Direct asymmetric aldol reaction co-catalyzed by amphiphilic prolinamide phenol and lewis acidic metal on water

Article abstract of DOI:10.1002/cjoc.201201017

An approach based on combinations of various water compatible Lewis acids and lipophilic group containing amphiphilic prolinamide co-catalysts has been evaluated for the direct asymmetric Aldol reaction. From the broad screening of chloride salts from alk

Full text of DOI:10.1002/cjoc.201201017

FULL PAPER
DOI: 10.1002/cjoc.201201017
Direct Asymmetric Aldol Reaction Co-catalyzed by Amphiphilic
Prolinamide Phenol and Lewis Acidic Metal on Water
Tao Zhang, Yunxiao Zhang, Zaichun Li, Zhongtai Song, Hao Liu, and Jingchao Tao*
College of Chemistry and Molecular Engineering, Zhengzhou University, 75 Daxue Road, Zhengzhou,
Henan 450052, China
An approach based on combinations of various water compatible Lewis acids and lipophilic group containing
amphiphilic prolinamide co-catalysts has been evaluated for the direct asymmetric Aldol reaction. From the broad
screening of chloride salts from alkali metal to transition metal, LiCl, ZnCl2 and SnCl2 lead to the highest stereose-
lectivities. The optimized catalytic conditions (10 mol% prolinamide with 10 mol% MCl2 or 20 mol% LiCl at room
temperature on water) gave anti-products with improved enantioselectivities (up to 99% ee) compared to the mod-
erately stereoselective procedure based on prolinamide activation only.
Keywords Aldol reaction, amphiphilic prolinamide, Lewis acidic metal, co-cayalyst, asymmetric catalysis
Introduction
prolinamide. Despite the great potential of direct asym-
metric Aldol reactions, only a few methods have been
reported for the metal-assisted activation of donor and
acceptor. Chiral complexes mimicking the mode of ac-
tion of type II aldolases have been developed recently;
however, they are water sensitive and thus reactions
must be carried out under anhydrous conditions in or-
ganic solvents.[11] The application of Lewis acidic metal
complexes bearing chiral ligands as catalysts in aqueous
solvents is still difficult. Mlynarski and coworkers
demonstrated that the in situ generated zinc(II) complex
of zinc triflate and chiral prolinamide ligand is efficient
for asymmetric Aldol reactions in the ketone/water
mixture to give products with up to 90% ee.[12] The
catalyst was also proved to be selective in biphasic sys-
tems and the essential role of water in the catalytic sys-
tem was observed.
In addition, water is an ideal reaction medium, of-
fering an unparalleled and unique range of features, be-
ing cheap, easy to handle, hazardless, and environmen-
tally benign.[13] Hence, the search for new amphipathic
prolinamide catalysts remains a worthwhile and desir-
able endeavor. Moreover, long chain alkyl[14] and poly-
cyclic naphthene such as terpenes,[9b,15] are usually em-
ployed as lipophilic groups in the construction of am-
phiphilic molecules. As a part of our continuing interest
in prolinamide catalyzed Aldol reaction, herein we re-
port the synthesis of two kinds of chiral amphiphilic
L-prolinamide ligands (1－3) based on lipophilic group
containing o-aminophenol and 1,2-amino alcohol (Fig-
ure 1). And the application of the in situ generated metal
In the past decade, asymmetric catalysis has wit-
nessed a tremendous growth for its use in construction
of complex chiral architectures.[1] Aldol reaction is one
of the most efficient and powerful atom-economical
carbon-carbon bond-forming reactions in synthetic
chemistry.[2] As a consequence, a large number of cata-
lysts and reagents have been developed in order to
achieve an efficient Aldol addition with high diastereo-
and enantioselectivities.[3] Since the first example of the
direct Aldol reaction catalyzed by L-proline under a
mild reaction condition reported in 2000 by List et al.,[4]
asymmetric reaction catalyzed by proline and its deriva-
tives has received great attention. Among the various
types of proline-derived catalysts reported, prolinamides
obtain continuing attention. For example, Gong’s
group[5] reported that 1,2-amino alcohol derived prolin-
amide could catalyze Aldol reaction between acetone
and aldehydes efficiently. Our previous work[6] proved
that prolinamide phenols were effective catalysts for the
reaction of aromatic aldehydes with cyclohexanone in
neat ketone and in water. Nájera et al.[7] reported the
BINAM-prolinamides as recoverable catalysts in the
direct Aldol condensation. And very recently, silica-
supported prolinamide organocatalyst was recyclable
for direct asymmetric Aldol reaction in water without
the need for catalyst regeneration.[8]
Previous work has indicated that introduction of
protonic function group such as hydroxyl and thiourea
group,[9] as well as addition of acid[10] as co-catalyst
could improve the catalytic performance of proline and
*
E-mail: jctao@zzu.edu.cn; Tel.: 0086-371-67767200; Fax: 0086-371-67767200
Received October 18, 2012; accepted November 21, 2012; published online January 8, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201017 or from the author.
Chin. J. Chem. 2013, 31, 247—255
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Zhang et al.
FULL PAPER
lipophilic group
O
H
(CH2)11CH3
N
O
HN
R
OH
N
H
NH
Hydrophilic
catalytic group
Hydrophilic
catalytic group
HO
COOEt
1 R = H
2 R = OH
3
Figure 1 Structure of compounds 1－3.
complex of general metal salts and the o-hydroxyl con-
taining chiral prolinamide ligands in mimicking the ac-
tion of type II aldolases in catalytic asymmetric Aldol
reaction in aqueous medium was also studied.
with SeO2 gave 8 as an orange crystal. Followed oxima-
tion reaction of 8 with hydroxylamine hydrochloride in
the presence of NaHCO3 in ethanol, afforded compound
9. The oximido and carbonyl groups were reduced by
H2/Ni and NaBH4 successively to give compound 10
stereoselectively with the amino- and hydroxyl groups
in cis relationship. The absolute configuration of the
two chiral centers (C15 and C16) had been confirmed in
our earlier work.[16] The N-selective acylation of com-
pound 10 by N-Boc L-proline and following deprotec-
tion of the acylate afforded 3 in high yield.
Results and Discussion
The synthetic approach employed to prepare 1 and 2,
prolinamide with a long chain alkyl lipophilic group,
was outlined in Scheme 1. Firstly, nitration reaction of 4
with 7% HNO3 generated 5 in moderate yield. Then the
nitro group was catalytically hydrogenated with Pd/C in
ethanol to give compound 6. Finally, 6 and N-Cbz-L-
proline or N-Cbz-cis-4-hydroxy-L-proline were treated
with DCC in the presence of catalytic amount of DMAP
in DCM to give the correspond amide which was then
hydrogenolysized in ethanol catalyzed by Pd/C to fur-
nish compounds 1 and 2.
Scheme 2 The synthesis of catalyst 2
O
O
SeO2
Ac2O
O
COOEt
COOEt
8
7
Scheme 1 Synthetic route of catalyst 1
.
(1) H2/Ni
NH2OH HCl
NOH
HO
OH
(2) NaBH4
NaHCO3, EtOH
O2N
7% HNO3
Pd/C, H2
EtOH
O
CH2Cl2, TBAB
COOEt
9
H3C(H2C)11
(CH2)11CH3
5
4
R
COOH
N
NH2
Boc
OH
COOH
N
Cbz
(1) DCC, DMAP, DCM
(2) TFA, DCM
H2N
OH
(1) DCC, CH2Cl2
(2) Pd/C, H2
COOEt
(CH2)11CH3
10
6
H
N
O
(CH2)11CH3
O
HN
R
OH
N
COOEt
H
NH
HO
3
1 R = H
2 R = OH
Performing organic reactions in aqueous media is
one of the most fundamental and challenging goals in
modern organic chemistry. Firstly, with the three proli-
namides 1－3 as organocatalysts, their catalytic per-
formances for the direct asymmetric Aldol reactions
were investigated by using the reaction of different ni-
trobenzaldehydes and cyclohexanone as a model with
Compound 3, with the similar prolinamide coordina-
tion segment as in compound 1, was constructed from
the N-Boc protected L-proline and the cis-1,2-amino
alcohol derivative (10) of a tetracyclic diterpene, which
could be obtained easily from the natural available
isosteviol.[16] As shown in Scheme 2, oxidation of 7
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Chin. J. Chem. 2013, 31, 247—255

Direct Asymmetric Aldol Reaction Co-catalyzed by Amphiphilic Prolinamide Phenol
10 mol% catalyst loading on 0.4 mL of water. The re-
sults were summarized in Table 1.
of the two kinds of catalyst molecules are of their dif-
ferent hydrophobic subunits and the different OH acidi-
ties, therefore, the lower catalytic activity of catalyst 2
may ascribe to its lower Brønsted acidities and disad-
vantage in forming organo microenvironment on water.
In the case of catalyst 1, except p-nitrobenzaldehyde
which afforded syn-isomer as main product in 89%
yield with 71∶29 dr (syn∶anti) and 35% ee value, the
orther two nitrobenzaldehydes afforded anti-isomer as
main products in up to 94% yield, 79∶21 dr, and 52%
ee (Table 1, Entries 1－3). Meanwhile, catalyst 2 af-
forded anti-isomer as main product with low catalytic
activity and stereoselectivities (Table 1, Entries 4－6).
Therefore, compound 1 was chosen as catalyst for the
direct Aldol reaction in further studies.
Using the o-, m-, p-nitrobenzaldehydes as the Aldol
acceptors, cyclohexanone as Aldol donor and compound
1 as the chiral catalyst, the catalytic reaction conditions
were optimized on water. As shown in Table 2, higher
yields were obtained when the catalyst loading raised
from 5 mol% to 10 mol%. Besides, the condition of 0.4
mL of water and 10 equiv. of cyclohexanone afforded
better results both in yield and stereoselectivities. Inter-
estingly, in the cases of p-nitrobenzaldehyde, the main
products were syn-isomers (Table 2, Entries 1－6),
whereas the main products of o- or m-nitrobenzalde-
hydes were anti-isomers (Table 2, Entries 7－15). Both
the diastereoselectivity and anti-enantioselectivity were
poor for m-nitrobenzaldehyde (Table 2, Entries 7－12).
When o-nitrobenzaldehyde was used, the diastereose-
lectivity and anti-enantioselectivity were somewhat
better (Table 2, Entries 13－15), that may be in relation
Table 1 Catalyst screening
O
CHO
Cat. (10 mol%)
R
R
+
H2O, r.t.
OH
O
Entrya
R
Cat Time/h Yieldb/% drc (anti/syn) eec (anti, %)
1
2
3
4
5
6
7
8
9
p-NO2
m-NO2
o-NO2
p-NO2
m-NO2
o-NO2
p-NO2
m-NO2
o-NO2
1
1
1
2
2
2
3
3
3
48
48
48
48
48
48
72
72
72
89
94
63
70
25
50
67
63
60
29∶71
67∶33
79∶21
72∶28
70∶30
74∶26
58∶42
60∶40
62∶38
35
36
52
65
62
67
29
24
35
a Nitrobenzaldehyde (0.33 mmol), cyclohexanone (3.3 mmol, 10
b
c
equiv.) in 0.4 mL water. Isolated yields. Determined by chiral
HPLC.
As can be seen, both the diastereoselectivities and
the anti-enantioselectivities of the Aldol products cata-
lyzed by prolinamide phenol 1 and 2 were higher than
that of the prolinamide alcohol 3. The main differences
Table 2 Screening of the reaction conditions with catalyst 1 on watera
O
OH O
CHO
Cat. 1 (x mol%)
R
+
R
H2O, r.t., 48 h
Entry
1
R
Cat./mol%
Cyclohexanone/equiv.
H2O/mL
Yieldb/%
81
drc anti/syn
52∶48
29∶71
30∶70
41∶59
28∶72
41∶59
65∶35
67∶33
62∶38
62∶38
65∶35
54∶36
80∶20
79∶21
75∶25
eec (anti, %)
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
m-NO2
m-NO2
m-NO2
m-NO2
m-NO2
m-NO2
o-NO2
o-NO2
o-NO2
10
10
10
5
15
10
5
0.2
0.4
0.6
0.2
0.4
0.6
0.2
0.4
0.6
0.2
0.4
0.6
0.2
0.4
0.6
23
35
35
39
62
44
24
36
25
10
21
22
49
52
45
2
89
3
86
4
15
10
5
65
5
5
77
6
5
73
7
10
10
10
5
15
10
5
92
8
94
9
82
10
11
12
13
14
15
15
10
5
57
5
52
5
49
10
10
10
15
10
5
73
63
53
a Nitrobenzaldehyde (0.33 mmol). b Isolated yield. c Determined by chiral HPLC.
Chin. J. Chem. 2013, 31, 247—255
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249

Zhang et al.
FULL PAPER
to the steric hindrance and strong electron-withdrawing
effect of nitro group at o-position, which made the fa-
vorable formation of anti-transition state.
behaviours are observed in metallo-enzymes.[19] In our
case, the lipophilic group containing L-prolinamide
phenol/alcohol derivatives could activate the ketone via
an enamine intermediate on water and at the same time
interact with various metal salts to activate the aldehyde
partner. Furthermore, the nature of the metal may have
important effects on both stereo- and chemical selectivi-
ties.
In order to evaluate this approach, we first decided
to screen known water compatible Lewis acids in the
model reaction between cyclohexanone and o-nitro-
benzaldehyde catalyzed by compound 1 with water as
solvent (Table 3). These reaction conditions are suitable
to evaluate the different effects of Lewis acids on both
stereo- and chemical selectivities and on the rate of the
reaction by comparison with more standard conditions
based on compound 1 alone. Excitingly, the dr (anti/syn
93∶7) and ee (93%) values were improved greatly
when 20 mol% LiCl was added (Entry 2) while 10
mol% LiCl displayed low activity (Entry 1). Higher
yield was obtained by addition of 30 mol% LiCl (83%),
but the diastereoselectivity was decreased (83∶17 dr).
Inspired by these results, ZnCl2 was investigated (En-
tries 4 and 5) and the results indicated that 10 mol% of
In the past several years, applications of different
metal complexes in tuning the reactivity of organocata-
lyst-promoted transformations have attracted increasing
attention in the synthetic community.[17] Efforts in this
direction have led to the discovery of unprecedented
reactivities, which are not accessible through the use of
either of these two catalytic systems separately. The
driving force behind these efforts is to discover more
efficient approaches for complex molecule synthesis
with good chemo- and stereoselectivity. The develop-
ment of organocatalysis has been applied in combina-
tion with transition metal complexes in the search for
more valuable chemical transformations, taking advan-
tages of both forms of catalysis while maximizing their
compatibility.
Lewis acids in aqueous media are known to coordi-
nate to a molecule of water to generate metallo-hy-
droxonium species leading to a nearly neutral pKa
value.[18] In the presence of ligands, those metallohy-
droxonium species are able to dissociate and equilibrate
with different ligand-metal complexes. Such dynamic
Table 3 Screening of the additivesa
NO2 OH
O
NO2
O
Cat. (10 mol%)
Additive
CHO
+
H2O, r.t., 48 h
Entry
1
Cat.
1
Additive
LiCl
Add. amount/mol%
Yieldb/%
41
drc anti/syn
69∶31
93∶7
eec (anti, %)
10
20
30
10
20
10
10
10
10
10
10
10
10
20
10
20
20
20
10
10
75
93
93
97
89
99
92
94
76
92
80
98
91
79
95
83
72
85
82
89
2
1
LiCl
52
3
1
LiCl
83
83∶17
86∶14
79∶21
97∶3
4
1
ZnCl2
ZnCl2
SnCl2
CuCl2
PbCl2
HgCl2
CdCl2
CoCl2
CuCl
FeCl3
NaCl
SnCl2
77
5
1
70
6
1
35
7
1
42
92∶8
8
1
80
79∶21
83∶17
75∶25
69∶31
88∶12
80∶20
50∶50
76∶24
81∶19
74∶26
78∶22
80∶20
82∶18
9
1
87
10
11
12
13
14
15d
16e
17e
18
19
20
1
72
1
70
1
53
1
55
1
42
1
70
1
C6H5COOH
C17H35COOH
LiCl
93
1
87
2
72
2
ZnCl2
65
2
SnCl2
50
a Unless otherwise specified, all reactions were carried out with p-nitrobenzaldehyde (0.33 mmol), cyclohexanone (10 equiv.), 10 mol% 1
or 2 and corresponding metal salt in 0.4 mL water at room temperature. b Isolated yields. c Determined by chiral HPLC. d Reaction carried
out at 40 ℃. e Reaction completed in 3 h.
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Direct Asymmetric Aldol Reaction Co-catalyzed by Amphiphilic Prolinamide Phenol
of ZnCl2 was similar to LiCl. Nevertheless, different
ZnCl2 afforded 97% ee, 77% yield and 86∶14 dr,
which were better than 20 mol% loading. Meanwhile,
10 mol% Zn(OAc)2 displayd a low catalytic activity
(Entry 13). Further studies on other metal salts with 10
mol% amount provided the anti-Aldol products with
good to excellent stereoselectivities (Entries 6－15,
72%－99% ee). It should be noted that when SnCl2 was
used as co-catalyst, 99% ee and 97∶3 de value was
obtained, but with a low yield. When the temperature
raised to 40 ℃, the yield improved from 35% to 75%,
but a loss of stereoselectivity was also accompanied
(Entries 6 and 15). CuCl2 and CuCl performed similar
behavior at room temperature (Entries 7 and 12). It was
also found that no diastereoselectivity was observed
while NaCl was used as co-catalyst. In addition, when
benzoic acid or stearic acid was used as additive, the
reaction completed in 3 h with good stereoselectivities.
In view of the excellent co-catalytic properties of LiCl,
ZnCl2 and SnCl2, we next evaluated Aldol reactions of
o-nitrobenzaldehyde and cyclohexanone catalyzed by 2
and the three metal salts on water (Table 3, Entries 18－
20). Compared with standard conditions based on com-
pound 2 alone, the dr and ee values were improved, but
the co-catalyzed properties were worse than 1 (Entries
2/18, 4/19 and 6/20).
from LiCl and ZnCl2, SnCl2 exhibited good stereoselec-
tivities for the three types of substituted benzaldehyde.
Especially, for Aldol reaction of p-nitrobenzaldehyde
and cyclohexanone, co-catalysis of SnCl2 afforded 94%
ee in high yield (Entry 6). Herein, the substrate scope
was then investigated under the optimal conditions of 10
mol% 1 with 10 mol% SnCl2 (Table 4, Entries 7－14).
For o-methyl and 3,4-dimethoxy benzaldehyde, only
trace amount of products were detected while
o-methoxy benzaldehyde afforded 20% yield with
90∶10 dr and 99% ee (Entries 7－9). Good catalytic
performance was also observed for benzaldehyde under
the optimal conditions (Entry 10, 93% ee). Moreover,
the Aldol products of electron-poor aromatic aldehydes
exhibited high dr (up to 99∶1) and ee (up to 99%) val-
ues (Entries 11－14), and the yields were higher com-
pared to electron-rich aromatic aldehydes. The results
proved that the electronic nature of substituents of al-
dehydes had little effect on diastereo- and enantioselec-
tivities, whereas it influenced the reactivities greatly.
The reaction conditions were also employed suc-
cessfully on cyclopentanone and acetone with o-nitro-
benzaldehyde, but only low enantioselectivities were
obtained (Scheme 3).
We next evaluated Aldol reactions of m- and
p-nitrobenzaldehyde and cyclohexanone co-catalyzed
by 1 and metal salt on water (Table 4, Entries 1－6).
The results indicated that the stereoselectivity depended
on the substituted position of nitro group when LiCl was
used as co-catalyst (Table 3, Entry 2 and Table 4, En-
tries 1 and 4, 25%－93% ee). The co-catalytic activity
Conclusions
In summary, we have succeeded in carrying out the
metal-assisted direct asymmetric direct Aldol reaction in
aqueous media. Three kinds of amphiphilic prolinamide
phenol/alcohol, 1, 2 and 3, derived from L-proline were
synthesized and evaluated for their ability to catalyze
Table 4 Direct Aldol reaction of cyclohexanone with aldehydes catalyzed by 1 and metal saltsa
Cat. 1 (10 mol%)
Salt (x mol%)
OH
O
O
CHO
+
R
R
H2O, r.t., 48 h
Entry
1
R
Additive
LiCl
Loading/mol%
Yieldb/%
80
drc anti/syn
71∶29
69∶31
79∶21
57∶43
48∶52
78∶22
90∶10
－
eec (anti, %)
m-NO2
20
10
10
20
10
10
10
10
10
10
10
10
10
10
59
46
79
25
71
94
99
2
m-NO2
m-NO2
p-NO2
p-NO2
p-NO2
o-OCH3
p-CH3
ZnCl2
SnCl2
LiCl
98
3
67
4
66
5
ZnCl2
SnCl2
SnCl2
SnCl2
SnCl2
SnCl2
SnCl2
SnCl2
SnCl2
SnCl2
42
6
92
7
20
d
8
Trace
Trace
35
－
9
3,4-dimethoxy
－
－
93
99
96
94
95
10
11
12
13
14
H
85∶15
95∶5
99∶1
93∶6
90∶10
p-Cl
p-Br
p-F
45
40
50
p-CF3
60
a
Unless otherwise specified, all reactions were carried out with aldehyde (0.33 mmol), cyclohexanone (10 equiv.), 10 mol% 1 and
corresponding metal salt on 0.4 mL water at room temperature. b Isolated yields. c Determined by chiral HPLC. d No detection.
Chin. J. Chem. 2013, 31, 247—255
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Zhang et al.
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Scheme 3 Reactions of cyclopentanone and acetone with
o-nitrobenzaldehyde
Labtech UV600 ultra detector with Chiralcel OD-H (4.6
mm×250 mm) and Chiralpak AD-H (4.6 mm×250
mm).
Cat. 1 (10 mol%)
SnCl2 (10 mol%)
H2O, r.t., 48 h
NO2 OH
O
General procedure for the catalysts 1 and 2
For catalysts 1 and 2, the synthetic routes were out-
lined in Scheme 1.
NO2
Yield: 70%, anti:syn: 60: 40
ee: anti 10%, syn 55%
CHO
Synthesis of compound 5: p-Dodecylphenol (2.265 g,
10.0 mmol), TBAB (0.325 g, 1.0 mmol) and CH2Cl2 (24
mL) were added to a 100 mL three necked flask. Then
7% HNO3 (18.2 mL) was added dropwise under ice bath.
After the system color changed brown, the reaction was
continued for 1 h at room temperature. The aqueous
phase was extracted with CH2Cl2 after the separation of
the organic phase. Combined organic phase was washed
with sodium bicarbonate solution, water and brine then
dried with NaSO4. After filtration and evaporation of
solvent, the black crude product was purified by column
chromatography (petroleum ether). Yellow solid; yield:
41%, m.p. 61.0－61.8 ℃; 1H NMR (400 MHz, CDCl3)
Cat. 1 (10 mol%)
SnCl2 (10 mol%)
H2O, r.t., 48 h
NO2 OH
O
Yield: 52%
ee: 50%
the direct Aldol reaction of aldehyde with cyclohexa-
none on water with different Lewis acids as co-catalysts.
The study of the effect of various water compatible
Lewis acids on prolinamide organocatalysis on water
led us to new findings. Compound 1, the long chain al-
kyl substituted prolinamide phenol demonstrated good
to excellent activity, diastereoselectivity and enantiose-
lectivity on the direct asymmetric Aldol reaction of sub-
stituted benzaldehyde with cyclohexanone by the
co-catalysis of different Lewis acids in water. From this
broad screening, SnCl2 led to the highest stereoselectiv-
ities and electron-withdrawing groups on aromatic al-
dehyde led to high conversions. The optimized catalytic
conditions (10 mol% ligand 1 and 10 mol% SnCl2 at
room temperature on water) gave anti-products in high
stereoselectivities (up to 99∶1 dr and 99% ee), whereas
moderate stereoselective procedure was obtained with-
out Lewis acid. The present results suggest that Aldol
catalysis with salt under hydrophilic conditions could
provide a chiral influence in prebiotic chemistry. This
procedure appears to be an excellent and readily avail-
able biomimetic model analogous to Class II aldolases
that opens new interrogations concerning the exact na-
ture of the chemical bonds involved in such enzymes.
Further studies on the influences of the salt in aqueous
media and the application of 1, 2 and 3 in other impor-
tant reactions are under our intensive investigations and
will be reported in due course.
3
δ: 7.89 (d, J＝1.9 Hz, 1H, ArH), 7.40 (dd, J＝8.6 Hz,
4J＝2.1 Hz, 2H, ArH), 7.07 (d, J＝8.5 Hz, 1H, ArH),
2.59 (t, J＝7.8 Hz, 3H, ArCH2CH2), 1.59 (m, 2H,
ArCH2CH2), 1.25－1.30 [m, 18H, (CH2)9], 0.88 (t, J＝
8.0 Hz, 3H, CH3); IR (KBr) v: 3298, 3076, 2916, 2848,
1632, 1577, 1535, 850, 823, 721 cm−1.
Synthesis of catalyst 1: Compound 5 (1.532 g, 4.0
mmol) and Pd/C (0.144 g, 5%) were added to 150 mL
95% ethanol in a catalytic hydrogenation flask. The re-
action was stirred under 50 psi H2 at room temperature
for 1.5 h. After filtration of Pd/C and evaporation of
solvent, the crude product 6 was obtained and used di-
rectly for the next step without further purification.
Then added 6 (555 mg, 2.0 mmol), DCC (453 mg, 2.2
mmol) and N-Cbz-L-proline or N-Cbz-cis-4-hydroxyl-
proline (2.0 mmol) to 10 mL CH2Cl2 and stirred at am-
bient temperature for 5 h. After filtration of the white
solid (DCU) and evaporation of solvent, the crud white
product was hydrogenated by Pd/C at 50 psi H2 in
ethanol for 5 h. Pd/C was filtrated and compound 1 (2)
was recrystallized from EtOH.
Compound 1: Yield: 77%; m.p. 123.0－124.8 ℃;
1H NMR (400 MHz, CDCl3) δ: 9.91 (s, 1H, ArNH),
6.91 (d, J＝0.68 Hz, 2H, ArH), 6.72 (s, 1H, ArH), 3.94
－ 3.98 (m, 1H, NHCHCO), 3.08 － 3.14 (m, 1H,
CHHN), 2.99－3.05 (m, 1H, CHHN), 2.49 (t, J＝7.56
Hz, 2H, ArCH2CH2), 2.19－2.29 (m, 1H, CHHCH),
2.01－2.08 (m, 1H, CHHCH), 1.77－1.81 (m, 2H,
NCH2CH2), 1.55 (m, 2H, ArCH2CH2), 1.25－1.29 [m,
18H, (CH2)9], 0.88 (t, J＝6.96 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ: 175.0, 147.0, 134.7, 127.1, 124.6,
121.7, 119.7, 60.3, 47.4, 34.9, 31.9, 31.7, 31.0, 29.7,
29.7, 29.6, 29.5, 29.4, 29.3, 26.3, 22.7,14.1; IR (KBr) v:
3354, 3241, 3062, 3023, 2922, 2849, 2743, 1649, 1596,
1546, 1503, 1444, 1377, 1283, 1207, 1098, 889, 874,
816,720 cm−1; HRMS calcd for C23H38N2O2 [M＋H]＋
375.3012, found 375.3008.
Experimental
All chemicals were used as received unless other-
wise noted. Reagent grade solvents were distilled prior
to use. All reported 1H NMR and 13C NMR spectra were
collected on Bruker DPX 400 NMR spectrometer with
TMS as an internal reference. IR spectra were deter-
mined on a Thermo Nicolet IR200 unit. High resolution
mass spectra (HRMS) were obtained on a Waters Mi-
cromass Q-Tof MicroTM instrument using the ESI
technique. Chromatography was performed on silica gel
(200－300 mesh). Melting points were determined us-
ing an XT5A apparatus and are uncorrected. Enantio-
meric excess was measured by chiral HPLC at room
temperature using Labtech 2006 pump equipped with
Compound 2: Yield: 75%; m.p. 111.2－112.4 ℃;
252
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 247—255

Direct Asymmetric Aldol Reaction Co-catalyzed by Amphiphilic Prolinamide Phenol
1H NMR (400 MHz, CDCl3) δ: 9.95 (s, 1H, ArNH),
6.91 (s, 2H, ArH), 6.78 (s, 1H, ArH), 4.49 (s, 1H,
CHOH), 4.15－4.20 (m, 1H, NHCHCO), 3.09－3.12
(m, 1H, CHHNH), 2.87－2.91 (m, 1H, CHHNH),
2.49 (t, J＝7.6 Hz, 2H, ArCH2CH2), 2.34－2.39 (m, 1H,
CHHCH), 1.98－2.05 (m, 2H, NCH2CH2), 1.53－1.55
(m, 2H, ArCH2CH2), 1.25－1.27 [m, 18H, (CH2)9], 0.88
(t, J＝7.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ:
174.8, 146.7, 135.0, 127.2, 124.5, 121.8, 119.6, 73.3,
59.7, 55.3, 39.9, 34.9, 31.9, 31.7, 29.7, 29.7, 29.6, 29.6,
29.4, 29.3, 22.7, 14.2; HRMS calcd for C23H39N2O3 [M
＋H]＋ 391.2955, found 391.2953.
Synthesis of compound 8: Compound 7 (6.92 g, 20
mmol) and SeO2 (2.23 g, 20 mmol) were added to 60
mL acetic anhydride. The mixture was heated to reflux
and black solid appeared. After 3 h, the system became
yellow and was cooled to room temperature. After addi-
tion of another 2.23 g SeO2, the mixture was heated to
reflux again for 6 h. The system was cooled and added
20 mL chloroform and 20 mL toluene then filtrated
through diatomaceous earth. Evaporation of the orange
filtrate afforded an orange solid. Further recrystalliza-
tion in EtOAc gave compound 8 as an orange crystal in
83% yield. m.p. 207.8－208.8 ℃; 1H NMR (400 MHz,
CDCl3) δ: 4.08－4.18 (m, 2H), 2.37－2.41 (m, 1H),
2.18－2.21 (m, 1H), 2.01－2.05 (m, 1H), 1.92－1.96
(m, 2H), 1.83－1.87 (m, 1H), 1.82 (d, J＝4.0 Hz, 1H),
1.74－1.79 (m, 2H), 1.64－1.67 (m, 2H), 1.55－1.61
(m, 2H), 1.42－1.45 (m, 1H), 1.31 (t, J＝8.0 Hz, 3H),
1.22 (s, 3H), 1.19 (s, 1H), 1.14 (s, 3H), 1.01－1.05 (m,
1H), 0.86－0.89 (m, 1H), 0.59 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 210.2, 209.0, 177.1, 60.2, 59.6, 56.3,
50.6, 47.3, 47.0, 43.7, 39.9, 39.8, 38.9, 38.0, 34.2, 28.8,
21.5, 20.9, 20.1, 19.0, 14.1, 11.7; FT-IR (KBr) v: 2977,
2952, 2869, 1753, 1733, 1724, 1465, 1451, 1243, 1228,
1148, 1028, 956 cm−1; HRMS calcd for C22H32NaO4 [M
＋Na]＋ 383.2193, found 383.2199.
57.4, 56.5, 51.5, 51.4, 43.7, 42.1, 40.0, 38.7, 38.1, 36.5,
33.8, 28.8, 22.9, 21.2, 20.9, 19.1, 14.1, 11.8; IR (KBr) v:
3260, 2954, 2931, 2850, 1741, 1717, 1649, 1457, 1236,
1183, 1154, 1030, 894, 830 cm−1; HRMS calcd for
C22H34NO4 [M＋H]＋ 376.2482, found 376.2488.
Synthesis of compound 10: 3 g (8 mmol) of com-
pound 9 and Raney Ni were added to 40 mL THF. The
yellow system was hydrogenated under 50 psi H2 at 50
℃ for 4 h and became colorless. Filtration of Ni and
evaporation of solvent provide a white solid. After the
solid was dried, 30 mL dried methanol was added. Then
0.912 g (24 mmol) NaBH4 was added carefully under
ice bath. After the release of gas, the system was al-
lowed to stir at ambient temperature for 10 h. The re-
sultant mixture was concentrated under reduced pres-
sure and 20 mL water was added to the residue, then
extracted with chloroform and dried with MgSO4. After
filtration, the solvent was removed under reduced pres-
sure and the crude product was purified by column
chromatography eluting with CHCl3/MeOH (30∶1).
Yield: 80%; 1H NMR (400 MHz, CDCl3) δ: 4.08－4.10
(m, 2H), 3.54 (d, J＝8.0 Hz, 1H), 2.96 (d, J＝8.0 Hz,
1H), 2.16－2.20 (m, 3H), 1.77－1.91 (m, 3H), 1.70 (d,
J＝12.0 Hz, 1H), 1.60－1.64 (m, 1H), 1.48－1.55 (m,
2H), 1.35－1.43 (m, 2H), 1.24－1.28 (m, 6H), 1.17 (s,
3H), 1.10－1.12 (m, 1H), 0.97－1.04 (m, 3H), 0.94 (s,
3H), 0.88 (s, 3H), 0.84－0.80 (m, 1H); 13C NMR (100
MHz, CDCl3) δ: 177.9, 79.5, 59.9, 59.7, 58.4, 57.8, 53.2,
47.5, 43.6, 42.6, 41.3, 40.9, 38.2, 37.7, 34.3, 28.9, 26.3,
22.0, 20.6, 19.7, 14.3, 14.2; FT-IR (KBr) v: 3406, 3342,
3224, 2937, 2850, 1718, 1462, 1232, 1179, 1151, 1096,
1034, 779, 629 cm−1; HRMS (ESI, m/z) calcd for
C22H38NO3 [M＋H]＋ 364.2846, found 364.2848.
Synthesis of catalysis 3: 1,2-diamino alcohol 10 (181
mg, 0.5 mmol), DCC (123 mg, 0.6 mmol) and 107 mg
(0.5 mmol) N-Boc-L-proline were added into 5 mL
CH2Cl2 with catalytic amount DMAP. The reaction
mixture was stirred at room temperature and a white
solid was formed in the system (DCU). The solid was
filtrated and the solvent was evaporated. Then 4 mL
TFA/DCM (1∶1) mixture was added to the residue and
kept stirring for about 3 h. The solvent was evaporated
and 10 mL saturated sodium bicarbonate solution was
added, filtrated with EtOAc and dried with MgSO4. Af-
ter filtration, the solvent was removed under reduced
pressure and the crude product was purified by column
chromatography eluting with CHCl3/MeOH (20∶1).
Yield: 85%; m.p. 184.6－186.2 ℃; 1H NMR (400 MHz,
CDCl3) δ: 8.01 (d, J＝0.68 Hz, 1H), 4.01－4.09 (m, 3H),
3.93 (t, J＝4.4 Hz, 1H), 3.80 (q, J＝4.8 Hz, 1H), 3.04－
3.06 (m, 1H), 2.90－2.93 (m, 1H), 2.16－2.22 (m, 4H),
1.82－1.94 (m, 1H), 1.70－1.79 (m, 6H), 1.52－1.67
(m, 3H), 1.39－1.45 (m, 2H), 1.32－1.36 (m, 2H), 1.24
(t, J＝7.2 Hz, 3H), 1.16 (s, 3H), 0.98－1.08 (m, 3H),
0.91 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 177.8, 176.3, 80.6, 60.7, 59.9, 58.9, 58.2, 58.1, 53.4,
47.3, 47.1, 43.6, 42.3, 41.3, 41.2, 38.1, 37.6, 34.9, 31.1,
28.9, 26.2, 26.1, 21.9, 20.7, 19.7, 14.3, 14.1; FT-IR
Synthesis of compound 9: 3.6 g (10 mmol) com-
pound 8, 0.76 g (1.1 mmol) hydroxylamine hydrochlo-
ride were dissolved in 30 mL ethanol with 1.08 g Na-
HCO3 (1.2 mmol). The system was stirred under reflux
and the mixture turned orange to yellow. The reaction
completed in 4 h determined by TLC. The resultant
mixture was concentrated under reduced pressure. The
residue was added 20 mL water and extracted with 10
mL × 3 EtOAc. The combined organic layer was
washed with water and brine and then dried with
MgSO4. After filtration and evaporation of solvent, the
yellow product 9 was obtained and used directly for the
next step without further purification. yield 90%; m.p.
1
180.5－182.0 ℃; H NMR (400 MHz, CDCl3) δ: 9.27
(s, 1H), 4.08－2.14 (m, 2H), 2.34－2.38 (m, 1H),
2.25 (d, J＝12.0 Hz, 1H), 2.15 (d, J＝12.0 Hz, 1H),
1.79－1.93 (m, 4H), 1.65 (d, J＝12.0 Hz, 1H), 1.50－
1.61 (m, 1H), 1.43 (m, 4H), 1.31－1.35 (m, 3H), 1.29 (t,
J＝7.2 Hz, 3H), 1.18－1.20 (m, 4H), 1.08－1.12 (m,
1H), 0.98－0.99 (m, 1H), 0.84－0.87 (m, 1H), 0.61 (s,
13
3H); C NMR (100 MHz) δ: 207.3, 177.4, 160.1, 60.2,
Chin. J. Chem. 2013, 31, 247—255
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
253

Zhang et al.
FULL PAPER
(KBr) v: 3358, 2943, 2868, 1721, 1703, 1646, 1521,
1465, 1233, 1179, 1153, 1120, 1029, 974 cm−1; HRMS
(ESI, m/z) calcd for C27H45N2O4 [M＋H]＋ 461.3374,
found 461.3376.
2H); HPLC (for anti): Chiralcel OD-H, UV 254,
i-PrOH/Hexane＝5/95, flow rate 1.0 mL/min, tR 34 min
(major), tR 45 min (minor).
2-[Hydroxy-(2-methoxyphenyl)methyl]cyclohexan-
one: 1H NMR (400 MHz, CDCl3) δ syn: 1.49－1.87 (m,
5H), 1.84－1.89 (m, 1H), 2.36－2.56 (m, 3H), 3.05 (br,
1H), 5.39 (d, J＝1.6 Hz, 1H), 6.85 (d, J＝8.0 Hz, 1H,
ArH), 6.97 (t, J＝8.0 Hz, 1H, ArH), 7.24 (t, J＝8.0 Hz,
1H, ArH), 7.43 (d, J＝8.0 Hz, 1H, ArH); anti: 1.30－
1.98 (m, 6H), 2.30－2.46 (m, 3H), 3.00 (br, 1H), 4.78 (d,
J＝1.6 Hz, 1H), 6.88 (d, J＝8.0 Hz, 1H, ArH), 6.97 (t,
J＝8.0 Hz, 1H, ArH), 7.25 (t, J＝8.0 Hz, 1H, ArH),
7.46 (d, J＝8.0 Hz, 1H, ArH); HPLC (for anti): Chiral-
pak AD-H, UV 254, i-PrOH/Hexane＝5/95, flow rate
0.5 mL/min, tR＝41 min (major), tR＝40 min (minor).
2-[Hydroxy-phenylmethyl] cyclohexanone: 1H NMR
(400 MHz, CDCl3) δ anti: 1.30－1.33 (m, 1H), 1.57－
1.78 (m, 4H), 2.08－2.09 (m, 1H), 2.37－2.48 (m, 2H),
2.62－2.64 (m, 1H), 4.79－4.82 (d, J＝8.8 Hz, 1H),
7.28－7.36 (m, 5H); syn: 1.61－1.78 (m, 4H), 2.08－
2.09 (m, 1H), 2.38－2.48 (m, 2H), 2.60－2.64 (m, 1H),
5.41 (s, 1H), 7.31－7.36 (m, 5H); HPLC (for anti):
Chiralcel OD-H, UV 254 nm, i-PrOH/Hexane＝5/95,
flow rate 1.0 mL/min, tR＝13.4 min (major), tR＝24.0
min (minor).
2-[Hydroxy-(4-chlorophenyl)methyl]cyclohexanone:
1H NMR (400 MHz, CDCl3) δ syn: 1.42－2.11 (m, 6H),
2.32－2.45 (m, 2H), 2.53－2.56 (m, 1H), 3.05 (s, 1H),
5.36 (d, J＝2.0 Hz, 1H), 7.24 (d, J＝8.4 Hz, 2H), 7.32
(d, J＝8.4 Hz, 2H); anti: 1.27－1.31 (m, 1H), 1.53－
1.82 (m, 4H), 2.07－2.11 (m, 1H), 2.35－2.56 (m, 3H),
4.76 (d, J＝8.8 Hz, 1H), 7.26 (d, J＝8.0 Hz, 2H), 7.32
(d, J＝8.0 Hz, 2H); HPLC (for anti): Chiralpak AD-H,
UV 254 nm, i-PrOH/Hexane ＝ 5/95, flow rate 0.9
mL/min, tR＝33 min (major), tR＝27 min (minor).
2-[Hydroxy-(4-bromophenyl)methyl]cyclohexanone:
1H NMR (400 MHz, CDCl3) δ syn: 1.55－1.86 (m, 5H,
CH2), 2.06－2.09 (m, 1H, CH2), 2.44－2.46 (m, 3H,
CH), 3.06 (s, 1H, OH), 5.33 (s, 1H, CH), 7.19 (d, J＝8.4
Hz, 2H, ArH), 7.48 (d, J＝8.4 Hz, 2H, ArH); anti: 1.20
－1.35 (m, 1H, CH2), 1.40－1.85 (m, 4H, CH2), 2.05－
2.08 (m, 1H, CH2), 2.36－2.37 (m, 2H, CH2), 2.53－
2.55 (m, 1H, CH), 3.98 (br s, 1H, OH), 4.73－4.76 (d,
J＝8.8 Hz, 1H, CH), 7.17 (d, J＝8.4 Hz, 2H, ArH), 7.47
(d, J＝8.4 Hz, 2H, ArH); HPLC (for anti): Chiralpak
AD-H, UV 254 nm, i-PrOH/Hexane＝10/90, flow rate
0.6 mL/min, tR＝29 min (major), tR＝25 min (minor).
2-[Hydroxy-(4-flurophenyl)methyl]cyclohexanone:
1H NMR (400 MHz, CDCl3) δ syn: 1.50－1.87 (m, 5H),
1.84－1.88 (m, 1H), 2.36－2.56 (m, 3H), 3.05 (br, 1H),
5.36 (d, J＝1.6 Hz, 1H), 7.00－7.05 (m, 2H), 7.25－
7.29 (m, 2H); anti: 1.24－1.33 (m, 1H), 1.53－1.82 (m,
4H), 2.07－2.12 (m, 1H), 2.35－2.59 (m, 3H), 4.01 (s,
1H), 4.77 (d, J＝8.8 Hz, 1H), 7.01－7.05 (m, 2H),
7.27－7.31 (m, 2H); HPLC (for anti): Chiralpak AD-H,
UV 254 nm, i-PrOH/Hexane＝10/90, flow rate 0.6
mL/min, tR＝25 min (major), tR＝22 min (minor).
2-[Hydroxy-(4-trifluoromethylphenyl)methyl]cyclo-
General procedure for the Aldol reaction
0.33 mmol of aldehyde was added to a solution of
specified amount of catalyst 1, 2 or 3, cyclohexanone
and water. After being stirred for the indicated time, the
mixture was treated with saturated ammonium chloride
solution and extracted with ethyl acetate. The organic
layer was dried over MgSO4, filtered, and concentrated
to give pure aldol product after thin layer chroma-
tographic purification on silica gel (petroleum ether/
ethyl acetate).
Aldol reaction on water with additive: Aldehyde
(0.33 mmol) was added to the mixture of 0.4 mL cyclo-
hexanone, 0.4 mL water, 10 mol% of catalyst and speci-
fied additive. After being stirred at room temperature
for the indicated time, the aldol product was obtained by
treatment of the reaction system with the same method
as reaction without additive mentioned above.
2-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone:
1H NMR (400 MHz, CDCl3) δ syn: 1.53－1.87 (m, 6H,
3CH2), 2.08－2.12 (m, 1H), 2.42－2.47 (m, 2H), 2.87－
2.91 (dd, J＝13.2, 4.8 Hz, 1H, CH), 3.15 (br, 1H, OH),
5.96 (d, J＝1.6 Hz, 1H, CHOH), 7.46 (td, J＝8.0, 0.8
Hz, 1H, ArH), 7.66 (td, J＝8.0, 0.8 Hz, 1H, ArH), 7.84
(dd, J＝8.0, 0.8 Hz, 1H, Ar), 8.02 (dd, J＝8.0, 0.8 Hz,
1H, ArH); anti: 1.61－1.87 (m, 6H), 2.08－2.11 (m,
1H), 2.34－2.47 (m, 2H), 2.76－2.80 (m, 1H), 3.95 (br,
1H), 5.45 (d, J＝7.2 Hz, 1H), 7.44 (td, J＝8.0, 0.8 Hz,
1H, ArH), 7.66 (td, J＝8.0, 0.8 Hz, 1H, ArH), 7.78 (dd,
J＝8.0, 0.8 Hz, 1H), 7.86 (dd, J＝8.0, 0.8 Hz, 1H);
HPLC (for anti): Chiralcel OD-H, UV 254, i-PrOH/
Hexane＝5/95, flow rate 0.5 mL/min, tR＝38 min (ma-
jor), tR＝47 min (minor).
2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone:
1H NMR (400 MHz, CDCl3) δ syn: 1.48－2.10 (m, 6H),
2.33－2.48 (m, 2H), 2.62－2.66 (m, 1H), 3.16 (s, 1H),
5.48 (d, J＝2.0 Hz, 1H), 7.52 (t, J＝8.0 Hz, 1H), 7.66 (d,
J＝1.4 Hz, 1H), 8.11 (d, J＝8.0 Hz, 1H), 8.20 (d, J＝
8.0 Hz, 1H); anti: 1.33－2.10 (m, 6H), 2.32－2.48 (m,
2H), 2.69－2.72 (m, 1H), 3.16 (s, 1H), 4.91 (d, J＝8.4
Hz, 1H), 7.54 (t, J＝8.0 Hz, 1H), 7.68 (d, J＝0.8 Hz,
1H), 8.13－8.17 (m, 1H), 8.20 (d, J＝8.0 Hz, 1H);
HPLC (for anti): Chiralcel OD-H, UV 254, i-PrOH/
Hexane＝5/95, flow rate 1.0 mL/min, tR＝22 min (ma-
jor), tR＝31 min (minor).
2-(Hydroxy(4-nitrophenyl)methyl)cyclohexanone:
1H NMR (400 MHz, CDCl3) δ syn: 1.50－1.88 (m, 5H),
2.09－2.15 (m, 1H), 2.37－2.52 (m, 2H), 2.62－2.66
(m, 1H), 3.10 (br, 1H), 5.49 (d, J＝1.6 Hz, 1H), 7.49 (d,
J＝8.4 Hz, 2H), 8.22 (d, J＝8.4 Hz, 2H), anti: 1.36－
1.44 (m, 1H), 1.51－1.73 (m, 3H), 1.81－1.84 (m, 1H),
2.10－2.15 (m, 1H), 2.33－2.46 (m, 1H), 2.48－2.52
(m, 1H), 2.57－2.63 (m, 1H), 3.80 (br, 1H), 4.90 (d, J＝
8.4 Hz, 1H), 7.51 (d, J＝8.4 Hz, 2H), 7.22 (d, J＝8.4 Hz,
254
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 247—255

Direct Asymmetric Aldol Reaction Co-catalyzed by Amphiphilic Prolinamide Phenol
1
[3] (a) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata, N.;
hexanone: H NMR (400 MHz, CDCl3) δ anti: 7.74－
7.55 (m, 3H), 7.40 (t, J＝7.2 Hz, 1H), 5.30 (d, J＝9.3
Hz, 1H), 4.03 (t, J＝3.0 Hz, 1H), 2.81－2.69 (m, 1H),
2.55－2.45 (m, 1H), 2.37 (td, J＝12.9, 4.8 Hz, 1H),
2.15－2.03 (m, 1H), 1.81－149 (m, 3 H), 1.48－1.23
(m, 1H). HPLC (for anti): Chiralpak AD-H, UV 254 nm,
i-PrOH/Hexane＝5/95, flow rate 0.9 mL/min, tR＝26
min (major), tR＝19 min (minor).
Toru, T. Chem. Eur. J. 2008, 14, 8079; (b) Fotaras, S.; Kokotos, C.
G.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011, 2011, 1310; (c)
Banon-Caballero, A.; Guillena, G.; Najera, C. Green Chem. 2010,
12, 1599; (d) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798; (e) Chen, W. B.; Wu, Z. J.; Hu, J.; Cun, L. F.;
Zhang, X. M.; Yuan, W. C. Org. Lett. 2011, 13, 2472; (f) Malkov, A.
V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.;
Pluháčková, K.; Kočovský, P. Org. Lett. 2007, 9, 5473; (g) Wu, Y.
S.; Chen, Y.; Deng, D. S.; Cai, J. Synlett 2005, 2005, 1627; (h) Zhao,
J.; Chen, A.; Liu, Q. Chin. J. Chem. 2009, 27, 930; (i) Yu, G.; Ge, Z.
M.; Cheng, T. M.; Li, R. T. Chin. J. Chem. 2008, 26, 911.
[4] List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122,
2395.
[5] Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang,
Y. Z.; Wu, Y. D. J. Am. Chem. Soc. 2003, 125, 5262.
[6] Fu, Y. Q.; Li, Z. C.; Ding, L. N.; Tao, J. C.; Zhang, S. H.; Tang, M.
S. Tetrahedron: Asymmetry 2006, 17, 3351.
[7] Guillena, G.; del Carmen Hita, M.; Nájera, C. Tetrahedron:
Asymmetry 2006, 17, 729.
[8] Monge-Marcet, A.; Cattoen, X.; Alonso, D. A.; Najera, C.; Man, M.
W. C.; Pleixats, R. Green Chem. 2012, 14, 1601.
[9] (a) Almaşi, D.; Alonso, D. A.; Balaguer, A. N.; Nájera, C. Adv.
Synth. Catal. 2009, 351, 1123; (b) Reddy, R. J.; Kuan, H. H.; Chou,
T. Y.; Chen, K. Chem. Eur. J. 2009, 15, 9294.
[10] (a) Andreu, C.; del Olmo, M. L.; Asensio, G. Tetrahedron 2012, 68,
7966; (b) Bhowmick, S.; Bhowmick, K. C. Tetrahedron: Asymmetry
2011, 22, 1945.
[11] Shibasaki, M.; Matsunaga, S.; Kumagai, N.; Mahrwald, R. In
Modern Aldol Reactions, Wiley-VCH, Weinheim, 2004, p. 197.
[12] Paradowska, J.; Stodulski, M.; Mlynarski, J. Adv. Synth. Catal. 2007,
349, 1041.
[13] Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.
[14] Liu, Y. X.; Sun, Y. N.; Tan, H. H.; Liu, W.; Tao, J. C. Tetrahedron:
Asymmetry 2007, 18, 2649.
2-[Hydroxy-(2-nitrophenyl)methyl]cyclopentanone:
1H NMR (400 MHz, CDCl3) δ syn: 1.70－1.78 (m, 2H),
2.03－2.19 (m, 3H), 2.37 (dd, J＝8.0, 1.6 Hz, 1H), 2.60
(br, 1H), 2.72－2.76 (m, 1H), 5.92 (d, J＝2.4 Hz, 1H)
7.44 (td, J＝8.0, 0.8 Hz, 1H, ArH), 7.66 (t, J＝8.0 Hz,
1H, ArH), 7.89 (d, J＝8.0 Hz, 1H, Ar), 8.02 (d, J＝8.0
Hz, 1H, ArH); anti: 1.70－2.03 (m, 4H), 2.19－2.38 (m,
2H), 2.68 (d, J＝7.6 Hz, 1H), 2.90 (br, 1H), 5.21 (d, J＝
7.2 Hz, 1H), 7.44 (t, J＝8.0 Hz, 1H, ArH), 7.66 (t, J＝
8.0 Hz, 1H, ArH), 7.89 (d, J＝8.0 Hz, 1H), 8.00 (dd,
J＝8.0, 0.8 Hz, 1H); HPLC: syn: Chiralcel OD-H, UV
254, i-PrOH/Hexane＝5/95, flow rate 1.0 mL/min, tR＝
17 min (major), tR＝13 min (minor); anti: Chiralcel
OD-H, UV 254, i-PrOH/Hexane＝5/95, flow rate 1.0
mL/min, tR＝23 min (major), tR＝26 min (minor).
1
4-Hydroxy-4-(2-nitrophenyl)butan-2-one: H NMR
(CDCl3) δ: 2.24 (s, 3H), 2.74 (dd, J＝17.8, 9.4 Hz, 1H),
3.13 (dd, J＝17.8, 1.8 Hz, 1H), 3.89 (s, 1H), 5.68 (dd,
J＝9.4, 1.8 Hz, 1H), 7.44 (t, J＝8.0 Hz, 1H), 7.67 (t,
J＝8.0 Hz, 1H), 7.80 (d, J＝8.0 Hz, 1H), 7.96 (d, J＝
8.0 Hz, 1H); HPLC: Chiralcel OD-H, UV 254, i-PrOH/
Hexane＝5/95, flow rate 1.0 mL/min, S-isomer, tR＝18
min, R-isomer, tR＝21 min.
[15] (a) Almaşi, D.; Alonso, D. A.; Gómez-Bengoa, E.; Nagel, Y.; Nájera,
C. Eur. J. Org. Chem. 2007, 2007, 2328; (b) An, Y. J.; Qin, Q.;
Wang, C. C.; Tao, J. C. Chin. J. Chem. 2011, 29, 1511.
References
[16] Zhang, T.; Lu, L. H.; Liu, H.; Wang, J. W.; Wang, R. X.; Zhang, Y.
X.; Tao, J. C. Bioorg. Med. Chem. Lett. 2012, 22, 5827.
[17] Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2010, 2999.
[18] Kobayashi, S.; Manabe, K. Pure Appl. Chem. 2000, 72, 1373.
[19] Kimura, E.; Kikuta, E. J. Biol. Inorg. Chem. 2000, 5, 139.
[1] MacMillan, D. W. C. Nature 2008, 455, 304.
[2] (a) Machajewski, T. D.; Wong, C. H. Angew. Chem., Int. Ed. 2000,
39, 1352; (b) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.;
Zanardi, F. Chem. Rev. 2011, 111, 3076; (c) Palomo, C.; Oiarbide,
M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65.
(Pan, B.; Fan, Y.)
Chin. J. Chem. 2013, 31, 247—255
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www.cjc.wiley-vch.de
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