Amino alcohol-modified β-cyclodextrin inducing biomimetic asymmetric oxidation of thioanisole in water

Article abstract of DOI:10.1016/j.carres.2012.03.034

Inspired by β-CD, a macrocyclic oligomers of d-(+)-glucopyranose and a renewable material, which could be obtained from starch, that can promote a lot of organic reactions in water, a green solvent, several amino alcohol-modified β-CDs CD-1 to CD-7 were synthesized in the yields of 36-61%. Their conformations in vacuum and in aqueous solution were optimized by quantum calculation. Their complexes with sodium molybdate prepared in situ were characterized by ¹H NMR and were applied in the asymmetric oxidation of thioanisole. Their performance in inducing enantioselectivity was investigated in detail. For the optimal one, CD-1, moderate enantioselectivity (56% ee) was achieved in aqueous CH₃COONa-HCl buffer solution (pH 7.0). The abilities of CD-1 to CD-7 to induce asymmetry are highly dependent on the pH value of the reaction medium and the structure of the modifying group. The origin of the moderate enantioselectivity and the reaction mechanism were investigated with the aid of ¹H ROESY NMR studies and quantum calculation. The moderate enantioselectivity was attributed to the two different binding models between CD-1 and thioanisole, which could be defined as intramolecular catalysis and intermolecular catalysis, in which intramolecular catalysis gave (S)-methyl phenyl sulfoxide and intermolecular catalysis gave (R,S)-methyl phenyl sulfoxide.

Full text of DOI:10.1016/j.carres.2012.03.034

Carbohydrate Research 354 (2012) 49–58
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Amino alcohol-modified b-cyclodextrin inducing biomimetic asymmetric
oxidation of thioanisole in water
⇑
Hai-Min Shen, Hong-Bing Ji
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Inspired by b-CD, a macrocyclic oligomers of D-(+)-glucopyranose and a renewable material, which could
Received 8 November 2011
Received in revised form 31 January 2012
Accepted 27 March 2012
be obtained from starch, that can promote a lot of organic reactions in water, a green solvent, several
amino alcohol-modified b-CDs CD-1 to CD-7 were synthesized in the yields of 36–61%. Their conforma-
tions in vacuum and in aqueous solution were optimized by quantum calculation. Their complexes with
sodium molybdate prepared in situ were characterized by 1H NMR and were applied in the asymmetric
oxidation of thioanisole. Their performance in inducing enantioselectivity was investigated in detail. For
Available online 2 April 2012
Keywords:
b-Cyclodextrin
Modification
Oxidation
Enantioselectivity
Quantum calculation
3
the optimal one, CD-1, moderate enantioselectivity (56% ee) was achieved in aqueous CH COONa–HCl
buffer solution (pH 7.0). The abilities of CD-1 to CD-7 to induce asymmetry are highly dependent on
the pH value of the reaction medium and the structure of the modifying group. The origin of the moderate
enantioselectivity and the reaction mechanism were investigated with the aid of 1H ROESY NMR studies
and quantum calculation. The moderate enantioselectivity was attributed to the two different binding
models between CD-1 and thioanisole, which could be defined as intramolecular catalysis and intermo-
lecular catalysis, in which intramolecular catalysis gave (S)-methyl phenyl sulfoxide and intermolecular
catalysis gave (R,S)-methyl phenyl sulfoxide.
Ó 2012 Elsevier Ltd. All rights reserved.
1
. Introduction
reaction to them.10,11 However, the utility of native b-CD in organic
synthesis is rather limited, especially in asymmetric organic reac-
Cyclodextrins (CDs), possessing a hydrophilic exterior and a
hydrophobic cavity, are a family of water-soluble macrocyclic olig-
omers of -(+)-glucopyranosyl units linked by -1,4-glycosidic
bonds, which can form inclusion complexes with a wide range of
guest molecules possessing suitable shape and size. In the cyclo-
tion for the native b-CD is a rigid molecule because of the intramo-
lecular hydrogen network, which makes b-CD difficult to be
subjected to topological changes. Moreover, hydroxyl is the only
functional group in b-CD. Through modification of native b-CD,
the utility of b-CD in organic synthesis expands obviously. Appro-
priate modification permits b-CD derivatives performing as artifi-
D
a
1
2
dextrin family, there are three main members known as
CD (Fig. 1), and -CD with six, seven, and eight glucose units,
Among them, b-CD is most readily available in
a-CD, b-
c
cial enzymes directly or ligands in metal catalysis mimicking the
1
–3
13,14
respectively.
hydrophobic pockets in metalloenzymes.
b-CD derivatives
commerce, thus it is employed widely as drug carriers, microvessel
reactors, enzyme mimics, and so on.4 The ability of b-CD to
accommodate hydrophobic guest molecules in its hydrophobic
cavity in aqueous solution makes it an attractive component in
the construction of artificial enzymes, in which b-CD acts as host
to hydrophobic guest molecules and its hydrophobic cavity mimics
the hydrophobic pockets in enzymes. The driving forces in the for-
mation of host–guest inclusion complexes between b-CD and guest
molecules in aqueous medium could be attributed to several fac-
tors, but the primary driving force is the hydrophobic interactions
between the guest molecules and water.8
coordinating to metal ions forms artificial metalloenzymes, com-
bining molecular recognition, phase transfer catalysis, and metal
catalysis in one same water-soluble catalyst, in which b-CD deriv-
atives play the role of substrate transportation, immobilization,
and asymmetric induction, and metal ions act as catalytic active
–7
8
site. In biomimetic reactions catalyzed by artificial metalloen-
zymes based on b-CD derivatives, b-CD derivatives transfer
water-insoluble substrates to aqueous phase where the catalytic
metal center exists, and immobilize substrates near the catalytic
metal center by forming inclusion complexes as molecular scaf-
,9
15
folds. In the inclusion complexes, weak interactions between
Besides, b-CD can also provide an asymmetric environment for
the guest molecules bound in its cavity and induce asymmetric
substrates and the hydrophobic cavity of b-CD offer substrates a
beneficial orientation and conformation. Hence, enhanced catalytic
activity, obvious acceleration in reaction rate, excellent substrate
selectivity, regioselectivity, and enantioselectivity can usually be
achieved. One of successful artificial metalloenzymes based on
⇑
Corresponding author. Tel.: +86 20 8411 3658; fax: +86 20 8411 3654.
E-mail address: jihb@mail.sysu.edu.cn (H.-B. Ji).
0
008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.03.034

5
0
H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
R
OH
5
6
O
4
O
1
3
HO
2
OH
7
CD-1: R = NHCH CH OH
2
2
Figure 1. Schematic structure of b-cyclodextrin (b-CD).
CD-2 :R = N(CH CH OH)
2
2
2
CD-3: R = NHCH CH CH OH
2
2
2
b-CD derivatives is the cytochrome P-450 mimics reported by Bre-
slow and co-workers. Their work demonstrated that metallopor-
phyrins possessing two or four b-CD units could oxidize and
hydroxylate substrates bound in the cavity of b-CD with excellent
regioselectivity in the presence of more reactive functional
CD-4: R = NHCH CH(CH )OH
2
3
CD-5: R = (S)-NHCH CH(CH )OH
2
3
CD-6: R = N[CH CH(CH )OH]
2
2
3
1
6–21
22,23
groups.
French et al.
also reported metalloporphyrins with
CD-7: R = N(CH3)CH2CH2OH
CD-8: R = NHCH CH NH
two b-CD units mimicking the carotene dioxygenases, catalyzed
2
2
2
0
the central cleavage of carotenoids in 15,15 double bond regiose-
lectively. The origin of these excellent regioselectivity should be
attributed to that b-CD units immobilize substrates in a reactive
conformation, in which reaction is directed to certain substrate
atoms. Application of artificial metalloenzymes based on b-CD
derivatives in catalytic hydrolysis of esters has been investigated
extensively too, because of their remarkable acceleration in reac-
Figure 2. Schematic structures of the amino alcohol-modified b-cyclodextrins (b-
CDs) and CD-8.
reported the application of rhodium and ruthenium complexes
coordinating to amino alcohol-modified b-CDs in the asymmetric
hydrogenation of olefins, aromatic, and aliphatic ketones with high
2
4–28
tion rate by up to more than four orders of magnitude.
In
asymmetric organic reaction, Bonchio and Sakuraba2
9,30
reported
2
9
enantioselectivity. Bonchio
applied the complex of sodium
the asymmetric oxidation of thioanisole catalyzed by the com-
molybdate and ethylenediamine-modified b-CD in the asymmetric
oxidation of thioanisole. Inspired by their works, a series of amino
alcohol-modified b-CDs CD-1 to CD-7 were synthesized and ap-
plied in the asymmetric oxidation of thioanisole to evaluate their
catalytic performance. It should be mentioned that this research
might give some information about sulfur metabolism in life cycle
during medication, since amino acids widely exist in body and
many medicines use b-CD as drug carrier.
plexes of b-CD derivatives and metal ions, respectively, with mod-
erate enantiomeric excesses (ee). Wong and Schlatter3
1–33
attached
rhodium and ruthenium complexes to b-CD derivatives forming
artificial metalloenzymes and applied them in asymmetric hydro-
genation of prochiral olefins, aromatic, and aliphatic ketones. High
enantiomeric excesses (ee) have been achieved, up to 98%,
although the origin of enantioselectivity is still in speculation to
some extent. But to my best knowledge, the application of artificial
metalloenzymes based on b-CD derivatives in asymmetric organic
reaction is rather limited, despite there are a large number of re-
ports on remarkable acceleration in reaction rate and obvious
enhancement of regioselectivity.
The amino alcohol-modified b-CDs (setting CD-1 as an example)
were synthesized as illustrated in Scheme 1. Firstly, mono(6-O-p-
tolylsulfonyl)-b-CD was synthesized by tosylation of b-CD with
p-toluenesulfonyl chloride in basic aqueous solution according to
literature procedure, which could be obtained in a large scale after
3
7
We have reported b-CD catalyzed the deprotection of acetals
and ketals, oxidation of alcohols and hydrolysis of cinnamaldehyde
in aqueous medium, and remarkable rate acceleration and sub-
filtration and washing with acetone and water. Then the amino
alcohol-modified b-CDs, CD-1 to CD-7, were readily synthesized
by nucleophilic substitution of mono(6-O-p-tolylsulfonyl)-b-CD
with an excess of the corresponding amino alcohol at 70 °C or
34–36
strate selectivity were observed.
We also found that weak
interactions between hydroxyls of b-CD and substrates played a
crucial role in the catalytic reaction. Herein, we report the synthe-
sis of several amino alcohol-modified b-CDs (Fig. 2) and the char-
acterization of their complexes with sodium molybdate. The
catalytic performances of these complexes in the asymmetric oxi-
dation of thioanisole were investigated in detail. Their inclusion
complexes between amino alcohol-modified b-CDs and thioanisole
9
0 °C. After precipitation in a large quantity of acetone–ethanol
mixture and recrystallization in water, pure amino alcohol-modi-
fied b-CD in a gram scale could be obtained. 2-Amino-1-ethanol,
2
0
,2 -iminodiethanol, 3-amino-1-propanol, (R,S)-1-amino-2-propa-
0
nol, (S)-1-amino-2-propanol, 1,1 -iminodi-2-propanol, and 2-
methylamino-1-ethanol were selected as modifying groups on
the purpose of illustrating the effect of modifying groups’ structure
on the catalytic performance in the asymmetric oxidation of thio-
anisole. To our best knowledge, these amino alcohol-modified b-
CDs had not yet been employed as ligands in organic synthesis ex-
cept for 2-amino-1-ethanol and (S)-1-amino-2-propanol-modified
b-CDs employed in the asymmetric hydrogenation of olefins, aro-
matic, and aliphatic ketones. Ethylenediamine-modified b-CD
1
were characterized by H ROESY NMR spectrum and quantum cal-
culation, respectively. To illustrate the moderate enantioselectivity
and reaction mechanism in the asymmetric oxidation of thioani-
sole, quantum calculation was employed.
2
2
. Results and discussion
(
CD-8) was also synthesized as comparison accordingly. All of the
1
13
.1. Design and synthesis of amino alcohol-modified b-CDs
b-CD has become a universal structure unit in the design of arti-
modified b-CDs were characterized by H NMR, C NMR and ESI-
MS. Interestingly, compared with native b-CD, the heterogeneous
aqueous solution of the modified b-CDs mentioned above might
become homogeneous when guest molecule thioanisole was
added, which could not be observed from the native b-CD.
The conformation of CD-1 in vacuum and in aqueous solution
was optimized by GAUSSIAN 03 program at the level of PM3 and
B3LYP/6-31G(d), respectively (Fig. 3). The optimized conforma-
tion of CD-1 in aqueous solution is nearly the same as in vacuum
ficial enzymes and artificial metalloenzymes for its unique proper-
ties to accommodate hydrophobic molecules in aqueous medium,
and be soluble in water, readily available from starch by enzymatic
degradation and possible to modify selectively. Appropriate modi-
fication enhances its ability to bind metal ions and improves its po-
3
8
3
1–33
tential applications in organic synthesis. Wong and Schlatter

H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
51
OTs
HN
OH
H NCH CH OH
TsCl, NaOH
CH CN/H O
2
2
2
3
2
Scheme 1. Schematic synthesis of the modified b-cyclodextrin (CD-1).
the H atoms at C-2 linking to the amino in the modifying group
–NH–CH –CH –OH) nearly remained at the same chemical-shift.
(
2
2
Meanwhile, no obvious chemical-shift changes were observed
from the H atoms belonged to the parent b-CD too. For 3-amino-
1
-propanol-modified b-CD (CD-3), the triplets assigned to the H
0
atoms at C-1 linking to the hydroxyl in the modifying group
2 2 2
(–NH–CH –CH –CH –OH) shifted downfield by 0.018 ppm, and the
other H atoms belonged to the modifying group and parent b-CD
nearly remained at the same chemical-shift as shown in CD-1. Sim-
ilar changes in chemical-shift occurred in all the other modified b-
CDs. This indicates that the amino alcohol-modified b-CDs formed
complexes with molybdate by means of coordination of the oxygen
atoms in the amino alcohols with the molybdenum. The oxygen
atoms in the hydroxyls of the parent b-CD and the nitrogen atoms
in the modifying groups may not be involved in the formation of
the catalytic complexes, which is consistent with that the parent
b-CD possesses low coordinating ability to metal ions commented
1
4
by Bellia. But unfortunately, we could not obtain the crystals
suitable for X-ray crystallographic analysis of these complexes,
hence the precise structure of these complexes still remained in
speculation.
Based on the 1H NMR studies, the structure of complexes
formed by amino alcohol-modified b-CDs (setting CD-1 as an
example) and molybdate were surmised as shown in Figure 5.
The modified b-CDs coordinated to the Mo atom through the oxy-
gen atom in the modifying group, forming catalytic metal com-
plexes and combining the catalytic active center molybdate and
modified b-CDs together.
Figure 3. Optimized conformations of CD-1 in vacuum (1a, side view; 1b, vertical
view) and in aqueous solution (2a, side view; 2b, vertical view) obtained at the level
of PM3 and B3LYP/6-31G(d), respectively.
with the modifying group pointing to the outside of the parent b-
CD because of the high solubility of the modifying group in water.
The result is in good consistency with the 1H ROESY NMR studies
for CD-1, no obvious correlation peak between the H atoms in
the modifying group and the H-3, H-5 in the cavity of the parent
2.3. Asymmetric oxidation of thioanisole
To evaluate the catalytic properties of the amino alcohol-mod-
ified b-CDs, asymmetric oxidation of thioanisole was conducted
as a model reaction employing the complexes of amino alcohol-
modified b-CDs and molybdate as catalysts. The asymmetric oxida-
1
b-CD observed from the H ROESY NMR spectrum of CD-1. Similar
optimized conformations were also observed from the other mod-
ified b-CDs, CD-2 to CD-8. No obvious self-inclusion occurred be-
cause all modifying groups are soluble in water, and no
hydrophobic interaction exists. Therefore, as mentioned above,
hydrophobic interaction is the key driving force in the formation
of inclusion complexes based on b-CD.
tion was carried out in aqueous CH
(1 mol/L) at 0 °C with the catalyst/substrate ratio of 1:10 and
as oxidant. After 8.0 h, the corresponding oxidized product
3
COONa–HCl buffer solution
2 2
H O
sulfoxide was obtained with S-configuration as the favorable iso-
mer. The performances of CD-1 to CD-8 in the reaction were stud-
ied in detail. Surprisingly, the enantioselectivity is very sensitive to
the pH value of the reaction medium and the structure of the mod-
ifying groups in the modified b-CDs. For example, when CD-1 was
employed as ligand, the ee value increased from 9% to 56% as the
pH value of the reaction medium rose from 5.5 to 7.0 (Table 1). Fur-
ther increase in the pH value of the reaction medium from 7.0 to
8.0 led to no rise in the enantioselectivity, but a sharp decrease
in the ee value from 56% to 37%. This might be due to the effect
of the pH value on the structure of CD-1. The pH value of the med-
ium exerts high influence on the conformation of native b-CD and
2
.2. Preparation and characterization of complexes between
amino alcohol-modified b-CD and sodium molybdate
With amino alcohol-modified b-CDs in hand, we prepared the
complexes of amino alcohol-modified b-CDs and sodium molyb-
date in situ prior to catalytic experiments by stirring modified b-
3
CDs and sodium molybdate in aqueous CH COONa–HCl buffer
solution at room temperature. The complexes of amino alcohol-
1
modified b-CDs and sodium molybdate were characterized by
H
3
9,40
NMR studies (400 MHz, D O). For example, significant chemical-
2
modified b-CDs being illustrated in the literature.
As for CD-3,
shift changes were observed from the H atoms at C-1 in the 2-ami-
no-1-ethanol-modified b-CD (CD-1) when sodium molybdate was
added (Fig. 4). The multiplets assigned to the H atoms at C-1 link-
the ee value increased from 7% to 11% as the pH value of the reac-
tion medium from 5.5 to 8.0 (Table 1), exhibiting a different pH-
enantioselectivity profile. Furthermore, the enantioselectivity of
CD-3 was much poorer compared with CD-1. Comprehensive stud-
ies were conducted to investigate the pH-enantioselectivity
ing to the hydroxyl in the modifying group (–NH–CH
2 2
–CH –OH)
shifted downfield by 0.017 ppm, however the triplets assigned to

5
2
H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
H-5
H-6
H-1
H-3
H at C2
H at C1
H-2 H-4
H-5
H-6
H-1
H-3
H-2 H-4
5.7
5.5
5.3
5.1
4.9
4.7
4.5
4.3
4.1
δ(ppm)
3.9
3.7
3.5
3.3
3.1
2.9
2.7
2.5
H at C2
H-5
H-6
H at C1
H-3
H-2 H-4
4
.15
4.05
3.95
3.85
3.75
δ(ppm)
3.65
3.55
3.45
3.35
3.04
2.96
2.88
2.80
δ(ppm)
2.72
2.64
Figure 4. 1H NMR spectra of CD-1 and CD-1 + Na
2 4 2
MoO in D O.
H
O
O
O Mo O
O
HN
Figure 5. Proposed structure of the complex between CD-1 and molybdate.
profiles of CD-1 to CD-8. In general, the pH-enantioselectivity pro-
files could be divided into two types. In the first type, containing
CD-1, CD-4, CD-5, and CD-8, the enantioselectivity increased as
the rise in the pH value. When reaching a maximum, a moderate
enantioselectivity could be achieved, and then decreased as further
increase in the pH value of the reaction medium. The second type
contained CD-2, CD-3, CD-6, and CD-7, in which the enantioselec-
tivity increased as the rise in the pH value from 5.5 to 8.0 to some
extent, but lower ee values. The optimal pH values of the reaction
medium and maximal ee values for CD-1 to CD-8 were listed in

H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
53
Table 1
Table 2
Effect of pH value and modifying groups’ structure on the enantioselectivity in the
asymmetric oxidation of thioanisole
Control experiments of CD-1 in the asymmetric oxidation of thioanisolea
a
Entry Catalyst
Conversionb Yieldb eec Configurationd
Entry Ligand pH Conversionb
%)
Yieldb
(%)
eec
(%)
Configurationd
(%)
(%)
(%)
(
1
2
3
CD-1
Na MoO
b-CD + H
+ Na MoO
trace
100
OH 90
trace
92
74
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
CD-1
CD-1
CD-1
CD-1
CD-1
CD-1
CD-2
CD-2
CD-2
CD-2
CD-2
CD-2
CD-3
CD-3
CD-3
CD-3
CD-3
CD-3
CD-4
CD-4
CD-4
CD-4
CD-4
CD-4
CD-5
CD-5
CD-5
CD-5
CD-5
CD-5
CD-6
CD-6
CD-6
CD-6
CD-6
CD-6
CD-7
CD-7
CD-7
CD-7
CD-7
CD-7
CD-8
CD-8
CD-8
CD-8
CD-8
CD-8
5.5 100
6.0 100
6.5 100
7.0 100
7.5 100
86
87
86
84
78
76
86
88
83
83
75
70
83
84
87
83
71
72
89
86
84
85
83
79
88
86
86
82
85
88
85
86
85
78
73
72
89
89
89
81
77
71
87
84
80
67
64
63
9
19
42
56
51
37
8
10
11
12
16
18
7
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2
4
0
1
2
NCH
2
CH
2
S
2
4
4
5
CD-1 + Na
CD-1 + Na
2
MoO
MoO
4
4
100
100
84
91
56
8
S
S
e
2
8.0
90
a
Reaction conditions: thioanisole (0.5 mmol), catalyst (0.05 mmol) and 30% H
0.05 mL) in aqueous CH COONa–HCl buffer solution (10 mL, 1 mol/L, pH 7.0) for
.0 h at 0 °C.
2 2
O
5.5 100
6.0 100
(
8
3
6.5
7.0
7.5
8.0
94
92
87
85
b
Determined by HPLC analysis employing toluene as internal standard.
Determined by HPLC analysis with a Chiralcel OD-H column.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
c
d
Determined by comparison of the eluting sequence of the enantiomers with the
authentic sample and literature.
5.5 100
6.0 100
6.5 100
e
1-Adamantanecarboxylic acid (0.05 mmol) was added.
8
8
8
7.0
7.5
8.0
96
87
89
11
11
12
22
43
51
35
28
14
25
43
53
35
27
11
14
17
17
19
18
6
decreased sharply from 56% to 18%. However, compared with
CD-1, CD-4, and CD-5 having one more CH unit linking to the car-
bon atom next to the hydroxyl in the modifying groups, their
enantioselectivity in the asymmetric oxidation of thioanisole did
not decrease so much (51% and 53%), nearly remained at the same
3
5.5 100
6.0 99
6.5 100
7.0 100
7.5
8.0
98
95
level. However, when a CH
the modifying group (CD-7), the ee value decreased sharply from
6% to 15%. From the results of CD-4 and CD-5, we could learn that
3
unit was linked to the nitrogen atom in
5.5 100
6.0 100
6.5 100
7.0 100
7.5 100
8.0 100
5.5 100
6.0 100
5
the effect of the absolute configuration of the modifying group on
the enantioselectivity could be ignored. As for CD-6, the difference
in the enantioselectivity between CD-4 and CD-6 is similar to that
between CD-1 and CD-2. The hydrogen atom linking to the nitro-
gen atom may be indispensable in inducing enantioselectivity in
the asymmetric oxidation of thioanisole. CD-8 was applied in the
asymmetric oxidation of thioanisole as comparison, and moderate
enantioselectivity (55%) was achieved. Therefore, in the asymmet-
ric oxidation of thioanisole catalyzed by the complexes of amino
alcohol-modified b-CDs and molybdate, 2-amino-1-ethanol modi-
fied b-CD (CD-1) exhibited the optimal performance in inducing
enantioselectivity, a moderate ee value being achieved. The struc-
tures of the modifying groups in CD-1 to CD-8 exert a heavy influ-
ence on their performance in the asymmetric oxidation of
thioanisole. When there are two carbon atoms between the hydro-
xyl and the nitrogen atom in the modifying groups, and one hydro-
gen atom in the corresponding nitrogen atom, better
enantioselectivity can be achieved. Both a longer alkyl chain be-
tween the hydroxyl and the nitrogen atom, and trisubstitution of
ammonia can reduce the enantioselectivity in the asymmetric oxi-
dation of thioanisole. The delicate cooperation between the parent
b-CD and the modified groups in CD-1 to CD-8 determines the
enantioselectivity in the model reaction.
6.5
7.0
7.5
8.0
97
87
86
87
5.5 100
6.0 100
6.5 100
8
10
12
15
15
22
42
55
25
15
12
7.0
7.5
8.0
91
89
86
5.5 100
6.0 100
6.5
7.0
7.5
8.0
94
84
83
83
a
Reaction conditions: thioanisole (0.5 mmol), modified CDs (0.05 mmol),
MoO O (0.05 mmol) and 30% H (0.05 mL) in aqueous CH COONa–HCl
ꢀ2H
Na
2
4
2
2
O
2
3
buffer solution (10 mL, 1 mol/L) for 8.0 h at 0 °C.
b
Determined by HPLC analysis employing toluene as internal standard.
Determined by HPLC analysis with a Chiralcel OD-H column.
Determined by comparison of the eluting sequence of the enantiomers with the
c
d
Control experiments were carried out next to gain more com-
prehension to the asymmetric oxidation induced by amino alco-
hol-modified b-CDs (Table 2). When CD-1 was utilized as the
catalyst alone, no reaction occurred under the standard reaction
conditions. This means that CD-1 could not promote the oxidation
authentic sample and literature.
Table 1, from which we could conclude that the modified b-CDs in
the first type exhibited higher performance in the asymmetric oxi-
dation of thioanisole than those in the second type.
Besides the pH value, the enantioselectivity in the asymmetric
oxidation of thioanisole is also heavily dependent on the structure
of the modifying groups (Table 1). The ability of b-CD to induce
asymmetry in the oxidation of thioanisole depends on its
modifying groups deeply. Compared with CD-1, CD-3 just has
2 2
of thioanisole with H O herein. Sodium molybdate could do it
when employed as the only catalyst, but unfortunately there was
no enantioselectivity observed. As illustrated in Table 2, the metal
complex formed by CD-1 and sodium molybdate, not only pro-
motes the oxidation of thioanisole but also induces moderate
enantioselectivity, from which we can learn that in this catalytic
system, sodium molybdate is the catalytic active center and CD-1
plays the role of asymmetric induction. In addition, the enantiose-
lectivity induced by CD-1 could be inhibited by addition of 1-ada-
mantanecarboxylic acid which is known as a good guest molecule
for the cavity of b-CD, the ee value sharply dropping from 56% to
8%. Thus the cavity in the parent b-CD is indispensable in inducing
one more CH
2
unit, but the ee value decreased sharply from 56%
unit differ-
to 11% at their optimal pH values, respectively. One CH
2
ence not only affects the pH-enantioselectivity profile, but also in-
duces sharp decrease in the optimal ee value. CD-2 has two
hydroxyethyls compared with CD-1 having one, the ee value also

5
4
H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
Figure 6. Partial 1H ROESY NMR spectrum of the inclusion complex between CD-1 and thioanisole.
enantioselectivity in the asymmetric oxidation of thioanisole. To
get more detail about this catalytic reaction, the physical mixture
of native b-CD, 2-amino-1-ethanol, and sodium molybdate was
employed as catalyst, applied in the model reaction under the stan-
dard reaction conditions. The oxidation occurred, but the ee value
was nearly zero, no enantioselectivity induced. Therefore it must
be necessary to attach 2-amino-1-ethanol to the parent b-CD and
the ability of native b-CD to induce enantioselectivity in this cata-
lytic system is extremely poor. Consequently, we can get the con-
clusion that the enantioselectivity induced by amino alcohol-
modified b-CDs in the oxidation of thioanisole is controlled by
the delicate structure of the modified b-CDs, and the exquisite
cooperation between the modified groups and the parent b-CD,
especially the cavity in the parent b-CD, playing a decisive role in
inducing enantioselectivity, which are similar to the enzymatic
catalysis practiced in nature.
although their abilities to induce enantioselectivity in the asym-
metric oxidation of thioanisole differ from each other.
The 2-amino-1-ethanol modified b-CD (CD-1) exhibits the opti-
mal performance in inducing enantioselectivity in present work,
yet we must acknowledge that the enantioselectivity achieved is
moderate, 56% ee. To gain more details about this intriguing asym-
metric oxidation, we firstly speculated the moderate ee value
might be ascribed to the oxidation proceeding in aqueous solution,
in which racemic oxidation products were obtained, as illustrated
in Table 2 when 1-adamantanecarboxylic acid was added or so-
dium molybdate was employed as catalyst alone, the ee value al-
most was zero, not in the cavity of the parent b-CD, in which
enantioselectivity could be achieved. To verify our speculation,
we increased the amount of catalyst and ligand, respectively, in
the asymmetric oxidation of thioanisole on the purpose to reduce
the oxidation proceeding in the aqueous solution and to reduce
the amount of free sodium molybdate in the aqueous solution.
The results are presented in Tables 3 and 4. Unexpected to us, both
increase in the amount of catalyst and ligand did not lead to any
increase in the ee value, but a slightly decrease. The enantioselec-
tivity maintained in a moderate level. Therefore the nonenantiose-
lective oxidation of thioanisole proceeding in aqueous solution
could not account for the moderate ee value in our present work.
Similar phenomenon was also observed from CD-4, CD-5 and CD-
8. When the amount of catalyst increased, all of them gave moder-
ate ee values, about 50%, a meaningful figure.
Inspired by the figure 50% ee, we presumed the moderate ee
values induced by CD-1, CD-4, CD-5, and CD-8 might be ascribed
to the two different binding models between the modified b-CD
and thioanisole as shown in Figure 7 (setting CD-1 as an example).
In model a (intramolecular catalysis), the sulfur atom in thioanisole
is located in the same rim of CD-1 with the modifying group. When
the oxidation takes place, there may be a favorable face attack,
leading to chiral sulfoxide. In model b (intermolecular catalysis),
the sulfur atom in thioanisole and the modifying group in CD-1
are located in two different rims of CD-1. When the oxidation
2
.4. Mechanism studies
As illustrated in Table 2, the formation of inclusion complex
played an essential role in the asymmetric oxidation of thioanisole,
therefore the inclusion complex of CD-1 and thioanisole was
1
probed with the aid of H ROESY NMR study. Obvious correlation
peaks between the H atoms located in the phenyl ring of thioani-
sole and the H-3, H-5 in the cavity of the parent b-CD can be ob-
served (Fig. 6). Obviously, there is no correlation peak observed
between the H atoms located in the phenyl ring of thioanisole
and the H-2, H-4 in the outside of the parent b-CD. Thus, in the
complex of CD-1 and thioanisole, almost all the thioanisole mole-
cules are included into the cavity of the parent b-CD, no thioanisole
absorbed on the outside of the parent b-CD. Similar correlation
peaks were also observed from the 1H ROESY NMR spectra of the
inclusion complexes formed by CD-2 to CD-8 and thioanisole
except for CD-6 for its low solubility in water. All the modified
b-CDs, CD-1 to CD-8, can form stable inclusion complexes with
thioanisole in aqueous medium, giving obvious correlation peaks,

H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
55
Table 3
The optimized geometries of the inclusion complexes between
CD-1 and thioanisole in model a and model b are shown in Figure 8,
and the binding energies in model a and b are ꢂ30.1773 kJ/mol and
ꢂ33.3004 kJ/mol, respectively. The negative binding energy indi-
cated the formation of inclusion complex of CD-1 and thioanisole
is thermodynamically favorable and spontaneous. In addition, we
also obtained that the difference in the binding energies between
model a and b is just 3.1231 kJ/mol, a very low energy barrier. As
a comparison, the energy required to pass the barrier to rotation
around the C–C bond in ethane is about 12.0499 kJ/mol.42 Thus,
the BE difference between models a and b can be ignored. The
intramolecular catalysis and intermolecular catalysis exist in the
oxidation of thioanisole concurrently which is in good consistency
with our hypothesis and can account for the moderate ee value. In
intramolecular catalysis, the sulfur atom in thioanisole is located in
the same rim of CD-1 with the modifying group which has coordi-
nated to the catalytic center molybdate. When the modifying
group coordinates to the molybate rotates to point toward the cav-
ity of CD-1, the oxidation occurs with a favorable face attack, giving
S-configuration isomer. In intermolecular catalysis, the sulfur atom
in thioanisole and the modifying group of CD-1 coordinating to the
molybate are located in two different rims in which the oxidation
takes place with the aid of another molecular complex whose mod-
ifying group coordinating to the molybate points to the outside of
CD-1, both the Re-face and the Si-face of the sulfur atom being
accessible and giving racemic products. Herein, the quantum cal-
culation also provides a useful access to predict the outcome of or-
ganic reaction. In the model reaction employed here, if the binding
energy between the substrate and CD-1 in model a was lower than
in model b, the inclusion complex would exist in model a more
than in model b. Therefore, the intramolecular catalysis based on
the inclusion complex in model a would have advantage over the
intermolecular catalysis based on the inclusion complex in model
b, better enantioselectivity might be obtained.
Effect of the amount of catalyst on enantioselectivity of CD-1 in the asymmetric
oxidation of thioanisolea
Entry
Catalyst
mmol)
Conversionb
(%)
Yieldb
(%)
eec
(%)
Configurationd
(
1
2
3
4
5
0.05
0.10
0.15
0.20
0.25
100
100
100
100
100
84
87
87
88
88
56
54
49
51
52
S
S
S
S
S
a
Reaction conditions: thioanisole (0.5 mmol), catalyst (CD-1 + Na
and 30% H (0.05 mL) in aqueous CH COONa–HCl buffer solution (10 mL, 1 mol/L,
pH 7.0) for 8.0 h at 0 °C.
2
4
MoO ꢀ2H
2
O)
2
O
2
3
b
Determined by HPLC analysis employing toluene as internal standard.
Determined by HPLC analysis with a Chiralcel OD-H column.
Determined by comparison of the eluting sequence of the enantiomers with the
c
d
authentic sample and literature.
Table 4
Effect of the amount of ligand (CD-1) on the enantioselectivity in the asymmetric
oxidation of thioanisolea
Entry
CD-1
mmol)
Conversionb
(%)
Yieldb
(%)
eec
(%)
Configurationd
(
1
2
3
0.05
0.15
0.25
100
100
100
84
89
88
56
53
50
S
S
S
a
Reaction conditions: thioanisole (0.5 mmol), Na
0% H (0.05 mL) in aqueous CH
.0) for 8.0 h at 0 °C.
2
MoO
4
ꢀ2H
2
O (0.05 mmol) and
3
7
2
O
2
3
COONa–HCl buffer solution (10 mL, 1 mol/L, pH
b
Determined by HPLC analysis employing toluene as internal standard.
Determined by HPLC analysis with a Chiralcel OD-H column.
c
d
Determined by comparison of the eluting sequence of the enantiomers with the
authentic sample and literature.
On the basis of data analysis and quantum calculation, we pro-
posed the catalytic cycle for CD-1 as illustrated in Scheme 2: (1)
coordination of CD-1 to molybdate (I); (2) formation of inclusion
HN
OH
HN
OH
CH3
S
0
complexes of CD-1 and thioanisole in models a and b (II and II );
0
(
3) oxidation of thioanisole in models a and b (III and III ); (4) lib-
eration of the generated sulfoxide from the cavity of CD-1 and
regeneration of the catalyst (IV and IV ). This is also the origin of
the moderate enantioselectivity.
S
CH3
0
a
b
The binding energies (BE) for CD-2 to CD-8 with thioanisole in
model a and model b have also been calculated at the level of ONI-
OM(B3LYP/6-31G(d):PM3). The results are listed in Table 5. All the
binding energies (BE) for CD-1 to CD-8 are negative, indicating that
all of them can form thermodynamically favorable inclusion com-
plexes with thioanisole spontaneously, which is consistent with
Figure 7. Two proposed binding models for CD-1 and thioanisole.
happens, both the Re-face and the Si-face of the sulfur atom are
accessible, leading to racemic sulfoxide. Since the probabilities of
thioanisole to be oxidized in model a and model b are nearly the
same, moderate enantioselectivity is achieved. To verify our spec-
ulation, the quantum calculation was employed to calculate the
binding energy of CD-1 and thioanisole in model a and model b.
The geometries of the inclusion complexes between CD-1 and thio-
anisole were firstly optimized by GAUSSIAN 03 program at the level of
PM3, and then the output files were employed as input files for
optimization at the level of ONIOM(B3LYP/6-31G(d):PM3), in
which CD-1 and thioanisole were optimized at the level of PM3
and B3LYP/6-31G(d), respectively, and the binding energy (BE) at
the level of ONIOM(B3LYP/6-31G(d):PM3) was obtained according
to Eq. 1:
1
the H ROESY NMR studies in which obvious correlation peaks be-
tween the H atoms located in the phenyl ring of thioanisole and the
H-3, H-5 in the cavity of the parent b-CD are observed. However,
we must acknowledge that, as shown in Table 5, the differences
of the binding energies in model a and model b stay at the same
level for CD-1 to CD-8, but CD-2, CD-3, CD-6, and CD-7 exhibit
low enantioselectivity compared with CD-1, CD-4, CD-5, and CD-
3
8
8
. This may be caused by the difference in the modifying groups’
structure. When the inclusion complexes are formed in model a,
the modifying groups’ structure of CD-2, CD-3, CD-6, and CD-7 dis-
favor the enantioselective oxidation of the sulfur atom in thioani-
sole from the Si-face exclusively. The oxidation may take place to
both the Re-face and Si-face of the sulfur atom producing some
racemic sulfoxide. In model b, racemic sulfoxide is produced for
all of CD-1 to CD-8, thus resulting in the low enantiomeric excesses
(ee). Hence, the delicate cooperation between the modifying
groups and the parent b-CD plays the decisive role in inducing
OPT
ONIOM
OPT
PM3
OPT
BE ¼ E½Cꢁ
ꢂ E½Hꢁ
ꢂ E½Gꢁ
ð1Þ
B3LYP=6-31GðdÞ
OPT
ONIOM
OPT
PM3
OPT
where E½Cꢁ
; E½Hꢁ
and E½Gꢁ
B3LYP=6-31GðdÞ
represent the total
optimized energy of the inclusion complex at the level of ONI-
OM(B3LYP/6-31G(d):PM3), the free CD-1 at the level of PM3 and
the free thioanisole at the level of B3LYP/6-31G(d).41

5
6
H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
Figure 8. Optimized geometries of the inclusion complex between CD-1 and thioanisole in model a (a1, side view; a2, vertical view) and in model b (b1, side view; b2, vertical
view) obtained at the level of ONIOM(B3LYP/6-31G(d):PM3).
enantioselectivity in the asymmetric oxidation of thioanisole cata-
lyzed by the complexes of CD-1 to CD-8 and sodium molybdate.
acetonitrile (30 mL) was added dropwise at 10–15 °C over about
45 min forming white precipitate immediately. The resultant solu-
tion was kept stirring for 3.0 h, and rose to room temperature. The
precipitate formed was collected by suction filtration and then sus-
pended in water (300 mL) with magnetic stirring at room temper-
ature for 3.0 h. The precipitate collected by suction filtration was
washed successively with acetone (100 mL) and water (160 mL),
and then dried in vacuum at 80 °C for 8.0 h to afford white solid
powder 8.1746 g in 13% yield.
3
3
. Experimental
.1. Materials and methods
b-CD in 99% purity was purchased from Shanghai Boao Biologi-
cal Technology Co. Ltd, China. p-Toluenesulfonyl chloride, 3-amino-
1
1
-propanol, (R,S)-1-amino-2-propanol, (S)-1-amino-2-propanol,
,1 -iminodi-2-propanol, 2-methylamino-1-ethanol, and thioani-
0
3
.3. Typical procedure for the synthesis of amino alcohol-
sole in 98% purity were purchased from Aladdin. 2-Amino-1-etha-
nol, 2,2 -iminodiethanol and ethylenediamine of analytical grade
modified b-CDs, CD-1 to CD-7
0
were purchased from Tianjin Damao Chemical Reagent factory,
China. Methyl phenyl sulfoxide was obtained from Alfa Aesar. All
the other common reagents were of analytical grade. All of the
reagents were used as received without further purification unless
otherwise noted. NMR spectra were recorded on a Bruker AvanceIII
A solution of mono[6-O-(p-toluenesulfonyl)]-b-CD (6.4459 g,
mmol) in amino alcohol (375 mmol) was stirred at 70 °C for
2.0 h, and then cooled to room temperature. Water (20 mL) was
added to dilute the mixture, and resultant solution was poured into
a mixture of acetone (200 mL) and ethanol (200 mL) slowly form-
ing white precipitate immediately. The white precipitate was col-
lected by suction filtration and recrystallized two times in water
5
1
4
00 spectrometer in DMSO-d
as the internal standard (0.00 ppm) in DMSO-d
as the internal standard (4.79 ppm) in D O. The quantum calcula-
6
or D
2
O. Tetramethylsilane was used
6
and H O was used
2
2
(
2 ꢃ 10 mL), dried in vacuum at 80 °C for 8.0 h to afford white
tion was carried out by using GAUSSIAN 03 program at the level of
PM3 and B3LYP/6-31G(d). The ee value was determined by HPLC
analysis (SHIMADZU LC-20AT chromatography, UV–vis detector,
crystal.
2
54 nm, Chiralcel OD-H column, eluted with n-hexane/isopropyl
3.4. Typical procedure for asymmetric oxidation of thioanisole
to methyl phenyl sulfoxide
alcohol = 4:1, 0.9 mL/min). The absolute configuration was deter-
mined by comparison of the eluting sequence of the enantiomers
with the authentic sample and literature.43
A solution of modified b-CD (0.05 mmol) and Na
2
MoO
4
ꢀ2H
2
O
(
0.0121 g, 0.05 mmol) in aqueous CH COONa–HCl buffer solution
3
3
.2. Synthesis of mono[6-O-(p-toluenesulfonyl)]-b-CD
(10 mL, 1 mol/L) was stirred at room temperature for 1.0 h, and
then thioanisole (0.0621 g, 0.5 mmol) was added. After the resul-
tant mixture was stirred at room temperature for another 1.0 h,
A solution of sodium hydroxide (6.0000 g, 150 mmol) in water
(
5
20 mL) was added dropwise to a solution of b-CD (56.7490 g,
0 mmol) in water (500 mL) with magnetic stirring at 10–15 °C
the mixture was cooled to 0 °C and 30% H
After stirring at 0 °C for 8.0 h, 0.1 mol/L aqueous Na
was added to stop deep oxidation. The obtained solution was
extracted with CH Cl
(3 ꢃ 10 mL), and the combined organic
2
O
2
(0.05 mL) was added.
2 2 3
S O
(5 mL)
over about 15 min. The solution became homogeneous, and then
a solution of p-toluenesulfonyl chloride (11.4384 g, 60 mmol) in
2
2

H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
57
HN
OH
Na2MoO4
I
H
O
O
CH3
CH3
S
O Mo O
O
HN
S
II
II′
H
O
H
O
O
CH3
O
O
S
O
CH3
S
O Mo O
O
O Mo O
O
HN
HN
(S) -
(R,S) -
CH3
S
IV
IV′
S
CH3
H
H
O
O
O
Mo
O
O
O
O
Mo
O
O
O
O
O
III
III′
H2O2
HN
HN
H2O2
O
O
CH3
S
S
CH3
or
O
Mo
O
O
O
HO
O
O
N
H
S
H3C
Scheme 2. Proposed catalytic cycle for CD-1 in the asymmetric oxidation of thioanisole.
Table 5
a
3.5. Quantum calculation
Binding energies (BE) of D-1 to CD-8 with thioanisole in model a and model b
Entry
CDs
BE
a
(kJ/mol)
BE
b
(kJ/mol)
D
BEb (kJ/mol)
All calculations were carried out by using GAUSSIAN 03 program at
the level of PM3, B3LYP and ONIOM(B3LYP/6-31G(d):PM3).38 The
initial structure of b-CD was constructed with the aid of the avail-
able crystallographic data obtained from XRD without any optimi-
zation. The initial structures of thioanisole and amino alcohols
were constructed with the aid of ChemBioOffice 3D Ultra (Version
1
2
3
4
5
6
7
8
CD-1
CD-2
CD-3
CD-4
CD-5
CD-6
CD-7
CD-8
ꢂ30.1773
ꢂ34.6727
ꢂ35.8970
ꢂ40.6133
ꢂ30.8773
ꢂ39.4868
ꢂ37.2553
ꢂ35.3275
ꢂ33.3004
ꢂ32.3497
ꢂ36.2708
ꢂ43.9479
ꢂ34.9031
ꢂ29.4137
ꢂ39.3855
ꢂ38.7153
3.1231
ꢂ2.3231
0.3738
3.3347
4.0257
4
4
ꢂ10.0731
2.1302
3.3878
1
2.0, Cambridge software) and were fully optimized at the level of
B3LYP/6-31G(d). Then the optimized amino alcohols were attached
to the C-6 of b-CD forming amino alcohol-modified b-CDs which
were fully optimized at the level of PM3 and B3LYP/6-31G(d) with-
out any symmetrical restrictions. The coordinate system for
describing the inclusion complexes between native b-CD and guest
a
All calculations were carried out by using the GAUSSIAN 03 program at the level of
ONIOM (B3LYP/6-31G(d):PM3). See Section 3 for detail.
b
D
BE = BE
a
b
ꢂ BE .
4
1,45–48
phase was washed with saturated brine (10 mL), dried over anhy-
drous Na SO4, and evaporated under reduced pressure to afford the
crude product which was analyzed by HPLC to determine the yield
and ee value.
molecules has been reported in many literatures.
In general,
2
all the glycosidic oxygen atoms in the parent b-CD were located
onto the XY plane, and their center was defined as the origin of this
coordinate system. The C-6 hydroxyls were located pointing to the

5
8
H.-M. Shen, H.-B. Ji / Carbohydrate Research 354 (2012) 49–58
4. Uekama, K.; Hirayama, F.; Irie, T. Chem. Rev. 1998, 98, 2045–2076.
positive Z axis. The coordinate of the guest molecule thioanisole
was determined with the aid of three dummy atoms, one in the
Z axis and two in the XY plane. The relative position between the
modified b-CDs and thioanisole was determined by the distance,
angle and dihedral angle between the labeled carbon atom in thio-
anisole and the three dummy atoms. To facilitate the calculation,
the carbon atom linking to the sulfur atom in the benzene ring of
thioanisole was appointed to be the labeled carbon atom. All the
inclusion complexes were firstly optimized at the level of PM3,
and then the output files were employed as input files for optimi-
zation at the level of ONIOM(B3LYP/6-31G(d):PM3) to obtain opti-
mized energies.
5
6
.
.
Takahashi, K. Chem. Rev. 1998, 98, 2013–2033.
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Reetz, M. T. Top. Catal. 1997, 4, 187–200.
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Org. Lett. 2001, 3, 1173–1175.
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. Conclusion
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Acknowledgements
The authors thank the National Natural Science Foundation of
China (Nos. 21036009 and 21176268), higher-level talent project
for Guangdong provincial universities and the Fundamental Re-
search Funds for the Central Universities for providing financial
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