Highly diastereo- and enantioselective direct aldol reaction under solvent-free conditions

Article abstract of DOI:10.1016/j.tetasy.2013.02.013

An efficient, solvent-free protocol for the asymmetric aldol reaction between aldehydes and ketones using prolinamides 1-4 as organocatalysts is reported. Catalysts 2-4, in the presence of TFA (the ratio of catalyst and TFA = 1/1.5), proved to be excellen

Full text of DOI:10.1016/j.tetasy.2013.02.013

Tetrahedron: Asymmetry 24 (2013) 380–388
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly diastereo- and enantioselective direct aldol reaction under
solvent-free conditions
⇑
Furen Zhang, Chunmei Li, Chenze Qi
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 December 2012
Accepted 25 February 2013
An efficient, solvent-free protocol for the asymmetric aldol reaction between aldehydes and ketones
using prolinamides 1–4 as organocatalysts is reported. Catalysts 2–4, in the presence of TFA (the ratio
of catalyst and TFA = 1/1.5), proved to be excellent catalysts, giving the aldol products between aromatic
aldehydes and ketones with nearly perfect diastereo- and enantioselectivities (up to >99:1 dr and >99%
ee). This catalytic system can also be applied in the cross-aldol reaction of isatin with ketones and the
Michael reaction between cyclohexane and nitroalkenes. A mechanism is proposed to account for the for-
mation of the major enantiomer in this reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
requirements being a serious shortcoming for the general applica-
tion of this procedure. Therefore, developing more efficient and
Asymmetric organocatalysis has become a major, intensively
active field in organic synthesis, providing operationally simple,
economic, and environmentally friendly strategies to prepare
chiral adducts.1 Over the past few decades, a wide range of organ-
ocatalysis has been used in various reactions including organocat-
alyzed cycloaddition reactions, desymmetrization reactions, and
total synthesis.2 On the other hand, the necessity to further en-
hance the ‘green’ alignment of organocatalysts has led to a growing
interest in the development of this reaction in aqueous media and
under solvent-free conditions.3 The use of solvent-free conditions
to carry out organic transformations usually leads to shorter reac-
tion times, simpler reactors, and results in simpler and more effi-
cient work-up procedures. As a result, organocatalyzed processes
under solvent-free conditions have gained popularity in green
chemistry.
greener conditions for asymmetric aldol reactions has attracted a
great deal of attention.15
In the context of our interest in the design and development of
useful tactics and strategies for the synthesis of enantioenriched
compounds,16 herein, we design and synthesize several new proli-
namide organocatalysts 1–4 (Fig. 1) that exhibit excellent
H
N
H
N
N
N
O
S
O
O
O
O
NH
NH
H
N
H
N
O
O
The aldol reaction is one of the most powerful strategies in the
stereocontrolled preparation of small optically active molecules,
since it allows the formation of new C–C bonds.4 Since Hajos and
Parrish described the first organocatalyzed aldol reaction using
1
2
O
O
O
S
N
-proline as the catalyst5 and the pioneering work by List et al. pub-
N
L
lished in 2000,6 numerous proline-derived organocatalysts such as
prolinamindes,7–10 prolinethioamides,11 sulfonamides,12 chiral
amines13 and organic salts14 have been designed for direct aldol
reactions. Meanwhile, in order to obtain high yields and stereose-
lectivities, the use of a large excess of nucleophile, long reaction
times, high catalyst loadings (ꢀ30 mol %) and unfriendly solvents
(such as DMF or DMSO) are usually required, with these
O
O
NH
NH
NH
NH
O
O
NH
NH
3
4
⇑
Corresponding author. Tel./fax: +86 575 88345682.
E-mail address: qichenze@usx.edu.cn (C. Qi).
Figure 1. Different organocatalysts.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.02.013

F. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 380–388
381
O
O
O
O
N
N
N
O
COOH
COOH
N
N
N
S
O
NH
NH
NH
NH
O
N
O
Boc
Boc
O
NH
O
S
NH
O
NMM, ClCO2Et, 0oC
NMM, ClCO2Et, 0oC
O
Boc
Boc
NH2
N
NH2
11
6
12
7
TFA, DCM
N
TFA, DCM
ClCO2Et
NMM, -20oC
NH2
NH2
NH2
NH2
ClCO2Et
NMM, -20oC
O
O
N
S
NH
NH
O
O
O
SO2Cl
COCl
NH
NH
H
N
H
N
O
O
COOH
COOH
N
N
1
O
2
O
S
COOH
N
H
Et3N, 0oC-
rt
Et3N, 0oC-
rt
O
O
O
O
5
S
10
N
N
O
O
NH
NH
NH
NH
O
O
ClCO2Et
NH2
NH2
ClCO2Et
NMM, -20oC
NMM, -20oC
NH2
NH2
NH
NH
3
4
TFA, DCM
TFA, DCM
O
O
O
O
O
S
N
O
N
S
N
O
N
O
COOH
N
COOH
N
O
O
O
Boc
NH
NH
N
H
Boc
NH
NMM, ClCO2Et, 0oC
N
H
O
NMM, ClCO2Et, 0oC
NH
NH2
NH2
Boc
Boc
N
N
9
8
13
14
Scheme 1. Synthesis of organocatalysts 1–4.
diastereoselectivities (up to >99:1) and enantioselectivities (up to
>99%) with relatively low loadings (5 mol %) in asymmetric aldol
reactions under solvent-free conditions.
Table 1
Reaction parameter screening in the direct asymmetric aldol reaction of 4-nitro-
benzaldehyde with cyclohexanonea
2. Results and discussion
O
O
OH
Organocatalysts 1 and 3 were synthesized starting from
line and 2,4,6-trimethylbenzoyl chloride in four steps, in moderate
to good yields, as summarized in Scheme 1. The reaction of -pro-
L-pro-
OHC
catalyst 1-4
+
L
NO2
NO2
line with 2,4,6-trimethylbenzoyl chloride led to 5, which was
transformed into compounds 7 and 9. Subsequently, treatment of
compounds 7 and 9 with TFA in DCM gave the desired organocat-
alysts 1 and 3, respectively (Scheme 1). Similarly, the same
procedure as described in the preparation of catalysts 1 and 3
was followed with 2,4,6-trimethylbenzenesulfonyl chloride being
used instead of 2,4,6-trimethylbenzoyl chloride to furnish
organocatalysts 2 and 4.
In our initial studies, the efficacies of new organocatalysts 1–4
were examined for the direct aldol reaction between 4-nitrobenz-
aldehyde and cyclohexanone as the model by using TFA as an addi-
tive under solvent-free conditions (Table 1, entries 1–4). All
catalysts exhibited a high catalytic efficiency in the model reaction.
Excellent stereoselectivities could be obtained in the presence of 2,
3, or 4, whereas a moderate ee value was obtained with 1. A slight
improvement in stereoselectivities was observed when organocat-
alysts 2 and 4 were used (Table 1, entries 2 and 4). No noticeable
differences were observed in the reaction with 2 and 4 as catalysts.
After the preliminary screening of the catalytic activity of 1–4,
to obtain higher enantioselectivity, 4 was chosen as the preferred
catalyst in order to investigate different parameters, such as addi-
c
Entry
Cat.
Solvent
T (h)
Yieldb (%)
87
anti/syn
eed (%)
1e
1/TFA
None
None
None
None
None
None
None
None
None
None
None
None
DCM
Toluene
THF
12
12
12
12
16
16
16
16
30
12
36
36
24
24
24
30
24
70:30
92:8
90:10
92:8
75:25
79:21
65:35
75:25
—
70
92
87
93
79
80
60
76
—
97
94
91
85
84
89
95
91
2e
2/TFA
3/TFA
4/TFA
88
86
90
84
81
83
80
Trace
98
84
51
80
85
91
73
86
3e
4e
5e
4/AcOH
4/PhCOOH
4/TfOH
4/HCl
4
6e
7e
8e
9
10f
11g
12h
13f
14f
15f
16f
17f
4/TFA
4/TFA
4/TFA
4/TFA
4/TFA
4/TFA
4/TFA
4/TFA
>99:1
94:6
90:10
80:20
85:15
88:12
98:2
H2O
Brine
80:20
(continued on next page)

382
F. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 380–388
yield (98%) when TFA was employed with 4 with a ratio of 1.5/1
Table 1 (continued)
(Table 1, entry 10). The effect of the solvent was then studied
and the results are presented in Table 1 (entries 13–21). The results
show that the reaction occurs in a variety of solvents. However,
none of them proved to be better than the neat conditions. Water
and isopropanol afforded diastereomeric ratios and enantioselec-
tivities similar to those of the solvent-free conditions, but the reac-
tion was found to be considerably slower in water and isopropanol
than under solvent-free conditions, since the consumption of the
starting 4-nitrobenzaldehyde remained incomplete in the former
two solvents after 30 h. A decrease in the catalyst loading to
5 mol % could still afford the product in high yield and enantiose-
lectivity (Table 1, entry 22). When further decreasing the amount
of catalyst 4 to 1 mol %, a poor yield and a moderate ee value were
obtained (Table 1, entry 23). In an attempt to further increase the
enantioselectivity of the reaction, we decided to carry out the reac-
tion at lower temperature (0 °C). However, a better enantioselec-
tivity was not achieved but instead an obvious loss of the yield
was observed, even after longer reaction times (Table 1, entry
24). Extensive screening showed that the optimized conditions
were 4/TFA = 1/1.5, 5 mol % catalyst loading, at room temperature
and without the addition of any solvent (Table 1, entry 22).
The scope of aldol catalysis using 4 against a variety of aromatic
aldehydes and ketones as the substrate was explored under the
optimal conditions. The nitro, chloro, and bromo substituents were
chosen as the electron-withdrawing group, and the methyl substi-
tuent as a representative electron-donating group. As depicted in
Table 2, benzaldehydes substituted by electron-withdrawing
groups were converted into the corresponding aldol products in
c
Entry
Cat.
Solvent
T (h)
Yieldb (%)
anti/syn
eed (%)
18f
4/TFA
4/TFA
4/TFA
4/TFA
4/TFA
4/TFA
4/TFA
MeOH
iPrOH
CHCl3
DMF
None
None
None
30
30
24
24
12
36
30
88
77
91
89
98
49
55
75:25
>99:1
87:13
85:15
>99:1
79:21
>99:1
83
96
86
87
97
73
97
19f
20f
21f
22f,i
23f,j
24f,k
a
Unless otherwise specified, the reaction was carried out using 4-nitrobenzal-
dehyde (0.5 mmol), cyclohexanone (1.0 mmol), and catalyst (0.05 mmol) at rt.
b
Isolated yield (anti/syn).
Determined by 1H NMR of the crude mixture.
c
d
Determined for the anti-isomer by HPLC analysis.
Catalyst/acid = 1/1.
4/TFA = 1/1.5.
4/TFA = 1/2.
4/TFA = 1/2.5.
5 mol % catalyst loading.
1 mol % catalyst loading.
Reaction temperature: 0 °C.
e
f
g
h
i
j
k
tives, the solvents, the temperature, and the loading of the catalyst.
Based on research of the acidic proton being advantageous to the
aldol reaction,1b we carried out a study on the effect of acidic addi-
tives (Table 1, entries 5–12). As depicted in Table 1, in the presence
of TFA, the yield and enantioselectivity dramatically increased, that
is, the combination of organocatalyst 4 and TFA is crucial for the
reactivity of this catalytic system. Furthermore, it is noteworthy
that the aldol reaction afforded the desired product with the high-
est diastereo- and enantioselectivity (>99:1 dr and 97% ee) and
Table 2
Direct asymmetric aldol reaction of aldehydes with ketonesa
O
OH
O
O
catalyst 2-4 (5 mol%)
R1
R1
H
R3
R2
TFA (7.5 mol%), rt
R2
R3
c
Entry
R1
R2, R3
Cat.
T (h)
Yieldb (%)
anti/syn
eed (%)
1
2
3
4
5
6
7
8
4-NO2-C6H4
4-Cl-C6H4
4-Br-C6H4
2-Cl-C6H4
2-Br-C6H4
2,4-Cl-C6H3
2,6-Cl-C6H3
C6H5
4-Me-C6H4
Thiophen-2-yl
4-NO2-C6H4
2-Cl-C6H4
2-Br-C6H4
2,4-Cl-C6H3
2,6-Cl-C6H3
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
2-Cl-C6H4
2-Br-C6H4
2,4-Cl-C6H3
2,6-Cl-C6H3
4-NO2-C6H4
2-Cl-C6H4
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–H, –H
–CH3, –H
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3-
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3
3
3
3
3
2
2
2
2
2
12
16
24
36
36
36
48
48
60
48
24
36
36
36
36
48
48
16
16
36
48
48
24
36
36
48
48
98
96
93
89
91
94
90
82
90
88
96
83
84
93
80
95
22
98
92
89
87
89
98
90
87
84
88
>99:1
80:20
75:25
98:2
97
95
94
96
95
98
>99
80
81
75
73
78
76
89
99
71
53
93
88
89
96
97
95
93
87
93
96
96:4
80:20
>99:1
89:11
90:10
70:30
25:75
35:65
30:70
25:75
35:65
—
9
10
11
12
13
14
15
16e
17e
18
19
20
21
22
23
24
25
26
27
—
98:2
96:4
90:10
70:30
>99:1
85:15
98:2
93:7
65:35
>99:1
2-Br-C6H4
2,4-Cl-C6H3
2,6-Cl-C6H3
a
Unless otherwise specified, the asymmetric aldol reaction was carried out using aldehydes (0.5 mmol), ketones (1.0 mmol) and catalysts (0.025 mmol) under solvent-free
conditions.
b
Isolated yields (anti/syn).
c
d
e
Determined by 1H NMR of the crude products.
Determined for the anti-isomer by HPLC analysis using a chiral column.
Ketones (2.5 mmol) were used.

F. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 380–388
383
R
high yields and with excellent enantioselectivities (Table 2, entries
1–7). Moreover, due to the strong electronic effect and steric hin-
drance, 2,6-dichlorobenzaldehyde gave excellent enantioselectivi-
ty (superior to 99%) and diastereoselectivity (superior to 99:1).
Substituted benzaldehydes containing electron-donating groups
required longer reaction times to achieve good isolated yield, but
the diastereo- and enantioselectivity remain good (Table 2, entry
9). The reaction of non-activated benzaldehyde with cyclohexa-
none afforded the product in 82% yield with 80% ee (Table 2, entry
8). It is worth noting that less reactive heterocyclic aldehydes, such
as thiophene-2-carbaldehyde still displayed high reactivity and led
to the aldol product with good yield (88%) and enantioselectivity
(75% ee) (Table 2, entry 10). With a broad range of aromatic alde-
hydes examined, our attention turned to using other ketones, such
as cyclopentanone, acetone, and butanone. As a result, when cyclo-
pentanone and acetone were used under the optimized conditions,
the desired aldol products were obtained in high yield and with
moderate to excellent enantioselectivities. Moreover, the reactions
of cyclopentanone with various aromatic aldehydes generated the
syn products as the predominant diastereomer. When butanone
was used, the desired product was obtained in poor yield and with
moderate enantioselectivity (Table 2, entry 17). Instead, the dehy-
drated product of (E)-3-methyl-4-(4-nitrophenyl)-3-en-2-one was
obtained.
O
NO2
O
4
catalyst
NO2
+
(5 mol%)
R
R = 4-OMe, 94% yield, 92:8 syn/anti, 60% ee
2-Cl, 89% yield, 95:5 syn/anti, 77% ee
2,4-Cl, 87% yield, 99:1 syn/anti, 93% ee
Scheme 3. Direct asymmetric Michael reaction of cyclohexane with nitroalkenes.
via an enamine intermediate.8b,10a The hydrogen bond involving
the organocatalysts and substrates together with electrostatic as
well as steric interactions may account for the stereochemical bias
of the reaction. The presence of additional hydrogen bond donors
can have a beneficial effect on the functional organocatalysts in
the aldol reaction. The bifunctional organocatalyst pyrrolidine
moiety reacts with cyclohexanone to form a nucleophilic enamine
in the presence of an acidic additive (Fig. 2). The aldehydes are acti-
When catalyst 2 or 3 was employed under these optimized con-
ditions as described above, a number of aromatic aldehydes were
also suitable substrates to give the corresponding products in high
yields (84–98%) and with excellent enantiomeric excess (87–97%).
The results show that organocatalysts derived from (S)-2,20-diami-
no-6,60-dimethyl-1,10-biphenyl gave higher diaseteroselectivities
than those derived from o-phenylenediamine while organocata-
lysts derived from 2,4,6-trimethylbenzenesulfonyl chloride gave
higher enantioselectivity than those derived from 2,4,6-trim-
ethylbenzoyl chloride.
O
N
O
N
N
O
N
O
H
H
H
H
O
O
N
N
N
N
O
O
O
S
O
S
H
R
R
H
Subsequently, we were interested in whether the catalytic sys-
tem would work for activated ketones instead of aldehydes, while
modifying the conditions slightly. Fortunately, catalyst 4 exhibited
a high catalytic efficiency for the cross-aldol reaction between isat-
in and ketones to give the desired products in good yield and mod-
erate to good stereoselectivities (Scheme 2).
Si face attack
Re face attack
favored
disfavored
Figure 2. Proposed transition-state models for the aldol reaction catalyzed by
catalyst 4.
Finally, in order to further expand upon the scope of the appli-
cation of these prolinamide catalysts, the asymmetric Michael
reaction of cyclohexane with nitroalkenes was studied under sol-
vent-free conditions (Scheme 3). The Michael reaction proceeded
to give the desired products in good yields (up to 94%), high diaste-
reoselectivities (up to 99:1), and good to excellent enantioselectiv-
ities (up to 93%).
vated by bifurcated H-bonding with NH of the two amides through
hydrogen bond interactions. Under solvent-free conditions, there is
direct H-bonding between the aldehyde and the N–H groups of
amides, which leads to nucleophilic addition of the enamine to
the Re-face of the carbonyl group leading to the major (2S,10R)-
product. Due to the steric effect, organocatalysts 2 and 4 gave high-
er enantioselectivity in the aldol products than organocatalysts 1
and 3.
The mechanism of the reaction using organocatalysts 1–4 is be-
lieved to be similar to that of the previously reported prolineamine
3. Conclusions
O
O
HO
O
In conclusion, four prolinamide catalysts, derived from dia-
mines, were synthesized and their catalytic activities in aldol reac-
tions studied. In all cases, the catalysts exhibited high catalytic
efficiency. Screening of various acid additives revealed the great
importance of their presence and their ratio with the catalyst for
improving both the yield and the enantioselectivity. Catalysts 2–
4, in the presence of TFA (the ratio of catalyst and TFA = 1/1.5),
proved to be excellent catalysts, providing the products between
various aromatic aldehydes and ketones in good to excellent yields
(up to 98%) and with good stereoselectivities (up to >99:1 dr and
>99% ee). In addition, these catalysts can also be applied to Michael
reactions between cyclohexane and nitroalkenes with high diaste-
reoselectivities and good to excellent enantioselectivities. This
catalyst 4 (5 mol%)
TFA (7.5 mol%), 0oC
O
+
O
N
H
N
H
91% yield, 63% ee
O
O
O
HO
catalyst 4 (5mol%)
TFA (7.5 mol%), 0oC
+
O
O
N
N
H
H
81% yield, 94:6 dr, 53% ee
Scheme 2. Cross-aldol reaction of isatin with acetone and cyclohexanone.

384
F. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 380–388
solvent-free catalytic system is, to some extent a green and atom
economical approach.
(Ar), 128.1 (Ar), 125.8 (Ar), 125.6 (Ar), 124.4 (Ar), 124.1 (Ar), 61.1
(NHCH), 59.8 (NHCH), 48.4 (NHCH2), 47.2 (NCH2), 30.6 (CH2),
27.9 (CH2), 26.2 (CH2), 24.9 (CH2), 21.1 (CH3), 18.9 (CH3), 18.7
(CH3) ppm. IR (KBr):
m = 3249, 2975, 1672, 1517, 1454, 1310,
4. Experimental
4.1. General
1151, 756 cmꢂ1. C26H32N4O3 (448.56): Calcd C, 69.62; H, 7.19; N,
12.49. Found: C, 69.36; H, 6.91; N, 12.67.
4.2.2. Preparation of catalyst 2
All reagents were commercial products without further purifi-
cation, unless otherwise stated. The reactions were monitored by
TLC (thin layer chromatography). Column and preparative TLC
purification was carried out using silica gel. Flash column chroma-
tography was performed on silica gel (200–300 mesh). Melting
The same procedure as described in the preparation of catalyst 1
was followed with 2,4,6-trimethylbenzenesulfonyl chloride being
used instead of 2,4,6-trimethylbenzoyl chloride to furnish organo-
catalyst 2 as a yellow oil. Total yield: 69%, oil. ½a D20
¼ ꢂ82:8 (c
ꢃ
0.01, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): d = 9.74 (br s, 1H,
NH), 8.90 (br s, 1H, NH), 7.47–7.49 (m, 1H, ArH), 7.40–7.42 (m,
1H, ArH), 7.14–7.16 (m, 2H, ArH), 6.95 (s, 2H, ArH), 4.33–4.36 (m,
1H, CH), 3.97–3.99 (m, 1H, CH), 3.55–3.57 (m, 1H, CH2), 3.38–3.43
(m, 1H, CH2), 2.99–3.07 (m, 2H, CH2), 2.65 (s, 6H, CH3), 2.28 (s,
3H, CH3), 2.16–2.21 (m, 3H, CH2), 1.92–2.02 (m, 3H, CH2), 1.76–
1.80 (m, 2H, CH2) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
d = 174.8 (NHCO), 170.4 (NHCO), 143.2 (Ar), 140.3 (Ar), 132.4 (Ar),
131.3 (Ar), 130.1 (Ar), 129.5 (Ar), 125.9 (Ar), 125.8 (Ar), 124.6
(Ar), 124.3 (Ar), 62.2 (NHCH), 60.9 (NHCH), 49.0 (NHCH2), 47.2
(NCH2), 31.5 (CH2), 30.6 (CH2), 26.2 (CH2), 24.7 (CH2), 23.5 (CH3),
points were measured on
a digital melting point apparatus
(TAQ100). Optical rotations were measured with a Rudolph Auto-
polÒ IV automatic polarimeter. IR spectra were recorded with a
Nicolet Nexus 670 FT-IR spectrometer. 1H NMR spectra were re-
corded on a 400 MHz instrument (Bruker Avance 400 Spectrome-
ter). Chemical shifts (d) are given in ppm relative to TMS as the
internal reference, with coupling constants (J) in Hz. 13C NMR spec-
tra were recorded at 100 MHz. Chemical shifts are reported in ppm
with the internal chloroform signal at 77.0 ppm as a standard. Ele-
mental analysis was carried out on Euro EA 3000 elemental ana-
lyzer. The enantiomeric excesses of the products were
determined by chiral HPLC using a Shimadzu LC-20A instrument
with the ChiralPakÒ AD-H (4.6 mm ꢁ 250 mm), ChiralCelÒ OD-H
(4.6 mm ꢁ 250 mm) and ChiralCelÒ OJ-H (4.6 mm ꢁ 250 mm).
20.9 (CH3) ppm. IR (KBr):
m = 3253, 2969, 1682, 1621, 1515, 1467,
1203, 783 cmꢂ1. C25H32N4O4S (484.61): Calcd C, 61.96; H, 6.66; N,
11.56. Found: C, 61.66; H, 6.52; N, 11.48.
4.2.3. Preparation of catalyst 3
4.2. Preparation of the catalyst
The same procedure as described in the preparation of catalyst
1 was followed with (S)-2,20-diamino-6,60-dimethyl-1,10-biphenyl
being used instead of o-phenylenediamine to furnish organocata-
lyst 3 as a pale yellow solid. Total yield: 79%, mp: 54–56 °C.
4.2.1. Preparation of catalyst 1
2,4,6-Trimethylbenzoyl chloride (2.06 mL, 12.5 mmol) was
added dropwise to a cold solution of L-proline (1.15 g, 10 mmol)
½ ꢃ
a 2D0
¼ ꢂ6:5 (c 0.01, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C):
and Et3N (5 mL) in dry DCM (15 mL). The solution was allowed
to reach room temperature and stirring was continued for approx-
imately 8 h. Next, the mixture was acidified with 1 M HCl and puri-
fied to afford compound 5 (2.53 g, yield: 97%). To a solution of 5
(2.35 g, 9 mmol) in THF, was added NMM (1.10 mL, 9.9 mmol),
ClCOOEt (0.97 g, 9 mmol) at ꢂ20 °C under stirring. After approxi-
mately 30 min o-phenylenediamine (0.96 g, 9 mmol) was added
dropwise, and the reaction was stirred for approximately 10 h.
Then, the mixture was washed with 0.5 mol/L KHSO4 solution
and purified by flash chromatography (EtOAc/petroleum
ether = 1:10) product 6 as an oil (2.51 g, yield: 79%). Then to a solu-
d = 9.55 (br s, 1H, NH), 8.28 (d, J = 8.0 Hz, 1H, ArH), 7.97 (d,
J = 8.0 Hz, 1H, ArH), 7.70 (br s, 1H, NH), 7.27–7.37 (m, 2H, ArH),
7.10–7.16 (m, 2H, ArH), 6.81 (d, J = 8.4 Hz, 2H, ArH), 4.42–4.45
(m, 1H, CH), 3.59–3.63 (m, 1H, CH), 3.00–3.05 (m, 2H, CH2),
2.70–2.76 (m, 1H, CH2), 2.42–2.47 (m, 1H, CH2), 2.25 (s, 3H, CH3),
2.17 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.04–2.09 (m, 2H, CH2), 2.03
(s, 3H, CH3), 1.94 (s, 3H, CH3), 1.86–1.92 (m, 3H, CH2), 1.75–1.80
(s, 1H, CH2), 1.89 (s, 3H, CH3), 1.75–1.77 (m, 1H, CH2), 1.57–1.60
(m, 1H, CH2), 1.43–1.48 (m, 1H, CH2) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): d = 173.7 (NHCO), 170.9 (CO), 169.9 (NHCO), 138.2
(Ar), 137.5 (Ar), 137.5 (Ar), 135.7 (Ar), 135.6 (Ar), 133.9 (Ar),
133.7 (Ar), 132.6 (Ar), 129.0 (Ar), 128.6 (Ar), 128.3 (Ar), 128.1
(Ar), 128.0 (Ar), 126.7 (Ar), 125.9 (Ar), 125.7 (Ar), 121.1 (Ar),
117.6 (Ar), 60.7 (NCH), 59.7 (NHCH), 48.1 (NCH2), 46.8 (NHCH2),
30.7 (CH2), 28.5 (CH2), 25.7 (CH2), 24.8 (CH2), 21.1 (CH3), 19.8
tion of Boc-L-proline (1.94 g, 9 mmol) in THF, were added NMM
(1.10 mL, 9.9 mmol), and ClCOOEt (0.97 g, 9 mmol), at 0 °C under
stirring. After approximately 30 min, the above product 6 (1.05 g,
3 mmol) was added (detected by TLC). The mixture was washed
with 1.0 mol/L KHSO4 solution and purified by flash chromatogra-
phy (EtOAc/petroleum ether = 1:4) to give product 7 as an oil
(1.56 g, 95%). Then, TFA was added to the DCM solution of com-
pound 7 and stirred until reaction was finished. The pH value of
the mixture was brought to 12 by the addition of NaOH solution.
The aqueous phase was extracted with DCM, after removal of the
solvent under reduced pressure, the residue was purified by flash
column chromatography on silica gel (EtOAc/MeOH, 10:1–5:1) to
furnish organocatalyst 1 as a colorless solid (1.27 g, yield: 98%). To-
(CH3), 19.7 (CH3), 18.9 (CH3), 18.6 (CH3) ppm. IR (KBr):
m = 3344,
2973, 1683, 1508, 1466, 1154, 784 cmꢂ1. C34H40N4O3 (552.71):
Calcd C, 73.88; H, 7.29; N, 10.14. Found: C, 73.50; H, 7.42; N, 10.43.
4.2.4. Preparation of catalyst 4
The same procedure as described in the preparation of catalyst
3
was followed with 2,4,6-trimethylbenzenesulfonyl chloride
being used instead of 2,4,6-trimethylbenzoyl chloride to furnish
organocatalyst
4
as
a yellow oil. Total yield: 74%, oil.
tal yield: 72%; mp 94–96 °C. ½a D20
ꢃ
¼ þ22:0 (c 0.01, CHCl3). 1H NMR
½
a 2D0
ꢃ
¼ ꢂ29:9 (c 0.01, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C):
(400 MHz, CDCl3, 25 °C): d = 9.81 (br s, 1H, NH), 9.50 (br s, 1H, NH),
7.66–7.70 (m, 2H, ArH), 7.14–7.18 (m, 2H, ArH), 6.84 (s, 2H, ArH),
4.88–4.91 (m, 1H, CH), 3.83–3.87 (m, 1H, CH), 3.00–3.22 (m, 2H,
CH2), 2.99 (t, J = 6.4 Hz, 2H, CH2), 2.52–2.55 (m, 1H, CH2), 2.27 (s,
3H, CH3), 2.21 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.09–2.17 (m, 4H,
CH2), 1.87–1.90 (m, 1H, CH2), 1.68–1.82 (m, 2H, CH2) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): d = 174.2 (NHCO), 171.7 (NCO),
169.8 (NHCO), 138.5 (Ar), 133.8 (Ar), 132.4 (Ar), 129.9 (Ar), 128.6
d = 9.58 (br s, 1H, NH), 8.34 (d, J = 8.0 Hz, 1H, ArH), 7.90 (d,
J = 8.0 Hz, 1H, ArH), 7.66 (br s, 1H, NH), 7.31–7.36 (m, 2H, ArH),
7.15 (d, J = 7.6 Hz, 1H, ArH), 7.03 (d, J = 7.6 Hz, 1H, ArH), 6.91 (s,
2H, ArH), 4.26–4.29 (m, 1H, CH), 3.70–3.73 (m, 1H, CH), 2.91–
2.97 (m, 1H, CH2), 2.68–2.78 (m, 2H, CH2), 2.50 (s, 6H, CH3),
2.41–2.46 (m, 1H, CH2), 2.28 (s, 3H, CH3), 1.91–2.02 (s, 3H, CH2),
1.94 (s, 3H, CH3), 1.92 (s, 3H, CH3), 1.84–1.90 (m, 1H, CH2), 1.69–
1.76 (m, 1H, CH2), 1.57–1.62 (m, 1H, CH2), 1.41–1.48 (m, 2H,

F. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 380–388
385
CH2) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 173.8 (NHCO),
170.0 (NHCO), 143.0 (Ar), 140.2 (Ar), 137.5 (Ar), 137.1 (Ar), 136.2
(Ar), 135.0 (Ar), 132.2 (Ar), 131.1 (Ar), 129.0 (Ar), 128.7 (Ar),
127.8 (Ar), 126.9 (Ar), 125.7 (Ar), 125.4 (Ar), 120.6 (Ar), 118.0
(Ar), 62.4 (NCH), 60.8 (NHCH), 47.7 (NCH2), 46.8 (NHCH2), 31.0
(CH2), 30.7 (CH2), 25.8 (CH2), 24.3 (CH2), 23.2 (CH3), 20.9 (CH3),
4.3.5. (S)-2-[(R)-(2-Bromophenyl)(hydroxy)methyl]cyclohexan-
one15c
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.52–7.56 (m, 2H, ArH),
7.34–7.38 (m, 1H, ArH), 7.13–7.17 (m, 1H, ArH), 5.32 (d,
J = 8.0 Hz, 1H, CH), 2.68–2.71 (m, 1H, CH), 2.45–2.49 (m, 1H,
CH2), 2.35–2.38 (m, 1H, CH2), 2.07–2.10 (m, 1H, CH2), 1.83–1.86
(m, 1H, CH2), 1.69–1.72 (m, 1H, CH2), 1.58–1.68 (m, 3H, CH2)
ppm. The enantiomeric excess was determined by HPLC with an
19.8 (CH3), 19.6 (CH3) ppm. IR (KBr):
m = 3258, 2973, 1682, 1604,
1518, 1447, 1176, 754 cmꢂ1. C33H40N4O4S (588.76): Calcd C,
67.32; H, 6.85; N, 9.52. Found C, 67.68; H, 6.64; N, 9.74.
Daicel Chiralpak AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propa-
nol = 95:5, flow rate 0.5 mL minꢂ1, k = 221 nm; tR (anti) = 30.29 -
4.3. Typical procedure for the direct asymmetric aldol reaction
min (major) and 35.07 min (minor).
The aldehyde (0.50 mmol) was added to a stirring ketone
(1.00 mmol). The catalyst (0.025 mmol) was added at room tem-
perature, followed by the addition of TFA (0.038 mmol). The reac-
tion mixture was left stirring until the reaction was complete (by
TLC). The crude product was purified by flash column chromatog-
raphy with elution with various mixtures of petroleum ether/
EtOAc to afford the desired products.
4.3.6. (S)-2-[(R)-(2,4-Dichlorophenyl)(hydroxy)methyl]cyclohex-
anone3b
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.50 (d, J = 8.4 Hz, 1H,
ArH), 7.35–7.36 (m, 1H, ArH), 7.27–7.31 (m, 1H, ArH), 5.29 (d,
J = 8.0 Hz, 1H), 2.63–2.65 (m, 1H, CH), 2.46–2.50 (m, 1H, CH2),
2.34–2.38 (m, 1H, CH2), 2.08–2.13 (m, 1H, CH2), 1.84–1.86 (m,
1H, CH2), 1.55–1.77 (m, 4H, CH2) ppm. The enantiomeric excess
was determined by HPLC with an Daicel Chiralpak AD-H column
0.46
u
ꢁ 25 cm,
n-hexane/2-propanol = 95:5,
k = 221 nm; tR (anti) = 28.46 min (major) and
flow
rate
4.3.1. (S)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]cyclohex-
anone15h
0.5 mL minꢂ1
,
1H NMR (400 MHz, CDCl3, 25 °C): d = 8.21 (d, J = 8.4 Hz, 2H,
ArH), 7.50 (d, J = 8.8 Hz, 2H, ArH), 4.89 (d, J = 8.4 Hz, 1H, CH),
2.56–2.60 (m, 1H, CH), 2.48–2.52 (m, 1H, CH2), 2.36–2.40 (m, 1H,
CH2), 2.09–2.14 (m, 1H, CH2), 1.50–1.69 (m, 5H, CH2) ppm. The
enantiomeric excess was determined by HPLC with an Daicel Chir-
34.75 min (minor).
4.3.7. (S)-2-[(R)-(2,6-Dichlorophenyl)(hydroxy)methyl]cyclohex-
anone8e
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.31 (d, J = 8.0 Hz, 2H,
ArH), 7.16 (t, J = 7.6 Hz, 1H, ArH), 5.84 (d, J = 9.6 Hz, 1H, CH),
3.46–3.53 (m, 1H, CH), 2.50–2.54 (m, 1H, CH2), 2.40–2.45 (m, 1H,
CH2), 2.08–2.12 (m, 1H, CH2), 1.81–1.84 (m, 1H, CH2), 1.61–1.73
(m, 2H, CH2), 1.51–1.55 (m, 1H, CH2),1.36–1.43 (m, 1H, CH2)
ppm. The enantiomeric excess was determined by HPLC with an
alpak AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propanol = 90:10,
flow rate 1.0 mL minꢂ1, k = 254 nm; tR (anti) = 23.87 min (minor)
and 31.94 min (major).
4.3.2. (S)-2-[(R)-(4-Chlorophenyl)(hydroxy)methyl]cyclohex-
anone15h
Daicel Chiralpak AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propa-
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.28–7.35 (m, 2H, ArH),
7.21–7.26 (m, 2H, ArH), 4.75 (d, J = 8.8 Hz, 1H, CH), 2.51–2.57 (m,
1H, CH), 2.43–2.50 (m, 1H, CH2), 2.31–2.39 (m, 1H, CH2), 2.05–
2.12 (m, 1H, CH2), 1.73–1.84 (m, 1H, CH2), 1.45–1.72 (m, 3H,
CH2) 1.25–1.32 (m, 1H, CH2) ppm. The enantiomeric excess was
determined by HPLC with an Daicel Chiralpak AD-H column 0.46
nol = 95:5, flow rate 0.5 mL minꢂ1, k = 221 nm; tR (anti) = 34.63 -
min (major) and 44.76 min (minor).
4.3.8. (S)-2-[(R)-Hydroxy(phenyl)methyl]cyclohexanone15h
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.30–7.37 (m, 5H, ArH),
4.80 (d, J = 8.8 Hz, 1H, CH), 2.62–2.65 (m, 1H, CH), 2.47–2.62 (m,
1H, CH2), 2.37–2.42 (m, 1H, CH2), 2.08–2.12 (m, 1H, CH2), 1.77–
1.82 (m, 1H, CH2), 1.66–1.70 (m, 1H, CH2), 1.54–1.61 (m, 2H,
CH2), 1.27–1.33 (m, 1H, CH2) ppm. The enantiomeric excess was
determined by HPLC with an Daicel ChiralCel OD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propanol = 90:10, flow rate 0.5 mL minꢂ1
,
k = 221 nm; tR (anti) = 26.11 min (minor) and 30.57 min (major).
4.3.3. (S)-2-[(R)-(4-Bromophenyl)(hydroxy)methyl]cyclohex-
ꢁ 25 cm, n-hexane/2-propanol = 90:10, flow rate 0.5 mL minꢂ1
,
anone15h
u
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.46–7.49 (m, 2H, ArH),
7.08–7.22 (m, 2H, ArH), 4.76 (d, J = 8.4 Hz, 1H, CH), 2.51–2.59 (m,
1H, CH), 2.45–2.47 (m, 1H, CH2), 2.32–2.42 (m, 1H, CH2), 2.08–
2.12 (m, 1H, CH2), 1.79–1.88 (m, 1H, CH2), 1.50–1.72 (m, 3H,
CH2), 1.31–1.35 (m, 1H, CH2) ppm. The enantiomeric excess was
determined by HPLC with an Daicel Chiralpak AD-H column 0.46
k = 221 nm; tR (anti) = 21.36 min (minor) and 31.71 min (major).
4.3.9. (S)-2-[(R)-Hydroxy(4-tolylphenyl)methyl]cyclohexanone
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.14–7.21 (m, 4H, ArH),
4.75 (d, J = 8.8 Hz, 1H, CH), 2.57–2.62 (m, 1H, CH), 2.45–2.50 (m,
1H, CH2), 2.29–2.40 (m, 4H, CH2, and CH3), 2.05–2.11 (m, 1H,
CH2), 1.92–1.95 (m, 1H, CH2), 1.77–1.80 (m, 1H, CH2),1.53–1.62
(m, 2H, CH2), 1.26–1.30 (m, 1H, CH2) ppm. The enantiomeric excess
was determined by HPLC with an Daicel ChiralCel OD-H column
u
ꢁ 25 cm, n-hexane/2-propanol = 90:10, flow rate 0.8 mL minꢂ1
,
k = 221 nm; tR (anti) = 23.89 min (minor) and 27.81 min (major).
4.3.4. (S)-2-[(R)-(2-Chlorophenyl)(hydroxy)methyl]cyclohexan-
0.46
u
ꢁ 25 cm,
n-hexane/2-propanol = 90:10,
k = 221 nm; tR (anti) = 33.91 min (minor) and
flow
rate
one15g
0.5 mL minꢂ1
,
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.57 (dd, J = 7.6 Hz, 1H,
ArH), 7.32–7.35 (m, 2H, ArH), 7.20–7.25 (m, 1H, ArH), 5.36 (d,
J = 8.0 Hz, 1H, CH), 2.68–2.71 (m, 1H, CH), 2.45–2.50 (m, 1H,
CH2), 2.35–2.38 (m, 1H, CH2), 2.08–2.12 (m, 1H, CH2), 1.83–1.85
(m, 1H, CH2), 1.66–1.69 (m, 1H, CH2), 1.57–1.65 (m, 3H, CH2)
ppm. The enantiomeric excess was determined by HPLC with an
46.71 min (major).
4.3.10. (S)-2-((R)-Hydroxy(thiophene-2-yl)methyl)cyclohex-
anone15g
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.31–7.33 (m, 1H, ArH),
7.20–7.21 (m, 1H, ArH), 7.08–7.10 (m, 1H, ArH), 4.93 (d,
J = 8.8 Hz, 1H, CH), 2.63–2.66 (m, 1H, CH), 2.37–2.39 (m, 1H,
CH2), 2.33–2.36 (m, 1H, CH2), 2.09–2.10 (m, 1H, CH2), 1.71–1.73
(m, 1H, CH2), 1.57–1.69 (m, 4H, CH2) ppm. The enantiomeric excess
Daicel Chiralpak AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propa-
nol = 95:5, flow rate 0.5 mL minꢂ1, k = 221 nm; tR (anti) = 26.58 -
min (major) and 30.21 min (minor).

386
F. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 380–388
was determined by HPLC with an Daicel Chiralpak AD-H column
0.46 n-hexane/2-propanol = 90:10, flow rate
ꢁ 25 cm,
1.0 mL minꢂ1
k = 214 nm; tR (anti) = 12.33 min (minor) and
4.4. Typical procedure for the cross-aldol reaction17
u
,
The isatin (0.50 mmol) was added to stirring ketone
a
16.42 min (major).
(1.00 mmol). The catalyst (0.025 mmol) was added at 0 °C, fol-
lowed by the addition TFA (0.038 mmol). The reaction mixture
was left stirring until the reaction was complete (by TLC). The
crude product was purified by flash column chromatography with
elution with various mixtures of petroleum ether/EtOAc to afford
the desired products.
4.3.11. (S)-2-(R)-Hydroxy(4-nitrophenyl)methyl)cyclopentan-
one15h
1H NMR (400 MHz, CDCl3, 25 °C): d = 8.22–8.25 (m, 2H, ArH),
7.52–7.56 (m, 2H, ArH), 4.86 (d, J = 9.2 Hz, 1H, CH), 2.40–2.52 (m,
2H, CH and CH2), 2.12–2.22 (m, 1H, CH2), 1.94–2.08 (m, 2H, CH2),
1.70–1.78 (m, 2H, CH2) ppm. The enantiomeric excess was deter-
mined by HPLC with an Daicel Chiralpak AD-H column 0.46
4.4.1. (R)-3-Hydroxy-3-(2-oxopropyl)indolin-2-one17
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.63 (d, J = 7.8 Hz, 1H, ArH),
7.37 (d, J = 7.6 Hz, 1H, ArH), 7.07 (t, J = 7.4 Hz, 1H, ArH), 6.89 (d,
J = 7.6 Hz, 1H, ArH), 3.20 (d, J = 17.2 Hz, 1H, CH2), 2.98 (d,
J = 17.2 Hz, 1H, CH2), 2.22 (s, 3H, CH3) ppm. The enantiomeric excess
was determined by HPLC with an Daicel ChiralCel OJ-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propanol = 95:5, flow rate 1.0 mL minꢂ1
,
k = 254 nm; tR (anti) = 44.47 min (minor) and 47.42 min (major).
4.3.12. (S)-2-(R)-Hydroxyl(2-chlorophenyl)methyl)-cyclopentan-
one8e
u
ꢁ 25 cm, n-hexane/2-propanol = 80:20, flow rate 0.8 mL minꢂ1
,
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.63 (s, 1H, ArH), 7.23–
7.57 (m, 2H, ArH), 7.13–7.25 (m, 1H, ArH), 5.65 (m, J = 2.8 Hz, 1H,
CH), 2.30–2.45 (m, 2H, CH and CH2), 2.26–2.30 (m, 1H, CH2),
1.97–2.06 (m, 2H, CH2), 1.67–1.81 (m, 2H, CH2) ppm. The enantio-
meric excess was determined by HPLC with an Daicel Chiralpak
k = 254 nm; tR = 15.61 min (major) and 20.34 min (minor).
4.4.2. (S)-3-Hydroxy-3-[(R)-2-oxocyclohexyl]indolin-2-one17b,c
1H NMR (400 MHz, DMSO, 25 °C): d = 9.24 (br s, 1H, NH), 8.01 (d,
J = 7.2 Hz, 1H, ArH), 7.47 (t, J = 7.6 Hz, 1H, ArH), 7.19 (t, J = 7.6 Hz,
1H, ArH), 6.88 (d, J = 7.6 Hz, 1H, ArH), 3.15 (d, J = 8.0 Hz, 1H, CH),
2.50–2.56 (m, 2H, CH2), 2.35 (m, 2H, CH2), 1.76–1.97 (m, 2H, CH2),
1.50–1.63 (m, 2H, CH2) ppm. The enantiomeric excess was deter-
mined by HPLC with an Daicel ChiralCel OJ-H column 0.46
AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propanol = 95:5, flow
rate 1.0 mL minꢂ1, k = 221 nm; tR (anti) = 16.51 min (major) and
18.3 min (minor).
4.3.13. (S)-2-(R)-Hydroxyl(2-bromophenyl)methyl)-cyclopentan-
one15c
u
ꢁ 25 cm, n-hexane/2-propanol = 80:20, flow rate 0.8 mL minꢂ1
,
k = 254 nm; tR = 18.70 min (major) and 22.14 min (minor).
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.65 (s, 1H, ArH), 7.20–
7.55 (m, 2H, ArH), 7.11–7.24 (m, 1H, ArH), 5.67 (m, J = 2.8 Hz, 1H,
CH), 2.31–2.47 (m, 2H, CH and CH2), 2.28–2.31 (m, 1H, CH2),
1.96–2.09 (m, 2H, CH2), 1.69–1.82 (m, 2H, CH2) ppm. The enantio-
meric excess was determined by HPLC with an Daicel Chiralpak
4.5. Typical procedure for the Michael reaction18
The nitroalkene (0.50 mmol) was added to a stirring ketone
(1.00 mmol). The catalyst (0.025 mmol) was added at room tem-
perature. The reaction mixture was left stirring until the reaction
was complete (by TLC). The crude product was purified by flash
column chromatography with elution with various mixtures of
petroleum ether/EtOAc to afford the desired products.
AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propanol = 95:5, flow
rate 1.0 mL minꢂ1, k = 221 nm; tR (anti) = 22.05 min (major) and
26.93 min (minor).
4.3.14. (S)-2-[(R)-(2,4-Dichlorophenyl)(hydroxy)methyl]cyclo-
pentanone
4.5.1. (S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohex-
anone18
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.53–7.56 (m, 1H, ArH),
7.35–7.37 (m, 1H, ArH), 7.30–7.32 (m, 1H, ArH), 5.26 (d,
J = 9.6 Hz, 1H, CH), 2.64–2.67 (m, 2H, CH and CH2), 2.36–2.45 (m,
2H, CH2), 2.11–2.19 (m, 1H, CH2), 1.94–2.04 (m, 2H, CH2), 1.65–
1.69 (m, 1H, CH2). The enantiomeric excess was determined by
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.08 (d, J = 8.4 Hz, 2H,
ArH), 6.85 (d, J = 8.4 Hz, 2H, ArH), 4.61–4.93 (m, 1H, CH2), 4.56–
4.59 (m, 1H, CH2), 3.78 (s, 1H, OMe), 3.68–3.74 (m, 1H, CH),
2.64–2.66 (m, 1H, CH2), 2.37–2.49 (m, 2H, CH2), 2.05–2.10 (m,
1H, CH2) 1.55–1.81 (m, 4H, CH2), 1.21–1.25 (m, 1H, CH2) ppm.
The enantiomeric excess was determined by HPLC with an Daicel
HPLC with an Daicel Chiralpak AD-H column 0.46
u
ꢁ 25 cm, n-
hexane/2-propanol = 95:5, flow rate 0.5 mL minꢂ1, k = 221 nm; tR
(anti) = 26.10 min (major) and 27.53 min (minor).
Chiralpak AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propa-
nol = 90:10, flow rate 0.8 mL minꢂ1, k = 210 nm; tR (syn) = 11.46 -
4.3.15. (S)-2-[(R)-(2,6-Dichlorophenyl)(hydroxy)methyl]cyclo-
pentanone
min (minor) and 13.66 min (major).
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.32 (d, J = 8.0 Hz, 2H,
ArH), 7.15–7.19 (m, 1H, ArH), 5.63 (d, J = 9.6 Hz, 1H, CH), 3.30–
3.36 (m, 1H, CH), 2.22–2.45 (m, 2H, CH2), 1.75–1.86 (m, 2H, CH2),
1.54–1.60 (m, 2H, CH2) ppm. The enantiomeric excess was deter-
mined by HPLC with an Daicel Chiralpak AD-H column 0.46
4.5.2. (S)-2-((R)-1-(2-Chlorophenyl)-2-nitroethyl)cyclohex-
anone18
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.58–7.61 (m, 1H, ArH),
7.29–7.33 (m, 1H, ArH), 7.21–7.24 (m, 1H, ArH), 7.12–7.16 (m,
1H, ArH), 4.87–4.94 (m, 2H, CH2), 4.29–4.35 (m, 1H, CH), 2.89–
2.93 (m, 1H, CH), 2.39–2.51 (m, 2H, CH2), 2.09–2.13 (m, 1H, CH2),
1.69–1.86 (m, 4H, CH2), 1.23–1.27 (m, 1H, CH2) ppm. The enantio-
meric excess was determined by HPLC with an Daicel Chiralpak
u
ꢁ 25 cm, n-hexane/2-propanol = 95:5, flow rate 0.5 mL minꢂ1
,
k = 221 nm; tR (anti) = 35.10 min (major) and 39.38 min (minor).
4.3.16. (R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one15h
AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propanol = 90:10, flow
1H NMR (400 MHz, CDCl3, 25 °C): d = 8.26 (d, J = 8.8 Hz, 2H,
ArH), 7.71 (d, J = 8.8 Hz, 2H, ArH), 5.25 (m, 1H, CH), 3.65 (br, 1H,
OH), 2.85 (m, 2H, CH2), 2.21 (s, 3H, CH3) ppm. The enantiomeric ex-
cess was determined by HPLC with an Daicel Chiralpak AD-H col-
rate 0.8 mL minꢂ1, k = 210 nm; tR (syn) = 13.21 min (minor) and
19.27 min (major).
4.5.3. (S)-2-((R)-1-(2,4-Dichlorophenyl)-2-nitroethyl)cyclohex-
anone18c
umn 0.46
0.5 mL minꢂ1
49.36 min (major).
u
,
ꢁ 25 cm, n-hexane/2-propanol = 95:5, flow rate
k = 254 nm; tR (anti) = 48.10 min (minor) and
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.35–7.38 (m, 1H, ArH),
7.27–7.31 (m, 1H, ArH), 7.16 (t, 1H, J = 8.0 Hz, ArH), 5.03–5.12

F. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 380–388
387
Houk, K. N.; Schafmeister, C. E. J. Org. Chem. 2012, 77, 4784–4792; (l) Hong, B.-
C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2011, 13,
1338–1341.
(m, 2H, CH2), 4.89–4.92 (m, 1H, CH), 3.23–3.25 (m, 1H, CH), 2.50–
2.55 (m, 1H, CH2), 2.39–2.42 (m, 1H, CH2), 2.09–2.13 (m, 1H, CH2),
1.61–1.64 (m, 4H, CH2), 1.28–1.32 (m, 1H, CH2) ppm. The enantio-
meric excess was determined by HPLC with an Daicel Chiralpak
9. For recent examples of aldol reactions catalyzed by prolinamindes, see: (a)
Delaney, J. P.; Henderson, L. C. Adv. Synth. Catal. 2012, 354, 197–204; (b) Aitken,
D. J.; Bernard, A. M.; Capitta, F.; Frongia, A.; Guillot, R.; Ollivier, J.; Piras, P. P.;
Secci, F.; Spiga, M. Org. Biomol. Chem. 2012, 10, 5045–5048; (c) Revelou, P.;
Kokotos, C. G.; Moutevelis-Minakakis, P. Tetrahedron 2012, 68, 8732–8738; (d)
Tang, G. K.; Gün, Ü.; Altenbach, H.-J. Tetrahedron 2012, 68, 10230–10235; (e)
Thorat, P. B.; Goswami, S. V.; Khade, B. C.; Bhusare, S. R. Tetrahedron Lett. 2012,
53, 6083–6086.
10. For recent examples of aldol reactions catalyzed by prolinamindes, see: (a)
Morrthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 739–748; (b) Pedrosa, R.; Andrés,
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S.; Kokotos, C. G.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011, 1310–1317; (d)
Maycock, C. D.; Ventura, M. R. Tetrahedron: Asymmetry 2012, 23, 1262–1271;
(e) Kokotos, C. G. J. Org. Chem. 2012, 77, 1131–1135.
AD-H column 0.46
u
ꢁ 25 cm, n-hexane/2-propanol = 90:10, flow
rate 0.8 mL minꢂ1, k = 210 nm; tR (syn) = 14.48 min (major) and
15.26 min (minor).
Acknowledgments
We are grateful to financial support from the Natural Science
Foundation of China (No. Y4080450) and the Research Funds of
Shaoxing University (No. 20115025).
11. For recent examples of aldol reactions catalyzed by prolinethioamides, see: (a)
Gryko, D.; Lipinski, R. Adv. Synth. Catal. 2005, 347, 1948–1952; (b) Almaßsi, D.;
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