4, 138.3, 138.1, 138.0, (Cipso) 134.7
C
2
2
(
C
allyl), 128.2, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3,
27.2, 126.9 (CAr), 116.870 (Callyl), 98.8, 98.7, 98.6 (C-1), 80.9,
9.5, 79.1, 79.0, 78.9, 78.8, 75.6, 75.5, 73.3, 73.3, 72.7, 72.7, 72.2,
4
1
7
7
2
f
1.4, 71.3, 68.9. MALDI-TOF, m/z calcd. for C154
H
164
O30Na:
f
1
516.1205, found: 2515.7367.
3
, 400 MHz) d :
H
7
.43–7.03, (m, 80H, Ph), 5.51 (dd, J = 2.9, J = 10.9, 2H), 5.35
A
D
A-F
A-F
6
6
,6 -Di-O-(but-2-ene-1,4-diyl)-2 , 3
,
(d, J = 3.6, 1H), 5.29 (d, J = 10.5, 2H), 5.23 (d, J = 3.6), 5.04
B,C,E,F
-hexadecakis-O-benzyl-a-cyclodextrin (10)
(d, J = 10.9, 1H), 5.01 (d, J = 10.9, 1H), 4.96–4.81 (m, 8H), 4.77
(
dd, J = 2.7, J = 9.7, 2H), 4.68 (d, J = 9.5, 1H), 4.65 (d, J = 9.4,
Compound 9 (2.98 g, 1.19 mmol) was dissolved in 350 ml CH
in a three-neck round bottomed flask with condenser, under N
2
Cl
2
,
.
1
3
1
d
H), 4.55–4.22 (m, 24H), 4.08–3.71 (m, 17H), 3.64–3.49 (m, 6H),
2
.48–3.21 (m, 10H), 3.17–3.10 (m, 2H), 2.78 (s, 1H, OH), 1.60–
.49 (m, 2H, CH
nd
Grubbs cat. (2 gen, 0.11 g, 0.13 mmol), dissolved in 10 ml
CH Cl was added dropwise under stirring. The mixture was
refluxed under N for 2.5 h, before the heater was turned off,
allowing cooling to rt. Pb(OAc) (0.10 g, 2.14 mmol) was added
and the mixture left stirring overnight. The reaction mixture
was filtered through silica, washed vigorously with CH Cl and
evaporated. The product was purified by flash chromatography
EtOAc:pentane, 1:4, to afford 2.60 g of 10 (88% yield) as a
colourless foam. H-NMR (CDCl
13
2
-CH
2
(OH)(CH
2
). C-NMR (CDCl
3
, 100 MHz)
2
2
C
: 139.7, 139.5, 139.4, 139.3, 138.8, 138.3, 138.2, 138.1, 137.9,
ipso), 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 127.4,
27.1, 127.0, 126.9, 126.7, 126.5, 126.1, (CAr), 100.9, 100.3, 98.6,
2
(
C
4
1
9
8
7
6
8.5, 97.9, 97.8 (C-1), 82.5, 82.2, 81.8, 81.6, 81.5, 81.2, 80.6, 80.6,
0.5, 80.4, 80.2, 80.1, 79.6, 78.8, 77.8, 77.6, 76.4, 76.0, 75.3, 74.2,
3.3, 73.1, 73.0, 72.6, 72.0, 71.8, 71.7, 71.6, 71.2, 70.6, 70.1, 69.2,
2
2
9.0, 33.0 (CH
2
-CH
31Na: 2506.0998 found: 2505.8652.
, 400 MHz) d : 7.37–7.04 (m, 80 H, Ph),
2
(OH)(CH )). MALDI-TOF, m/z calcd. for
2
1
3
, 400 MHz) d : 7.42–7.07 (m,
H
C
152
H
162
1
O
8
0H, Ph), 5.56 (m, 1H), 5.48 (m, 2H), 5.41 (m, 1H), 5.35 (d,
1
4: H-NMR (CDCl
3
H
J = 10.5, 1H), 5.26 (d, J = 10.5, 1H), 5.17 (d, J = 3.6, 1H),
5
5
.52 (m, 1H), 5.46 (m, 1H), 5.40 (m, 1H), 5.34 (m, 1H), 5.25–
.14 (m, 2H), 4.98–4.79 (m, 12H), 4.73–4.66 (m, 2H), 4.59–4.32
5
3
.07–4.96 (m, 4H), 4.93–4.72 (m, 10H), 4.66–4.59 (m, 1H), 4.56–
1
3
.76 (m, 43H), 3.70–3.61 (m, 2H), 3.58–3.32 (m, 14H). C-NMR
, 100 MHz) d : 139.7, 139.5, 139.4, 139.3, 139.2, 138.7,
38.3, 138.2, 138.1, 138,0, 137.8, (Cipso) 128.7, 128.4–125.9 (CAr
alken), 100.8, 99.4, 99.3, 98.5, (C-1) 82.3, 82.0, 81.7 81.2, 81.0, 80.8,
(m, 4H), 4.25–4.15 (m, 3H), 4.07–3.82 (m, 16H), 3.80–3.62 (m,
(
CDCl
1
C
3
C
6
1
1
1
1
H), 3.60–3.39 (m, 11H), 3.36–3.22 (m, 3H), 2.30 (bs, 2H, OH),
,
13
.56–1.44 (m, 4H, -CH
2
-CH
2
-). C-NMR (CDCl
3
, 100 MHz) d
C
:
39.3, 139.2, 139.1, 138.5, 138.4, 138.2, 138.1, 138.0, 137.8, (CIpso
28.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3,
27.2, 127.1, 127.0, 126.7, (CAr), 98.7, 98.6, 98.3, 98.1, 98.0, 97.9,
)
80.6, 80.6, 79.8, 79.6, 78.70, 78.5, 78.0, 77.8, 76.4, 75.9, 74.5, 73.2,
73.2, 73.1, 73.0, 72.9, 72.8, 72.6, 72.2, 71.8, 71.7, 71.5, 71.4, 71.3,
70.9, 69.9, 69.7, 69.2, 68.7, 68.6, 60.3. MALDI-TOF, m/z calcd.
(C-1), 81.3, 81.1, 81.0, 80.7, 80.5, 80.2, 80.1, 79.5, 79.1, 78.9, 78.3,
for C152
H
160
O
30Na: 2488.0892, found: 2487.7099.
7
7.8, 76.1, 75.9, 75.8, 75.7, 74.5, 73.3, 73.2, 72.8, 72.3, 72.3, 71.8,
1.6, 71.6, 71.4, 71.3, 71.0, 70.0, 69.3, 69.2, 68.9, 29.7 (CH ), 26.4
). MALDI-TOF, m/z calcd. for C152 31Na: 2508.1154
found: 2507.8845.
7
2
A
D
6
,6 -Di-O-(butane-1,4-diyl)-a-cyclodextrin (11)
(CH
2
164
H O
The capped CD 10 (0.16 g, 0.07 mmol) was dissolved in 20 ml
MeOH:EtOAc, 1:1. TFA (cat.) and Pd/C (10%, 0.12 g) were
A
D
A-F
A-F
added. The mixture was flushed with N
2
and afterwards H
2
6 ,6 -Di-O-(but-2-one-1,4-diyl)-2 , 3 ,
B,C,E,F
was introduced, and left stirring for 48 h. The reaction mixture
6
-hexadecakis-O-benzyl-a-cyclodextrin (15)
was filtered through celite, washed with water (3 ¥ 10 ml) and
Compound 13 (0.65 g, 0.03 mmol) was dissolved in 40 ml CH
under N , and Dess–Martin periodinane (0.56 g, 1.33 mmol) was
added and stirred at rt for 3 h. The mixture was diluted with 30 ml
Et O and a solution of 30 ml sat. NaHCO containing 1.30 g
Na was added and stirred for 1 h. The organic phase was
washed with sat. NaHCO (3 ¥ 20 ml) and water (2 ¥ 20 ml)
followed by drying with MgSO . The residue was purified by flash
chromatography, EtOAc:pentane, 1:4, to give 0.54 g of 15 (84%
2
Cl
2
EtOAc (3 ¥ 10 ml). Evaporation and freeze drying gave 0.07 g of
1
2
compound 11 (100% yield) as a colourless solid. H-NMR (D
2
O,
4
3
4
1
7
2
1
00 MHz) d
H
: 5.14–5.03 (m, 6H, H-1), 4.79 (m, 16H, OH), 4.20–
2
3
.58 (m, 33H), 3.58–3.49 (m, 3H), 3.47–3.33 (m, 4H), 1.77–1.46 (m,
1
3
2
S
2
O
3
H, O-CH
2
-CH
2
-). C-NMR (DMSO-d
6
, 100 MHz) d : 102.1,
C
3
01.5, 101.0 (C-1), 83.4, 82.0, 81.7, 81.2, 74.1, 73.2, 73.0, 72.9,
2.1, 72.0, 71.9, 71.7, 71.5, 70.7, 69.5, 68.4, 60.0, 59.9, 59.8, 59.2,
6.1 (-O-CH
4
2
-CH
2
-). MALDI-TOF, m/z calcd. for C40
66
H O30Na:
1
yield) as a colourless foam. R
f
= 0.38, EtOAc:pentane, 1:2.5. H-
049.3537, found: 1049.7639.
NMR (CDCl , 400 MHz) d
3
H
: 7.51–7.11 (m, 80H, Ph), 5.73 (m,
A
D
A-F
A-F
B,C,E,F
1H), 5.68–5.61 (m, 2H), 5.43–5.34 (m, 3H), 5.18–4.79 (m, 15H),
4.73–4.52 (m, 14H), 4.50–4.29 (m, 9H), 4.26–3.95 (m, 13H), 3.945–
3.74 (m, 8H), 3.74–3.65 (m, 3H), 3.63–3.51 (m, 5H), 3.44–3.35 (m,
6
,6 -Di-O-(2-hydroxy-butane-1,4-diyl)-2 , 3 , 6
-
A
hexadecakis-O-benzyl-a-cyclodextrin (13) and 6 -O-(4-
hydroxybutyl)-2 , 3 , 6
a-cyclodextrin (14)
A-F
A-F
B,C,E,F
-hexadecakis-O-benzyl-
1
3
3
H), 3.23 (m, 2H), 2.43–2.34 (m, 2H, CH
2
CO). C-NMR (CDCl ,
3
100 MHz) d
C
: 206.2 (C=O), 139.7, 139.5, 139.4, 139.3, 139.2,
Compound 10, (2.60 g, 0.25 mmol) dissolved in 30 ml THF, was
138.9, 138.7, 138.4, 138.3, 138.2, 138.1, 138.0, 137.8 (CIpso), 128.3,
128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2,
126.9, 126.7, 126.6, 126.1 (CAr), 100.5, 100.3, 99.8, 99.0, 98.6, 96.9
added to 9-BBN (0.5M in THF, 32 ml, 16.0 mmol) and stirred for
◦
24 h at rt under N
2
. The mixture was cooled to 0 C, 8 ml 3M
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 933–943 | 939

View Article Online
A
D
A-F
A-F
(
C-1), 82.2, 82.1, 81.8, 81.7, 80.9, 80.8, 80.6, 79.9, 79.6, 78.9, 78.6,
6 , 6 -Di-O-(prop-2-ol-1,3-diyl)-2 , 3 ,
B,C,E,F
7
7.8, 76.5, 76.4, 76.0, 74.0, 73.7, 73.5, 73.3, 73.2, 73.1, 72.7, 72.1,
2.1, 71.8, 71.7, 71.5, 71.0, 70.6, 69.6, 69.2, 69.1, 67.1, 38.1 (CH
CO). MALDI-TOF, m/z calcd. for C152 31Na: 2504.0841
found: 2503.8251.
6
-hexadecakis-O-benzyl-a-cyclodextrin (24)
7
CH
2
-
To a solution of compound 23 (2.58 g, 1.05 mmol) in 60 ml
THF, NaBH (0.10 g, 2.70 mmol) was added, and stirred for
h. 50 ml HCl (1M) and 150 ml CH Cl were added. The water
phase was extracted with CH Cl (3 ¥ 50 ml) and the combined
organic phases washed with brine (4 ¥ 75 ml). The organic mixture
was dried with MgSO and evaporated, to give 2.40 g (93%
yield) of the desired product 24 as a colourless foam. R
= 0.14,
EtOAc:pentane, 1:3. MALDI-TOF, m/z calcd. for C151
492.0841, found: 2492.2189.
2
160
H O
4
2
2
2
2
2
A
D
6
,6 -Di-O-(butan-2-on-1,4-diyl)-a-cyclodextrin (16)
4
Compound 15 (0.42 g, 0.17 mmol) was dissolved in 40 ml
MeOH:EtOAc, 1:1. Cat. TFA and 208 mg Pd/C (10%) were added.
f
160
H O31Na:
The mixture was flushed with N
the mixture was filtered through Celite, and washed with water (3 ¥
0 ml) and EtOAc (3 ¥ 10 ml). The solvents were evaporated to
2
before introducing H
2
. After 24 h
2
1
A
D
A-F
A-F
1
3
6 , 6 -Di-O-(prop-2yl-O-THP-1,3-diyl)-2 , 3 ,
afford compound 16 as a colourless solid (0.18 g, ~100%). C-
NMR (DMSO-d , 100 MHz) d
: 205.0 (C=O), 102.21, 102.16,
01.9, 101.8, 100.8, 100.6, (C-1), 83.6, 82.3, 82.1, 81.4, 81.2, 74.3,
B,C,E,F
6
-hexadecakis-O-benzyl-a -cyclodextrin (25)
6
C
1
7
6
Compound 24 (2.39 g, 0.97 mmol) was dissolved in 15 ml dry
CH Cl , and camphor sulfonic acid (5.00 mg, 0.02 mmol) was
added under N . After 10 min 3,4-dihydro-[2H]-pyran (DHP,
.27 ml, 2.97 mmol) was added and the reaction mixture was
stirred for 3.5 h. 1.4 ml triethylamine and 120 ml CH Cl were
added and the mixture was washed with water (3 ¥ 50 ml), dried
with MgSO and evaporated. The product was purified by flash
chromatography, EtOAc:pentane, 1:4, to obtain 2.37 g of 25 (96%
4.1, 73.0, 72.9, 72.0, 71.9, 71.8, 71.7, 71.6, 71.5, 70.6, 70.4,
8.7, 68.4, 64.2, 60.1, 59.9, 59.4. MALDI-TOF, m/z calcd. for
2
2
2
C
40
H
64
O31Na: 1063.3329, found: 1063.7561.
0
2
2
A
D
A-F
A-F
6
6
,6 -Di-O-(pentane-1,5-diyl)-2 , 3
,
B,C,E,F
-hexadecakis-O-benzyl-a-cyclodextrin (17)
4
Hexadecabenzylated a-CD diol (8, 0.74 g, 0.31 mmol) was dis-
solved in 60 ml dry DMF under N , NaH (60%, 0.05 g, 1.25 mmol)
was added and stirred for 30 min, at rt. 1.5-Dicloropentane
0.04 ml, 0.05 g, 0.326 mmol) was added dropwise over 15 min,
and left stirring overnight. 50 ml water and 50 ml Et O were added
and stirred for 15 min prior to extraction with Et O (3 ¥ 20 ml),
the combined organic phases were washed with water (5 ¥ 20 ml),
0 ml brine and dried with MgSO . The product was purified by
flash chromatography, EtOAc:pentane, 1:5, to obtain 0.41 g of 17
1
yield) as a colourless foam. R
NMR (CDCl , 400 MHz) d : 7.41–7.01 (m, 80H, Ph), 5.68–5.57
m, 4H), 5.34–5.27 (m, 2H), 5.07–5.00 (m, 2H), 4.95–4.73 (m,
f
= 0.45, EtOAc:pentane, 1:3. H-
2
3
H
(
(
1
3H), 4.68 (t, 1H, O-CH(CH )-O), 4.63–4.49 (m, 9H), 4.47–4.43
2
2
(
m, 4H), 4.40–4.27 (m, 7H), 4.25–4.09 (m, 8H), 4.07–3.86 (m,
0H), 3.83–3.65 (m, 6H), 3.63–3.57 (m, 3H), 3.55–3.39 (m, 10H),
.36–3.31 (m, 1H), 3.29–3.18 (m, 2H), 1.88–1.77 (m, 2H, CH ),
: 139.6,
2
1
3
1
1
1
1
9
8
7
7
3
2
2
2
4
13
.63–1.43 (m, 4H, CH
2
). C-NMR (CDCl
3
, 100 MHz) d
C
39.3, 138.8, 138.6, 138.4, 138.3, 138.2, 138.1, 137.8, 137.7 (CIpso),
28.2, 128.1, 127.9, 127.7, 127.6, 127.4, 127.3, 127.0, 126.8, 126.5,
26.4, 125.9 (CAr), 99.9, 99.7, 99.6, 99.4, 99.3, 99.2, 99.0, 97.9,
7.6, 97.5, 96.6 (C-1), 82.1, 81.8, 81.5, 81.5, 81.4, 81.3, 81.2,
1.1, 80.6, 80.1, 80.0, 79.8, 79.2, 79.1, 78.9, 78.8, 77.8, 76.1, 74.4,
3.5, 73.4, 73.3, 73.0, 72.8, 72.7, 72.4, 72.2, 72.0, 71.9, 71.8, 71.5,
1.4, 70.0, 69.6, 69.5, 69.3, 69.1, 68.8, 68.5, 68.4, 62.5, 62.4, 31.1,
1
(
53% yield) as a colourless foam. H-NMR (CDCl
3
, 400 MHz)
),
), 5.14 (d, 2H, J = 3.6 Hz, H-1),
), 4.93–4.79 (m, 9H), 4.61 (d,
d
5
4
2
1
H
: 7.38–7.04 (m, 80H, Ph), 5.47 (d, 2H, J = 10.6 Hz, PhCH
2
.26 (d, 2H, J = 10.7 Hz, PhCH
2
.96 (d, 2H, J = 10.8 Hz, PhCH
2
H, J = 12.7 Hz, PhCH
2
), 4.55–4.37 (m, 14H), 4.35 (d, 2H, J =
2.7 Hz, PhCH ), 4.30–4.17 (m, 7H), 4.16–4.08 (m, 5H), 4.07–3.98
2
(
m, 6H), 3.92–3.86 (m, 4H), 3.73 (d, 2H, J = 9.8 Hz), 3.63 (d, 2H,
J = 9.3 Hz), 3.52 (d, 1H, J = 3.8 Hz), 3.52–3.42 (m, 7H), 3.34 (d,
H, J = 3.0 Hz), 3.32 (d, 1H, J = 3.0 Hz), 3.30–3.23 (m, 5H), 2.92
m, 2H), 1.69 (m, 2H), 1.32 (m, 4H). MALDI-TOF, m/z calcd. for
0.8, 25.4, 19.7, 19.6. MALDI-TOF, m/z calcd. for C156
576.1416, found: 2576.0254.
168
H O32Na:
1
(
C
A
D
6
, 6 -Di-O-(prop-2-yl-THP-1,3-diyl)-a-cyclodextrin (26)
153
H
164
O30Na: 2504.1205, found: 2504.4237.
Compound 25 (2.10 g, 0.82 mmol) was dissolved in 150 ml THF
A
D
and 60 ml water. Pd/C (10%, 1.96 g) was added, and the mixture
6
,6 -Di-O-(pentane-1,5-diyl)-a-cyclodextrin (18)
was flushed with N
2
, afterwards H was introduced, and the
2
The capped cyclodextrin 17 (0.41 g, 0.16 mmol) was dissolved in
0 ml MeOH:EtOAc, 1:1 with cat. TFA and 191 mg Pd/C (10%).
The mixture was flushed with N before introducing H . After 24 h
mixture was stirred for 48 h at rt. The reaction mixture was filtered
4
through paper and 2 ¥ Millipore filters and evaporated to give
1
2
2
0.87 g of 26 (95% yield), to be used directly in the next step. H-
the mixture was filtered through paper and Millipore filters. The
NMR (D
(d, 2H, J = 3.2 Hz, H-1), 5.04 (m, 2H, H-1), 4.96–4.90 (m, 1H,
O-CH(CH )O), 4.23–3.89 (m, 19H), 3.88–3.62 (m, 20H), 3.61–
3.37 (m, 6H), 1.95–1.82 (m, 2H O-CH(CH )O), 1.71–1.55 (m, 4H,
: 101.8, 101.7, 101.2, 100.7,
)-O), 82.2, 82.0, 81.5, 81.3, 80.6,
74.5, 74.3, 72.9, 72.9, 72.7, 72.6, 72.5, 72.0, 71.7, 71.7, 71.6, 71.5,
71.2, 71.1, 70.8, 69.9, 69.0, 64.7, 60.9, 60.8, 60.4 (O-CH ), 32.1
(CH ), 30.7 (CH ), 25.3 (CH ), 21.0 (CH ). MALDI-TOF, m/z
calcd. for C44 32Na: 1135.3904, found: 1135.0479.
2
O, 400 MHz) d
H
: 5.19 (d, 2H, J = 3.6 Hz, H-1), 5.08
solvents were evaporated to afford compound 18 as a colourless
1
solid, 0.17 g (~100% yield). H-NMR (D
2
O, 400 MHz) d
H
: 4.86–
2
4
.74 (m, H-1, OH), 4.03–4.00 (d), 3.84–3.26 (m), 3.20–3.14 (k),
.10–3.06 (t), 1.38 (m, OCH -CH -), 1.17 (m, CH -CH -CH ).
, 100 MHz) d : 102.1, 101.8, 101.1 (C-1),
3.5, 82.2, 82.0, 81.5, 81.2, 74.0, 73.3, 73.0, 72.9, 72.2, 71.8, 70.6,
0.4, 70.2, 70.0, 68.9, 59.6, 59.3, 28.9 (s, 2C, OCH -CH -), 22.4 (s,
C, CH -CH -CH ). MALDI-TOF, m/z calcd. for C41
2
1
3
3
2
2
2
2
2
CH
2
). C-NMR (D
2
O, 100 MHz) d
C
1
3
C-NMR (DMSO-d
6
C
100.4, 100.1 (C-1), 94.5 (O-C(CH
2
8
7
1
1
2
2
2
2
2
2
H
68
O
30Na:
2
2
2
2
063.3693, found: 1063.2753.
72
H O
9
40 | Org. Biomol. Chem., 2009, 7, 933–943
This journal is © The Royal Society of Chemistry 2009

View Article Online
A
D
A-F
A-F
A
D
B
E
6
6
,6 -Di-O-(prop-2-ol-1,3-diyl)-2 , 3
,
6 ,6 -Di-O-(prop-2-methylidene-1,3-dienyl)-6 ,6 -di-O-methyl-
tetradeca-O-benzyl-a-cyclodextrin (31)
B,C,E,F
-hexadecakis-O-methyl-a-cyclodextrin (27)
Compound 26 (0.47 g, 0.43 mmol) was dissolved in 50 ml dry
DMF, cooled to 0 C and NaH 55% (1.21 g, 27.7 mmol), was
To a stirred solution of 30 (0.5 g, 0.22 mmol) in dry THF (10 mL)
◦
was added NaH 50% (0.042 g, 0.88 mmol, 4 eq.) under N . After
2
◦
added. After stirring for 30 min MeI (3.65 g, 25.9 mmol) was
added and allowed to warm to rt. The reaction mixture was stirred
30 min MeI (0.055 mL, 0.88 mmol, 4 eq.) was added at 0 C. The
reaction was kept stirring at rt for 5 h, and after that time, it was
◦
◦
for 24 h, and then 100 ml water was added at 0 C. The mixture
quenched by addition of water at 0 C (10 mL). The product was
was extracted with Et
The residue was evaporated and then coevaporated with toluene
2 ¥ 25 ml) and used directly for the next step. MALDI-TOF,
m/z calcd. for C60 32Na: 1359.6408, found: 1359.2131. The
residue was dissolved in 30 ml 50% AcOH and left stirring for 4 h.
TLC (i-PrOH:EtOAc:H O, 3:2:1) showed the alcohol at R
= 0.35,
and the fully methylated at R
= 0.39. The reaction mixture was
evaporated, and the product was purified by flash chromatography,
CH Cl :MeOH, 100:3, to obtain 0.18 g of 27 (34% yield) as a
colourless foam. H-NMR (CDCl
2
O (5 ¥ 100 ml) and dried with MgSO
4
.
extracted with EtOAc (3 ¥ 15 mL), and the organic layer was
separated and washed with brine, dried over MgSO , filtered and
4
(
the filtrate was concentrated to dryness and purified by column
H
104
O
chromatography (pentane→1:3 EtOAc/pentane) to afford 31 as
1
a foam (0.501 g, 98%). H-NMR (400 MHz, CDCl
3
), d (ppm):
H
2
f
7.30–7.00 (m, 70H, Ar-H), 5.55–5.51 (2d, 4H, JH,H= 10.6 Hz, J1,2
3.8 Hz, CH
, H-1), 5.22 (d, 2H, Jgem = 10.6 Hz, H-CHPh), 5.06 (bs,
2H, CH
=
f
2
2
), 4.97 (d, 2H, Jgem = 10.4 Hz, H-CHPh), 4.84–4.71 (m,
2
2
8H), 4.65–4.63 (m, 4H), 4.45–4.35 (m, 10H), 4.30–4.21 (m, 8H),
4.09–4.03 (m, 4H), 3.93–3.81 (m, 12H), 3.75–3.54 (m, 8H), 3.48–
3.39 (m, 8H), 3.28 (dd, 2H, J = 3.4, J = 9.3 Hz), 3.28–3.36 (m,
1
3
, 400 MHz) d : 5.04 (d, 2H,
H
J = 3.1 Hz, H-1), 5.02 (d, 2H, J = 3.2 Hz, H-1), 4.94 (d, 1H,
1
3
J = 3.5 Hz, H-1), 4.90 (d, 1H, J = 3.5 Hz, H-1), 4.15–4.04 (m,
2H), 3.27 (bs, 3H), 3.24 (bs, 3H). C-NMR (100 MHz, CDCl
3
), d
C
3
3
H), 3.98–3.31 (m, 81H (high peaks, O-CH
3
, 3.70, 3.65, 3.64,
(ppm): 142.46 (C=), 139.81, 139.77, 139.42, 139.26, 138.94, 138.90,
138.46, 138.43, 138.17, 138.11, 137.89 (Cipso), 128.43, 128.37,
128.33, 128.28, 128.21, 128.08, 128.06, 128.02, 127.86, 127.80,
127.77, 127.67, 127.53, 127.21, 127.13, 127.05, 126.97, 126.74,
.58, 3.52, 3.48, 3.48, 3.45, 3.39, 3.38, 3.35)), 3.20–3.04 (m, 8H).
1
3
C-NMR (CDCl
3
, 100 MHz) d : 100.7, 100.6, 99.4, 99.1, 98.2,
C
9
8
7
5
7.9 (C-1), 82.8, 82.7, 82.6, 82.6, 82.4, 82.3, 82.2, 82.1, 82.0, 81.8,
1.4, 81.3, 81.2, 72.8, 72.5, 72.1, 71.8, 71.8, 71.7, 71.4, 71.0, 70.7,
0.3, 69.4, 62.1, 61.8, 61.3, 61.2, 59.4, 59.3, 59.2, 59.1, 59.0, 57.6,
126.65, 126.30, 126.02 (CHPh),114.64 (CH
=), 100.06, 99.74, 97.93
2
(C-1), 82.59, 81.53, 81.19, 81.14, 81.04, 80.97, 80.84, 80.79, 80.16,
79.63, 78.82, 77.91, 77.85, 77.47, 77.36, 77.16, 76.84, 76.74, 76.47,
76.41, 73.66, 73.59, 73.38, 73.28, 73.22, 72.23, 72.05, 71.99, 71.81,
7.5, 57.4. MALDI-TOF, m/z calcd. for C55
96
H O31Na: 1275.5833,
found 1275.8515.
7
0.68 (CH
2
), 69.27, 69.04 (C-6), 68.96 (CH
2
), 63.19 (CH ). MS:
3
A
D
A-F
A-F
calcd for C140H152O Na: 2337.677, found 2337.593.
6
6
, 6 -Di-O-(prop-2-one-1,3-diyl)-2 , 3
,
30
B,C,E,F
-hexadecakis-O-methyl-a-cyclodextrin (28)
A
D
B
E
2
7 (0.18 g, 0.14 mmol) was dissolved in 9 ml CH
2
Cl
2
under N
2
.
6 ,6 -Di-O-(prop-2-one-1,3-dienyl)-6 ,6 -di-O-methyl-tetradeca-
O-benzyl-a-cyclodextrin (32)
Dess–Martin periodinane (0.31 g, 0.73 mmol) was added and the
mixture was stirred for 2 h at rt. 30 ml CH Cl and a solution
of 30 ml sat. NaHCO containing 1.30 g Na were added
and stirred for 1 h. The organic phase was washed with sat.
NaHCO (3 ¥ 20 ml) and brine (2 ¥ 20 ml) followed by drying
with MgSO . The residue was purified by flash chromatography,
CH Cl :MeOH, 100:2, to give the desired product 28 in 0.12 g (63%
yield) as a colourless foam. R
NMR (CDCl , 400 MHz) d
2
2
Compound 31 (0.5 g, 0.216 mmol) was dissolved in a 4/3 mixture
3
2
S
2
O
3
THF/water (12 mL) and NaIO
added slowly together with a solution 2.5% wt OsO
0.1 mL). The reaction mixture was stirred for ca. 12 h when a
solution of 10% Na was added to quench the reaction. The
product was extracted with EtOAc (3 ¥ 50 mL). The combined
organic fractions were concentrated to dryness to afford the
corresponding diol as white foam. The diol was dissolved in
4
(0.235 g, 1.1 mmol, 5 eq.) was
4
in butanol
3
(
4
2
S
2
O
3
2
2
1
f
= 0.45, acetone:toluene, 1:1. H-
: 5.02 (d, 2H, J = 3.6 Hz, H-1), 4.98
3
H
(
1
d, 2H, J = 3.2 Hz, H-1), 4.94 (d, 2H, J = 3.4 Hz, H-1), 4.29 (s,
CH
SiO
2
Cl
2
(3.5 mL) and 1.3 g of NaIO
4
/SiO
2
(2.54 g NaIO /10 g
4
H), 4.24 (s, 1H), 4.13–4.05 (m, 4H), 3.99–3.90 (m, 4H), 3.83–3.69
2
, 5 eq.) was added. After stirring for 3 h, the suspension
(
m, 13H), 3.64–3.55 (m, 20H), 3.51–3.43 (m, 24H), 3.39–3.25 (m,
was filtered and after the evaporation of the solvent and flash
chromatography (pentane/EtOAc, 5/2) 0.405 g (81%) of the
corresponding ketone was obtained as a white foam. H-NMR
1
3
1
2), 3.18–3.04 (m, 9H). C-NMR (CDCl
3
, 100 MHz) d : 203.9
C
(
C=O), 100.5, 99.0, 98.2 (C-1), 82.8, 82.6, 82.3, 81.9, 81.8, 81.8,
1
8
5
1
1.4, 81.2, 81.1, 73.7, 72.6, 71.6, 70.8, 69.0, 62.0, 61.7, 61.2, 59.1,
9.0, 58.9, 57.6, 57.5, MALDI-TOF, m/z calcd. for C55
273.5677, found: 1273.7667.
(
400 MHz, CDCl
3
), d (ppm): 7.34–7.03 (m, 70H, Ar-H), 5.51
H
94
H O31Na:
(
d, 2H, Jgem = 10.6 Hz, H-CHPh), 5.34 (d, 2H, J = 3.9 Hz, H-
1
1
CH
), 5.27 (d, 2H, Jgem = 10.6 Hz, H-CHPh), 4.99 (d, 2H, Jgem
0.6 Hz, H-CHPh), 4.89–4.81 (m, 6H, CH Ph), 4.73–4.67 (m, 6H,
Ph, H-1), 4.48–4.22 (m, 18H), 4.16–3.97 (m, 10H), 3.89–3.71
=
2
A
D
6
,6 -Di-O-(prop-2-methylidene-1,3-dienyl)-hexadeca-O-benzyl-
2
a-cyclodextrin (29)
(
m, 14H), 3.59–3.50 (m, 6H), 3.44 (dd, 2H, J = 3.2, J = 9.9 Hz),
1
3
3
.38–3.33 (m, 4H), 3.23 (bs, 6H). C-NMR (100 MHz, CDCl
3
),
In reference 27.
d
C
(ppm): 203.72 (C=O), 139.72, 139.44, 139.41, 138.76, 138.36,
A
D
A-F A-F
C
F
137.93 (Cipso), 128.58, 128.40, 128.36, 128.29, 128.25, 128.02,
6
,6 -Di-O-(prop-2-methylidene-1,3-dienyl)-2 ,3 ,6 ,6 -
127.97, 127.76, 127.73, 127.66, 127.28, 127.16, 127.06, 126.97,
26.05 (CHPh), 100.67, 100.08, 98.48 (C-1), 82.38, 82.03, 80.91,
tetradeca-O-benzyl-a-cyclodextrin (30)
1
In reference 34.
80.73, 80.60, 80.02, 78.94, 77.47, 77.16, 76.84, 76.70, 76.03, 74.00,
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 933–943 | 941

View Article Online
7
3.90, 73.33, 73.09, 72.90, 72.11, 71.93, 71.68, 68.75, 68.57, 58.97
reaction. The product was extracted with EtOAc (3 ¥ 50 mL).
The combined organic fractions were concentrated to dryness
to afford the corresponding diol as white foam. The diol was
(
CH ).
3
MS: calcd for C139
150
H O31Na: 2338.006, found 2338.005.
dissolved in CH
2
Cl
2
(3 mL) and 1.17 g of NaIO
4
/SiO (2.54 g
2
A
D
B
E
6
,6 -Di-O-(prop-2-one-1,3-dienyl)-6 ,6 -di-O-methyl-a-
NaIO4/10 g SiO2, 5 eq.) was added. After stirring for 3 h, the
suspension was filtered and after the evaporation of the solvent
and flash chromatography (pentane/EtOAc, 5/2) 0.362 g (76%) of
cyclodextrin (33)
Compound 32 (0.200 g, 0.086 mmol) was dissolved in a 1:1 mixture
MeOH/AcOEt (15 mL). Then Pd/C (200 mg) and TFA (cat.) were
added and the mixture was kept stirring overnight under hydrogen
atmosphere. Filtration and removal of the solvents gave 33 as foam
88.2 mg, 97%). H-NMR (400 MHz, D
1
the corresponding ketone was obtained as a white foam. H-NMR
(
400 MHz, CDCl
H, Jgem = 10.4 Hz, H-CHPh), 5.49 (2d, 4H, J = 3.9, J = 10.4 Hz,
H-1, H-CHPh), 5.20 (d, 2H, Jgem = 10.4 Hz, H-CHPh), 5.07–5.02
m, 6H, CH Ph), 4.99–4.95 (m, 4H, CH
Ph, H-1), 4.87 (d, 2H, J =
.2 Hz, H-1), 4.78–4.62 (m, 12H, H-1, H-CHPh), 4.54–4.42 (m,
3
), d
H
(ppm): 7.54–7.24 (m, 70H, Ar-H), 5.72 (d,
2
1
(
(
2
O), d (ppm): 5.12–5.01
H
(
2
2
m, 6H, H-1), 4.82–4.74 (m), 4.14–4.11 (m, 2H), 4.08–4.01 (m, 6H),
.95–3.87 (m, 8H), 3.84–3.75 (m, 8H), 3.72–3.55 (m, 14H), 3.42
3
1
3
9
d
1
1
1
9
7
7
3
0H), 4.36–4.24 (m, 10H), 4.20–4.11 (m, 6H), 4.05–3.92 (m, 6H),
1
3
(
(
bs, 6H, CH
3
). C-NMR (100 MHz, DMSO), d (ppm): 208.98
C
.79–3.72 (m, 4H), 3.70–3.65 (m, 4H), 3.54 (dd, 2H, J = 3.2, J =
C=O), 101.56, 101.40, 99.96 (C-1), 82.93, 82.58, 81.79, 81.72,
13
.7 Hz, H-2), 1.40 (bs, 18H, CH
3
). C-NMR (100 MHz, CDCl
3
),
80.18, 79.86, 74.03, 73.35, 72.64, 72.57, 72.02, 71.91, 71.72, 71.32,
(ppm): 202.95 (C=O), 177.84 (C=O), 139.72, 139.39, 139.23,
C
71.06, 70.90, 59.09 (CH
3
). MS: calcd for C41
H
66
O31Na: 1077.934,
38.79, 138.32, 137.97, 137.85 (Cipso), 128.41, 128.33, 128.30,
28.23, 128.20, 128.09, 128.06, 128.01, 127.94, 127.80, 127.64,
27.52, 127.20, 127.11, 126.89, 126.69, 126.03 (CHPh), 100.25,
8.29 (C-1), 82.63, 81.96, 80.76, 80.69, 80.67, 80.56, 80.02, 78.75,
7.78, 77.47, 77.16, 76.84, 76.69, 76.26, 73.89, 73.44, 73.23, 72.97,
found 1077.986.
A
D
B
E
6
,6 -Di-O-(prop-2-methylidene-1,3-dienyl)-6 ,6 -di-pivalate-
tetradeca-O-benzyl-a-cyclodextrin (34)
2.29, 72.17, 70.76, 68.97, 68.65, 63.00 (C-6), 38.97 (CCH
3
), 27.44
To a stirred solution of 30 (0.5 g, 0.22 mmol) in dry CH
5 mL) was added Et
0.87 mL, 7.04 mmol) under N
rt for 5h, and after that time, water was added and the product
2
Cl
2
(CH
3
). MS: calcd for C147
162
H O33Na: 2478.090, found 2478.64.
(
(
3
N (0.98 mL, 7.04 mmol) and pivaloyl chloride
. The reaction was kept stirring at
2
A
D
B
E
6 ,6 -Di-O-(prop-2-one-1,3-dienyl)-6 ,6 -di-O-pivalate-a-
was extracted with EtOAc (3 ¥ 25 mL). The organic layer was
cyclodextrin (36)
separated and washed with brine, dried over MgSO , filtered and
the filtrate was concentrated to dryness and purified by column
4
Compound 35 (0.200 g, 0.083 mmol) was dissolved in a 1:1 mixture
MeOH/EtOAc (15 mL). Then Pd/C (200 mg) and TFA (cat.)
were added and the mixture was kept stirring overnight under a
chromatography (pentane→1:3 EtOAc/pentane) to afford 34 as
1
a foam (0.48 g, 98%). H-NMR (400 MHz, CDCl
7
(
3
), d
H
(ppm):
), 5.44
hydrogen atmosphere. Filtration and removal of the solvents gave
.33–7.04 (m, 70H, Ar-H), 5.57 (d, 2H, J = 10.1 Hz, CH
2
1
3
6 as foam (98,3 mg, 99%). H-NMR (400 MHz, D
2
O), d (ppm):
H
d, 2H, J = 3.5 Hz, H-1), 5.28 (d, 2H, Jgem = 10 Hz, H-CHPh),
5
.19–5.04 (m, 6H, H-1), 4.92–4.74 (m), 4.57 (q, 4H, H-5), 4.36 (t,
5
.12 (bs, 2H, CH
2
), 4.99 (d, 2H, Jgem = 10.2 Hz, H-CHPh), 4.87–
J = 4.26 Hz, 2H, H-3), 4.20 (d, J = 12 Hz, 2H, H-CHCO), 4.19–
4
4
3
J
.81 (m, 6H), 4.77–4.72 (m, 4H), 4.69 (d, J = 3.2 Hz, 1H, H-1),
.52–4.42 (m, 9H), 4.36–4.23 (m, 10H), 4.14–4.01 (m, 8H), 3.96–
.85 (m, 6H), 3.78 (d, 2H, Jgem = 10.4 Hz, H-CHPh), 3.64 (d, 2H,
gem = 10 Hz, H-CHPh), 3.57–3.44 (m, 14H), 3.34 (dd, 2H, J =
4
.01 (m, 12H), 3.89–3.84 (m, 6H), 3.79–3.63 (m, 16H), 3.49–3.34
1
3
(
m, 4H, H-4), 1.31 (bs, 18H, CH
ppm): 208.10 (C=O), 180.79 (C=O), 102.33, 101.67, 98.26 (C-1),
3.09, 81.30, 79.21, 74.24, 74.22, 74.20, 73.47, 73.25, 72.58, 72.46,
71.47, 71.40, 71.33, 70.30, 68.94, 63.27 (CH ), 60.95 (CH ), 39.00
CCH ), 27.04 (CH ). MS: calcd for C49 33Na: 1217.432 found
217.457.
3
). C-NMR (100 MHz, D
2
O), d
C
(
8
3
CH
.4, J = 9.6 Hz), 3.17–3.08 (m, 2H), 1.30 (s, 3H, CH
3
), 1.26 (s, 3H,
), d (ppm):
1
3
2
2
3
), 1.21 (s, 12H, CH
3
). C-NMR (100 MHz, CDCl
3
C
(
1
3
3
78
H O
1
1
1
1
1
1
7
7
6
77.91 (C=O), 142.46 (C=), 139.81, 139.77, 139.42, 139.26, 138.94,
38.90, 138.46, 138.43, 138.17, 138.11, 137.89 (Cipso), 128.43,
28.37, 128.33, 128.28, 128.21, 128.08, 128.06, 128.02, 127.86,
27.80, 127.76, 127.67, 127.53, 127.21, 127.13, 127.05, 126.74,
Procedure for determining the rate of oxidation
26.65, 126.01 (CHPh), 114.64 (CH
=), 100.05, 99.74, 97.93 (C-
2
Each assay was performed on 8 samples (2 mL each) of the
appropriate substrate at different concentrations in 190 mM
), 82.59, 81.53, 81.13, 80.97, 80.84, 80.79, 80.16, 79.62, 78.82,
7.90, 77.85, 77.47, 77.36, 77.16, 76.84, 76.74, 76.47, 76.41, 73.66,
phosphate buffer containing 64 mM H
2
O
2
, and either the catalyst
3.59, 73.38, 73.27, 73.21, 72.23, 72.04, 71.98, 70.68 (CH
8.96 (C-6), 63.19 (C-6), 39.00 (CCH ), 28.63, 27.47, 27.14 (CH
32Na: 2477.856, found 2477.593.
2
), 69.26,
◦
(
1 mg) or nothing as control. The reactions were followed at 25 C
3
3
).
using UV absorption at an appropriate wavelength (see below)
and typically monitored for 30 min for benzyl amines and 5 h
for benzyl alcohols. Velocities were determined as the slope of
the progress curve of each reaction. Uncatalysed velocities were
obtained directly from the control samples. Catalysed velocities
were calculated by subtracting the uncatalysed rate from the
total rate of the appropriate cyclodextrin containing sample.
The catalysed velocities were used to construct Hanes plots
([S]/V vs. [S]) to ensure that the reaction followed Michaelis-
MS: calcd for C148
164
H O
A
D
B
E
6
,6 -Di-O-(prop-2-one-1,3-dienyl)-6 ,6 -di-pivalate-tetradeca-
O-benzyl-a-cyclodextrin (35)
Compound 34 (0.48 g, 0.195 mmol) was dissolved in a 4/3 mixture
of THF/water (11 mL) and NaIO (0.208 g, 0.975 mmol, 5
eq.) was added slowly together with a solution 2.5% wt OsO
in butanol (0.2 mL). The reaction mixture was stirred for ca.
4
4
1
2 h when a solution of 10% Na
2
S
2
O
3
was added to quench the
Menten kinetics. In that case K
m
and Vmax were determined
9
42 | Org. Biomol. Chem., 2009, 7, 933–943
This journal is © The Royal Society of Chemistry 2009

View Article Online
using least square non-linear regression fitting to the Vmax vs.
S curve. kcat was calculated as Vmax/[cyclodextrin]. kuncat was
determined as the slope from a plot of Vuncat vs. [S]. The following
7 R. Breslow and B. Zhang, J. Am. Chem. Soc., 1992, 114, 5882–5883.
8
T. Akiike, Y. Nagano, Y. Yamamoto, A. Nakamura, H. Ikeda, A. Veno
and F. Toda, Chem. Lett., 1994, 1089–1092.
R. Breslow and B. Zhang, J. Am. Chem. Soc., 1994, 116, 7893–7894.
9
◦
extinction coefficients (25 C, pH 7) and wavelengths were
10 R. Breslow and S. D. Dong, Chem. Rev., 1998, 98, 1997–2011.
11 H. Ikeda, Y. Horimoto, M. Nakata and A. Ueno, Tetrahedron Lett.,
2000, 41, 6483–6487.
2 D. T. H. Chou, J. Zhu, X. C. Huang and A. J. Bennet, J. Chem. Soc.,
Perkin Trans. 2, 2001, 83–89.
13 M. Kunishima, K. Yoshimura, H. Morigaki, R. Kawamata, K. Terao
and S. Tani, J. Am. Chem. Soc., 2001, 123, 10760–10761.
4 X. J. Ren, Y. Xue, K. Zhang, J. Q. Liu, G. M. Luo, J. Zheng, Y. Mu and
J. C. Shen, FEBS Lett., 2001, 507, 377–380.
5 J. X. Yu, Y. Z. Zhao, M. Holterman and D. L. Venton, Bioorg. Med.
Chem., 2002, 10, 3291–3299.
6 X. J. Ren, Y. Xue, J. Q. Liu, K. Zhang, J. Zheng, G. Luo, C. H. Guo, Y.
Mu and J. C. Shen, ChemBioChem, 2002, 3, 356–363.
7 Y. Liu, B. Li, L. Li and H. Y. Zhang, Helv. Chim. Acta, 2002, 85, 9–18.
8 J. Yang, B. Gabriele, S. Belvedere, Y. Huang and R. Breslow, J. Org.
Chem., 2002, 67, 5057–5067.
-
1
-1
determined and used: 3-aminophenoxazone-2, 0.42 mM cm at
-
1
-1
4
1
3
00 nm; 4-nitrophenol, 9.03 mM cm at 400 nm; benzaldehyde,
1
.23 mM- cm at 285 nm; acetophenone, 0.32 mM cm at
1
-1
-1
-1
-
1
-1
00 nm; 2-hydroxybenzaldehyde, 2.92 mM cm at 325 nm; 4-
-
1
-1
methoxybenzaldehyde, 7.53 mM cm at 300 nm.
1
1
1
Experimental procedure for NMR binding data
To a solution of the corresponding cyclodextrin in D O (10 mM)
2
in a NMR tube at ambient temperature was added the substrate
2- or 4-aminophenol) in small portions (0.2–0.6 mg/portion)
1
1
(
until the change in the chemical shift (DdH-3) of the cyclodextrin
was negligible. The exact mole ratio of substrate to cyclodextrin
was determined from the integration ratios of the NMR-signals.
Very small amount of DMSO was used as an internal reference.
19 R. Kataky and E. Morgan, Biosens. Bioelectron., 2003, 18, 1407–1417.
20 W. K. Chan, W. Y. Yu, C. M. Che and M. K. Wong, J. Org. Chem.,
2
003, 68, 6576–6582.
1 N. M. Milovic, J. D. Badjic and N. M. Kostic, J. Am. Chem. Soc., 2004,
26, 696–697.
22 C. Rousseau, N. Nielsen and M. Bols, Tetrahedron Lett., 2004, 45,
709–8711.
2
1
A H NMR titration curve was obtained by plotting DdH-3 of
1
27
cyclodextrin against the mole ratio of cyclodextrin and substrate.
For the calculation of the association constant in D O the
fallowing nonlinear equation was used and resolved by using
8
2
2
2
2
3 M. Fukudome, Y. Okabe, M. Sakaguchi, H. Morikawa, T. Fujioka,
D. Q. Yuan and K. Fujjta, Tetrahedron Lett., 2004, 45, 9045–9048.
4 Z. Y. Dong, J. Q. Liu, S. Z. Mao, X. Huang, B. Yang, X. J. Ren, G. M.
Luo and J. C. Shen, J. Am. Chem. Soc., 2004, 126, 16395–16404.
5 M. McNaughton, L. Engman, A. Birmingham, G. Powis and I. A.
Cotgreave, J. Med. Chem., 2004, 47, 233–239.
27
EASYPLOT fitting program: y = b*(x+1+a-(sqrt((x + 1+a)∧2-
*x)))/2.
4
Acknowledgements
26 S. H. Yoo, B. J. Lee, H. Kim and J. Suh, J. Am. Chem. Soc., 2005, 127,
593–9602.
9
We thank the Lundbeck foundation and FNU for financial
support.
27 C. Rousseau, B. Christensen, T. E. Pedersen and M. Bols, Org. Biomol.
Chem., 2004, 2, 3476–3482.
2
2
8 C. Rousseau, B. Christensen and M. Bols, Eur. J. Org. Chem., 2005,
734–2739.
9 L. Marinescu, M. Mølbach, C. Rousseau and M. Bols, J. Am. Chem.
Soc., 2005, 127, 17578–17579.
2
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This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 933–943 | 943