Highly enantioselective α-aminoxylation reactions catalyzed by isosteviol-proline conjugates in buffered aqueous media

Article abstract of DOI:10.1007/s10562-011-0574-6

Chiral amphiphilic conjugate catalysts were designed and synthesized by covalently connecting l-proline with an inexpensive natural product, isosteviol. These catalysts demonstrated remarkable efficiency in the asymmetric α-aminoxylation of aldehydes and

Full text of DOI:10.1007/s10562-011-0574-6

Catal Lett (2011) 141:1123–1129
DOI 10.1007/s10562-011-0574-6
Highly Enantioselective a-aminoxylation Reactions Catalyzed
by Isosteviol-proline Conjugates in Buffered Aqueous Media
•
Ya-Jie An Chuan-Chuan Wang Yuan-Zhen Xu
•
•
•
Wei-Juan Wang Jing-Chao Tao
Received: 29 December 2010 / Accepted: 24 February 2011 / Published online: 8 March 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Chiral amphiphilic conjugate catalysts were
designed and synthesized by covalently connecting L-pro-
line with an inexpensive natural product, isosteviol. These
catalysts demonstrated remarkable efficiency in the asym-
metric a-aminoxylation of aldehydes and ketones using
nitrosobenzene in phosphate buffer solution, resulting in
good to high yields and excellent enantioselectivities
without using any additives. At pH 9.1, the amphiphilic
catalysts showed a pH responsive ability in phosphate
buffer solution, which facilitated the excellent O-selectiv-
ity reactions, illustrating a viable approach for the devel-
opment of asymmetric supra-molecular catalysts.
[5]. The asymmetric a-hydroxylation of enolates and enol
derivatives utilizing transition metal complexes as catalysts
is one of the simplest and most frequently used methods.
Yamamoto [6] used catalyst (R)-BINAPÁPd(ClO4)2 for the
catalytic enantioselective introduction of an oxy group at
the a-position of ketone enolates using nitrosobenzene and
the asymmetric synthesis of chiral R-hydroxy ketone in up
to 97% ee.
Comparing with the corresponding transition metal
catalysts, the organic catalysts showed more fine qualities:
operational simplicity, availability, non-toxicity, high effi-
ciency and selectivity. In 2003, the first organocatalyst was
utilized to catalyze the direct a-aminoxylation of aldehydes
with nitrosobenzene has reported by Zhong [7], MacMillan
[8], and Hayashi [9] independently. The scope of the
L-proline-catalyzed reaction was then extended to ketones
Keywords Amphiphilic conjugate Á Aminoxylation Á
Buffered media Á pH responsibility
´
by Hayashi [10] and Cordova [11, 12]. After this initial
1 Introduction
breakthrough in the organo-catalyst field, several modified
L-proline catalysts have been developed to improve the
enantioselectivity and reactivity, such as 4-siloxyproline
[13], polymers-supported prolines [14], a,a-diphenylpro-
linol trimethylsilyl ether [15] and the substitution of the
carboxylic acid moiety of L-proline with an amide [16–18]
or tetrazole function [19]. However, most of the reported
catalytic reactions were carried out in organic solvents such
as DMSO, DMF, CH3CN, CHCl3, CH2Cl2, etc., and little
work was done considering environmentally friendly
reaction protocols.
Optically active a-hydroxy carbonyl and 1,2-diol moieties
are frequently found in a large number of biologically
active natural products [1–4], which motivated chemists
finding the ways to explore highly effective catalytic sys-
tems for diastereoselective and enantioselective synthesis
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-011-0574-6) contains supplementary
material, which is available to authorized users.
Water is the least expensive and environmentally
benign solvent. Therefore, it has been accepted as a
convenient solvent in organo-catalysis reactions consid-
ering its great advantages as described below: (1) accel-
erates reaction and enhances selectivity; (2) facilitates the
formation of intermolecular hydrogen bond in the transi-
tion state; (3) easily recycles the water-soluble catalysts
Y.-J. An Á C.-C. Wang Á Y.-Z. Xu Á W.-J. Wang Á J.-C. Tao (&)
Department of Chemistry, New Drug Research and Development
Center, Zhengzhou University, 450052 Zhengzhou,
People’s Republic of China
e-mail: jctao@zzu.edu.cn
123

1124
Y.-J. An et al.
2.2 Synthesis of Catalysts
after separation of the insoluble reaction products [20–24].
In 2009, Zhong and co-workers [25] reported the L-thia-
proline-catalyzed a-aminoxylation of aldehydes in the
presence of water and tetrabutylammonium bromide in
good to high yields (74–88%) and with excellent enanti-
oselectivities (93 to [99%). Wang and co-workers [26]
reported that the addition of water could facilitate the
hydrolysis of the iminium salt intermediate to a-amin-
oxyaldehyde, which regenerating the proline catalyst.
Although initial enamine formation produced 1 equiv of
water, it seemed that this was not sufficient to maintain a
smooth catalytic cycle and additional amount of water
might be required. In addition, L-proline has been shown
to mechanistically mimic aldolase I with good enantiose-
lectivity, and several examples of aldol reaction catalyzed
under enzymatic conditions, i.e. buffered aqueous media,
have also been reported [27–31]. Amino acid moieties
covalently attached to long hydrocarbon chains are also
reported for the preparation of pH-sensitive hydrogelators.
Recently, Lin et al. [32] reported the formation of pH-
responsive worm-like micelles in a mixture of cationic
surfactants and hydrotropes with a carboxyl functional
group. Herein, we present the first example of isostevioL-
proline conjugate catalysts that promote a-aminoxylation
of aldehydes or ketones with high efficiency and enanti-
oselectivity in aqueous buffer (pH 9.1). In this catalyst
system, amphiphilic amino acids are used as pH-respon-
sive micelle through self-assembly in aqueous buffer,
which facilitate the O-selective reactions and stereose-
lectivity. Moreover, the effects of non-covalent interac-
tions between the catalysts and substrates in aqueous
buffer are also discovered.
2.2.1 Synthesis of Catalyst 1a
Isosteviol (6.36 g, 20 mmol) was dissolved in SOCl2
(20 mL), and the mixture was stirred at room temperature
for 1 h. After evaporating the solvent under vacuum, trans-
4-hydroxy-L-proline (2.62 g, 20 mmol) and CF3COOH
(20 mL) were added. The resulted solution was stirred at
room temperature for 2 h. Under cooling with an ice/water
bath, Et2O (40 mL) was added carefully to give a fine
white precipitate that was vacuum-filtered, washed with
Et2O (5 mL 9 2) and dried at room temperature for 2 h to
give the hydrochloride as a fine white powder. The white
powder was dissolved in 40 mL of warmed 95% EtOH,
and propylene oxide (10 mL) was then added. Stirring was
discontinued and the solution left for crystallization at
room temperature for 7 h. The crystalline product was
vacuum-filtered and dried at room temperature in vacuo to
give product 1a (7.16 g, 83%). m.p.:176–178 °C, [a]D20
=
-56.7 (c 0.13, CHCl3); IR (KBr, cm-1): 3601, 3448, 2955,
2849, 1733, 1654, 1149, 1130; 1H NMR (400 MHz,
CDCl3) d: 5.23 (s, 1H), 4.13 (s, 1H), 3.60 (s, 1H), 3.38
(s, 1H), 2.64–2.59 (d, J = 20 Hz, 1H), 2.20 (m, 3H),
1.85–1.78 (m, 2H), 1.66–1.38 (m, 10H), 1.18 (s, 3H),
1.12–1.09 (m, 2H), 0.95 (s, 3H), 0.98–0.88 (m, 2H), 0.69
(s, 3H); 13C NMR (100 MHz, CDCl3) d: 222.5, 176.5,
173.1, 72.3, 59.7, 57.0, 54.5, 54.1, 49.8, 48.6, 48.4, 43.8,
41.4, 39.6, 39.4, 38.0, 37.5, 37.2, 35.4, 28.9, 21.5, 20.3,
19.8, 19.0, 13.8; HR-MS (ESI, m/z) calcd. for
C25H37NNaO5 [M ? Na]? 454.2569, found: 454.2570.
2.2.2 Synthesis of Catalyst 1b
A solution of compound 1a (8.62 g, 20 mmol) and sodium
borohydride (1.71 g, 30 mmol) in dry ethanol (100 mL)
was stirred at 0 °C for 2 h. The reaction mixture was then
concentrated under vacuum, and treated with CHCl3 and
H2O. The organic layer was separated and washed with
saturated NaCl aqueous solution. Then the solvent was
dried over anhydrous MgSO4 and evaporated under vac-
uum to afford crude product. After methanol re-crystal-
2 Experimental
2.1 General
All chemicals were used as received unless otherwise
noted. Reagent grade solvents were distilled prior to use.
All reported 1H NMR and 13C NMR spectra were collected
on a Bruker DPX 400 NMR spectrometer with TMS as an
internal reference. IR spectra were determined on a
Thermo Nicolet IR200 unit. High resolution mass spectra
(HRMS) were obtained on a Waters Micromass Q-Tof
MicroTM instrument using the ESI technique. Chromatog-
raphy was performed on silica gel (200–300 mesh). Melt-
ing points were determined using a XT5A apparatus and
are uncorrected. Optical rotations were determined on a
Perkin Elmer 341 polarimeter. Enantiomeric excess was
measured by chiral HPLC at room temperature using
Labtech 2006 pump equipped with Labtech UV600 ultra
detector with Chiralpak AD-H (4.6 mm 9 250 mm).
lized, the catalyst 1b was obtained as
a white
20
powder(8.31 g, 96%). m.p.: 167–170 °C, [a] = -50.0
589
(c 0.12, CH3OH); IR (KBr, cm-1): 3422, 2926, 2847, 1719,
1596, 1438, 1384, 1176, 1150; 1H NMR (400 MHz,
CDCl3) d: 5.26 (s,1H), 4.20 (s, 1H), 3.81–3.80 (d,
J = 5.6 Hz, 2H), 3.320–3.279 (d, J = 16.4 Hz, 1H),
2.394–2.308 (m, 2H), 2.16–2.12 (d, J = 16.4 Hz, 1H),
1.74–1.23 (m, 13H), 1.17 (s, 3H), 1.07–0.73 (m, 9H), 0.89
(s, 3H), 0.73 (s, 3H); 13C NMR (100 MHz, CDCl3) d:
177.0, 80.1, 72.7, 60.6, 57.0, 55.7, 55.0, 50.2, 43.8, 42.5,
42.0, 41.9, 41.6, 40.3, 39.7, 38.1, 37.7, 35.0, 33.7, 28.9,
123

a-Aminoxylation Reactions in Buffered Aqueous Media
1125
24.9, 21.7, 20.4, 18.8, 13.8; HR-MS (ESI, m/z) calcd. for
C25H39NNaO5 [M ? Na]? 456.2726, found: 456.2726.
Fig. 1 Structure of Isosteviol
16
D
C
O
2.3 General Procedure for the a-Aminoxylation
of Aldehydes
A
B
cis
COOH
19
PBS (phosphate buffered solutions, 0.20 mL) was added to
a stirred mixture of corresponding aldehydes and catalyst at
0 °C, followed by nitrosobenzene. The reaction was stirred
at room temperature until the green solution turned yellow
which indicated complete consumption of the nitrosoben-
zene. The reaction mixture was then treated with NaBH4 in
EtOH at 0 °C. The excess NaBH4 was quenched by the
addition of water, and the mixture was extracted with
CH2Cl2. The combined organic extracts were dried with
over anhydrous Na2SO4 and evaporated under vacuum.
The crude oil was purified by thin layer chromatography on
silica gel (petroleum ether/ethyl acetate).
lipophilic
Isosteviol
skeleton
hydrophilic
catalytic group
O
O
O
N
H
OH
X
assistant functional
group
2.4 General Procedure for the a-Aminoxylation
of Cyclohexanone
Fig. 2 Designed structure of catalyst with different functions
PBS (0.20 mL) was added to a stirred mixture of cyclo-
hexanone and catalyst at 0 °C, and then the substitute
nitrosobenzene was added. The reaction was stirred at
room temperature until the green solution turned yellow
which indicated complete consumption of the nitrosoben-
zene. The reaction mixture was then extracted with
CH2Cl2. The combined organic extracts were dried with
anhydrous Na2SO4 and evaporated under vacuum. The
crude oil was purified by thin layer chromatography on
silica gel (petroleum ether/ethyl acetate).
find that this kind of amphiphilic isosteviol-proline conju-
gates is indeed a viable catalyst for the a-aminoxylation of
carbonyl compounds in an aqueous buffer solution with good
activities and excellent enantioselectivities.
Amphiphilic conjugate 1a was readily synthesized in
high yield by the condensation of isosteviol with the anti-4-
hydroxy-L-proline via a one-pot process as previously
described (Scheme 1), and it can also be made on large-
scale. In order to investigate the efficiency of the
16-functional group in the isosteviol skeleton, the catalyst
1b was synthesized by the reduction of the 16-carbonyl
group with NaBH4 in C2H5OH. As previously reported,
only 16-R-configuration product was obtained, which
afforded a cis structure in account of the 16-hydroxyl and
19-carboxyl groups. The structures of these catalysts were
fully characterized by IR, 1H NMR, 13C NMR, and HR-MS
analyses.
3 Results and Discussion
3.1 Synthesis of Catalysts
Based on our previous research [33, 34], the special features
of isosleviol have been invoked our interest: hydrophobic
polycyclic skeleton and chiral concave structure consist of
the cis-junction of the 19-carboxyl group and D cyclopen-
tane rings (Fig. 1). Recently, we [35] discovered that
amphiphilic compound 1a was an efficient organocatalyst
in aldol reaction in a water system (Fig. 2), giving
b-hydroxy carbonyl derivatives with virtually complete ste-
reoselectivity. The hydrophobic effect of isosteviol subunit in
the catalyst allows the proline moiety away from water
phase, forming micelles on water surface, which facilitates
the cluster of the catalyst with the lipophilic reactants. And
the concave constructed by isosteviol and (2S, 4R)-4-
hydroxyproline would facilitate the enantioselective forma-
tion of the transition states. In this context, it is delightful to
3.2 The a-Aminoxylation Reaction of Carbonyl
Compounds Catalyzed by Different Catalysts
With the L-proline derived chiral amphiphilic catalysts in
hand, we proceeded to test their catalytic ability in asym-
metric reaction of carbonyl compounds. It was reported that
L-proline was efficient in catalyzing a-aminoxylation of
aldehyde/ketone in ionic liquids or in the presence of water
with phase-transfer catalyst as an additive. The amphiphilic
L-proline derivatives 1a and 1b have the combined catalytic
function of L-proline with the hydrophobic effect of the
isosteviol subunit, which prompted us to evaluate their
123

1126
Y.-J. An et al.
Scheme 1 Synthetic route of
catalysts 1a and 1b
OH
O
O
SOCl2, r.t.,1h
HO
NaBH4, C2H5OH
O
O
0
, 1h
O
O
COOH
COOH
Isosteviol
N
H
COOH
N
H
COOH
N
H
TFA
1b
1a
Fig. 3 Catalysts screened
OH
O
O
O
O
O
COOH
COOH
N
H
N
H
1a
1b
C11H23
O
C12H25
O
COOH
COOH
O
COOH
N
H
N
H
N
H
1c
1e
1d
catalytic performance for the asymmetric a-aminoxylation
reaction in aqueous media in the absence of any additive. To
compare the catalytic behavior of different amphiphilic
catalysts, the long-alkyl substituted proline derivatives 1c
[36] and 1d [37], as well as L-proline 1e, were also exam-
ined for the reactions (Fig. 3).
and 2). Then the screenings of various organic solvents
revealed that THF and DMSO were not suitable for this
reaction (Table 1, entries 6 and 8), and the enantioselec-
tivities were improved when CH3CN or CHCl3 was used as
solvent (Table 1, entries 7 and 9). The results revealed that
the hydrophobic group containing amphiphilic proline
catalysts, especially the isosteviol-proline conjugates 1b,
showed much higher catalytic activities for the a-amin-
oxylation reaction in aqueous media than other catalysts
tested.
The catalytic activities and stereoselectivities of cata-
lysts 1a–1e were first investigated in aqueous media as well
as in some organic solvents at room temperature by using
the a-aminoxylation of nitrosobenzene and butanal as a
model reaction (Table 1). After in situ conversion of the
intermediate into the more stable 2-aminoxy alcohol, the
corresponding O-regioselective addition product 4a was
isolated by silica gel chromatography. The absolute con-
figuration of the major a-aminoxylation product was
assigned as an R based on the optical rotation and HPLC
analysis according to reported data [12]. Meanwhile, it
is noteworthy that no apparent a-oxyamination by-products
were observed under such conditions. The desired
a-aminoxylation product was obtained with good yields
and high enantioselectivities using the designed catalysts
except L-proline (Table 1, entries 1–4 vs. 5). In all case, the
amphiphilic isosteviol-proline conjugates 1a and 1b caused
the reaction to completion in a short time with high cata-
lytic activities and enantioselectivities (Table 1, entries 1
Though the reaction time was short in aqueous media,
the enantioselectivity was barely satisfactory. The color of
the reaction mixture changed from green to orange at the
end of the reaction, which indicated the possible formation
of azobenzene or azoxybenzene from nitrosobenzene
according to IR and MS analyses of the reaction mixture.
Therefore, if the transformation process to the azo-type
by-products could be efficiently minimized, it would greatly
facilitate the desired a-aminoxylation reaction. Recently,
Hassan et al. [38] reported the pH-induced changes in the
rheology, and microstructure in an aqueous mixture of
polymer-like assemblies of a hydrophobic amino acid sur-
factant was studied by rheological measurements, small-
angle neutron scattering (SANS) and light scattering. We
were then inspired to perform the catalytic a-aminoxylation
123

a-Aminoxylation Reactions in Buffered Aqueous Media
Table 1 Catalyst screening
1127
Table 2 Optimization of reaction conditions
Yielda (%) eeb (%)
Entry Catalyst Solvent
Time
Yielda (%) eeb (%)
Entry Solvent pH (PBS) Time
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1b
1b
1b
1b
H2O
10 min
4 min
85
86
76
78
88
89
75
85
90
66
84
67
85
1
H2O
Brine
PBS
PBS
PBS
PBS
PBS
PBS
PBS
PBS
PBS
PBS
–
4 min
86
90
74
78
82
80
96
93
73
91
89
86
89
89
71
72
97
95
79
89
44
97
H2O
H2O
2
–
5 min
17 min
22 min
3
5.5
6.4
6.9
8.5
9.1
9.1
9.1
9.1
9.1
9.1
14 min
11 min
11 min
7 min
H2O
4
H2O
9 h 17 min 26
5
THF
33 min
15 min
36 min
83
82
77
80
6
CHCl3
DMSO
7
4 min
8c
9d
10e
11f
12
15 min
38 min
21 min
CH3CN 14 min
Conditions: Nitrosobenzene (0.5 mmol), butanal (10 equiv.), catalyst
(10 mol%), and solvent (0.20 mL) was added at 0 °C and then
warmed to RT
3 h 37 min 62
4 min 89
g
a
Isolated yields
Conditions: Nitrosobenzene (0.5 mmol), butanal (10 equiv.), catalyst
1b (10 mol%), and solvent (0.20 mL) was added at 0 °C and then
warmed to RT
b
The ee value was determined by chiral HPLC on a chiralcel AD-H
column
Bold values indicate the best result in that reaction condition
a
Isolated yields
b
The ee value was determined by chiral HPLC on a chiralcel AD-H
reaction in buffered aqueous solution in order to facilitate
the O-attack of the enamine intermediate on the nitros-
obebzene in a special pH region and to increase the e-
nantioselectivity. Therefore, the catalytic performances of
catalyst 1b were studied for the model reaction in different
phosphate buffered solutions (PBS), and the pH-activity/
stereoselectivity profiles were determined (Table 2).
Firstly, when the reaction was process in pH \7, we only
got poor ee value and low yield (Table 2, entries 3–5). Then
the pH were extended to 9.1 (Table 2, entry 7), which was
considered detrimental to O-regioselectivity because of its
alkaline. Surprisingly, we only obtained the O-regioselec-
tivity product with 96% yield and 97% ee value. The
solution used here was pure alkalescent buffered aqueous
media. No further improvements were observed when the
reaction was done at the different temperature (entries 8 and
9), and lower catalyst loading (Table 2, entries 10 and 11)
could obviously prolong the reaction time and give lower
yields and poorer stereoselectivities. Then, when less
amount of butanal was used, we got the same 97% ee value
although the yield was slightly lower than entry 7. From all
the results obtained such far, we chose the following as
optimum conditions: 10 mol% catalyst 1b, 0.2 mL of PBS
(pH 9.1), and 5 eq of butanal.
column
c
15 °C
d
0 °C
5 mol% catalyst loading
e
f
2 mol% catalyst loading
g
5 eq of butanal
Bold values indicate the best result in that reaction condition
chiral micelle-like organo-microenvironments in the buf-
fered aqueous solution, which could gather the hydropho-
bic reaction substrates into the small organic phase to
accelerate the reaction and improve the stereoselectivity.
3.3 Substrate Scope
We subsequently extended the scope of the reaction to a
variety of aldehydes, using the optimal reaction conditions
established. The results are summarized in Table 3. The
results indicated that the a-aminoxy alcohol products were
obtained in high yields (79–95%) and excellent enanti-
oselectivities (94–99%). It can also be seen that the reac-
tions between nitrosobenzene and the straight chain
aldehydes completed in only 4 min at room temperature
with high yields and excellent ee values (Table 3, entries
1–8). Although the yields were lower than using 10 eq of
aldehydes as reaction substrate, the ee values were
remained (Table 3, entries 1 vs. 2, 3 vs. 4, 5 vs. 6). The
enantioselectivity of the catalyzed reaction was improved
The observed results suggest that the relationship of pH-
activity/stereoselectivity plays a decisive role in controlling
stereoselectivity. Compared with the inefficiency of the
straight chain alkyl substituted prolines and L-proline itself
(1c, 1d and 1e), catalysts 1a and 1b preferentially form
123

1128
Y.-J. An et al.
Table 3 Generality for a-aminoxylation in PBS
Table 4 Reaction of a-aminoxylation with cyclohexanone in PBS
Entry
R
Products
Time
Yielda (%)
eeb (%)
Entry
R
Products
Time
Yielda (%)
eeb (%)
1
2c
Et
4a
4a
4b
4b
4c
4c
4d
4e
4f
4 min
4 min
4 min
4 min
4 min
4 min
4 min
4 min
9 min
10 min
9 min
89
96
95
98
91
95
90
91
80
82
79
97
97
1
2
3
4
5
6
H
6a
6b
6c
6d
6e
6f
4 min
4 min
4 min
5 min
3 min
4 min
87
96
88
83
67
57
[99
>99
Et
2-Me
3-Me
4-Me
4-Cl
4-F
3
Me
Me
Pr
95
[99
[99
[99
[99
4c
5
6c
95
98
Pr
98
7
Bu
[99
[99
99
Conditions: Substitute nitrosobenzene (0.5 mmol), cyclohexanone
(5 equiv.), catalyst 1b (10 mol %), and PBS (pH 9.1, 0.20 mL) was
added at 0 °C and then warmed to RT
8
C8H17
Ph
9
a
10
11d
PhCH2
Et
4g
4h
98
Isolated yields
b
94
The ee value was determined by chiral HPLC on a chiralcel AD-H
column
Conditions: Nitrosobenzene (0.5 mmol), aldehyde (5 equiv.), catalyst
1b (10 mol %), and PBS (pH 9.1, 0.20 mL) was added at 0 °C and
then warmed to RT
Bold values indicate the best result in that reaction condition
a
activities and stereoselectivities in the a-aminoxylation
with different substituted nitrosobenzenes as acceptors. It
was noteworthy that the o-methyl nitrosobenzene showed
the best activity (96% yield) and stereoselectivity ([99%
ee), whereas the halogenated nitrosobenzene gave lower
yields under the same reaction condition, but the enanti-
oselectivity always maintained unchanged. These results
indicate that the electron-donating substituents at the ortho
position of nitrosobenzene are in favor of the activities of
the a-aminoxylation reaction of cyclohexanone whereas the
electron-withdrawing substituents are disadvantageous for
this reaction (Table 4, entries 5 and 6).
Isolated yields
b
The ee value was determined by chiral HPLC on a chiralcel AD-H
column
c
10 eq of butanal
d
4-Nitrosotoluene was used instead of nitrosobenzene
with increase of the length of carbon chain whereas the
yields were decreased slightly (Table 3, entries 7 and 8).
This phenomenon may be due to the different efficiency of
the hydrophobic interaction between aldehydes and the
amphiphilic catalysts in the buffered aqueous solution.
When aldehydes containing an aromatic moiety, such as
phenylacetaldehyde or 3-phenylpropanal, were used in the
reaction (Table 3, entries 9 and 10), the reaction time was
significantly protracted, which may be mainly due to the
unmatched hydrophobic-hydrophobic interactions between
aldehydes and catalysts. When 4-nitrosotoluene instead of
nitrosobenzene was treated with butantal under the opti-
mized conditions, the corresponding a-aminoxy alcohols
were obtained in 79% yield with an enantioselecitivity of
94% (Table 3, entry 11), which is slightly lower than that
from nitrosobenzene.
4 Mechanistic Insights
To firmly establish the origin of the enantioselectivity in
the present catalytic system, we postulated a possible
transition state for the formation of the C–O bond in the
reaction between aldehyde/ketone and nitrosobenzene,
promoted by the amphiphilic catalyst 1b in phosphate
buffered solution. In the buffered aqueous media, the
amphiphilic catalyst molecules may form some micelle-
like asymmetric organic microenvironments with the
assistance of hydrogen bonds, which could easily gather
the lipophilic organic substrates around the catalyst.
Therefore, the reaction was completed in a short time with
high activity and stereoselectivity. In this case, amino acids
are attractive molecules to the buffered solutions to create
pH-responsive structures through self-assembly. In addi-
tion, the observed enantioselectivities of the catalytic
a-aminoxylation of aldehydes and cyclohexanone can be
In addition, when ketones were used as the donor mol-
ecules in the a-aminoxylation reactions of carbonyl com-
pounds, only cyclohexanone gave the corresponding
a-aminoxylated product with[99% ee value and 87% yield
in the PBS (pH, 9.1), but no reaction occurred in the case of
both cyclopentanone and butanone. We then turned our
attention to use the substituted nitrosobenzenes as acceptor
molecules in a-aminoxylation reactions of cyclohexanone
under the optimal reaction condition (Table 4). The results
obtained showed that cyclohexanone performed high
123

a-Aminoxylation Reactions in Buffered Aqueous Media
1129
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´ ´
11. Bøgevig A, Sunden H, Cordova A (2004) Angew Chem Int Ed
Organic micro phase
Bu ered aqueous phase
O
O
O
H O
O
ONa
P
P
ONa
ONa
O
N
Ph
N
H
O
O
R1
O
ONa
R2
O
H
43:1109
´
12. Cordova A, Sunden H, Bogevig A, Johansson M, Himo F (2004)
Chem Eur J 10:3673
Fig. 4 Proposed transition state of the reaction
13. Hayashi Y, Yamaguchi J, Hibino K, Sumiya T, Urushima T,
Shoji M, Hashizume D, Koshino K (2004) Adv Synth Catal
346:1435
rationalized by invoking an enamine mechanism. The
catalyst 1b forms an (E)-anti enamine with aldehyde or
cyclohexanone, which approaches the oxygen atom of the
nitrosobenzene, providing a chiral a-aminoxyaldehyde
with R configuration (Fig. 4). Meanwhile, the concave
constructed by isosteviol and (2S, 4R)-4-hydroxyproline
would facilitate the enantioselective formation of the
transition states. This mechanism is in accord with the
previously proposed models extremely well [6, 7, 25].
`
14. Font D, Bastero A, Sayalero S, Jimeno C, Pericas MA (2007) Org
Lett 9:1943
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Org Chem 16:496
´
16. Wang W, Wang J, Lia H, Liao LX (2004) Tetrahedron Lett
45:7235
17. Wang W, Wang J, Li H (2004) Tetrahedron Lett 45:7243
´
´
18. Sunden H, Dahlin N, Ibrahem I, Adolfsson H, Cordova A (2005)
Tetrahedron Lett 46:3385
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48:3333
20. Gruttadauria M, Salvo AMP, Giacalone F, Agrigento P, Noto R
(2009) Eur J Org Chem 31:5437
5 Conclusions
21. Alza E, Cambeiro XC, Jimeno C, Pericas MA (2007) Org Lett
9:3717
22. Liu YX, Sun YN, Tan HH, Tao JC (2008) Catal Lett 120:281
23. Liu YX, Sun YN, Tan HH, Liu W, Tao JC (2007) Tetrahedron
Asymmetr 18:264
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Eur J 16:7852
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In conclusion, asymmetric amphiphilic catalysts have been
evolved by covalently connecting L-proline with a natu-
rally available isosteviol subunit, illustrating a viable
approach for the development of asymmetric supra-
molecular catalysts. The amphiphilic isosteviol-L-proline
conjugate 1b was found to be a remarkable catalyst for the
asymmetric a-aminoxylation of aldehydes/cyclohexanone
in PBS (pH 9.1) with good to high yields and excellent
enantioselectivities without any other additive. In a manner
closely resembling enzymatic catalysis, the amphiphilic
catalyst selectively binds and situates substrates in the
asymmetric microenvironment by the synergistic action of
a hydrophobic effect and non-covalent interactions on the
surface of the aqueous phosphate buffer solution. Further
investigations on the application of the amphiphilic iso-
steviol-proline conjugates in different asymmetric catalysis
are in progress and will be reported in due course.
`
27. Font D, Jimeno C, Pericas MA (2006) Org Lett 8:4653
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`
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Acknowledgment The authors are thankful to the financial support
of the Natural Science Foundation of China (NSFC 20772113).
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