Simple, inexpensive, and facile l-prolinamide used as a recyclable organocatalyst for highly efficient large-scale asymmetric direct aldol reactions

Article abstract of DOI:10.1016/j.tetasy.2011.05.008

In order to discover a simple, inexpensive, and efficient route to obtain highly enantiomerically enriched anti-aldol products for applications in industry, a series of prolinamides 1-5 with different carbocyclic rings have been synthesized from achiral c

Full text of DOI:10.1016/j.tetasy.2011.05.008

Tetrahedron: Asymmetry 22 (2011) 840–850
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Simple, inexpensive, and facile L-prolinamide used as a recyclable
organocatalyst for highly efficient large-scale asymmetric direct aldol reactions
⇑
Jiangwei Xu, Xiangkai Fu , Chuanlong Wu, Xiaoyan Hu
College of Chemistry and Chemical Engineering Southwest University, Research Institute of Applied Chemistry Southwest University, The Key Laboratory of Applied
Chemistry of Chongqing Municipality, The Key Laboratory of Eco-environments in Three Gorges Reservoir Region (Ministry of Education Chongqing), Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to discover a simple, inexpensive, and efficient route to obtain highly enantiomerically enriched
anti-aldol products for applications in industry, a series of prolinamides 1–5 with different carbocyclic
rings have been synthesized from achiral cycloalkylamine, and prolinamides 6–9 have been synthesized
from aniline with different substituents. The organocatalysts obtained catalyzed the asymmetric aldol
reaction and showed that no matter carbocyclic rings or aromatic rings were found to play a significant
role in the formation of the aldol products. Moreover, the prolinamide 6 exhibited efficient catalytic activ-
ity in the asymmetric aldol reaction only with 5 mol % catalyst loading and 4 equiv of ketone, and affor-
ded aldol products in high diastereoselectivity (up to anti/syn 99:1) and enantioselectivity (99%) and
Received 23 March 2011
Accepted 11 May 2011
Available online 21 June 2011
significantly enhanced the reaction yield (99%). These results were much better than L-proline-3-nitroan-
ilide which had the strongest electron-withdrawing group on the aromatic ring. Furthermore, catalyst 6
can be easily recovered and reused, without a significant decrease of enantioselectivity after five cycles.
This inexpensive, simple, and recyclable catalyst can be efficiently used in large-scale reactions with the
enantioselectivities being maintained at the same level, which offers a great possibility for application in
industry.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
major limitations is the high catalyst loading (20–30 mol %) of
N-arylprolinamides that is generally required to complete the
Asymmetric organocatalysis has emerged as a rapidly growing
and important field in organic chemistry.1–4 The search for small
molecules that are able to act as catalysts in enantioselective
transformations has received extensive attention over the last dec-
ade,5–7 and small molecules used as organocatalysts have brought
the prospect of a complementary mode of catalysis, with the
potential for savings in cost, time and energy, an easier experimen-
tal procedure, and reductions in chemical waste.6 Unsurprisingly,
the aldol reaction constitutes as one of the most investigated C–C
bond forming reactions in organocatalysis. Since the pioneering
work of List et al.8 who demonstrated the use of proline in catalyz-
ing the direct aldol reaction of p-nitrobenzaldehyde with acetone, a
number of organocatalysts based on the principle of ‘enamine
catalysis’ have been reported.4 These compounds are generally
prolinamide derivatives that differ in the nature of the amine
component attached to the carboxylic functionality of proline,
and generally contain an additional stereogenic center and hydro-
gen-bonding site.9 Therefore, these catalysts are not only complex
but also generally expensive. According to reports,10 the shortcom-
ings of N-arylprolinamides have also been realized; one of the
transformations with large equivalents of ketone in long time-
scales. Meanwhile, (S)-N-phenyl-pyrrolidine-2-carboxamide cata-
lyzed the asymmetric direct intermolecular aldol reaction to give
the product with no more than 88% ee. This will raise a cost
concern when large amounts of chiral materials are used for a
large-scale synthesis in industrial applications. In spite of the
significant efforts devoted to the development of highly active
organocatalysts aimed at lowering catalyst loading, it has proven
to be a significant challenging task, and only limited success has
been achieved so far.
In this context, a series of simple compounds 1–10 were synthe-
sized.8,9 It is shown that prolinamides 1–9 exhibited great catalytic
activity in the asymmetric aldol reaction in m-xylene at ꢀ20 °C with
only 5 mol % catalyst loading in 4 equiv of ketone. However, com-
pound 10 synthesized with an alkylamine and proline demonstrated
lower catalytic activity. These results indicated that either carbocy-
clic rings or aromatic rings could in some way enhance the enanti-
oselectivity in m-xylene at low temperatures. The simplest and
least expensive catalyst 6 obtained the best catalytic activity (up
to anti/syn 99:1, ee 99%, yield 99%). This is much higher than those
of
L-proline-3-nitroanilide which had the strongest electron-
withdrawing group on the aromatic ring, and is in sharp contrast
to the literature results. Furthermore, catalyst 6 can be easily
⇑
Corresponding author. Tel.: +86 23 6825 3704; fax: +86 23 6825 4000.
E-mail address: fxk@swu.edu.cn (X. Fu).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.008

J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
841
recovered and reused without a significant decrease of enantioselec-
tivity for five cycles. In addition, this inexpensive, simple and
recyclable catalyst can be efficiently used in large-scale reactions
with the enantioselectivities being maintained at the same level,
which offers a great possibility for application in industry.
observations are not in agreement with other literatures reported
earlier by Gong et al.,11 where N-arylprolinamides used as organo-
catalysts showed that the stereoselectivity in aldol reactions in-
creases as the electron-withdrawing nature of the substituent in
the N-arylprolinamide increases (Table 2).
To establish the best reaction conditions that would promote
the reactivity as well stereoselectivity, prolinamide 6 was consid-
ered as a representative case. Amongst the solvents tested, polar
solvent systems gave relatively poor enantioselectivities (e.g.,
DMSO, DMF, CH3CN), while nonpolar solvent systems get relatively
high enantioselectivity (e.g., n-hexane, toluene, m-xylene).
Moreover, the best enantioselectivity of 97% ee was obtained with
m-xylene as the solvent in the shortest time (entry 5).
2. Results and discussion
With the aim of discovering a simple, inexpensive and efficient
route to obtain highly enantiomerically enriched anti-aldol prod-
ucts catalyzed by simple prolinamides and offer a great possibility
for applications in industry, we prepared proline derivatives 1–10.
All compounds 1–10 were easily prepared from commercially
While numerous examples of organocatalyzed aldol reactions
have been reported based on proline, we were struck by the fact
that the vast majority of these catalyst systems employed polar,
aprotic solvent systems (e.g., DMSO, DMF). This solvent choice is
primarily based on the poor solubility of proline and related deriv-
atives in nonpolar, aprotic solvents. However, prolinamide 6 has
greatly improved solubility properties in m-xylene, as compared
to proline. Comparable weights (300 mg) of proline and our proli-
namide 6 were mixed with 1.0 ml of m-xylene. Proline is essen-
tially insoluble in this solvent (calculated solubility <10 mg/ml in
m-xylene). In contrast, prolinamide 6 is completely soluble under
these conditions. Accordingly, the solvent of m-xylene was consid-
ered exceptional for examining the organocatalytic activity of 6 for
performing aldol reactions.
It is well-known that a Brønsted acid additive should be
involved in the intricate iminium-enamine equilibrium, and can
also play an important role in the activation of the aldol acceptor
by hydrogen bonding.12 Therefore, a series of Brønsted acids and
p-nitrophenol were examined as the cocatalysts in the direct
asymmetric aldol reaction. As can be seen from Table 3, the cata-
lytic activity increased when increasing the acidity of cocatalyst
(entries 2–4),and decreased if the acidity of the cocatalyst became
too high (entries 4–8). The reaction did not occur in relatively
strong acids (entries 8–10). An enantioselectivity/cocatalyst profile
revealed that optimal enantiocontrol could be achieved when ace-
tic acid was used as the cocatalyst (Table 3, entry 4). Further study
showed that the reaction efficiency could be improved if the ratio
of acetic acid to catalyst 6 was changed (entries 4 and 11–12).
Therefore, acetic acid was chosen as the optimum cocatalyst, and
the optimal molar ratio of acetic acid to catalyst 6 was 1:1.
Using m-xylene as the reaction medium, we next investigated
the different amounts of catalyst 6; it is noteworthy that the dr
available Boc-protected L-proline and the corresponding amine
component according to the synthetic route shown in Scheme 1.
The products were obtained in 65–85% overall yields.
These were evaluated for direct aldol reactions between benzal-
dehyde and cyclohexanone in m-xylene (Table 1). Compounds 1–5
with different carbocyclic rings were synthesized from achiral
cycloalkylamine, and compounds 6–9 were synthesized from ani-
line with different substituents. These organic compounds were
used in 10 mol %, and the reactions were studied at different tem-
peratures. As can be seen from the results summarized in Table 1,
when the reaction temperature was lowered from room tempera-
ture to ꢀ20 °C, with the exception of prolinamide 10, which was
synthesized by alkylamine and praline, and demonstrated lower
catalytic activity, all other compounds 1–9 gave products in in-
creased diastereoselectivities and enantioselectivities, meaning
that both carbocyclic rings and aromatic rings enhanced the enan-
tiocontrol as well as the diastereocontrol. From Table 1, it became
clear that the organic compounds 1 and 6 were found to be the
more efficient catalysts, providing excellent enantioselectivities
of 97% at ꢀ20 °C. A slight decrease in diastereoselectivity was ob-
served by further lowering the temperature from ꢀ20 °C to
ꢀ40 °C. It is worth mentioning here, following the decrease of
the reaction temperature, that the reaction rate and yield were de-
creased when using N-cycloalkylprolinamides, but the reaction
rate and yield were increased when using N-arylprolinamides.
Hence in addition to being the least expensive, catalyst 6 also gave
a higher catalytic activity than catalyst 1. A comparison of the re-
sults with catalysts 6–9 clearly showed that the catalytic activity
for no modification of aniline was better than the substitution of
a group in m-xylene at ꢀ20 °C. Furthermore,
L-proline-3-nitroani-
lide, which had the strongest electron-withdrawing group on the
aromatic ring, gave the lowest enantioselectivity. However, these
O
O
O
N
TFA / DCM
N
amine, EDCI, DMAP
CH2Cl2, rt.
HN
R
OH
N
H
HN
R
O
O
0 °C to rt, 5h
O
O
R2
R1
R3
R=
4
n
1
: n=1
: n=3
: n=4
n=5
1
2
3
6
7
8
9
: R =R =R =H
10
2
1
2
3
: R =R =H; R =CH3
3
4:
5
1
3
2
: R =R =CH3; R =H
1
3
2
: n=6
: R =R =H; R =NO2
Scheme 1. Synthesis of catalysts 1–10.

842
J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
Table 1
Direct aldol reaction of cyclohexanone and p-nitrobenaldehyde catalyzed by 1–10a
O
O
OH
CHO
Catalyst 10 mol%
AcOH 10 mol%, m-xylene
NO2
NO2
b
Entry
1
Catalyst
Temperature (°C)
Time (h)
Yield (%)
anti/sync
eed (%) anti (syn)
1
rt
0
ꢀ20
ꢀ40
rt
3
5
16
36
5
24
5
24
5
24
5
24
30
16
8
99
99
99
90
99
88
99
79
99
76
99
75
85
99
99
99
95
99
85
90
88
99
99
95
72
80
86:14
84:16
94:6
93:7
82:18
93:7
78:22
94:6
85:15
93:7
84:16
95:5
77:23
86:14
96:4
93:7
73:27
95:5
77:23
93:7
70:30
98:2
73:27
92:8
79:21
84:16
82 (58)
90 (82)
97 (87)
97 (83)
69 (51)
94 (78)
66 (44.5)
93 (77)
76 (49)
95 (83)
74 (47)
94 (76)
84 (79)
89 (85)
97 (80)
97 (86)
84 (85)
95 (88)
75 (84)
93 (86)
88 (82)
90 (86)
80 (69)
78 (73)
68 (58)
75 (31)
2
3
4
5
6
2
3
4
5
6
ꢀ20
rt
ꢀ20
rt
ꢀ20
rt
ꢀ20
rt
0
ꢀ20
ꢀ40
rt
8
7
8
7
35
12
40
30
40
12
8
17
24
36
ꢀ20
8
rt
ꢀ20
rt
9
9
ꢀ20
10
11
10
rt
ꢀ20
rt
ꢀ20
Prolinee
a
b
c
The reaction was performed with p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (10 equiv), catalyst (10 mol %), acetic acid (10 mol %) in the specified solvent (1.0 ml).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
Determined by chiral HPLC.
d
e
Catalyst 20 mol %.
and ee values were not obviously reduced by decreasing the
amount of catalyst from 10 mol % to 1 mol % (Table 4, entries
1–4). Furthermore, when using 5 mol % of catalyst after 8 h, we ob-
tained an almost quantitative yield with excellent stereoselectivity
(Table 4, entry 2). Consequently, the optimized catalyst loading
was chosen as 5 mol %.
The reaction was as fast under the experimental conditions as
described above (Table 4, entry 2), but required a large amount
of cyclohexanone, which left ample scope for further improvement.
We also investigated if a lower amount of cyclohexanone could be
employed. The data showed that the reactions were decelerated by
decreasing the amount of ketone from 10 to 2 equiv, yields also
greatly decreased, although ee and dr values were not significantly
changed. Hence, 4 equiv of cyclohexanone were chosen as the opti-
mized amount of ketone, because higher stereoselectivity was
observed.
As can be seen from the results summarized above, catalyst 6
can efficiently catalyze the direct asymmetric aldol reaction with
a high level of stereoselectivity. In order to increase the scope of
the methodology, we carried out several aldol reactions using cata-
lyst 6 in order to demonstrate the catalytic activity. The reactions of
various aromatic aldehydes with cyclohexanone were studied un-
der the optimized conditions. The results are summarized in Table 5.
It can be seen that a wide range of aromatic and heteroaromatic
aldehydes can effectively participate in the reaction. In general,
the reaction between cyclohexanone and aromatic aldehydes bear-
ing electron-withdrawing substituents furnished b-hydroxy
carbonyl aldol products in excellent yields (92–99%) within 36 h
(entries 1–9). In contrast, longer reaction times were required for
aromatic aldehydes containing an electron-donating group to give
comparatively lower yields (70–78%) (entries 10–12). This can be
explained by the fact that electron-withdrawing groups enhance
the electrophilicity of carbonyl carbons in aldehydes which facili-
tate the reaction, while electron-donating groups lessen the elec-
trophilicity. Moreover, both the neutral aromatic aldehydes and
heteroaromatic aldehydes 2-thiophenaldehyde reacted smoothly
with cyclohexanone under optimal conditions to give the corre-
sponding aldol products in moderate yields of 83–88% (entries
13–16). In fact, catalyst 6 could efficiently catalyze the direct aldol
reactions of cyclohexanone with aldehydes generating the products
with high diastereoselectivity and excellent enantioselectivity with
electron-withdrawing or electron-rich systems.
The use of other cyclic and acyclic ketones as aldol donors was
then examined. As shown in Table 6, when 4-methylclohexanone
and cyclopentanone were used as aldol donors, good yield with
excellent stereoselectivity (anti/syn 99:1, 97% ee and anti/syn
96:4, 95% ee, respectively, entries 1–2) for the anti-isomer were
achieved. Moreover, other cyclopentanone aldol donors tested
gave moderate enantioselectivities (anti/syn 74:26, 80% ee). We
also examined the feasibility of using acyclic ketones, such as
acetone and hydroxyacetone, as aldol donors. Although longer
reaction times were required in comparison to cyclic ketones, sat-
isfactory results were obtained, when the aldol reaction of
p-nitrobenzaldehyde and o-chlorobenzaldehyde with acetone
was conducted; the aldol product was obtained with high enanti-
oselectivities (90% and 94% ee, entries 4 and 5). When the aldol

J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
843
Table 2
Effect of the solvent on the catalytic aldol reaction between cyclohexanone and p-nitrobenzaldehydes catalyzed by 6a
O
O
OH
CHO
Catalyst 6 10 mol%
AcOH 10 mol%
NO2
NO2
Entry
Solvent
Temperature (°C)
Time (h)
Yieldb (%)
anti/sync
eed (%) anti (syn)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Neat
Water
rt
rt
rt
rt
5
24
24
30
8
99
99
99
85
99
99
80
86
85
80
88
50
78
60
99
86:14
84:16
87:13
77:23
96:4
93:7
93:7
92:8
70:30
89:11
81:19
88:12
90:10
82:18
95:5
73 (63)
74 (52)
71 (32)
84 (79)
97 (80)
95 (80)
93 (45)
90 (81)
88 (94)
88 (91)
80 (73)
85 (81)
87 (85)
76 (65)
89 (78)
DMF–H2O
m-Xylene
m-Xylene
Toluene
n-Hexane
Ethyl ether
CH2Cl2
CHCl3
THF
CH3CN
DMF
DMSO
Neat
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
8
16
16
32
40
32
40
40
40
24
a
b
c
The reaction was performed with p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (10 equiv), catalyst 6 (10 mol %), acetic acid (10 mol %) in the specified solvent (1.0 ml).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
Determined by chiral HPLC.
d
Table 3
Organocatalyzed direct aldol reactions in the presence of various acid additivesa
O
O
OH
CHO
Catalyst 6 10 mol%
Cocatalyst x mol%
m-xylene, -20 °C
NO2
NO2
Entry
Cocatalyst
None
p-Nitrophenol (10 mol %)
Propannoic acid (10 mol %)
Acetic acid (10 mol %)
3-Methylbenzoic acid (10 mol %)
Benzoic acid (10 mol %)
3-Nitrobenzoic acid (10 mol %)
Trifluoroactic acid (10 mol %)
Methylsulfonic acid (10 mol %)
HBr (10 mol %)
Time (h)
Yieldb (%)
anti/sync
eed (%) anti (syn)
1
2
3
4
5
6
7
8
9
36
24
5
96
70
95
99
98
95
80
—
—
—
78
96
88:12
92:8
95:5
96:4
95:5
95:5
90:10
—
—
—
92:8
94:6
86 (61)
90 (69)
96 (85)
97 (80)
95 (83)
95 (81)
78 (76)
—
5
16
16
24
—
—
—
—
—
10
11
12
Acetic acid (5 mol %)
Acetic acid (20 mol %)
24
16
93 (79)
96 (82)
a
b
c
The reaction was performed with p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (10 equiv), catalyst 6 (10 mol %), cocatalyst (ꢁ mol %) in m-xylene (1.0 ml).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
Determined by chiral HPLC.
d
reaction of o-nitrobenzaldehyde with hydroxyacetone was carried
out, the aldol products were obtained in high yields (88%) with
satisfactory enantioselectivities (anti/syn 85:15, 88% ee).
was adjusted to pH 8 with NaOH (aqueous), and the aqueous layer
was extracted with m-xylene (20 ml). The reaction mixture was
placed in an ethanol bath (ꢀ20 °C) for 30 min. The organic layer
was poured out, and used directly in subsequent reaction cycles
without adding any new catalyst or m-xylene. For each reuse,
the same amount of substrates was used, and the recovered catalyst
Meanwhile, in order to verify that organocatalyst 6 could be
recovered and reused, we performed a recycling study of 6 using
the aldol reaction between cyclohexanoneand 4-nitrobenzaldehyde
(Table 7). The catalyst 6 could be easily recovered from the reaction
mixture after completion of the reaction by acid treatment; the aldol
product was extracted with ethyl ether (Et2O), and evaporation of
the organic solution was carried out in order to obtain the aldol
product. Catalyst 6 existed in the acidic aqueous layer. The pH value
6
essentially retained its catalytic activity without further
purification. When repeated once, about 4.5 mol % loading of the
catalyst was recovered, that is, probably 90% of catalyst 6 could be
reused. After five times, about 3.0 mol % loading of the catalyst could
be reused via the above method. No significant decrease in the

844
J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
Table 4
Effect of the amount of catalyst and cyclohexanone on the aldol reaction between cyclohexanone and p-nitrobenzaldehyde catalyzed by 6a
O
O
OH
CHO
Catalyst 6 / AcOH = 1 / 1
m-xylene, -20 °C
NO2
NO2
Entry
Ketone (equiv)
Cat. (mol %)
Time (h)
Yieldb (%)
anti/sync
eed (%) anti (syn)
1
2
3
4
5
6
10
10
10
10
4
10
5
3
1
5
5
8
24
48
16
30
99
99
80
60
98
81
96:4
97:3
94:6
93:7
98:2
94:6
97 (80)
97 (85)
97 (93)
98 (90)
98 (81)
97 (91)
2
5
a
b
c
The reaction was performed with p-nitrobenzaldehyde (0.5 mmol) and cyclohexanone in m-xylene (1.0 ml) with the ratio of acetic acid to catalyst as 1:1.
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
Determined by chiral HPLC.
d
Table 5
Catalytic aldol reactions between cyclohexanone and aldehydes catalyzed by 6a
O
O
OH
O
Catalyst 6 (5 mol%)
R
H
R
AcOH (5 mol%)
m-xylene, -20 °C
11
Entry
Product
Time (h)
Yieldb (%)
anti/sync
eed (%) anti (syn)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
11a (R = p-NO2–C6H4)
11b (R = o-NO2–C6H4)
11c (R = m-NO2–C6H4)
11d (R = p-CN–C6H4)
11e (R = p-Br–C6H4)
11f (R = p-Cl–C6H4)
11g (R = m-Cl–C6H4)
11h (R = o-Cl–C6H4)
11i (R = p-F–C6H4)
11j (R = p-CH3–C6H4)
11k (R = p-OMe–C6H4)
11l (R = m-OMe–C6H4)
11m (R = 2-naphthyl)
11n (R = 1-naphthyl)
11o (R = C6H5)
16
16
16
16
24
24
24
24
36
36
48
36
36
36
48
36
98
99
95
99
96
96
94
94
92
74
70
78
83
85
86
88
98:2
98:2
97:3
92:8
93:7
91:9
98:2
98:2
91:9
89:11
90:10
90:10
92:8
96:4
87:13
84:16
98 (81)
99 (72)
98 (66)
96 (31)
96 (87)
96 (78)
96 (67)
97 (87.5)
97 (53)
99 (87)
98 (53.5)
97 (88)
95 (80)
93 (40)
97 (45.5)
92 (86.5)
11p (R = 2-thiophenecarboxaldehyde)
a
b
c
The reaction was performed with aldehyde (0.5 mmol), cyclohexanone (4 equiv), catalyst 6 (5 mol %), acetic acid (5 mol %) in m-xylene (1.0 ml).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
d
Determined by chiral HPLC.
enantioselectivity was observed over five cycles. The decrease in the
catalyst after more cycles might be caused by a physical loss during
the extraction process.
with only 5 mol % catalyst loading in 4 equiv ketone. In particular,
the reactions that proceed with catalysts 6 afforded aldol products
in high diastereoselectivity (up to anti/syn 99:1) and enantioselec-
tivity (up to 99%) and significantly enhanced the reaction yield
(99%). However, compound 10 synthesized from an alkylamine
and proline demonstrated lower catalytic activity. The results indi-
cated that either carbocyclic rings or aryl rings could enhance the
enantioselectivity in m-xylene at low temperatures. Furthermore,
the simplest and least expensive catalyst 6 performed best with
no modification of aniline as compared to all of the other N-arylpr-
olinamides 7–9. The results uncovered for 6 are amongst the best
Large-scale asymmetric aldol reactions were then performed
with 150 mmol of aromatic aldehydes and 4 equiv of ketones. The
same catalyst loading of 5 mol % as used in the experimental scale
was used. The large-scale experiments proceeded smoothly using
the same procedure as for the experimental-scale reactions. As
can be seen from the results summarized in Table 8, the enantiose-
lectivities were maintained at the same level for the large-scale
reactions.
reported so far for N-arylprolinamides. However, L-proline-3-nitro-
anilide, which had the strongest electron-withdrawing group on
the aromatic ring, gave the lowest enantioselectivity in the same
conditions. These observations were different from the previous
reports in which N-arylprolinamides were used as organocatalysts
to catalyze the aldol reaction. In addition, catalyst 6 can be
3. Conclusion
In conclusion, it has been shown that all prolinamides 1–9
exhibited great catalytic activity in the asymmetric aldol reaction

J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
845
Table 6
Direct asymmetric aldol reactions between ketones and aromatic aldehydes catalyzed by 6a
O
O
OH
O
Catalyst 6 (5 mol%)
H
AcOH (5 mol%)
NO2
NO2
°
m-xylene, -20 C
11
Entry
1
Product
No.
Time (h)
24
Yieldb (%)
anti/sync
eed (%) anti (syn)
O
OH
4q
99
99:1
97 (42)
NO2
OH
O
O
2
3
4
11r
11s
11t
36
24
48
84
75
71
96:4
74:26
—
95 (58)
80 (47)
90
NO2
OH
OH
NO2
O
NO2
O
O
OH Cl
5
6
11u
11v
48
48
80
88
—
94
OH NO2
85:15
88 (45)
OH
a
b
c
The reaction was performed with aromatic aldehyde (0.5 mmol), ketone (4 equiv), catalyst 6 (5 mol %), acetic acid (5 mol %) in m-xylene (1.0 ml).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
d
Determined by chiral HPLC.
expediently recovered and reused without significant loss of cata-
lytic activity and stereoselectivity. It is interesting that this inex-
pensive, simple and recyclable catalyst can be efficiently used in
large-scale reactions with the enantioselectivities being main-
tained at the same level, which offers a great possibility for appli-
cation in industry.
spectra were recorded on a 300 MHz instrument. Chemical shifts
(d) are given in ppm relative to TMS as the internal reference, cou-
pling constants (J) in Hertz. IR spectra were recorded on a spec-
trometer. Melting points were measured on a digital melting
point apparatus. Mass spectra (MS) were measured with a spec-
trometer. Analytical high performance liquid chromatography
(HPLC) was carried out on Agilent 1200 instrument using Chiralpak
AD (4.6 mm ꢁ 250 mm), Chiralpak OJ-H (4.6 mm ꢁ 250 mm) and
Chiralcel OD-H (4.6 mm ꢁ 250 mm) columns. Optical rotations
were measured on a JASCO P-1010 Polarimeter at k = 589 nm.
4. Experimental
4.1. General information
4.2. General procedure for the preparation of catalysts 1–10
The starting reagents used during the course of preparing
organocatalysts 1–10 were purchased from the Aldrich Company.
All chemicals were used as received unless otherwise noted. Re-
agent grade solvents were distilled prior to use. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
0.25 mm silica gel plates visualized with UV light and/or by stain-
ing with ethanolic phosphomolybdic acid (PMA) and/or ninhydrin
both in ethanol stain. THF was freshly distilled from sodium-ben-
zophenone ketyl radical under argon atmosphere immediately
prior to use, CH2Cl2 was distilled after drying over anhydrous
CaH2 and stored over 4 Å molecular sieves. Flash column chroma-
tography was performed on silica gel (200–300 mesh). NMR
All prolinamides 1–10 were synthesized starting from N-Boc-
proline, under dry Ar atmosphere, to stirred solution of
N-Boc- -proline (215 mg, 1 mmol, 1 equiv), DMAP (42 mg,
L-
a
L
0.3 equiv), EDCI (244 mg, 1.1 equiv), and cycloalkyl amine
(0.8 equiv) dissolved in dichloromethane (10 ml). The resulting
mixture was stirred at room temperature for 2 days. Then the mix-
ture was concentrated to half of the volume in vacuo and the
resulting mixture was partitioned between EtOAc (100 ml) and
0.5 M aqueous HCl (50 ml). The organic layer was washed with
half-saturated brine (25 ml), dried (Na2SO4), filtered, and

846
J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
Table 7
The recycling and reuse of catalyst 6a
O
O
OH
CHO
NO2
Catalyst 6 (5 mol%)
AcOH (5 mol%)
m-xylene, -20 °C
NO2
Run
Time (h)
Yieldb (%)
anti/sync
eed (%) anti (syn)
1
2
3
4
5
16
16
24
24
48
98
95
91
89
80
98:2
96:4
94:6
93:7
91:9
98 (81)
97 (81)
97 (82)
95 (80)
93 (79)
a
b
c
The reaction was performed with p-nitrobenzaldehyde (10 mmol), cyclohexanone (4 equiv), catalyst 6 (0.5 mmol), acetic acid (0.5 mmol) in m-xylene (20.0 ml).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
Determined by chiral HPLC.
d
Table 8
Large-scale asymmetric aldol reactionsa
O
O
OH
O
Catalyst 6 (5 mol%)
R
H
R
AcOH (5 mol%)
m-xylene, -20 °C
11
Entry
1
Product
No.
Time (h)
30
Yieldb (%)
anti/sync
eed (%) anti (syn)
O
OH
11a
95
96:4
97 (86)
NO2
O
O
O
OH NO2
OH
2
3
11b
11c
30
30
96
92
97:3
95:5
98 (72)
96 (65)
NO2
OH
4
5
11f
40
48
89
80
90:10
84:16
95 (72)
95 (48)
Cl
O
OH
11o
a
b
c
The reaction was performed with aromatic aldehyde (150 mmol), cyclohexanone (600 mmol), catalyst 6 (5 mol %), acetic acid (5 mol %) in m-xylene (300.0 ml).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis, major product is anti.
Determined by chiral HPLC.
d
concentrated followed by flash column chromatography (AcOEt/
petroleum ether = 1:3) to give N-Boc- -prolinamide.
Compound 1 is referred to as an example: to a stirred solution of
N-Boc- -proline cyclopropylamine (255 mg, 1 mmol) in dichloro-
methane (10 ml), TFA (4.3 ml) was added and stirred at room
temperature for 5 h. After evaporation of the solvent, the resulting
residue was neutralized with 10% NaOH aqueous solution, and
extracted with EtOAc. The organic layer was dried over Na2SO4, fil-
tered, and concentrated followed by flash column chromatography
on silica gel (MeOH/CHCl3 = 1:10, v/v) to give 1a as a pale yellow oil.
L
L

J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
847
4.2.1. (S)-N-Cyclopropyl-pyrrolidine-2-carboxamide 1
4.2.7. (S)-N-(4-Methylphenyl) pyrrolidine-2-carboxamide 714
Light yellow oil. Yield: 80%; ½a D20
ꢂ
¼ ꢀ66:2 (c 1, CHCl3); FT-IR
Yield 85%, white solid, mp 103–105 °C. ½a D20
¼ ꢀ58:9 (c 0.5,
ꢂ
mmax (neat)/cmꢀ1: 3263.89, 2969.65, 2871.12, 1658.18, 1520.43,
EtOH). FT-IR mmax (neat)/cmꢀ1
: 3414.34, 3349.27, 3232.50,
1265.88, 1182.73, 1099.52, 731.42, 697.50 cmꢀ1
;
1H NMR
3033.46, 2970.55, 2875.73, 1664.87, 1614.68, 1589.47, 1522.12,
(300 MHz, CDCl3): d = 0.43–0.64 (m, 2H), 0.70–0.90 (m, 2H),
1.73–1.87 (m, 2H), 1.86–2.00 (m, 1H), 2.11–2.34 (m, 1H), 2.73
(t, J = 3 Hz, 1H), 2.98–3.21 (m, 2H), 3.94 (dd, J = 8.7, 5.7 Hz, 1H),
8.04 (s, 1H); 13C NMR (75 MHz, CDCl3): d = 5.9, 6.1, 22.2, 25.6,
30.5, 46.8, 60.0, 175.0; ESI-MS+ m/z: calcd for C8H14N2O 155.1184
[M+H]; found 155.1188.
1447.25, 1403.82, 1101.88, 817.80, 511.55, 453.54 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d = 1.97–2.13 (m, 2H), 2.14–2.27 (m, 2H), 2.30
(s, 3H), 2.92–3.04 (m, 1H), 3.04–3.15 (m, 1H), 3.88 (dd, J = 14.1,
8.7 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 9.67
(br s, 1H). 13C NMR (CDCl3, 75 MHz): d = 20.6, 26.0, 30.5, 47.1,
60.7, 119.0, 119.0, 129.2, 129.2, 133.2, 135.1, 172.7; ESI-MS+ m/z:
calcd for C12H16N2O 205.1341 [M+H]; found 205.1346.
4.2.2. (S)-N-Cyclopentyl-pyrrolidine-2-carboxamide 2
Light yellow oil. Yield: 72%; ½a D20
ꢂ
¼ ꢀ53:9 (c 1, CHCl3); FT-IR
4.2.8. (S)-N-(2,4-Dimethylphenyl) pyrrolidine-2-carboxamide 8
mmax (neat)/cmꢀ1: 3251.5, 2957.33, 2872.69, 1668.11, 1567.18,
Yield 78%, white solid, mp 94–96 °C. ½a D20
¼ ꢀ62:8 (c 0.5, EtOH).
ꢂ
1200.84, 1130.41, 831.70, 798.92, 720.43 cmꢀ1
;
1H NMR
FT-IR mmax (neat)/cmꢀ1
: 3414.71, 3337.29, 3245.03, 3085.94,
(300 MHz, CDCl3): d = 1.36–1.50 (m, 2H), 1.52–1.60 (m, 2H),
1.63–1.75 (m, 2H), 1.81–2.01 (m, 5H), 2.20–2.34 (m, 1H), 3.17 (t,
J = 6.15 Hz, 2H), 4.03–4.21 (m, 2H), 8.03 (d, J = 7.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3): d = 23.7, 25.2, 32.7, 46.7, 51.1, 59.9, 171.4;
ESI-MS+ m/z: calcd for C10H18N2O 183.1497 [M+H]; found
183.1497.
3024.61, 2944.96, 2860.62, 1683.19, 1589.45, 1522.90, 1444.84,
1300.49, 1102.17, 909.79, 882.36, 823.64 cmꢀ1 1H NMR (CDCl3,
.
300 MHz): d = 1.69–1.87 (m, 2H), 2.00–2.12 (m, 1H), 2.12 (s, 3H),
2.27 (s, 3H), 2.93–3.05 (m, 1H), 3.06–3.16 (m, 1H), 3.91 (dd,
J = 9.3, 5.4 Hz, 1H), 6.99 (t, J = 8.4 Hz, 2H), 7.93 (d, J = 7.8 Hz, 1H),
9.71 (br s, 1H). 13C NMR (CDCl3, 75 MHz): d = 17.3, 20.6, 26.1,
30.6, 47.2, 61.0, 120.9, 127.0, 127.5, 130.7, 133.0, 133.5, 172.7;
ESI-MS+ m/z: calcd for C13H18N2O 219.1497 [M+H]; found
219.1495.
4.2.3. (S)-N-Cyclohexyl-pyrrolidine-2-carboxamide 3
Light yellow oil. Yield: 71%; ½a D20
¼ ꢀ60:5 (c 1, CHCl3); FT-IR
ꢂ
mmax (neat)/cmꢀ1: 3256.03, 3070.10, 2937.53, 2855.39, 1664.46,
1557.65, 1523.33, 1451.18, 1201.24, 1176.27, 1132.25, 733.74,
4.2.9. (S)-N-(3-Nitrophenyl) pyrrolidine-2-carboxamide 910a
699.76 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d = 1.11–1.27(m, 3H),
Yield 66%, Gummy liquid, ½a D20
ꢂ
¼ ꢀ41:1 (c 0.5, EtOH). FT-IR mmax
1.27–1.44 (m, 1H), 1.55–1.65 (m, 1H), 1.65–1.79 (m, 4H), 2.09–
2.25 (m, 3H), 2.93–3.14 (m, 2H), 3.63–3.77 (m, 2H), 3.85 (dd,
J = 8.7, 5.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d = 24.7, 25.4, 30.7, 32.8, 46.9, 47.7, 60.3, 172.8; ESI-MS+
m/z: calcd for C11H20N2O 197.1654 [M+H]; found 197.1665.
(neat)/cmꢀ1: 1352, 1681, 2874, 2971, 3092, 3258 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d = 1.70–1.85 (m, 2H), 1.98–2.11 (m, 1H),
2.16–2.32 (m, 2H), 2.95–3.06 (m, 1H), 3.06–3.17 (m, 1H), 3.38 (br
s, 1H), 3.91 (dd, J = 9.3, 5.1 Hz), 7.48 (t, J = 8.1 Hz, 1H), 7.93 (d,
J = 7.8 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 8.45 (s, 1H), 10.20 (br s,
1H). 13C NMR (CDCl3, 75 MHz): d = 26.1, 30.5, 47.1, 60.7, 113.7,
118.1, 124.7, 129.5, 138.7, 148.3, 173.9; ESI-MS+ m/z: calcd for
4.2.4. (S)-N-Cycloheptyl-pyrrolidine-2-carboxamide 4
Light yellow oil. Yield: 68%; ½a D20
ꢂ
¼ ꢀ45:6 (c 1, CHCl3); FT-IR
C11H13N3O3 236.1035 [M+H]; found 236.1035.
mmax (neat)/cmꢀ1: 3418.01, 3254.27, 3074.07, 2929.91, 2858.93,
1664.58, 1557.74, 1459.27, 1200.98, 1132.43, 701.77 cmꢀ1
;
1H
4.2.10. (S)-N-n-Hexyl-pyrrolidine-2-carboxamide 10
NMR (300 MHz, CDCl3): d = 1.39–1.68 (m, 11H), 1.75–1.89 (m,
2H), 1.93–2.07 (m, 3H), 2.32–2.52 (m, 1H), 3.31–3.46 (m, 2H),
3.84 (dd, J = 9.0, 5.4 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d = 24.0, 24.9, 27.9, 31.2, 34.4, 34.6, 38.1, 46.7,
51.4, 59.6, 170.7; ESI-MS+ m/z: calcd for C12H22N2O 211.1810
[M+H]; found 211.1811.
Light yellow oil. Yield: 70%; ½a D20
¼ ꢀ48:6 (c 1, CHCl3); FT-IR
ꢂ
mmax (neat)/cmꢀ1: 3312.34, 3065.68, 2957.45, 2928.14, 2857.83,
1658.13, 1523.91, 1462.12, 1245.87, 1103.97, 731.94 cmꢀ1 1H
;
NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3H), 1.24–1.35 (m,
8H), 1.65–1.76 (m, 2H), 1.84–1.98 (m, 1H), 2.07–2.22 (m, 1H),
2.83–2.95 (m, 1H), 2.97–3.07 (m,1H), 3.22 (dd, J = 6.6, 6.9 Hz,
2H), 3.75 (dd, J = 8.4, 3.6 Hz, 1H); 7.70 (br s, 1H). 13C NMR
(75 MHz, CDCl3): d = 13.6, 22.2, 25.8, 26.2, 29.2, 30.4, 31.1, 38.5,
46.9, 60.2, 174.4; ESI-MS+ m/z: calcd for C11H22N2O 199.1810
[M+H]; found 199.1801.
4.2.5. (S)-N-Cyclooctyl-pyrrolidine-2-carboxamide 5
Light yellow oil. Yield: 68%; ½a D20
¼ ꢀ48:3 (c 1, CHCl3); FT-IR
ꢂ
mmax (neat)/cmꢀ1: 3254.25, 3072.09, 2923.47, 2855.61, 1561.35,
;
1200.86, 1176.73, 1131.33, 701.36 cmꢀ1 1H NMR (300 MHz,
CDCl3): d = 1.38–1.69 (m, 13H), 1.71–1.81 (m, 2H), 1.83–1.99 (m,
3H), 2.20–2.39 (m, 1H), 3.22 (t, J = 6.6 Hz, 2H), 3.82–3.99 (m, 1H),
4.16 (dd, J = 7.8, 5.7 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d = 23.6, 25.3, 27.0, 30.5, 31.7, 46.6, 49.7, 59.8,
169.9; ESI-MS+ m/z: calcd for C13H24N2O 225.1967 [M+H]; found
225.1963.
4.3. General procedure for the preparation of aldol products
A mixture of catalyst (0.025 mmol), ketone (2 mmol) and AcOH
(0.025 mmol) contained in 1.0 ml of m-xylene was stirred at room
temp for 10 min. Subsequently, the temperature was brought
down to ꢀ20 °C and the aldehyde (0.5 mmol) was introduced.
The reaction mixture was stirred at ꢀ20 °C until the reaction was
judged to be complete based on TLC analysis. The reaction was
quenched by adding saturated NH4Cl solution, and the organic
material was extracted with ethyl acetate (2 ꢁ 20 ml). The
combined organic extract was dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by silica gel column chro-
matography to give the pure aldol adduct.
The product after SiO2 chromatography was analyzed by HPLC
to determine the enantiomeric as well as the diastereomeric ratios;
the latter matched, within allowable limits, the values determined
by 1H NMR analysis. The syn- and anti-diastereomers of the aldols
were readily distinguished in 1H NMR spectroscopy by the
4.2.6. (S)-N-Phenyl-pyrrolidine-2-carboxamide 613
Yield 83%, white solid, mp 72–73 °C. ½a D20
¼ ꢀ44:2 (c 0.5, EtOH).
ꢂ
FT-IR mmax (neat)/cmꢀ1
: 3415.25, 3351.91, 3227.05, 3033.46,
2966.20, 2870.75, 1667.81, 1617.59, 1600.70, 1520.32, 1441.05,
1080.12, 755.37, 691.00 cmꢀ1 1H NMR (CDCl3, 300 MHz):
.
d = 1.69–1.84 (m, 2H), 1.99–2.10 (m, 1H), 2.16–2.26 (m, 1H), 2.96–
3.03 (m, 1H), 3.05–3.14 (m, 1H), 3.89 (dd, J = 12.3, 8.4 Hz, 1H), 7.09
(t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H),
9.74 (br s, 1H). 13C NMR (CDCl3, 75 MHz): d = 26.0, 30.5, 47.1, 60.7,
119.0, 119.0, 123.7, 128.7, 128.7, 137.6, 173.0; ESI-MS+ m/z: calcd
for C11H14N2O 191.1184 [M+H]; found 191.1184.

848
J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
diagnostic chemical shifts of –CHOH– proton, cf. SI for the chemical
shift data.
(300 MHz, CDCl3): d = 8.21 (d, 2H, J = 8.7 Hz), 7.51 (d, 2H,
J = 8.7 Hz), 4.90 (dd, 1H, J = 8.4, 3.0 Hz), 4.09 (d, 1H, J = 3.0 Hz),
2.65–2.45 (m, 2H), 2.36 (td, 1H, J = 13.2, 5.7 Hz), 2.17–2.06 (m,
1H), 1.87–1.78 (m, 1H), 1.67–1.51 (m, 3H), 1.45–1.31 (m, 1H).
4.4. Procedure for catalyst recovery
To a mixture of catalyst 6 (0.0951 g, 0.5 mmol) with equivalent
AcOH (0.5 mmol), m-xylene (20 ml) and cyclohexanone (40 mmol)
were added 4-nitrobenzaldehyde (1.5120 g, 10 mmol). The mix-
ture was stirred at ꢀ20 °C as specified in Table 7. The reaction mix-
ture was quenched with aqueous HCl (0.5 mmol, 6 mol/l) and then
diluted with diethyl ether (25 ml) and the reaction mixture was
vigorously stirred for 5 min. The reaction mixture was placed in
an ethanol bath (ꢀ20 °C) for 30 min. The organic layer was concen-
trated in vacuo to afford the crude aldol product, which was puri-
fied by column chromatography. Catalyst 6 existed in the acidic
aqueous layer, which was adjusted to pH 8 with NaOH aqueous,
and the aqueous layer was extracted with m-xylene (20 ml). The
reaction mixture was placed in an ethanol bath (ꢀ20 °C) for
30 min. The organic layer was directly poured out, dried over
Na2SO4, and used directly in subsequent reaction cycles without
adding any new catalyst or m-xylene. In each reuse, the same
amounts of substrates were used.
4.5.4. (2S,10R)-2-(Hydroxy-(4-cyanophenyl) methyl)
cyclohexan-1-one 11d
Yield 99%, anti/syn = 92:8, enantiomeric excess: 96% of anti-
isomer and 31% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 5:95, flow rate 0.5 ml/min, 20 °C,
k = 254 nm; tR = 35.3 min (anti, major), tR = 28.7 min (anti, minor);
tR = 25.8 min (syn, major), tR = 23.0 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.65 (d, 2H, J = 8.1 Hz), 7.45 (d, 2H,
J = 8.1 Hz), 4.85 (dd, 1H, J = 8.1, 3.0 Hz), 4.11 (d, 1H, J = 3.0 Hz),
2.65–2.44 (m, 2H), 2.37 (td, 1H, J = 12.9, 6.0 Hz), 2.17–2.06 (m,
1H), 1.88–1.77 (m, 1H), 1.72–1.47 (m, 3H), 1.44–1.31 (m, 1H).
4.5.5. (2S,10R)-2-(Hydroxy-(4-bromophenyl) methyl)
cyclohexan-1-one 11e
Yield 96%, anti/syn = 93:7, enantiomeric excess: 96% of anti-
isomer and 87% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 10:90; flow rate 0.5 ml/min, 20 °C,
k = 221 nm; tR = 43.3 min (anti, major), tR = 36.4 min (anti, minor);
tR = 26.7 min (syn, major), tR = 22.8 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.47 (d, 2H, J = 8.1 Hz), 7.20 (d, 2H,
J = 8.7 Hz), 4.75 (dd, 1H, J = 8.7, 2.7 Hz), 3.99 (d, 1H, J = 3.0 Hz),
2.61–2.44 (m, 2H), 2.35 (td, 1H, J = 12.9, 6.3 Hz), 2.15–2.04 (m,
1H), 1.85–1.75 (m, 1H), 1.70–1.50 (m, 3H), 1.37–1.20 (m, 1H).
4.5. General procedure for large-scale aldol reactions
To a mixture of catalyst 6 (7.5 mmol) with equivalent AcOH
(7.5 mmol), m-xylene (300 ml) and ketone (600 mmol) were added
aromatic aldehyde (150 mmol) using a 500 ml round-bottomed
flask. The resulting mixture was stirred at room temperature. The
reaction was monitored by TLC. It was then quenched with 50 ml
saturated NH4Cl solution, extracted with EtOAc (3 ꢁ 100 ml), and
dried over Na2SO4. Purification by flash chromatography afforded
the corresponding pure products.
4.5.6. (2S,10R)-2-(Hydroxy-(4-chlorophenyl) methyl)
cyclohexan-1-one 11f
Yield 96%, anti/syn = 91:9, enantiomeric excess: 96% of anti-
isomer and 78% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 10:90; flow rate 0.5 ml/min, 20 °C,
k = 221 nm; tR = 41.8 min (anti, major), tR = 35.7 min (anti, minor);
tR = 27.4 min (syn, major), tR = 23.1 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.29 (dd, 4H, J = 20.4, 8.4 Hz), 4.76 (dd, 1H,
J = 8.7, 2.7 Hz), 3.99 (d, 1H, J = 3.0 Hz), 2.61–2.44 (m, 2H), 2.35
(td, 1H, J = 12.9, 5.4 Hz), 2.15–2.05 (m, 1H), 1.85–1.75 (m, 1H),
1.70–1.50 (m, 3H), 1.37–1.20 (m, 1H).
4.5.1. (2S,10R)-2-(Hydroxy-(4-nitrophenyl) methyl) cyclohexan-
1-one 11a
Yield 98%, anti/syn = 98:2, enantiomeric excess: 98% of anti-
isomer and 81% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 20:80; flow rate 0.5 ml/min, 20 °C,
k = 254 nm; tR = 43.3 min (anti, major), tR = 34.0 min (anti, minor);
tR = 30.8 min (syn, major), tR = 28.9 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 8.21 (d, 2H, J = 8.7 Hz), 7.51 (d, 2H,
J = 8.7 Hz), 4.90 (dd, 1H, J = 8.4, 3.0 Hz), 4.09 (d, 1H, J = 3.0 Hz),
2.65–2.45 (m, 2H), 2.36 (td, 1H, J = 13.2, 5.7 Hz), 2.17–2.06
(m,1H), 1.87–1.78 (m, 1H), 1.67–1.51 (m,3H), 1.45–1.31 (m, 1H).
4.5.7. (2S,10R)-2-(Hydroxyl (3-chlorophenyl) methyl)
cyclohexan-1-one 11g
Yield 94%, anti/syn = 98:2, enantiomeric excess: 96% of anti-
isomer and 67% syn-isomer determined by HPLC (Daicel Chiralpak
OD-H column; i-PrOH/hexane = 4:96; flow rate 1.0 ml/min, 20 °C,
k = 221 nm; tR = 14.8 min (anti, major), tR = 21.2 min (anti, minor);
tR = 12.3 min (syn, major), tR = 11.4 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 1.31–2.08 (m, 6H), 2.30–2.45 (m, 3H), 4.80
(d, J = 8.8 Hz, 1H), 7.20–7.29 (m, 3H, Ar), 7.37 (s, 1H, Ar).
4.5.2. (2S,10R)-2-(Hydroxy-(2-nitrophenyl) methyl) cyclohexan-
1-one 11b
Yield 99%, anti/syn = 98:2, enantiomeric excess: 99% of anti-
isomer and 72% syn-isomer determined by HPLC (Daicel Chiralpak
OD-H column; i-PrOH/hexane = 5:95; flow rate 0.5 ml/min, 20 °C,
k = 254 nm; tR = 40.1 min (anti, major), tR = 50.0 min (anti, minor);
tR = 33.5 min (syn, major), tR = 31.6 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.84 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H,
J = 7.8 Hz), 7.63 (t, 1H, J = 7.5 Hz), 7.43 (t, 1H, J = 7.8 Hz), 5.45 (d,
1H, J = 6.6 Hz), 3.90 (br, 1H), 2.82–2.70 (m, 1H), 2.50–2.40 (m,
1H), 2.34 (td, 1H, J = 12.3, 5.7 Hz), 2.15–2.06 (m, 1H), 1.90–1.55
(m, 4H).
4.5.8. (2S,10R)-2-(Hydroxy-(2-chlorophenyl) methyl)
cyclohexan-1-one 11h
Yield 94%, anti/syn = 98:2, enantiomeric excess: 97% of anti-
isomer and 45% syn-isomer determined by HPLC (Daicel Chiralpak
OD-H column; i-PrOH/hexane = 5:95; flow rate 1.0 ml/min, 20 °C,
k = 221 nm; tR = 12.3 min (anti, major), tR = 16.5 min (anti, minor);
tR = 5.4 min (syn, major), tR = 4.1 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.56 (d, 1H, J = 8.4 Hz,) 7.20–7.34 (m, 3H),
5.35 (d, 1H, J = 8.0 Hz), 2.65–2.71 (m, 1H), 3.88 (s, 1H), 2.46–2.49
(m, 1H), 2.31–2.39 (m, 1H), 2.05–2.13 (m, 1H), 1.53–1.84 (m, 5H).
4.5.3. (2S,10R)-2-(Hydroxy-(3-nitrophenyl) methyl) cyclohexan-
1-one 11c
Yield 95%, anti/syn = 97:3, enantiomeric excess: 98% of anti-
isomer and 66% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 10:90; flow rate 1.0 ml/min, 20 °C,
k = 254 nm; tR = 49.6 min (anti, major), tR = 63.1 min (anti, minor);
tR = 43.1 min (syn, major), tR = 40.0 min (syn, minor)). 1H NMR
4.5.9. (2S,10R)-2-(Hydroxy-(4-fluor-phenyl) methyl)
cyclohex-an-1-one 11i
Yield 92%, anti/syn = 91:9, enantiomeric excess: 97% of anti-
isomer and 53% syn-isomer determined by HPLC (Daicel Chiralpak

J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
849
AD-H column; i-PrOH/hexane = 5:95; flow rate 1.0 ml/min, 20 °C,
k = 221 nm; tR = 28.5 min (anti, major), tR = 25.0 min (anti, minor);
tR = 17.9 min (syn, major), tR = 14.7 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.26–7.32 (m, 2H), 7.00–7.07 (m, 2H), 4.77
(d, J = 8.8 Hz, 1H), 3.99 (br, 1H), 2.45–2.56 (m, 2H), 2.34–2.48 (m,
1H), 2.06–2.11 (m, 1H), 1.77–1.82 (m, 1H), 1.51–1.68 (m, 3H),
1.25–1.30 (m, 1H).
4.5.15. (2S,10R)-2-(Hydroxy-(phenyl) methyl) cyclohexan-1-one
11o
Yield 86%, anti/syn = 87:13, enantiomeric excess: 97% of anti-
isomer and 45.5% syn-isomer determined by HPLC (Daicel Chir-
alpak OD-H column; i-PrOH/hexane = 10:90; flow rate 0.5 ml/
min, 20 °C, k = 221 nm; tR = 19.2 min (anti, major), tR = 31.0 min
(anti, minor); tR = 15.2 min (syn, major), tR = 14.2 min (syn, minor)).
1H NMR (300 MHz, CDCl3): d = 7.39–7.28 (5H, m), 4.80 (d, 1H,
J = 9.0 Hz), 4.00 (m, 1H), 2.70–2.56 (m, 1H), 2.55–2.44 (m, 1H),
2.34 (td, 1H, J = 12.3, 5.4 Hz), 2.16–2.03 (m, 1H), 1.87–1.73 (m,
1H), 1.72–1.50 (m, 3H), 1.40–1.22 (m, 1H).
4.5.10. (2S,10R)-2-(Hydroxy-(4-tolyl) methyl) cyclohexan-1-one
11j
Yield 74%, anti/syn = 89:11, enantiomeric excess: 99% of anti-
isomer and 87% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 10:90; flow rate 0.5 ml/min, 20 °C,
k = 221 nm; tR = 33.4 min (anti, major), tR = 45.1 min (anti, minor);
tR = 22.1 min (syn, major), tR = 19.2 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.18 (dd, 4H, J = 17.1, 8.4 Hz), 4.75 (dd, 1H,
J = 9.0, 2.7 Hz), 3.91 (d, 1H, J = 2.7 Hz), 2.66–2.54 (m, 1H), 2.51–
2.43 (m, 1H), 2.35 (td, 1H, J = 13.2, 6.0 Hz), 2.34 (s, 3H), 2.14–2.03
(m, 1H), 1.82–1.72 (m, 1H), 1.70–1.50 (m, 3H), 1.38–1.18 (m, 1H).
4.5.16. (2S,10R)-2-(Hydroxy-(thiophen-2-yl) methyl)
cyclohexan-1-one 11p
Yield 88%, anti/syn = 84:16, enantiomeric excess: 92% of
anti-isomer and 86.5% syn-isomer determined by HPLC (Daicel
Chiralpak AD-H column; i-PrOH/hexane = 10:90; flow rate 1.0 ml/
min, 20 °C, k = 254 nm; tR = 17.2 min (anti, major), tR = 19.0 min
(anti, minor); tR = 14.3 min (syn, major), tR = 13.0 min (syn, minor)).
1H NMR (300 MHz, CDCl3): d = 7.3 (m, 1H, Ar), 6.93–6.96 (m, 2H,
Ar), 5.09 (d, J = 8.2 Hz, 1H, CH), 4.11 (s, 1H, OH), 2.33–2.70
(m, 3H), 2.10–2.13 (m, 1H), 1.63–1.86 (m, 4H), 1.34–1.40 (m, 1H).
4.5.11. (2S,10R)-2-(Hydroxy-(4-methoxy-phenyl) methyl) cyclo-
hexan-1-one 11k
Yield 70%, anti/syn = 90:10, enantiomeric excess: 98% of anti-
isomer and 53.5% syn-isomer determined by HPLC (Daicel Chir-
alpak AD-H column; i-PrOH/hexane = 10:90; flow rate 0.8 ml/
min, 20 °C, k = 221 nm; tR = 34.2 min (anti, major), tR = 32.6 min
(anti, minor); tR = 22.5 min (syn, major), tR = 19.8 min (syn, minor)).
1H NMR (300 MHz, CDCl3): d = 7.27 (dd, J = 13.2, 8.4 Hz, 3H), 6.90
(d, J = 8.8 Hz, 3H), 4.76 (d, J = 7.6 Hz, 1H), 3.94 (s, 1H), 3.83 (s,
3H), 2.34–2.65 (m, 3H), 2.08–2.14 (m, 1H), 1.55–1.82 (m, 6H),
1.20–1.40 (m, 2H).
4.5.17. ((2S,4S)-2-((R)-Hydroxy (4-nitrophenyl) methyl)-4-meth-
ylcyclohexan-1-one 11q
Yield 99%, anti/syn = 99:1, enantiomeric excess: 97% of anti-iso-
mer and 42% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 10:90; flow rate 1.0 ml/min, 20 °C,
k = 254 nm; tR = 37.6 min (anti, major), tR = 43.0 min (anti, minor);
tR = 23.9 min (syn, major), tR = 20.1 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 8.18–8.23 (m, 2H), 7.47–7.52 (m, 2H), 4.92
(d, 1H, J = 8.6 Hz), 3.82 (br, 1H), 2.72–2.78 (m, 1H), 2.48–2.50 (m,
1H), 2.36–2.43 (m, 1H), 2.07–2.09 (m, 1H), 1.89–1.93 (m, 1H),1.78–
1.81 (m, 1H), 1.54–1.60 (m, 1H), 1.33 (m, 1H), 1.05 (d, J = 6.9 Hz, 3H).
4.5.12. (2S,10R)-2-(Hydroxy-(3-methoxy-phenyl) methyl) cyclo-
hexan-1-one 11l
Yield 78%, anti/syn = 90:10, enantiomeric excess: 97% of anti-
isomer and 88% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 10:90; flow rate 0.5 ml/min, 20 °C,
k = 221 nm; tR = 55.8 min (anti, major), tR = 51.0 min (anti, minor);
tR = 34.7 min (syn, major), tR = 31.5 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.28–7.33 (m, 1H), 6.80–7.00 (m, 3H), 4.80
(d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 2.30–2.75 (m, 3H), 2.00–2.15 (m,
1H), 1.55–1.90 (m, 4H), 1.20–1.40 (m, 1H).
4.5.18. (2S,10R)-2-((R)-Hydroxy (4-nitrophenyl) methyl)
cycloheptan-1-one 11r
Yield 84%, anti/syn = 96:4, enantiomeric excess: 95% of anti-iso-
mer and 58% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 10:90; flow rate 1.0 ml/min,
20 °C, k = 254 nm; tR = 46.5 min (anti, major), tR = 19.7 min (anti,
minor); tR = 15.9 min (syn, major), tR = 13.0 min (syn, minor)). 1H
NMR (CDCl3, 300 MHz) d = 8.21 (d, J = 8.8 Hz, 2H, Ar), 7.53 (d,
J = 8.8 Hz, 2H, Ar), 5.30 (br s, 1H), 4.93 (dd, J = 7.4, 4.7 Hz, 1H),
3.83 (d, J = 4.9 Hz, 1H), 3.70 (d, J = 3.0 Hz, 1H), 2.99 (ddd, J = 10.5,
7.5, 3.3 Hz, 1H), 2.87 (td, J = 10.5, 2.9 Hz, 1H), 2.70–2.39 (m, 2H),
2.00–1.15 (m, 8H).
4.5.13. (2S,10R)-2-(Hydroxy-(2-naphthyl) methyl) cyclohexan-1-
one 11m
Yield 83%, anti/syn = 92:8, enantiomeric excess: 95% of anti-
isomer and 80% syn-isomer determined by HPLC (Daicel Chiralpak
OD-H column; i-PrOH/hexane = 10:90; flow rate 1.0 ml/min, 20 °C,
k = 221 nm; tR = 15.2 min (anti, major), tR = 21.3 min (anti, minor) ;
tR = 11.8 min (syn, major), tR = 12.9 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 7.70–7.90 (m, 4H), 7.40–7.55 (m, 3H), 5.01
(d, J = 8.7 Hz, 1H), 4.10 (s, 1H), 2.71–2.78 (m, 1H), 2.37–2.55 (m,
2H), 2.09–2.14 (m, 1H), 1,52–1.80 (m, 5H), 1.28–1.42 (m, 2H).
4.5.19. (2S,10R)-2-(Hydroxy-(4-nitrophenyl) methyl)-cyclo-
pentan-1-one 11s
Yield 75%, anti/syn = 74:26, enantiomeric excess: 80% of anti-iso-
mer and 47% syn-isomer determined by HPLC (Dicael Chiralpak AD-
H column; i-PrOH/hexane = 5:95; flow rate 1.0 ml/min, 20 °C,
k = 254 nm; tR = 58.6 min (anti, major), tR = 55.4 min (anti, minor));
tR = 30.9 min (syn, major), tR = 43.8 min (syn, minor)). 1H NMR
4.5.14. (2S,10R)-2-(Hydroxy-(1-naphthyl) methyl) cyclohexan-1-
one 11n
(300 MHz, CDCl3):
d 8.21 (d, 2H, J = 8.7 Hz), 7.54 (d, 2H,
J = 9.0 Hz), 4.85 (d, 1H, J = 9.2 Hz), 4.76 (s, 1H), 2.54–2.18 (m, 3H),
2.08–1.95 (m, 1H), 1.81–1.48 (m, 3H).
Yield 85%, anti/syn = 96:4, enantiomeric excess: 93% of anti-iso-
mer and 40% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; i-PrOH/hexane = 5:95; flow rate 1.0 ml/min, 20 °C,
k = 254 nm; tR = 45.8 min (anti, major), tR = 36.9 min (anti, minor);
tR = 20.4 min (syn, major), tR = 17.1 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 8.24–8.27 (m, 1H), 7.84–7.89 (m, 1H),
7.81(d, J = 8.1 Hz, 1H), 7.57 (d, J = 6.3 Hz, 1H), 7.45–7.53 (m, 3H),
5.58 (dd, J = 8.7, 2.9 Hz, 1H), 4.15 (d, J = 2.9 Hz, 1H), 2.95–3.04 (m,
1H), 2.49–2.54 (m, 1H), 2.35–2.45 (m, 1H), 2.05–2.12 (m, 1H),
1.61–1.74 (m, 2H), 1.33–1.51 (m, 3H).
4.5.20. (4R)-Hydroxy-4-(4-nitrophenyl) butan-2-one 11t
Yield 71%; enantiomeric excess: 90% determined by HPLC (Dai-
cel Chiralpak OJ-H column; i-PrOH/hexane = 10:90; flow rate
1.0 ml/min, 20 °C, k = 254 nm; tR = 37.1 min (R-isomer, major),
tR = 31.8 min (S-isomer, minor)). 1H NMR (300 MHz, CDCl3):
d = 8.20 (d, 2H, J = 8.7 Hz), 7.54 (d, 2H, J = 8.7 Hz), 5.27 (t, 1H,
J = 6.0 Hz), 3.67 (s, 1H), 2.86 (d, 2H, J = 6.6 Hz), 2.22 (s, 3H).

850
J. Xu et al. / Tetrahedron: Asymmetry 22 (2011) 840–850
Chem., Int. Ed. 2006, 45, 7506–7525; (k) List, B. Chem. Commun. 2006, 8, 819–
824; (l) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471–5569; (m) Guillena, G.; Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry
2007, 18, 2249–2293; (n) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry
2009, 20, 131–173.
4.5.21. (4R)-4-(2-Chlorophenyl)-4-hydroxybutan-2-one 11u
Yield 80%; enantiomeric excess: 94% determined by HPLC (Dai-
cel Chiralpak AD-H column; iPrOH/hexane = 5:95; flow rate
1.0 ml/min, 20 °C, k = 262 nm; tR = 14.7 min (R-isomer, major),
tR = 12.6 min (S-isomer, minor)). 1H NMR (300 MHz, CDCl3):
d = 7.64 (dd, J = 7.6, 1.6 Hz, 1H, ArH), 7.19–7.34 (m, 3H, ArH), 5.56
(m, 1H), 3.61 (br, 1H), 2.64–3.03 (m, 2H), 2.22 (s, 3H) ppm.
5. Movassaghi, M.; Jacobsen, E. N. Science 2006, 298, 1904–1905.
6. Dalko, P. L.; Moisan, L. Angew. Chem. 2004, 116, 5248–5286. Angew. Chem., Int.
Ed. 2004, 43, 5138–5175.
7. (a) Li, C. J. Chem. Rev. 2005, 105, 3095–3165; (b) Palomo, C.; Oiarbide, M.; Garca,
J. M. Chem. Soc. Rev. 2004, 33, 65–75; (c) Alcaide, B.; Almendros, P. Angew. Chem.
2003, 115, 884–886. Angew. Chem., Int. Ed. 2003, 42, 858–860.
8. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–
2396; (b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387; (c)
Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125,
2475–2479; (d) List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. USA
2004, 101, 5839–5842.
4.5.22. (3R,4S)-3, 4-Dihydroxy-4-(4-nitrophenyl) butan-2-one
11v
Yield 88%; anti/syn = 85:15, enantiomeric excess: 88% of anti-
isomer and 45% syn-isomer determined by HPLC (Daicel Chiralpak
AD-H column; iPrOH/hexane = 20:80; flow rate 0.8 ml/min, 20 °C,
k = 254 nm; tR = 14.9 min (anti, major), tR = 14.3 min (anti, minor);
tR = 15.9 min (syn, major), tR = 17.8 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d = 8.27 (d, J = 8.8 Hz, 2H, ArH), 7.63 (d,
J = 8.8 Hz, 2H, ArH), 5.20–5.22 (m, 1H), 4.40–4.42 (m, 1H), 3.71
(d, J = 4.6 Hz, 1H), 2.68 (d, J = 8.1 Hz, 1H), 2.36–2.43 (m, 1H), 2.36
(s, 3H) ppm.
9. (a) Chen, J. R.; Liu, X. P.; Zhu, X. Y.; Li, L.; Qiao, Y. F.; Zhang, J. M.; Xiao, W. J.
Tetrahedron 2007, 63, 10437–10444; (b) Huang, W. P.; Chen, J. R.; Li, X. Y.; Cao,
Y. J.; Xiao, W. J. Can. J. Chem. 2007, 85, 208–213; (c) Guizzetti, S.; Benaglia, M.;
Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247–1250; (d) Guillena, G.;
Nájera, C.; Viózquez, S. F. Synlett 2008, 3031–3035; (e) Guillena, G.; Hita, M. d.
C.; Nájera, C.; Vióquez, S. F. J. Org. Chem. 2008, 73, 5933–5943; (f) Guo, H. M.;
Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Chem. Commun. 2005, 11, 1450–
1452; (g) Wang, C.; Jiang, Y.; Zhang, X. X.; Huang, Y.; Li, B. G.; Zhang, G. L.
Tetrahedron Lett. 2007, 48, 4281–4285; (h) Zhao, J. P.; He, L.; Jiang, J.; Tang, Z.;
Cun, L. F.; Gong, L. Z. Tetrahedron Lett. 2008, 49, 3372–3375; (i) Vishnumaya, M.
R.; Singh, V. K. J. Org. Chem. 2009, 74, 4289–4297; (j) Krattiger, P.; Kovasy, R.;
Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101–1103; (k) Dziezic,
P.; Zou, W.; Háfren, J.; Córdova, A. Org. Biomol. Chem. 2006, 4, 38–40; (l) Chen,
F.; Huang, S.; Zhang, H.; Liu, F.; Peng, Y. Tetrahedron 2008, 64, 9585–9591.
10. (a) Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 5, 739–748; (b) Chimni, S. S.;
Singh, S.; Mahajan, D. Tetrahedron: Asymmetry 2008, 19, 2276–2284; (c)
Sathapornvajana, S.; Vilaivan, T. Tetrahedron 2007, 63, 10253–10259; (d) Zeror,
S.; Collin, J.; Fiaud, J. C.; Zouioueche, L. A. Tetrahedron: Asymmetry 2010, 21,
1211–1215; (e) Lu, Z.; Mei, H.; Han, J.; Pan, Y. Chem. Biol. Drug Des. 2010, 76,
181–186; (f) Mitsui, K.; Hyatt, S. A.; Turner, D. A.; Hadad, C. M.; Parquette, J. R.
Chem. Commun. 2009, 22, 3261–3263; (g) Chimni, S. S.; Mahajan, D.
Tetrahedron: Asymmetry 2006, 17, 2108–2119; (h) Arriba, A. L. F. d.; Simón,
L.; Raposo, C.; Alcázar, V.; Sanz, F.; Muniza, F. M.; Morán, J. R. Org. Biomol. Chem.
2010, 8, 2979–2985; (i) Mitsui, K.; PaRquette, J. R. Israel J. Chem. 2009, 9, 119–
127; (j) Sato, K.; Kuriyama, M.; Shimazawa, R.; Morimoto, T.; Kakiuchi, K.;
Shirai, R. Tetrahedron Lett. 2008, 49, 2402–2406; (k) He, L.; Tang, Z.; Cun, L. F.;
Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. Tetrahedron 2006, 62, 346–351; (l) Huang, X. Y.;
Wang, H. J.; Shi, J. J. Phys. Chem. A 2010, 114, 1068–1081.
Acknowledgment
Authors are grateful to the Southwest University of China for
financial support.
References
1. (a)Books on Organocatalysis: Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Berkessel, A., Gröger, H.,
Eds.; Wiley-VCH: Weinheim, 2005; (b)Enantioselective Organocatalysis:
Reactions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH:
Weinheim, 2007.
2. (a) Tian, S. K.; Chen, Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem.
Res. 2004, 37, 621–631; (b) Adv. Synth. Catal. 2004, 346, 1007–1012.; (c)
Tetrahedron 2006, 62, 243–250.; (d) List, B. Chem. Rev. 2007, 107, 5413–5415.
3. For recent reviews, see: (a) Enders, D.; Grondal, C.; Hüttl, R. M. Angew. Chem.,
Int. Ed. 2007, 46, 1570–1581; (b) Pellissier, H. Tetrahedron 2007, 63, 9267–
9331; (c) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660; (d)
MacMillan, D. W. C. Nature 2008, 455, 304–308.
4. (a) Gröger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529–532; (b) List, B.
Synlett 2001, 1675–1686; (c) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298,
1904–1905; (d) List, B. Tetrahedron 2002, 58, 5573–5590; (e) List, B. Acc. Chem.
Res. 2004, 37, 548–557; (f) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37,
570–579; (g) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580–
591; (h) Kazmaier, U. Angew. Chem., Int. Ed. 2005, 44, 2186–2188; (i) Limbach,
M. Chem. Biodivers. 2005, 2, 825–836; (j) Schetter, B.; Mahrwald, R. Angew.
11. (a) Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc.
Natl. Acad. Sci. USA 2004, 101, 5755–5760; (b) Tang, Z.; Yang, Z. H.; Chen, X. H.;
Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. J. Am. Chem. Soc. 2005, 127, 9285–
9289.
12. Yang, Y.; He, Y. H.; Guan, Z.; Huang, W. D. Adv. Synth. Catal. 2010, 352, 2579–
2587.
13. (a) Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5755–5760.
14. Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. PNAS 2004,
101, 5755–5760.