Amino-acetone-bridged cyclodextrins - Artificial alcohol oxidases

Article abstract of DOI:10.1002/ejoc.200901099

A new series of α-and β-cyclodextrin derivatives containing a substituted amino-acetone bridge attached to the 6A and 6D positions of the cyclodextrin are reported. The synthesis starts from the known α-or β-cyclodextrin A,D-diols, which were either oxidized to α-or β-cyclodextrin A,D-dicarbaldehydes and then coupled with 1,3-diamino-2-propanol by a reductive amination reaction and further modified to give the final 6^A,6^D-diamino-6^A,6 ^D-dideoxy-N,N'-(2-oxopropa-1,3-dienyl)-N,N'-acetyl-α-or-β- cyclodextrin or the cyclodextrindiol was substituted with azide then reduced and after a few alkylation steps the final 6^A,6^D-dideoxy-N, N'-(2-oxopropa-1,3-dienyl)-6^A,6^D-(N,N,N'N'- tetramethyldiammonio)-α-cyclodextrin dibromide was obtained. The new compounds display very good enzymatic catalytic properties in the oxidation of benzyl alcohols with a rate increase of up to 18500 but only appreciable catalysis for aniline oxidations. Thus, unlike previously studied cyclodextrin ketones, these new amino-acetone-bridged cyclodextrins have high substrate selectivity and also exhibit stereoselectivity in the oxidation of different enantiomers.

Full text of DOI:10.1002/ejoc.200901099

FULL PAPER
DOI: 10.1002/ejoc.200901099
Amino–Acetone-Bridged Cyclodextrins Ϫ Artificial Alcohol Oxidases
Lavinia G. Marinescu,*[a] Elisa G. Doyagüez,[b] Marta Petrillo,[a]
Alfonso Fernández-Mayoralas,[b] and Mikael Bols[a]
Keywords: Amines / Enzyme catalysis / Alcohols / Oxidation / Cyclodextrins
A new series of α- and β-cyclodextrin derivatives containing
a substituted amino–acetone bridge attached to the 6A and
6D positions of the cyclodextrin are reported. The synthesis
starts from the known α- or β-cyclodextrin A,D-diols, which
were either oxidized to α- or β-cyclodextrin A,D-dicarbal-
dehydes and then coupled with 1,3-diamino-2-propanol by a
reductive amination reaction and further modified to give the
final 6A,6D-diamino-6A,6D-dideoxy-N,NЈ-(2-oxopropa-1,3-di-
enyl)-N,NЈ-acetyl-α- or -β-cyclodextrin or the cyclodextrin-
diol was substituted with azide then reduced and after a few
alkylation steps the final 6A,6D-dideoxy-N,NЈ-(2-oxopropa-
1,3-dienyl)-6A,6D-(N,N,NЈNЈ-tetramethyldiammonio)-α-cyclo-
dextrin dibromide was obtained. The new compounds dis-
play very good enzymatic catalytic properties in the oxi-
dation of benzyl alcohols with a rate increase of up to 18500
but only appreciable catalysis for aniline oxidations. Thus,
unlike previously studied cyclodextrin ketones, these new
amino–acetone-bridged cyclodextrins have high substrate
selectivity and also exhibit stereoselectivity in the oxidation
of different enantiomers.
was performed of the substituent effect on the efficiency of
several artificial enzymes by functional modification of the
amino moiety in the β position next to the acetone. It was
interesting to explore the effect of different substrates on
binding properties, including a more polar environment,
and to compare them with previous reported catalysts.[5]
Cyclodextrins are frequently used as host molecules be-
cause they can be synthetically modified with different
functional groups to create new artificial enzymes. Reac-
tions like alkene epoxidation[6] and aniline oxidation have
been catalysed by the bridged acetone-cyclodextrins 1 and
2 (Figure 1). The oxidation reactions were performed with
hydrogen peroxide and exhibited a kcat/kuncat value of up to
1070.[5] The oxidation reactions of different benzyl alcohols
to aldehydes were carried out by using the bridged acetone-
ester-cyclodextrin 2, which proved to be a remarkably good
artificial enzyme with a rate increase of up to 6.3ϫ104 in
the best case.[7]
Introduction
In recent years many chemists have devoted themselves
to creating small molecules that mimic complex enzymes
and to designing intelligent artificial catalysts that recognize
substrates and can be engineered to suit any reaction and
medium.[1] Enzymes catalyse reactions with a remarkable
rate and selectivity.[2] The basic principles behind their ac-
tivity are the molecular recognition and stabilization of the
transition state of the reaction. However, despite some im-
pressive advances in the field, the activity of natural en-
zymes is still not fully understood. Native[3] and modified[4]
cyclodextrins have been extensively studied as potential en-
zyme mimics and have proved to be valuable candidates
mostly due to their binding properties and their water solu-
bility. A big challenge for chemists is to produce a small
synthetic equivalent to the active site that can rival enzymes
in rate acceleration, turnover and specificity.
We report herein artificial alcohol dehydrogenases that
have an efficiency comparable per molecular weight to a
real enzyme. The oxidation of several benzyl alcohols to
aldehydes was performed with the catalysts in the presence
of a stoichiometric amount of hydrogen peroxide. A study
[a] Department of Chemistry and Nanoscience Center,
University of Copenhagen,
Universitetsparken 5, 2100, Copenhagen, Denmark
Fax: +45-35320200
E-mail: lavinia@kemi.ku.dk
[b] Departmento de Química Biológica, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901099.
Figure 1. Catalysts 1 and 2 consisting of a core of either α- or β-
cyclodextrin with dihydroxyacetone attached to the primary rim
through an ether or ester connection.
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The cup-shaped 1 and 2 bind the aromatic substrate into impossible to obtain pure sulfonyl esters even if many
their hydrophobic cavity (Km ≈ 1–5 m) and the acetone is highly selective sulfonylation reagents have been reported
believed to react with H2O2 to form a hydroperoxide adduct so far.[11] It was therefore a very important development
which is responsible for the oxidation of the bound amine when Sinaÿ and co-workers[12] discovered that DIBAL-H
or alcohol group.
could effect the regioselective de-O-benzylation of the pri-
Our promising results with 1 and 2 encouraged us to mary hydroxy groups in positions 6A and 6D of perbenzyl-
study further structural modifications of the β position with ated cyclodextrins as it allowed the use of these molecules
respect to the reactive acetone. We were particularly inter- in a protected form to ease the purification after each step.
ested in the incorporation of quaternary ammonium which
previously has been successfully used in ketone epoxidation
catalysts.[8] Thus, we describe herein the synthesis of new
By using this strategy, we prepared the A,D-bridged
amino-cyclodextrin derivatives 14, 15 and 21 (Scheme 1 and
Scheme 2) very efficiently starting from commercially avail-
able α- and β-cyclodextrins, which were, in the first step,
subjected to per-O-benzylation using BnCl and NaH in
DMSO as solvent. The per-O-benzylated cyclodextrins were
treated with DIBAL-H in anhydrous toluene under an inert
atmosphere to afford the cyclodextrin-diols 3 and 4 in 90
and 86% yields, respectively, as previously described.[13]
Oxidation of these diols with Dess–Martin periodinane in
dichloromethane gave the α- and β-cyclodextrin dialdehydes
5 and 6 in quantitative yields.[12] Although a number of
methods for the preparation of amino-cyclodextrins have
been reported, they have typically been applied to more
simple compounds[14] and because cyclodextrin-dialdehydes
are readily available, a reductive amination reaction was the
obvious starting point for secondary amine synthesis.
The reductive amination approach has been used on
cyclodextrins several times before for linking chitosan deriv-
atives,[15] hyaluronic acid derivatives[16] and porphyrins[17]
or for the N-glycosidation of 6-amino-6-deoxy-cyclodextrin
with various 6-oxogalactosides[18] with reaction yields of
15–70%.
bridged amino–acetone-cyclodextrin derivatives and
a
study of their activity when having different electron-with-
drawing amino-protecting groups close to the functional
acetone moiety.
Results and Discussion
Synthesis
Amino-cyclodextrins are interesting compounds mainly
due to their ability to form strong guest–host complexes
through van der Waals forces, hydrogen-bonding and
hydrophobic interactions with the cyclodextrin moiety but
also through molecular recognition by electrostatic interac-
tions between the substrate and the amino group at dif-
ferent pHs. Therefore several strategies for the synthesis of
amino-modified cyclodextrins have been reported using dif-
ferent methods for the selective modification of one, two or
the entire face of the cyclodextrin.[9] In general these strate-
gies present many problems concerning poor regioselectiv-
ity and the tedious separation of the mixtures, and so the
Herein we present the synthesis of different 6A,6D-modi-
preparation of regioselectively modified amino-cyclodex- fied cyclodextrin derivatives with an acetone bridge at-
trins is a difficult low-yielding task.[10] The general method tached to the amino groups (14 and 15) by a reductive am-
for the synthesis of amino-cyclodextrins involves the re- ination reaction of α- and β-cyclodextrin dialdehydes 5 and
gioselective preparation of different sulfonyl esters followed 6 with 1 equiv. of 1,3-diamino-2-propanol (7) in the pres-
by substitution with sodium azide and subsequent re- ence of sodium triacetoxyborohydride in dichloromethane
duction to the final amino compound, but it seemed almost at room temperature. Bridged amino compound 8 was ob-
Scheme 1. Synthesis of amino–acetone-cyclodextrins 13 and 14.
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Amino–Acetone-Bridged Cyclodextrins
tained in 42% yield starting from α-cyclodextrin-dialdehyde product was detected by TLC using EtOAc as eluent, prob-
5 and compound 9 in 50% yield starting with the β-cyclo- ably a result of further oxidations of the amino function-
dextrin-dialdehyde 6 (Scheme 1). No dimer formation was ality. The synthesis was finally achieved by the alternative
observed in this step by MALDI-TOF MS or TLC, but route shown in Scheme 2.
imine intermediates were isolated after column chromatog-
raphy.
Conversion of the 6A,6D-alcohols in compound 3 to io-
dides (Scheme 2) proceeded smoothly if care was taken
Further acetylation of the secondary amino group using when adding the iodine. The use of triphenylphosphane and
acetic anhydride in DMF/ethanol (1:1) afforded amide de- iodine can lead to the formation of insoluble adducts, which
rivatives 10 and 11 in 94 and 89% yield, respectively, after can be prevented by the addition of imidazole.[19] Diol 3
column chromatography. When the secondary alcohol moi- was dissolved in toluene, triphenylphosphane and imidazole
ety was treated with Dess–Martin periodinane, the corre- were added and the resulting mixture was warmed to 75 °C
sponding acetones 12 and 13 were obtained in 86 and 88% before adding the iodine in one portion to afford compound
yields. The presence of the ketone moiety was supported by 16 in 78% yield. Nucleophilic substitution of the 6A,6D-
13C NMR (200.9 ppm) and IR (1728 cm–1) spectroscopy. diiodide 16 to the diazide proceeded in excellent yield
The somewhat low yields in the reductive amination steps (Scheme 2). The substitution took place at 75 °C in DMF
are due to problems arising during purification. When com- overnight to afford the 6A,6D-diazide 17 in 90% yield after
pound 13 was prepared without purifying the intermediates flash chromatography. The reaction could in this case not
9 and 11 an overall yield of 80% was obtained after three be monitored by TLC because compounds 16 and 17 exhib-
steps. A final hydrogenolysis with H2 and 10% Pd/C as cat- ited identical Rf values. Reduction to the diamino com-
alyst in methanol/ethyl acetate (1:1) provided the final pound 18 was achieved by using styrene-supported tri-
amino–acetone-cyclodextrin derivatives 14 and 15 in 80% phenylphosphane in THF with further hydrolysis of the
and quantitative yields, respectively.
iminophosphorane intermediate using a 1  NaOH solu-
An enzyme mimic thought interesting to study was a tion at 66 °C to give an 81% yield. The α-cyclodextrin-di-
compound bearing positive charges next to the ketone moi- amine 18 was bis-dimethylated in 76% yield by a reductive-
ety to induce a better electronic activation of the ketone amination-type reaction using a mixture of formic acid/
functionality.[8] Therefore a bis(dimethylammonium salt), formaldehyde in dichloromethane and sodium cyano-
with the derivatizations at the β positions with respect to borohydride as a reducing reagent. Compound 19 was fur-
the ketone, was prepared. The synthesis of the bis(dimethyl- ther alkylated with 1,3-dibromoacetone to the bridged com-
amino)acetone-bridged cyclodextrin 21 proved not to be pound 20, which was recrystallized from acetone/water to
trivial. Attempts to follow the conventional route, a re- give the final bis-ammonium compound in 62% yield. The
ductive amination reaction to compound 8 followed by full presence of the ketone moiety was supported by 13C NMR
methylation of the secondary amino groups, were not suc- (194.1 ppm) and IR (1729 cm–1) spectroscopy and the am-
cessful due to problems during the purification of the final monium salts were indicated by the shift of the methyl sig-
1
product. Methylation of the diamino-bridged compound 8 nals in the H NMR spectra from 2.12 ppm in compound
with MeI/K2CO3 or, alternatively, with MeOTf/2,6-di-tert- 19 to 3.05 ppm in compound 20. Hydrogenolysis of the
butylpyridine gave mixtures in which the main product was benzyl groups with H2 and 10% Pd/C as catalyst in 2-me-
the trimethylated compound. The following oxidation step, thoxyethanol as solvent afforded the final bis-ammonium-
using either Dess–Martin periodinane or the Swern oxi- bridge acetone compound 21 in 97%, which was fully char-
dation approach, failed to afford the ketone. A very polar acterized by IR, NMR and MS (see the Exp. Sect.).
Scheme 2. Synthesis of the 1,3-bis(dimethylamino)acetone-bridged cyclodextrin 21.
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Catalysis
can accommodate bigger molecules. However, none of the
catalysts was as efficient in the aniline oxidation as the pre-
viously reported catalysts 1 and 2.[5,20] Interestingly, both
14 and 15 displayed better reactivity with o-substituted ani-
lines than with p-substituted derivatives, possibly due to the
formation of a hydrogen bond between the amino moiety
of the catalyst and the o-hydroxy group of the substrates,
which could influence the reaction path. This interaction is
not possible with the p-hydroxy group and therefore it has
a larger Km value compared with the ortho derivative (see
Table 1). The compound bearing the ammonium in close
proximity to the ketone is somewhat more efficient for ani-
line oxidation but showed no activity in benzyl alcohol oxi-
dation. This is probably due to two antagonistic effects: the
increase in the ketone reactivity towards nucleophilic attack
by hydrogen peroxide to form the active hydroperoxide in-
termediate and the electrostatic stabilization of the lone pair
from the amines and alcohols (Figure 3).
The kinetic data (Km and kcat) for the oxidation of a
range of benzyl alcohols were obtained from Vcat versus S
in the usual manner using non-linear least-squares fitting
and are shown in Table 2. The kcat values range from 10–4
to 2ϫ10–3 min–1 and the effect of the reaction taking place
inside the cavity was as high as 18450 under neutral condi-
tions at ambient temperature and with dilute hydrogen per-
oxide solutions. The Km values range from 0.2–3.4 m,
which are typical values for the binding of cyclodextrins to
small aromatics (see Table 2).
Oxidation experiments were carried out with the final
compounds 14, 15 and 21 to test their activity as catalysts
in hydrogen peroxide mediated oxidation of differently sub-
stituted anilines and benzylic alcohols. The kinetics experi-
ments were performed under enzymatic conditions (i.e.,
water, pH 7, ambient temperature) using a dilute solution
of hydrogen peroxide. The catalytic activity was quantified
by following the product formation at the appropriate wave-
length versus time with and without small concentrations
of catalyst (ca. 0.5 m). The reaction rate increases with an
increasing amount of catalyst (Figure 4) and follows Mi-
chaelis–Menten-type kinetics, which means that the sub-
strate binds to the catalyst cavity where the reaction takes
place faster than outside. The entire process was analysed
by using the Michaelis–Menten equation (1), in which Vcat
is the initial steady-state rate of the catalysed reaction, Vm
is the maximum rate, Km is the Michaelis–Menten constant
and S is the substrate concentration. The fit of the kinetics
was revealed by a Hanes plot, as shown in Figure 2, and
Vm and Km were obtained by a non-linear regression fit of
the data to the Michaelis–Menten equation. The value of
kcat was calculated from Vm/[enzyme] and the effect of the
catalyst is expressed as kcat/kuncat. Several substrates were
investigated and the kinetic parameters are summarized in
Tables 1 and 2.
Note that both α- and β-amino–acetone-cyclodextrin de-
rivatives 14 and 15 displayed good substrate selectivity, ex-
hibiting a very poor activity towards aniline oxidation but
a much better activity towards benzyl alcohol oxidation (see
Tables 1 and 2). This tendency could be an indication that,
in the case of benzyl alcohol, the reaction is facilitated by
hydrogen-bonding between the benzylic proton and the
amido groups of the bridged cyclodextrins. Compounds 14
and 15 exhibit good activity towards the oxidation of 1-
phenylethanol to acetophenone and notable enantiomer
selectivity (Table 2). The α-amino–acetone-bridged cyclo-
dextrin 14 is 1.4 times more reactive with the (R)-1-phenyle-
thanol enantiomer, whereas the β-amino–acetone-bridged
cyclodextrin 15 was more than three times more reactive
with the (S) enantiomer, although the binding properties of
both enantiomers are very similar.
(1)
The mechanisms, as they have been discussed before,[7,20]
show that the bridged ketone plays an essential role both
in amine and alcohol oxidation, and reacts initially with
hydrogen peroxide to form a hydroperoxide adduct which
is responsible for the oxidation of the bound substrate (Fig-
ure 3). The amine oxidation is a complex reaction that re-
sults in the formation of hydroxylamine and nitroso deriva-
Figure 2. Enzyme kinetic model, Michaelis–Menten equation and
an example of the Hanes plot for the oxidation of o-aminophenol
with 64 m H2O2 in phosphate buffer pH 7 and 25oC.
Not surprisingly, the amino–acetone-bridged cyclodex- tives in the initial step, which can be oxidized further to
trins 14, 15 and 21 displayed medium activity in aniline nitro compounds and also react further to give mixtures of
oxidations giving a kcat/kuncat ratio of up to 160, which dimers. The bridged amino–acetone-cyclodextrins catalyse
shows the improvement in the reaction when it takes place the oxidation of primary alcohols to aldehydes as well as
inside the functionalized cavity. The β-derivative 15 exhib- secondary alcohols to ketones. Substitution of the aromatic
ited somewhat better activity with most of the substrates, ring is accepted with certain differences in the rate of cataly-
probably due to the size of the β-cyclodextrin cavity, which sis (see Table 2).
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Amino–Acetone-Bridged Cyclodextrins
Table 1. Kinetic data for the oxidation of several anilines catalysed by 14, 15 or 21. Unless otherwise noted the experiments were performed
o
in phosphate buffer pH 7 at 25 C with a H2O2 concentration of 64 m and a catalyst concentration of ca. 0.5 m.
Table 2. Kinetic data for the oxidation of various benzylic alcohols catalysed by 14, 15 or 21. Experiments were performed in phosphate
buffer pH 7 at 25 °C with a H2O2 concentration of 64 m and a catalyst concentration of ca. 0.5 m.
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L. G. Marinescu et al.
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velocity was measured at three fixed substrate concentra-
tions with varying concentrations of inhibitor. A graph of
the reciprocal of the velocity against inhibitor concentration
was plotted for each of the substrate concentrations. The
lines corresponding to each substrate concentration inter-
sected to give a Ki value of 63.6 m and showed a good
competitive inhibition of the reaction (Figure 5).
Figure 3. Mechanism for the formation of the hydroperoxide inter-
mediate in aniline oxidation.
All these experiments followed Michaelis–Menten kinet-
ics and the reactions could be inhibited by the addition of
the 2-naphthalenesulfonic acid sodium salt, which confirms
again that the cyclodextrin cavity is involved in the process.
Neither acetone nor α- or β-cyclodextrin exhibited catalytic
behaviour under the same reaction conditions. The rate in-
creases with increasing enzyme concentration and can be
observed even with a concentration of less than 10 µ of
modified cyclodextrin (see Figure 4).
Figure 5. Dixon plot for the inhibition of 4-aminophenol oxidation
using 64 m H2O2 in phosphate buffer pH 7 at 25oC with different
concentrations of 2-naphthalenesulfonic acid sodium salt as inhibi-
tor.
The equilibrium constant for the addition of hydrogen
peroxide to the carbonyl moiety of the catalyst 15 was mea-
sured to be 2.9 m (Figure 6), which reveals a very good
affinity of the ketone in nucleophilic reactions in agreement
with previously reported studies of nucleophilic addition to
carbonyl compounds.[21] The experiments were carried out
with increasing hydrogen peroxide concentrations at fixed
enzyme and substrate concentrations and the binding con-
stants were calculated using non-linear least-squares re-
gression fitting to the V versus [H2O2] curve (Figure 6) for
two different substrates.
Figure 6. Effect of hydrogen peroxide concentration on the rate of
2-aminophenol oxidation in phosphate buffer pH 7 at 25 °C.
Figure 4. 2-Aminophenol oxidation with different concentrations
of catalyst 15 in phosphate buffer pH 7 with 64 m H2O2 at 25 °C.
Inhibition studies were carried out for the oxidation of
4-aminophenol using the 2-naphthalenesulfonic acid so-
dium salt as the inhibitor. A Dixon plot was used as a
graphical method to determine the dissociation constant Ki
Conclusions
We have prepared three new cyclodextrin catalysts bear-
of the enzyme–inhibitor complex (Figure 5). The reaction ing an active ketone site linked by two amine functionalities.
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Amino–Acetone-Bridged Cyclodextrins
O-Benzyl-2A–G,3A–G,6B,6C,6E,6F,6G-nonadecyl-β-cyclodextrin-6A,6D-
dicarbaldehyde (6): See ref.[22]
The amine was protected either by acetylation to give com-
pounds 14 and 15 or by full methylation to give the quater-
nary derivative 21. Their syntheses involve a facile reductive
amination followed by amine protection for derivatives 14
and 15 or a final alkylation of the bis-dimethylated-amino-
cyclodextrin derivative for compound 21. This last reaction
is a slow, low-yielding step that will need to be optimized
in the future. It may be anticipated that all amino-ketone-
6A,6D-Diamino-O-benzyl-2A–F,3A–F,6B,6C,6E,6F-hexadecyl-6A,6D-di-
deoxy-N,NЈ-(2-hydroxypropa-1,3-dienyl)-α-cyclodextrin (8): 1,3-Di-
amino-2-propanol (95.13 mg, 1.057 mmol) dissolved in DMF
(4 mL), NaBH(OAc)3 (10.57 mmol, 10 equiv.) and glacial AcOH
(80.61 µL, 0.528 mmol) were added to a solution of the aldehyde 5
(2.549 g, 1.057 mmol) in CH2Cl2 (42 mL) . The reaction mixture
bridged cyclodextrins may have a certain activity towards was stirred at room temp. overnight. Then, the mixture was washed
with satd. NaHCO3 (3ϫ25 mL) and brine (3ϫ25 mL) and the or-
ganic phases were separated, dried with MgSO4 and evaporated.
The residue was purified by column chromatography (3:1 mixture
of EtOAc/pentane) to give the product as a white foam in 42%
yield. Rf (EtOAc) = 0.62. 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 7.35–6.91 (m, 80 H, Ar-H), 5.55 (dd, J = 3.5, 10.5 Hz,
2 H), 5.39 (t, J = 5.2 Hz, 2 H, CHPh-H), 5.26 (d, J = 10.5 Hz, 2
H, CHPh-H), 5.03 (dd, J = 5.5, 10.5 Hz, 2 H), 4.83–4.69 (m, 8 H),
4.57 (d, J = 3.2 Hz, 1 H, 1-H), 4.54 (d, J = 3.2 Hz, 1 H, 1-H), 4.51
(d, J = 2.9 Hz, 1 H, 1-H), 4.46–4.26 (m, 18 H), 4.18–3.70 (m, 20
H), 3.59–3.49 (m, 4 H), 3.40–3.21 (m, 8 H), 2.93 (d, J = 13.5 Hz,
1 H), 2.75 (d, J = 12.3 Hz, 1 H), 2.67–2.51 (m, 4 H), 2.46–2.33 (m,
3 H), 2.26–2.22 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 140.04, 139.74, 139.68, 139.12, 138.69, 138.57, 138.51,
138.39, 138.31, 137.97, 137.74 (Cipso), 128.71, 128.64, 128.60,
128.52, 128.49, 128.42, 128.35, 128.25, 128.15, 128.06, 127.99,
127.93, 127.89, 127.79, 127.71, 127.37, 127.32, 127.26, 127.10,
127.02 126.94, 126.84, 126.79, 126.17 (CHPh), 100.52, 100.36,
98.60, 98.19 (C-1), 82.74, 82.67, 81.89, 81.68, 81.22, 81.08, 80.97,
80.77, 80.65, 80.47, 78.78, 78.30, 76.86, 76.34, 73.95, 73.74, 73.65,
73.56, 72.90, 72.59, 72.29, 72.16, 72.04, 71.08, 70.62, 69.52, 69.21
(CH, CH2), 53.57, 53.35, 52.69, 52.52 (C-6) ppm. MS (MALDI-
TOF): calcd. for C151H162N2O29H+ 2469.14; found 2469.9.
aniline oxidation, but to our surprise they displayed impres-
sive substrate selectivity towards alcohols, probably due to
guest–host electrostatic interactions. Compounds 14 and 15
displayed enzyme activity in benzyl alcohol oxidation with
hydrogen peroxide with rate increases of up to 18500 under
neutral conditions, but increases of only up to 158 in aniline
oxidation. This feature of the catalysts will open the way to
new applications in asymmetric synthesis and in molecular
recognition studies in aqueous media for functional chemi-
cal sensors and molecular devices.
Experimental Section
General: 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 visualized by
spraying with cerium sulfate (1%) and molybdic acid (1.5%) in
10% H2SO4 and heating until coloured spots appeared. 1H, 13C
and COSY NMR experiments were carried out with a Varian Mer-
cury 300 instrument. Monoisotopic mass spectra (MALDI-TOF
MS) were obtained with a Bruker Daltonics mass spectrometer
using ditranol (1,8-dihydroxyanthron) as the matrix. Spectra were
calibrated with a standard peptide calibration solution.
6A,6D-Diamino-O-benzyl-2A–G,3A–G,6B,6C,6E,6F,6G-nonadecyl-
6A,6D-dideoxy-N,NЈ-(2-hydroxypropa-1,3-dienyl)-β-cyclodextrin (9):
1,3-Diamino-2-propanol (184.5 mg, 2.05 mmol) dissolved in DMF
(8 mL), NaBH(OAc)3 (4.34 g, 10 equiv.) and glacial AcOH
(180 µL) were added to a solution of the aldehyde 6 (5.83 g,
2.05 mmol) in CH2Cl2 (80 mL). The reaction mixture was stirred
at room temp. overnight. Then the mixture was washed with satd.
NaHCO3 (3 ϫ 25 mL) and brine (3 ϫ 25 mL) and the organic
O-Benzyl-2A–F,3A–F,6B,6C,6E,6F-hexadecyl-α-cyclodextrin-6A,6D-di-
carbaldehyde (5): Dess–Martin reagent (5 equiv., 6.21 mmol,
2.634 g) was added to a solution of diol 3 (3 g, 1.242 mmol) in dry
CH2Cl2 (100 mL). The reaction mixture was stirred at room temp. phases were separated, dried with MgSO4 and evaporated. The resi-
for 2.5 h and then was quenched with Et2O (25 mL) and a solution due was purified by column chromatography (3:1 to 1:1 mixture of
of satd. NaHCO3 (825 mL) containing Na2S2O3 (1.5 g) and was EtOAc/pentane) to give the product as a mixture of diastereoiso-
stirred for a further 1 h. The organic phase was washed with
NaHCO3 (6ϫ25 mL) and water (6ϫ25 mL), dried with MgSO4
and concentrated. The residue was purified by column chromatog-
raphy (4:1 mixture of pentane/EtOAc) to give the product as a
white foam (2.591 g, 87%). Rf (EtOAc/pentane, 1:3) = 0.75. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 9.41 (d, J = 2.6 Hz, 2
H, aldehyde-H), 7.27–7.11 (m, 80 H, Ar-H), 5.38 (d, J = 3.5 Hz, 1
H, 1-H), 5.31 (d, J = 10.8 Hz, 1 H, CHPh-H), 5.10 (d, J = 10.8 Hz,
1 H, CHPh-H), 4.98 (d, J = 3.2 Hz, 1 H, 1-H), 4.89–4.82 (m, 4 H),
4.79–4.70 (m, 6 H), 4.52–4.26 (m, 18 H), 4.18–3.9 (m, 20 H), 3.74–
mers in 50% yield. Rf (EtOAc/pentane, 1:1, + Et3N) = 0.25. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.40–7.26 (m, 95 H,
Ar-H), 5.89 (d, J = 3.5 Hz, 1 H, 1-H), 5.82 (d, J = 3.7 Hz, 1 H, 1-
H), 5.61 (d, J = 9.9 Hz, 1 H, CH2), 5.51 (d, J = 10.6 Hz, 1 H,
CH2), 5.39 (d, J = 10.5 Hz, 2 H, CH2), 5.31 (d, J = 10.4 Hz, 2 H,
CH2), 5.01 (m, 6 H), 4.82 (m, 6 H), 4.73 (d, J = 10.1 Hz, 4 H,
CH2), 4.53 (m, 20 H), 4.04 (m, 25 H), 3.52 (m, 16 H), 3.04 (m, 2
H), 2.54 (m, 6 H), 2.00 (br. s, 2 H, NH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 140.18, 139.73, 139.55, 139.13, 139.06,
138.76, 138.59, 138.54, 138.44, 138.25, 137.99, 137.64 (Cipso),
3.63 (m, 4 H), 3.59–3.35 (m, 14 H) ppm. 13C NMR (75 MHz, 128.71, 128.70, 128.64, 128.59, 128.50, 128.47, 128.43, 128.37,
CDCl3, 25 °C, TMS): δ = 196.86 (C=O), 139.51, 139.45, 139.04, 128.25, 128.19, 127.94, 127.89, 127.74, 127.79, 127.62, 127.53,
138.68, 138.52, 138.42, 138.33, 138.14 (Cipso), 128.64, 128.53,
127.39, 127.30, 127.25, 126.93, 126.86, 126.78, 126.58, 126.50,
128.37, 128.28, 128.17, 128.14, 128.12, 127.83, 127.80, 127.60, 126.45 (CHPh), 99.27, 99.19, 99.08, 98.84, 98.59, 98.32, 97.72, 97.65
127.35, 127.27, 127.19 (CHPh), 98.44, 98.17 (C-1), 81.05, 80.95,
80.69, 80.33 (C-3), 79.97, 79.42, 78.83, 78.50, 76.47, 76.27, 76.08,
75.77, 75.00, 74.18, 73.60, 73.52, 73.17, 72.72, 71.69, 71.41, 69.28
(CH2, CH) ppm. MS (MALDI-TOF): calcd. for C148H152O30Na+
2433.76; found 2434.8.
(C-1), 81.40, 81.21, 80.92, 80.47, 80.02, 79.18, 78.17, 77.95, 77.73,
77.53, 77.11, 76.85, 76.56, 76.31, 76.06, 73.92, 73.63, 73.19, 73.06,
72.86, 72.65, 72.19, 71.87, 70.25, 69.88, 69.49, 69.25, 68.54 (CH,
CH2), 53.78, 52.61, 52.41, 52.21, 51.98, 51.76 (C-6) ppm. MS (ES):
calcd. for C178H190O34N2 2899.32; found 2899.67.
Eur. J. Org. Chem. 2010, 157–167
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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163

L. G. Marinescu et al.
FULL PAPER
N,NЈ-Diacetyl-6A,6D-diamino-O-benzyl-2A–F,3A–F,6B,6C,6E,6F-hexa-
decyl-6A,6D-dideoxy-N,NЈ-(2-hydroxypropa-1,3-dienyl)-α-cyclodex-
trin (10): (Ac)2O (170.75 mg, 1.672 mmol) was gradually added to
a cooled solution of compound 8 (688.5 mg; 0.278 mmol) in DMF/
138.38, 138.22, 138.11, 137.80 (Cipso), 129.99, 128.88, 128.75,
128.66, 128.52, 128.42, 128.32, 128.22, 128.05, 127.73, 127.56,
127.40, 127.27, 127.16, 127.07, 126.81, 126.55, 126.38, 126.29,
126.17 (CHPh), 105.26, 101.01, 100.10, 98.37, 97.86 (C-1), 85.36,
EtOH (1:1, 80 mL) and the mixture was stirred at room temp. un- 83.81, 82.94, 82.36, 81.70, 80.72, 80.43, 79.39, 78.93, 78.05, 76.73,
der nitrogen overnight. Then, the solvent was evaporated and the
residue was dissolved in ethyl acetate and washed with water
(50 mLϫ4). The organic phases were dried (MgSO4) and evapo-
rated. The residue was purified by column chromatography
(EtOAc/pentane, 2:1) to give the product as a white foam (667 mg,
94 %). Rf (EtOAc/pentane, 1:1) = 0.47. 1H NMR (300 MHz,
CDCl3, 25 °C, TMS): δ = 7.33–6.95 (m, 80 H, Ar-H), 5.38–5.09
(m, 4 H), 5.09–4.21 (m, 37 H), 4.21–3.07 (m, 38 H), 2.06 (s, 3 H),
1.91 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
173.33 (C=O, Ac), 139.92, 139.79, 139.40, 139.11, 138.68, 138.54,
138.22, 138.02 (Cipso), 128.76, 128.61, 128.56, 128.46, 128.32,
128.23, 128.05, 127.97, 127.91, 127.86, 127.78, 127.67, 127.47,
127.29, 126.94, 126.82, 126.46, 126.31, 126.19, 126.05 (CHPh),
101.46, 101.05, 97.60 (C-1), 83.79, 83.08, 81.96, 81.52, 81.20, 80.91,
78.48, 78.19, 77.65, 75.50, 74.47, 73.19, 73.05, 72.90, 72.60, 72.28,
72.14, 71.87, 70.55, 69.78, 69.01, 67.99 (CH, CH2), 54.39, 52.85 (C-
6), 31.67, 29.97, 22.86, 22.57 (CH3) ppm. MS (MALDI-TOF):
calcd. for C155H166O31N2Na+ 2575.15; found 2576.9.
76.25, 75.79, 74.40, 73.97, 73.67, 73.58, 73.36, 73.15, 72.93, 72.59,
72.34, 72.19, 72.03, 71.54, 70.99, 70.28, 69.95, 69.63, 68.27 (CH,
CH2), 58.25, 53.98, 52.52, 51.07, 50.53 (C-6), 22.44, 22.29, 22.12,
2 1 . 5 5 ( C H 3 ) p p m . M S ( M A L D I - T O F ) : c a l c d . f o r
C
155H164O31N2Na+ 2573.12; found 2572.6.
N,NЈ-Diacetyl-6A,6D-diamino-2A–G,3A–G,6B,6C,6E,6F 6G-nonadecyl-
,
6A,6D-dideoxy-N,NЈ-(2-oxopropa-1,3-dienyl)-O-benzyl-β-cyclodex-
trin (13): Dess–Martin reagent (2.5 equiv., 3.8 mmol, 1.612 g) was
added to a solution of alcohol 11 (4.53 mg, 1.52 mmol) in anhy-
drous CH2Cl2 (45 mL). The reaction mixture was stirred at room
temp. for 2 h and then was quenched with Et2O (10 mL) and a
solution of satd. NaHCO3 (10 mL) containing Na2S2O3 (160 mg)
and was stirred for a further 1 h. Then it was extracted with Et2O
(6 ϫ 40 mL) and washed with NaHCO3 (6 ϫ 20 mL) and water
(6ϫ20 mL). The organic phases were dried with MgSO4 and con-
centrated. The residue was purified by column chromatography (5:1
to 3:1 mixture of toluene/EtOAc) to give the product as a mixture
of rotamers (3.66 g, 81 %). Rf (toluene/EtOAc, 3:1) = 0.45. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.38–7.22 (m, 95 H,
Ar-H), 5.87 (d, J = 3.6 Hz, 1 H, 1-H), 5.58 (d, J = 3.8 Hz, 1 H, 1-
H), 5.31 (m, 2 H), 5.08–4.71 (m, 13 H), 4.66 (d, J = 12.6 Hz, 1 H,
CH2), 4.59–4.32 (m, 25 H), 4.15–4.06 (m, 14 H), 3.97–3.84 (m, 12
H), 3.80–3.67 (m, 10 H), 3.58–3.44 (m, 10 H), 2.27 (d, 2 H), 2.07
(m, 6 H), 1.85 (s, 1 H), 1.73 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 200.9 (C=O), 172.05, 171.81, 139.26,
139.06, 138.57, 138.50, 138.39, 138.26, 138.22, 138.05, 137.95,
137.91, 137.61, 137.56 (Cipso), 128.36, 128.26, 128.16, 128.12,
128.05, 127.95, 127.86, 127.80, 127.77, 127.66, 127.58, 127.51,
127.46, 127.39, 127.25, 126.93, 126.86, 126.63 (CHPh), 100.23,
99.95, 99.51, 99.28, 98.78, 97.91, 97.57 (C-1), 80.93, 80.66, 80.52,
80.44, 80.38, 80.23, 80.18, 80.07, 80.03, 79.86, 78.83, 73.35, 73.18,
73.11, 73.04, 72.94, 72.81, 72.45, 72.32, 72.16, 71.84, 71.79, 71.63,
69.70, 69.40, 69.24, 69.12, 69.05, 69.01, 68.81, 68.52, 68.48, 66.33,
65.78, 64.86 (CH, CH2), 52.46, 51.92, 51,63, 50.42, 49.82 (C-6),
21.93, 21.55, 21.08 (CH ) ppm. IR: ν = 3054 (Csp2–H), 2985 (Csp3–
N,NЈ-Diacetyl-6A,6D-diamino-O-benzyl-2A–G,3A–G,6B,6C,6E,6F,6G-
nonadecyl-6A,6D-dideoxy-N,NЈ-(2-hydroxypropa-1,3-dienyl)-β-cyclo-
dextrin (11): (Ac)2O (254 mg, 2.5 mmol) was gradually added to a
cooled solution of compound 9 (1.2 g; 0.414 mmol) in DMF/EtOH
(1:1, 120 mL) and the mixture was stirred at room temp. under
nitrogen overnight. Then the solvent was evaporated and the resi-
due was dissolved in ethyl acetate and washed with water
(50 mLϫ4). The organic phases were dried with MgSO4 and evap-
orated. The residue was purified by column chromatography (2:1
to 1:1 mixture of EtOAc/pentane) to give the product as a mixture
of diastereoisomers and rotamers (1.09 g, 89%). Rf (EtOAc/pen-
1
tane, 1:1) = 0.53. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
7.41–7.15 (m, 95 H, Ar-H), 5.85 (d, J = 4.5 Hz, 1 H, 1-H), 5.76 (d,
J = 4.4 Hz, 1 H, 1-H), 5.59 (d, J = 8.3 Hz, 1 H, CH2), 5.40 (d, J
= 10.9 Hz, 1 H, CH2), 5.27 (d, J = 11.9 Hz, 1 H, CH2), 5.14 (d, J
= 3.8 Hz, 1 H, 1-H), 5.01–4.96 (m, 4 H), 4.86–4.75 (m, 10 H), 4.67–
4.30 (m, 21 H), 4.2–4.04 (m, 20 H), 3.89–3.69 (m, 14 H), 3.63–3.44
(m, 14 H), 2.95 (m, 1 H), 2.68 (m, 2 H), 2.15 (s, 1 H), 2.12 (s, 1
H), 2.10 (s, 2 H), 2.03 (m, 1 H), 1.87 (s, 1 H), 1.83 (s, 1 H) ppm.
˜
3
H), 1728 (C=O), 1649 (N–C=O), 1421, 1359, 1265 (C–N), 1040
(C–O), 744 (Ph) cm– 1 . MS (MALDI-TOF): calcd. for
C
182H194O36N2Na+ 3005.32; found 3005.2.
IR: ν = 3440 (OH), 3052 (Csp2–H), 2921 (Csp3–H), 1638 (N–C=O),
˜
1450, 1267 (C–N), 1092 (C–OH), 1033, 734 (Ph), 696 (C–C) cm–1.
MS (MALDI-TOF): calcd. for C182H194O36N2Na+ 3007.33; found
3007.2.
N,NЈ-Diacetyl-6A,6D-diamino-6A,6D-dideoxy-N,NЈ-(2-oxopropa-1,3-
dienyl)-α-cyclodextrin (14): Compound 12 (560 mg, 0.219 mmol)
was dissolved in a mixture of MeOH/EtOAc (1:1, 40 mL) and then
Pd/C (10%, 58 mg) and TFA (cat.) were added. The reaction mix-
ture was stirred overnight under H2. Filtration through a Millipore
membrane filter and evaporation of the solvent gave compound 14
N,NЈ-Diacetyl-6A,6D-diamino-O-benzyl-2A–F,3A–F,6B,6C,6E,6F-hexa-
decyl-6A,6D-dideoxy-N,NЈ-(2-oxopropa-1,3-dienyl)-α-cyclodextrin
(12): Dess–Martin reagent (2.5 equiv., 0.625 mmol, 265.15 mg) was
added to a solution of alcohol 10 (638.4 mg, 0.250 mmol), in anhy-
drous CH2Cl2 (56 mL). The reaction mixture was stirred at room
temp. for 2 h, and then was quenched with Et2O (8 mL) and a
solution of satd. NaHCO3 (8 mL) containing Na2S2O3 (160 mg)
and was then stirred for a further 1 h. Then it was extracted with
Et2O (6 ϫ 40 mL) and washed with NaHCO3 (6 ϫ 20 mL) and
water (6ϫ20 mL). The organic phases were dried (MgSO4) and
concentrated. The residue was purified by column chromatography
(EtOAc/pentane, 1:2) to give the product as a white foam
(560.2 mg, 86 %). Rf (EtOAc/pentane, 1:1.5) = 0.5. 1H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 7.49–7.16 (m, 80 H, Ar-H),
5.70–5.29 (m, 4 H), 5.01–3.52 (m, 74 H), 2.18–1.97 (m, 6 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 201.33 (C=O),
1
(193 mg, 80%) as a white solid. H NMR (300 MHz, D2O, 25 °C,
TMS): δ = 5.05–4.93 (m, 2 H), 4.92–4.80 (m, 4 H), 4.30–3.70 (m,
18 H), 3.70–3.20 (m, 22 H), 2.12–1.91 (m, 6 H) ppm. 13C NMR
(75 MHz, D2O, 25 °C, TMS): δ = 196.20 (C=O), 176.55, 175.46,
175.35 (C=O, Ac), 102.18, 101.86, 101.62, 101.37, 101.20, 100.95,
100.70, 100.30, 100.03, 99.79 (C-1), 84.10, 83.45, 83.28, 82.83,
82.61, 81.81, 81.54, 81.23, 80.70, 80.17, 79.97, 79.87, 73.86, 73.69,
73.62, 73.29, 73.20, 72.93, 72.83, 72.76, 72.62, 72.55, 72.47, 72.37,
72.08, 72.01, 71.92, 71.80, 71.67, 71.56, 71.43, 71.32, 71.22, 71.07,
70.23, 68.58 (CH, CH2), 64.67, 60.75, 60.44, 60.06, 59.88, 52.14,
46.33 (C-6), 21.09, 20.79, 20.71, 20.40, 20.22 (CH3) ppm. MS
(MALDI-TOF): calcd. for C43H68O31N2Na+ 1131.4; found 1132.5.
N,NЈ-Diacetyl-6A,6D-diamino-6A,6D-dideoxy-N,NЈ-(2-oxopropa-1,3-
172.08, 171.71, 139.96, 139.77, 139.24, 139.13, 138.77, 138.55, dienyl)-β-cyclodextrin (15): Compound 13 (265 mg, 0.09 mmol) was
164
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 157–167

Amino–Acetone-Bridged Cyclodextrins
dissolved in MeOH/EtOAc (1:1, 20 mL), and then Pd/C (10 %,
13C NMR (150 MHz, CDCl3, 25 °C, TMS): δ = 139.32, 139.28,
100 mg) and TFA (cat.) were added. The reaction mixture was 138.46, 138.27, 138.16, 138.06 (Cipso), 128.42, 128.29, 128.20,
stirred overnight under H2. Filtration through a Millipore mem-
brane filter and evaporation of the solvent gave the title compound
128.08, 128.03, 127.91, 127.78, 127.62, 127.53, 127.47, 127.42,
127.07, 127.00, 126.91 (CHPh), 98.99, 98.84, 98.28 (C-1), 80.89,
15 (114 mg, quantitative yield) as a white solid. 1H NMR 80.84, 80.70, 80.45, 80.03, 79.62, 79.31, 78.99, 78.43, 76.74, 75.92,
(300 MHz, D2O, 25 °C, TMS): δ = 5.09–5.06 (m, 7 H), 3.99–3.79 75.81, 75.10, 73.49, 73.15, 72.93, 72.63, 71.86, 71.64, 70.80, 69.47,
(m, 35 H), 3.73–3.54 (m, 30 H), 2.24 (br. s, 6 H, CH3) ppm. 13C
NMR (75 MHz, D2O, 25 °C, TMS): δ = 200.09 (C=O), 171.3,
170.94 (C=O, Ac), 102.35, 102.22, 101.98, 101.13, 99.95, 99.53 (C-
1), 82.34, 80.69, 79.47, 78.71, 74.73, 73.98, 72.81, 72.24, 71.93,
71.55, 70.99, 69.35, 66.55, 65.25, 62.77, 60.65, 59.49, 58.70, 58.12,
68.88 (CH, CH2), 52.34 (C-N3) ppm. MS (MALDI-TOF): calcd.
for C148H154N6O28Na+ 2487.07; found 2488.92.
6A,6D-Diamino-O-benzyl-2A–F,3A–F,6B,6C,6E,6F-hexadecyl-6A,6D-di-
deoxy-α-cyclodextrin (18): The α-CD-diazide 17 (1.36 g, 0.55 mmol)
was dissolved in THF (80 mL) under N2. Ph3P on styrene (loading
capacity = 1.7 mmol/g, 1.58 g) was added and the suspension was
stirred at room temperature for 3 h. A 1  aq. NaOH solution
(100 µL) was added and the reaction was heated at reflux at 66 °C
overnight. Filtration through a fritted funnel followed, the resin
beads were washed with water and EtOAc and finally the water
phase was extracted with EtOAc. The combined organic layers
were washed with satd. aq. NaCl, dried with MgSO4 and concen-
trated under vacuum. The pure compound (1.08 g, 0.45 mmol) was
obtained as a transparent syrup in 81% yield. Rf (EtOAc) = 0.33.
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.22 (m, 80 H,
aromatic H), 5.63 (d, J = 1.7 Hz, 1 H), 5.45 (d, J = 10.3 Hz, 1 H),
5.21 (d, J = 10.9 Hz, 2 H), 4.92 (d, J = 10.3 Hz, 2 H), 4.85 (d, J =
6.2 Hz, 4 H), 4.77 (m, 4 H), 4.59 (d, J = 5.1 Hz, 1 H), 4.54 (m, 4
H), 4.47 (dd, J = 5.9, 12.2 Hz, 6 H), 4.35 (m, 5 H), 4.23 (m, 3 H),
4.08 (m, 12 H), 3.86 (m, 10 H), 3.70 (dd, J = 10.5, 20.5 Hz, 6 H),
3.58 (d, J = 8.6 Hz, 3 H), 3.46 (d, J = 9.2 Hz, 3 H), 3.34 (d, J =
9.4 Hz, 3 H), 2.90 (d, J = 13.7 Hz, 2 H), 2.81 (d, J = 13.5 Hz, 2
H) ppm. 13C NMR (150 MHz, CDCl3, 25 °C, TMS): δ = 139.58,
54.98 (CH, CH ), 21.71, 21.52, 21.18 (CH ) ppm. IR: ν = 3414
˜
2
3
(OH), 2925 (Csp3–H), 1734 (C=O), 1633 (N–C=O), 1363, 1156 (C–
N), 1031 (C–O), 579 (C–C) cm–1. MS (MALDI-TOF): calcd. for
C49H78O36N2Na+ 1293,42; found 1293.42.
O-Benzyl-2A–F,3A–F,6B,6C,6E,6F-hexadecyl-6A,6D-dideoxy-6A,6D-di-
iodo-α-cyclodextrin (16): α-CD-diol 8 (1.88 g, 0.78 mmol), PPh3
(4.69 mmol) and imidazole (9.38 mmol) were dissolved in dry tolu-
ene (40 mL) under nitrogen at 75 °C. I2 (4.69 mmol) was then
added and the solution was stirred overnight at 75 °C. Satd. aq.
NaHCO3 (40 mL) was added and the reaction mixture was stirred
for 5 min. Dilution with EtOAc (80 mL) followed. The organic
layer was separated, washed with satd. aq. Na2S2O3 and satd. aq.
NaCl, dried with MgSO4 and concentrated under vacuum. Purifi-
cation by flash column chromatography (EtOAc/pentane, 1:6 Ǟ
1:3) gave the pure compound (1.61 g, 0.61 mmol) as a white foam
in 78% yield. Rf (EtOAc/pentane, 1:4) = 0.78. 1H NMR (300 MHz,
CDCl3, 25 °C, TMS): δ = 7.26–7.22 (m, 28 H, aromatic H), 7.15–
7.11 (m, 52 H, aromatic H), 5.20 (d, J = 11.5 Hz, 2 H), 5.13 (d, J
= 3.6 Hz, 2 H), 5.04 (d, J = 11.1 Hz, 2 H), 4.99 (d, J = 3.2 Hz, 2 139.55, 138.83, 138.60, 138.45, 138.34, 138.25 (Cipso), 132.41,
H), 4.93 (d, J = 3.1 Hz, 2 H), 4.86 (d, J = 12.7 Hz, 2 H), 4.79 (d, 132.28, 132.19, 129.72, 128.55, 128.49, 128.40, 128.24, 127.93,
J = 10.7 Hz, 2 H), 4.53 (d, J = 2.1 Hz, 2 H), 4.49 (m, 3 H), 4.42 127.83, 127.35, 126.63 (CHPh), 98.61, 98.52, 98.27 (C-1), 81.61,
(m, 14 H), 4.37 (m, 2 H), 4.11 (m, 8 H), 3.94 (m, 11 H), 3.75 (d, J 81.23, 81.16, 81.03, 80.91, 80.10, 79.32, 78.19, 77.48, 76.51, 76.22,
= 9.6 Hz, 2 H), 3.65 (m, 4 H), 3.57 (d, J = 3.3 Hz, 2 H), 3.51 (m, 75.76, 74.36, 73.73, 73.65, 73.59, 73.23, 72.48, 72.21, 72.13, 71.27,
6 H), 3.46 (d, J = 3.3 Hz, 2 H), 3.43 (d, J = 3.3 Hz, 2 H), 3.37 (dd, 69.92, 69.33 (CH, CH2), 42.87 (C-NH2) ppm. MS (MALDI-TOF):
J = 3.1, 9.8 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3, 25 °C, calcd. for C148H158N2O28 2412.10; found 2412.42.
TMS): δ = 139.65, 139.63, 139.56, 138.73, 138.53, 138.43, 138.39,
138.30 (Cipso), 129.34, 128.68, 128.63, 128.54, 128.49, 128.45,
128.43, 128.27, 128.15, 128.09, 128.07, 128.00, 127.92, 127.79,
6A,6D-Diamino-O-benzyl-6A,6D-dideoxy-2A–F,3A–F,6B,6C,6E,6F-hexa-
decyl-N,N,NЈ,NЈ-tetramethyl-α-cyclodextrin (19): The α-CD-di-
amine 18 (0.84 g, 0.35 mmol) was dissolved in dry CH2Cl2 (15 mL)
127.71, 127.48, 127.28, 127.22, 125.61 (CHPh), 99.66, 98.71 (C-1),
and added dropwise to 96% HCOOH (1.60 mmol) under N2. A
84.70, 81.16, 80.99, 80.86, 80.42, 79.62, 79.14, 78.88, 76.06, 75.83,
37 % HCOH solution in MeOH, (1.39 mmol) was then added
75.61, 73.88, 73.79, 73.20, 73.11, 72.92, 72.18, 71.61, 70.65, 69.78,
slowly to the solution and after 30 min NaCNBH3 (2.79 mmol) was
69. 52 (CH, CH2 ) ppm. MS (MALDI-TOF): calcd. for
added. After 48 h, H2O was added and the aqueous phase was
extracted with CH2Cl2. The organic layers were washed with
NaHCO3 and satd. aq. NaCl, dried with MgSO4 and concentrated
under vacuum. Purification by flash column chromatography fol-
C148H154I2O28Na+ 2656.86; found 2657.08.
6A,6D-Diazido-O-benzyl-2A–F,3A–F,6B,6C,6E,6F-hexadecyl-6A,6D-di-
deoxy-α-cyclodextrin (17): α-CD-diiodide 16 (1.61 g, 0.61 mmol)
and NaN3 (3.48 mmol) were dissolved in DMF (36 mL) under N2 lowed (EtOAc/pentane, 1:4, + 1% Et3N Ǟ EtOAc + 1% Et3N).
and stirred overnight at 75 °C. Satd. aq. NaCl (150 mL) and EtOAc
(300 mL) were added and the mixture was stirred for 10 min. The
aqueous phase was then extracted with EtOAc and the combined
organic layers were washed with satd. aq. NaCl, dried with MgSO4
and concentrated under vacuum. Flash column chromatography
followed (EtOAc/pentane, 1:4Ǟ1:2). The pure compound was ob-
tained as a white foam (1.36 g, 0.55 mmol) in 90 % yield. Rf
The pure product was obtained as a colourless syrup in 76% yield
(0.65 g, 0.26 mmol). Rf (EtOAc/pentane, 1:2) = 0.43. 1H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 7.22 (m, 80 H, aromatic H),
5.36 (d, J = 3.6 Hz, 2 H), 5.31 (s, 1 H), 5.22 (d, J = 10.9 Hz, 2 H),
5.15 (d, J = 3.0 Hz, 2 H), 5.10 (d, J = 11.3 Hz, 2 H), 4.96 (s, 1 H),
4.93 (d, J = 2.6 Hz, 2 H), 4.87 (d, J = 11.8 Hz, 5 H), 4.58 (d, J =
11.9 Hz, 3 H), 4.48 (m, 15 H), 4.36 (d, J = 12.1 Hz, 2 H), 4.19 (dd,
J = 6.7, 15.6 Hz, 4 H), 4.12 (d, J = 4.3 Hz, 2 H), 4.09 (d, J =
4.3 Hz, 2 H), 4.03 (d, J = 9.5 Hz, 7 H), 3.98 (d, J = 4.9 Hz, 2 H),
3.94 (d, J = 5.6 Hz, 2 H), 3.87 (m, 3 H), 3.62 (d, J = 10.4 Hz, 2
H), 3.53 (m, 6 H), 3.44 (s, 1 H), 3.39 (dd, J = 2.9, 9.7 Hz, 2 H),
1
(EtOAc/pentane, 1:4) = 0.78. H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 7.38–7.33 (m, 40 H, aromatic H), 7.27–7.22 (m, 40 H,
aromatic H), 5.36 (d, J = 10.9 Hz, 2 H), 5.28 (d, J = 3.8 Hz, 2 H),
5.25 (d, J = 11.7 Hz, 2 H), 5.11 (d, J = 11.3 Hz, 2 H), 5.00 (m, 4
H), 4.95 (d, J = 5.2 Hz, 4 H), 4.91 (d, J = 5.0 Hz, 2 H), 4.70 (d, J 3.03 (dd, J = 5.0, 13.4 Hz, 2 H), 2.27 (d, J = 13.7 Hz, 2 H), 2.12
= 12.4 Hz, 2 H), 4.61 (d, J = 11.9 Hz, 4 H), 4.55 (d, J = 5.1 Hz, 6 (s, 12 H) ppm. 13C NMR (150 MHz, CDCl3, 25 °C, TMS): δ =
H), 4.50 (br. s, 6 H), 4.45 (br. s, 1 H), 4.26–3.96 (m, 20 H), 3.81 (d, 139.84, 139.74, 139.72, 138.79, 138.71, 138.65, 138.51 (Cipso),
J = 9.4 Hz, 2 H), 3.78 (d, J = 8.8 Hz, 2 H), 3.69 (m, 3 H), 3.60 (m, 128.53, 128.45, 128.38, 128.32, 128.20, 128.07, 127.84, 127.80,
6 H), 3.53 (dd, J = 3.1, 7.8 Hz, 2 H), 3.48 (d, J = 3.1 Hz, 2 H) ppm.
127.70, 127.57, 127.15 (CHPh), 99.18, 98.98, 98.52 (C-1), 82.08,
Eur. J. Org. Chem. 2010, 157–167
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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165

L. G. Marinescu et al.
FULL PAPER
81.49, 81.27, 80.96, 80.51, 79.67, 78.83, 78.30, 76.02, 75.88, 75.28,
73.61, 73.50, 73.12, 72.87, 72.76, 71.82, 71.65, 71.46, 69.27, 69.08
N,NЈ-bis(p-hydroxyphenyl)-1,4-benzoquinonediimine: 1.59 m–1
cm–1 (pH 7.0); 4-methyl-2-nitrophenol: 1.06 m–1 cm–1 (pH 7.0); 5-
(CH, CH2), 59.38 (C-6), 47.14 (CH3) ppm. MS (MALDI-TOF): methyl-2-nitrophenol: 2.26 m–1 cm–1 (pH 7.0); benzaldehyde:
calcd. for C152H166N2O28 2468.17; found 2468.47.
1.23 m–1 cm–1 at 285 nm; acetophenone: 0.32 m–1 cm–1 at
300 nm; 2-hydroxybenzaldehyde: 2.92 m–1 cm–1 at 325 nm; 2-
methoxybenzaldehyde: 2.75 m–1 cm–1 at 323 nm.
6A,6D-Diammonio-O-benzyl-2A–F,3A–F,6B,6C,6E,6F-hexadecyl-6A,6D-
dideoxy-N,N,NЈ,NЈ-tetramethyl-N,NЈ-(2-oxopropa-1,3-dienyl)-α-
cyclodextrin Dibromide (20): The α-CD-tetramethyldiamine 19
(0.34 g, 0.14 mmol) was dissolved in dry acetone (15 mL) under
N2. 1,3-Dibromoacetone (0.83 mmol) was added in one portion.
After 24 h, the mixture was concentrated under vacuum and the
residue was recrystallized with acetone/water to give the pure prod-
uct (0.216 g, 0.09 mmol, 62%). Rf (CH2Cl2/MeOH, 9:1) = 0.27. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.28 (m, 80 H, aro-
matic H), 4.75 (m, 37 H), 4.14 (m, 7 H), 3.90 (m, 18 H), 3.51 (m,
18 H), 3.05 (m, 10 H) ppm. 13C NMR (150 MHz, CDCl3, 25 °C,
TMS): δ = 194.10 (C=O), 139.52, 139.44, 139.38, 139.25, 139.04,
138.80, 138.55, 138.41, 138.34, 138.24, 138.17, 138.01, 137.93,
137.83, 137.74, 137.61 (Cipso), 129.66–126.91 (CHPh), 98.63, 98.28,
98.03, 96.99 (C-1), 83.27, 82.87, 80.72, 80.34, 80.13, 79.76, 79.45,
79.25, 78.51, 76.41, 75.60, 74.46, 74.20, 73.92, 73.64, 73.53, 73.34,
73.14, 72.75, 72.47, 71.59, 71.44, 69.72, 69.53, 69.44, 69.23, 68.23,
67.68, 66.86, 66.66, 66.52, 53.43, 53.28, 52.59, 52.38 (CH, CH2,
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for compounds 5–21.
Acknowledgments
We thank the Lundbeck Foundation and the University of Copen-
hagen for financial support.
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CH ) ppm. IR: ν = 3062.35, 3030.11 (Csp2–H), 2923.70 2928.07
˜
3
(Csp3–H), 1728.94 (C=O), 1496.10, 1454.33, 1359.47, 1263.36,
1208.28 (C–N), 1097.91, 1027.86 (C–O) cm–1. MS (MALDI-TOF):
calcd. for C155H170N2O29 2524.19; found 2524.30.
6A,6D-Diammonio-6A,6D-dideoxy-N,N,NЈ,NЈ-tetramethyl-N,NЈ-(2-
oxopropa-1,3-dienyl)-α-cyclodextrin Dibromide (21): Compound 20
(108 mg, 0.04 mmol) was dissolved in HOCH2CH2OCH3 (10 mL),
Pd/C was added and the mixture was stirred under H2 for 24 h.
Filtration through a Millipore nylon membrane (0.45 µm, 47 mm)
followed and the solvent was then evaporated. The pure compound
1
was obtained in its hydrated form in 97% yield (42 mg). H NMR
(500 MHz, D2O, 25 °C): δ = 4.96 (m, 6 H, 1-H), 3.84 (m, 22 H),
3.65 (m, 6 H), 3.44 (m, 32 H), 3.24 (m, 8 H), 2.64 (s, 6 H) ppm.
13C NMR (250 MHz, D2O, 25 °C): δ = 101.76–101.28 (C-1), 83.87,
83.34, 81.93, 81.20, 77.05, 76.74, 76.24, 76.15, 75.36, 74.29, 74.04,
73.77, 73.40, 73.29, 73.20, 72.76, 72.52, 72.44, 71.88, 71.68, 71.62,
71.38, 66.91, 66.60, 66.46, 66.36, 65.27, 64.92, 64.86, 61.52, 60.89,
60.36, 58.71, 58.30–58.15, 53.78, 53.53, 53.48 (CH, CH2,
CH ) ppm. IR: ν = 3429.63 (OH), 2928.07 (Csp3–H), 1724.46
˜
3
(C=O), 1631.03, 1454.02, 1384.32, 1275.10, 1203.76 (C–N),
1151.28, 1091.60, 1039.88 (C–O) cm–1. MS (ES+): calcd. for
+
C43H75N2O29 1083.45; found 1083.50.
Procedure for Determining the Rate of Oxidation: Each assay was
performed on 14 samples (2 mL each) of the appropriate substrate
at different concentrations in 100 m phosphate buffer containing
64 m H2O2 and either 14 or 15 (1 mg, 2 mL) or with nothing as
a control. The reactions were followed at 25 oC by analysing the
UV absorption at an appropriate wavelength (see below) typically
for 30 min for aniline oxidation and for 5 h for benzyl alcohol oxi-
dation. The velocities were determined as the slope of the progress
curve of each reaction 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–Menten kinetics. In
that case Km and Vmax were determined by using non-linear least-
squares regression fitting to the Vmax versus S curve, kcat was calcu-
lated as Vmax/[cyclodextrin] and kuncat was determined as the slope
from a plot of Vuncat versus S. The following extinction coefficients
(25 oC, pH 7) and wavelengths were determined and used: 2-amino-
phenoxazine-3-one: 0.42 m–1 cm–1 (pH 7.0); 5-amino-2-hydroxy-
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Received: September 25, 2009
Published Online: November 24, 2009
Eur. J. Org. Chem. 2010, 157–167
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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