Direct asymmetric aldol reaction catalyzed by simple prolinamide phenols

Article abstract of DOI:10.1016/j.tetasy.2006.12.008

Simple prolinamides 1a-f were synthesized, and their catalytic effects on the direct asymmetric aldol reactions in organic solvents and in water were evaluated. Prolinamide phenols 1a-d were found to be effective catalysts for the reaction of aromatic ald

Full text of DOI:10.1016/j.tetasy.2006.12.008

Tetrahedron: Asymmetry 17 (2006) 3351–3357
Direct asymmetric aldol reaction catalyzed by simple
prolinamide phenols
Yu-Qin Fu, Zai-Chun Li, Li-Na Ding, Jing-Chao Tao,*
Sheng-Hong Zhang and Ming-Sheng Tang*
Department of Chemistry, New Drug Research and Development Center, Zhengzhou University, Zhengzhou 450052, PR China
Received 31 October 2006; accepted 7 December 2006
Available online 16 January 2007
Abstract—Simple prolinamides 1a–f were synthesized, and their catalytic effects on the direct asymmetric aldol reactions in organic sol-
vents and in water were evaluated. Prolinamide phenols 1a–d were found to be effective catalysts for the reaction of aromatic aldehydes
with cyclohexanone in neat ketone and in water. The anti-aldol products were obtained with up to 98/2 anti/syn ratio and 96% ee in neat
ketone, 98/2 anti/syn ratio and 99% ee in water, respectively.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
friendly, safe medium, which avoids the problems of pollu-
tion that are inherent with organic solvents.8 Although
some organocatalysts for the direct aldol reaction in
water/aqueous media have been developed in recent
years,5c,7b,9 highly efficient organocatalysts are still rare.9f,g
The asymmetric aldol reaction is one of the most powerful
methods for the construction of complex chiral polyol
architectures. Consequently, a large number of catalysts
and reagents have been developed in order to achieve an
efficient aldol addition with high diastereo- and enantio-
selectivities.1 Since the early discovery by List et al. that
L-proline can mimic type I aldolase to enantioselectively
catalyze intermolecular aldol reactions,2 the concept of
small organic molecules as catalysts (termed organocata-
lysts) has received much attention.3 Several organocatalysts
have been synthesized and applied to highly enantioselec-
tive direct aldol reactions over the past few years, for exam-
ple, 4-substituted-L-proline,4 N-sulfonylcarboxamides,5a
tetrazole,5b,c diamine-protonic acid,5d axially chiral amino
acids,5e,f small peptides,5g 3-pyrrolidinecarboxylic acid,5h
and prolinamides.6,7 However, highly efficient catalytic sys-
tems, which give high enantioselectivity for a broad range
of substrates with low catalyst loading, are still limited.
Therefore, the development of new and inexpensive organo-
catalysts or catalytic systems is still a frontier research topic
in asymmetric synthesis.
Considering that multiple-step acid–base catalysis is
thought to be involved in the formation and reaction of en-
amine intermediates,3 and inspired by the work of Gong,6
we presumed that prolinamide 1 may also induce the asym-
metric aldol reaction. The chirality, rigidity, and capability
of forming hydrogen bond within this class of compounds
would be responsible for enantioselectivity. Additionally,
the acidity of the amide and hydroxyl groups can be easily
adjusted through the modification of the aromatic ring.
2. Results and discussion
Prolinamides 1a–f were prepared from the commercially
available L-proline or trans-4-hydroxy-L-proline and corre-
sponding 2-aminophenol, 1-amino-2-naphthol or N-(2-
aminophenyl)-4-methylbenzenesulfonamide according to
the synthetic route shown in Scheme 1. The crystal struc-
ture of 1a was determined, with the molecular structure
as shown in Figure 1. 2-Amino-4,6-di-tert-butylphenol 3
was prepared by the nitration of 2,4-di-tert-butylphenol
with 6% nitric acid followed by the catalytic hydrogenation
with 10% Pd–C in ethanol in 36% overall yield. N-(2-Ami-
nophenyl)-4-methylbenzenesulfonamide was prepared by
Stereoselective reactions in water/aqueous media are an-
other important issue because water is an environmentally
*
Corresponding authors. Tel./fax: +86 371 67767200 (J.-C.T.); e-mail:
jctao@zzu.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.008

3352
Y.-Q. Fu et al. / Tetrahedron: Asymmetry 17 (2006) 3351–3357
R1
were poor (entries 5 and 6). When the loading of catalyst 1a
H2N
HO
R2
O
was decreased, and the reaction was run at lower tempera-
ture, both the yield and enantioselectivity were improved
upon (entries 1, 9 and 10, 75% yield and 78% ee was
obtained in the presence of 10 mol % 1a at 0 ꢁC).
i. DCC/CH2Cl2 , rt
+
OH
ii. TFA/CH2Cl2, rt
or HCl/acetone
N
Boc
R2
3
R2
R1
O
In order to increase the range of substrates, we investigated
cyclohexanone as an aldol donor in neat ketone at room
temperature, and the results are summarized in Table 2.
The catalytic efficiency of 1a–f was first evaluated using
o-nitrobenzaldehyde as an aldol acceptor. The results indi-
cated that 1a–f promoted this reaction, and the anti-iso-
mers were obtained with moderate to high yields, as well
as good to excellent diastereoselectivity and enantioselec-
tivity (entries 1–6). Compounds 1b, 1c, and 1d generated
better stereoselectivities than other catalysts (entries 2–4).
When 1b or 1d was used to catalyze the model reaction,
the aldol products were obtained with high yields (94–
98%), and with good to excellent diastereoselectivities
(anti/syn ratio 80:20–97:3) and enantioselectivities (95–
96% ee, entries 2 and 4). Compound 1c gave the highest ste-
reoselectivity (entry 3, the anti/syn ratio and enantiomeric
excess were up to 98:2 and 96%, respectively). However,
the catalytic activity of 1c was lower than that of 1b and
1d (entry 3 vs 2, 4; entry 8 vs 7, 9). When o-chlorobenzal-
dehyde was used as the aldol acceptor, 1d exhibited better
catalytic activity than 1b (entries 10 vs 11). Other aldehydes
generated aldol products in moderate yields and stereo-
selectivities (entries 13–16).
1a: R1 = H, R2 = H
1b: R1 = OH, R2 = H
N
H
1c: R1 = H, R2
= t-Bu
= t-Bu
R2
N
H
1d: R1 = OH, R2
HO
O
N
O
N
H
N
H
N
H
H
TsHN
HO
1f
1e
Scheme 1. Synthesis of prolinamides 1a–f.
In view of the good stereoselectivity in neat ketone, as well
as the amphiphilic character of 1a–d (there are hydrophilic
groups and hydrophobic groups simultaneously in the mole-
cules), we presumed that the asymmetric aldol reaction
may proceed in water. Cyclohexanones as aldol donors,
which react with aromatic aldehydes were tested, and the
results are summarized in Table 3.
Figure 1. Crystal structure of compound 1a.
the reaction of o-phenylene diamine with p-TsCl in
CH2Cl2/Na2CO3/H2O.
Initially, the catalytic effects of 1a–f were tested in the model
reaction of o-nitrobenzaldehyde with neat acetone in the
presence of 20 mol % catalyst at room temperature in air.
The best catalytic efficiency was observed with 1a (Table
1, entry 1, 53% yield and 73% ee). Compounds 1b–d exhib-
ited lower catalytic activity and moderate enantioselectivity
(entries 2–5, 16–36% yields and 47–68% ee). The enantio-
selectivities of the reactions utilizing 1e and 1f as catalysts
The application of these prolinamide phenol compounds
1a–d as catalysts to the aldol reaction of cyclohexanone
with o-nitrobenzaldehyde in water made the reaction pro-
ceed efficiently. The anti-aldol products were obtained with
good to excellent stereoselectivities (entries 1–4). Especially
when 1c was used, the anti-aldol product was obtained in
high yield (99%) with excellent diastereoselectivity (anti/
Table 1. Direct aldol reaction of aromatic aldehydes with acetone catalyzed by 1a–f
Entry
Aldehyde
Cat.
Cat. loading (mol %)
T (ꢁC)
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
o-NO2C6H4CHO
o-NO2C6H4CHO
o-NO2C6H4CHO
o-NO2C6H4CHO
o-NO2C6H4CHO
o-NO2C6H4CHO
p-NO2C6H4CHO
C6H5CHO
1a
1b
1c
1d
1e
1f
20
20
20
20
20
20
20
20
10
10
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
48
48
72
72
72
17
48
72
48
48
53
36
16
32
69
63
21
10
62
75
73
59
68
47
23
1
62
68c
75
78
1a
1a
1a
1a
o-NO2C6H4CHO
o-NO2C6H4CHO
10
a Isolated yields after thin layer chromatography on silica gel.
20
b The ee values were determined by chiral HPLC, and the major enantiomer was assigned to be (R) according to ½aꢀD and Ref. 2.
c In the literature the aldol product was obtained in 31% yield with 39% ee (determined by specific rotation).10

Y.-Q. Fu et al. / Tetrahedron: Asymmetry 17 (2006) 3351–3357
3353
Table 2. Direct aldol reaction of aldehydes with cyclohexanone catalyzed
by 10 mol % 1a–f in neat ketone
presence of 20 mol % of 1c than o-nitrobenzaldehyde and
halo-substituted benzaldehydes, while the enantioselectivi-
ties were in the moderate to good range (entries 3, 9–15).
Most of the halo-substituted benzaldehydes furnished the
corresponding aldol products in high yields with good dia-
stereoselectivities and high enantioselectivities (entries 11–
15, 86–94% ee). This result is much better than that
achieved in an organic solvent (Table 2). For the emulsion
that existed in the reaction mixture (the emulsion was more
stable in the case of 1c and 1d as catalysts than the cases of
1a and 1b), we reasoned that this type of catalysts, 1a–d,
could aggregate with reactants in water through hydropho-
bic interactions and sequester the transition state from
water. Therefore, the reaction proceeded more efficiently
in the aggregated organic phase, than in organic solvent,
to afford the aldol products with higher enantioselectivities
through a transition state similar to that in organic solvent.
O
OH O
CHO
1a-f
rt
+
R
R
Entry
Cat.
R
Time
(h)
Yielda
(%)
anti/synb
ee (%)
(anti)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
p-NO2
p-NO2
p-NO2
o-Cl
o-Cl
m-NO2
p-Cl
m-Br
m-Cl
48
48
48
48
48
48
48
48
24
96
48
72
72
72
72
72
79
98
37
94
74
33
96
70
92
51
71
66
31
57
40
28
85:15
97:3
98:2
90
95
96
96
66
89
70
82
74
90
87
68
63
73
56
53
80:20
63:37
82:18
83:17
78:22
74:26
89:11
91:9
79:21
87:13
89:11
85:15
75:25
1b
1c
1d
1b
1d
1d
1d
1d
1d
1d
Cyclopentanone was finally explored as an aldol donor.
The reaction of cyclopentanone with o-nitrobenzaldehyde
proceeded smoothly in water to give the corresponding
aldol product in 78% yield. The diastereomeric ratio of
anti/syn was 60:40. An enantioselectivity of 78% ee and
82% ee was observed for anti-isomers and syn-isomers,
respectively (Eq. 1).
p-F
a Isolated yields for (anti + syn) after thin layer chromatography on silica
gel.
1
b Determined by analysis of H NMR spectra of the mixture of anti- and
syn-products.
NO2
O
OH
NO2
O
O
c Determined by chiral HPLC on a chiralcel OD-H column.
1c (20 mol% )
H
+
H2O, rt, 48 h
syn ratio up to 96:4) and enantiomeric excess (ee >99%).
Even if the catalyst loading was reduced from 20 to
5 mol %, excellent results were still obtained (entries 3, 5,
and 6, anti/syn = 92:2 and 92% ee for anti-isomer were ob-
tained with 5 mol % of 1c). High diastereoseslectivity and
enantioselectivity were also achieved in the presence of only
5 mol % of 1d (entry 8, 98:2 of anti/syn and 92% ee). p-Ni-
tro and m-nitrobenzaldehyde were more reactive in the
ð1Þ
yield 78%
anti syn = 60:40
ee 78% (anti), 82% (syn
/
)
Previous experiments showed that if there was no ortho-
hydroxyl group attached to the amide in 1a, it catalyzed
the reaction of p-nitrobenzaldehyde with acetone at room
Table 3. Direct aldol reaction of cyclohexanone with aldehydes catalyzed by 1a–d in water at room temperature
O
OH
O
CHO
1a-d
H2O, rt
+
R
R
Entry
Cat.
R
Cat. loading (mol %)
Time (h)
Yielda (%)
anti/synb
ee (anti, %)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1c
1c
1d
1d
1c
1c
1c
1c
1c
1c
1c
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
p-NO2
m-NO2
o-Cl
20
20
20
20
10
5
48
48
48
48
72
72
72
72
24
24
72
72
72
72
72
80
77
99
98
96
95
90
80
98
98
85
90
94
90
80
79:21
86:14
96:4
90:10
94:6
92:8
94:6
98:2
89:11
85:15
93:7
78:22
86:14
81:19
92:8
86
85
>99
90
93
92
92
92
45
89
76
86
88
90
94
10
5
20
20
20
20
20
20
20
m-Cl
p-Cl
m-Br
p-F
a Isolated yields for (anti + syn) after thin layer chromatography on silica gel.
b Determined by analysis of 1H NMR spectra of the mixture of anti and syn products.
c Determined by chiral HPLC on a chiralcel OD-H column.

3354
Y.-Q. Fu et al. / Tetrahedron: Asymmetry 17 (2006) 3351–3357
temperature with only 37% ee.6c Therefore, we assumed
that the hydroxyl group participated in the catalytic pro-
cess. Analogous to the proline-catalyzed aldol reaction2
and the Gong’s prolinamide alcohol-catalyzed aldol reac-
tion,6 the mechanism through enamine intermediate was
proposed, and a model of the transition state is depicted
in Figure 2a. Theoretical calculations have been carried
out for the simple model reaction of benzaldehyde with
acetone to understand the high enantioselectivity (all calcu-
lations were implemented in the Gaussian 03 program).
Transition Structures in the stereo-controlling C–C bond
formation step were studied using Hartree–Fock method
at 6-31G (d) level. The best transition structure shown in
Figure 2b corresponds to the channel with the lowest active
energy; therefore, leading to the formation of the (R)-aldol
product. Both the amide and the hydroxyl groups are
hydrogen-bonded with the aldehyde. The hydroxyl group
appears to be the better hydrogen-bond donor as indicated
by the shorter hydrogen bond. This model is in agreement
with the above experimental results and the proposed
mechanism.
ence. FT-IR spectra were determined on a Thermo Nicolet
IR200 unit. High resolution mass spectra (HR-MS) were
obtained on a Waters Micromass Q-Tof MicroTM instru-
ment using the ESI technique. Chromatography was per-
formed on silica gel (200–300 mesh). Melting points were
determined using a XT5A apparatus and are uncorrected.
Optical rotations were determined on a Perkin Elmer341
polarimeter. The single crystal structure was determined
on a Bruker CCD area detector. Enantiomeric excess was
measured by chiral HPLC at room temperature using JAS-
CO PU-1580 pump equipped with JASCO UV-1575 ultra
detector (or Syltech 500 pump equipped with a UV 500
version 4.1 ultra-violet detector) with Chiralpak AD
(4.6 mm · 250 mm) or Chiralcel OD-H (4.6 mm · 250 mm)
columns.
4.2. General procedure for the preparation of 1a–f
Compound 1a is referred to as an example: To a stirred
solution of N-Boc-L-proline 2 (430 mg, 2.0 mmol) and
2-aminophenol 3 (240 mg, 2.2 mmol) in dichloromethane
(10 mL) was added dicyclohexylcarbodiimine (DCC,
453 mg, 2.2 mmol) at room temperature. After stirring
for about 5 h, the mixture was filtered. The filtrate was
concentrated and recrystallized from chloroform to afford
N-Boc protected prolinamide phenol as a white solid.
Deprotection of the Boc group was performed using 30%
TFA in dichloromethane for 2 h at room temperature.
After evaporation of the solvent, the resulting residue
was neutralized with aqueous Na2CO3 solution, and
extracted with n-butanol. The organic layer was dried over
Na2SO4, filtered, and concentrated followed by column
chromatography on silica gel (MeOH/CHCl3 = 1:10, v/v)
to give a semi-solid product, which was recrystallized from
methanol-chloroform to furnish 1a as a colorless crystal.
Figure 2. Transition structure of the aldol reaction of benzaldehyde with
acetone catalyzed by 1a: (a) proposed transition structure model and (b)
calculated transition structure.
4.2.1. (S)-N-(2-Hydroxyphenyl)pyrrolidine-2-carboxamide
1a. Colorless crystals, 312 mg, yield 76%; mp 166–
20
167 ꢁC; ½aꢀD ¼ ꢁ41:0 (c 1.41, EtOH); IR (KBr, cmꢁ1):
3311, 3224, 2983, 2741, 2570, 1667, 1618, 1602, 1549,
3. Conclusion
1
1458, 1199, 1183, 1142, 748; H NMR (D2O) d: 1.97 (m,
2H, CH2), 2.09 (m, 1H, CHHCH), 2.41 (m, 1H, CHHCH),
3.25–3.36 (m, 2H, NCH2), 4.43 (m, 1H, CH), 6.84 (t,
J = 8.0 Hz, 1H, Ar–H), 6.87 (d, J = 8.0 Hz, 1H, Ar–H),
7.08 (t, J = 8.0 Hz, 1H, Ar–H), 7.32 (d, J = 8.0 Hz, 1H,
Ar–H); 13C NMR (D2O) d: 25.3, 31.3, 48.0, 61.6, 117.8,
121.9, 124.5, 127.0, 129.5, 150.8, 170.4; HR MS; ESI;
m/z: calcd for C11H15N2O2 (M+H)+ 207.1134, found
207.1136.
In conclusion, a series of prolinamides 1a–f derived from
L-proline were synthesized and evaluated for their ability to
catalyze the direct aldol reaction of aldehydes with ketone
in neat ketone and in water. Compounds 1c and 1d demon-
strated good to excellent reactivity, diastereoselectivity,
and enantioselectivity on the reaction of arylaldehydes with
cyclohexanone both in neat ketone and in water. Further
studies on the influences of organic solvents, generality of
more substrates and the application of 1a–d in other reac-
tions are ongoing and will be reported in due course.
Crystals suitable for X-ray analysis were obtained by
recrystallization from chloroform/methanol at room
temperature.
4. Experimental
4.1. General
CCDC-603255 contains the supplementary crystallographic
data for this compound. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
All chemicals were used as received unless otherwise noted.
Reagent grade solvents were distilled prior to use. All re-
ported H NMR spectra were collected on a Bruker DPX
4.2.2. (2S,4R)-4-Hydroxy-N-(2-hydroxyphenyl)pyrrolidine-
2-carboxamide 1b. White solid, 275 mg, yield 62%: mp
136–138 ꢁC, ½aꢀD ¼ ꢁ20:0 (c 1.36, EtOH); IR (KBr,
1
20
400 NMR spectrometer with TMS as the internal refer-

Y.-Q. Fu et al. / Tetrahedron: Asymmetry 17 (2006) 3351–3357
3355
cmꢁ1): 3286, 3200, 3061, 2978, 2942, 2923, 2871, 2746,
2705, 1662, 1600, 1546, 1509, 1455, 755; H NMR (D2O)
2.18–2.22 (m, 1H, CHHCH), 2.39 (s, 3H, CH3), 2.97–3.01
(m, 1H, CHHNH), 3.06–3.11 (m, 1H, CHHNH), 3.94–
3.98 (m, 1H, CHCO), 5.10 (s, 3H, 3NH), 7.06–7.10 (m,
1H, Ar–H), 7.15–7.21 (m, 2H, Ar–H), 7.20 (d,
J = 8.4 Hz, 2H, Ar0–H), 7.43 (d, J = 8.0 Hz, 1H, Ar–H),
7.56 (d, J = 8.4 Hz, 2H, Ar0–H); 13C NMR (CDCl3) d:
21.5, 26.0, 30.5, 47.0, 60.5, 123.3 (Ar–C), 125.9 (Ar–C),
127.1 (2Ar0–C), 127.3 (Ar–C), 127.5 (Ar–C), 128.5 (Ar–
C), 129.4 (2Ar0–C), 132.5 (Ar–C), 137.1 (Ar0–C), 143.4
(Ar0–C), 173.4 (C@O); HRMS; ESI; m/z: calcd for
C18H22N3O3S (M+H+) 360.1382, found: 360.1379.
1
d: 2.00 (m, 1H, CHCHHCH), 2.22 (m, 1H, CHCHHCH),
2.95–3.09 (m, 2H, NCH2), 4.14 (t, J = 8.4 Hz, 1H, CH),
4.45 (m, 1H, CH), 6.82–6.89 (m, 2H, Ar–H), 7.08
(m, 1H, Ar–H), 7.43 (dd, J = 8.0, 1.2 Hz, 1H, Ar–H); 13C
NMR (D2O) d: 38.6, 53.9, 59.3, 72.0, 116.6, 119.6, 124.0,
124.5, 127.4, 150.0, 174.6; HR MS; ESI; m/z: calcd for
C11H15N2O3 (M+H)+ 223.1083, found 223.1084.
4.2.3. (S)-N-(3,5-Di-tert-butyl-2-hydroxyphenyl)pyrrolidine-
2-carboxamide 1c. White solid, 504 mg, yield 79%; mp
20
217–218 ꢁC; ½aꢀD ¼ ꢁ36:8 (c 1.18, EtOH); IR (KBr,
4.3. General procedure for the preparation of aldol products
cmꢁ1): 3200, 2960, 2756, 1702, 1660, 1595, 1558, 1482,
1
1390, 1362, 1227, 874; H NMR (CDCl3) d: 1.22 (s, 9H,
4.3.1. General procedure for the aldol reaction of acetone
with aldehydes in neat acetone. To a stirred mixture of
0.5 mmol aldehyde and 1.0 mL acetone was added the cat-
alyst at the indicated temperature. The mixture was stirred
for the indicated time, then was purified by thin layer chro-
matography on silica gel (petroleum ether/ethyl acetate).
t-Bu), 1.35 (s, 9H, t-Bu), 1.76–1.93 (m, 3H, CH2CHHCH),
2.15 (m, 1H, CHHCH), 3.21–3.31 (m, 2H, NCH2), 5.04 (m,
1H, CH), 7.07 (d, J = 2.4 Hz, 1H, Ar–H), 7.17 (d, J =
2.4 Hz, 1H, Ar–H), 7.95 (s, 1H, NH), 9.44 (s, 1H, NHCO),
10.04 (s, 1H, OH); 13C NMR (CDCl3) d: 24.1, 29.8 (3CH3),
30.2, 31.5 (3CH3), 34.2, 35.2, 46.8, 60.3, 120.5, 122.5, 124.1,
138.3, 142.3, 146.7, 169.4; HR MS; ESI; m/z: calcd for
C19H31N2O2 (M+H)+ 319.2385, found 319.2381.
4.3.1.1. 4-Hydroxyl-4-(2-nitrophenyl)-butan-2-one. 1H
NMR (CDCl3) d: 2.24 (s, 3H), 2.74 (dd, J = 17.8, 9.4 Hz,
1H), 3.13 (dd, J = 17.8, 1.8 Hz, 1H), 3.89 (s, 1H), 5.68
(dd, J = 9.4, 1.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.67
(t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.96 (d,
J = 8.0 Hz 1H); HPLC: Chiralcel OD-H, UV 254,
i-PrOH/hexane = 15/85, flow rate 0.5 mL/min, (S)-isomer,
tR 17.8 min, (R)-isomer, tR 20.4 min.
4.2.4. (2S,4R)-4-Hydroxy-N-(3,5-di-tert-butyl-2-hydroxy-
phenyl)pyrrolidine-2-carboxamide 1d. White solid, 514 mg,
20
yield 77%; mp 78.4–80.1 ꢁC; ½aꢀD ¼ ꢁ16:2 (c 1.07, EtOH);
IR (KBr, cmꢁ1): 3386, 3199, 2955, 1685, 1659, 1596, 1560,
1519, 1481, 1456, 1362, 1225, 1032, 869; 1H NMR
(DMSO-d6) d: 1.24 (s, 9H, t-Bu), 1.36 (s, 9H, t-Bu), 1.78–
1.84 (m, 1H, CHCHHCH), 2.04–2.09 (m, 1H,
CHCHHCH), 2.84–2.92 (m, 2H, NCH2), 3.40 (s, 1H,
OH), 3.96 (t, J = 8.0 Hz, 1H, CH), 4.24 (m, 1H, CH), 4.74
(s, 1H, OH), 7.03 (d, J = 2.0 Hz, 1H, ArH), 7.41 (d,
J = 2.0 Hz, 1H, ArH), 8.83 (s, 1H, CONH), 10.13 (s, 1H,
ArOH); 13C NMR (DMSO-d6) d: 29.9 (3CH3), 31.5
(3CH3), 34.2, 35.0, 39.5, 55.2, 59.9, 71.6, 117.4, 119.5,
127.7, 138.5, 141.7, 144.5, 174.9; HR MS; ESI; m/z: calcd
for C19H31N2O3 (M+H)+ 335.2334, found 335.2324.
4.3.1.2. 4-Hydroxyl-4-(4-nitrophenyl)-butan-2-one. 1H
NMR (CDCl3) d: 2.24 (s, 3H), 2.87 (d, J = 6.0 Hz, 2H),
3.61 (s, 1H), 5.28 (t, 1H, J = 6.0 Hz), 7.55 (d, J = 8.8 Hz,
2H), 8.20 (dd, J = 8.8, 2.0 Hz, 2H); HPLC: Chiralcel
OD-H, UV 254, i-PrOH/hexane = 10/90; flow rate
0.5 mL/min, (R)-isomer, tR 37.8 min, (S)-isomer, tR
40.3 min.
4.3.1.3. 4-Hydroxyl-4-phenyl-butan-2-one. 1H NMR
(CDCl3) d: 2.13 (s, 3H), 2.74 (dd, J = 17.2, 3.2 Hz, 1H),
2.85 (dd, J = 17.2, 9.6 Hz, 1H), 3.63 (s, 1H), 5.10 (dd,
J = 9.6, 3.2 Hz, 1H), 7.24–7.32 (m, 5H); HPLC: Chiralpak
AD, i-PrOH/hexane = 5/95, flow rate 0.6 mL/min, (R)-iso-
mer, tR 23.4 min, (S)-isomer, tR 25.6 min.
4.2.5. (S)-N-(2-Hydroxynaphthalen-1-yl)pyrrolidine-2-car-
boxamide 1e. White solid, 370 mg; yield 74%; mp: 179–
20
181 ꢁC, ½aꢀD ¼ ꢁ28:3 (c 0.64, MeOH). IR (KBr disc)
cmꢁ1: 3344, 3294, 3268, 3208, 3064, 2983, 2884, 1677,
1627, 1575, 1505, 1280, 752; 1H NMR (DMSO-d6) d:
1.70–1.79 (m, 2H, CH2), 1.90–1.94 (m, 1H, CHH), 2.09–
2.14 (m, 1H, CHH), 2.98 (m, 2H, NCH2), 3.87 (dd,
J = 8.8, 5.6 Hz, 1H, NCH), 7.20 (d, J = 8.8 Hz, 1H, Ar–
H), 7.31 (t, J = 7.6 Hz, 1H, Ar–H), 7.45 (t, J = 7.6 Hz,
1H, Ar–H), 7.62 (d, J = 8.4 Hz, 1H, Ar–H), 7.72
(d, J = 8.8 Hz, 1H, Ar–H), 7.82 (d, J = 8.0 Hz, 1H, Ar–
H), 9.77 (br, 2H, NHCO, OH); 13C NMR (DMSO-d6)
d: 26.2, 30.9, 47.0, 60.8, 116.8, 119.1, 121.9, 123.1, 126.4,
127.7, 128.1, 128.3, 130.9, 149.7, 174.9; HRMS; ESI; m/z:
4.3.2. General procedure for the aldol reaction of cyclo-
hexanone with aldehydes
4.3.2.1. Reaction in neat ketone. Catalyst (0.05 mmol)
was added to a solution of 0.5 mmol of aldehyde in
1.0 mL cyclohexanone. After being stirred for the indicated
time, the mixture was treated with saturated ammonium
chloride solution and extracted with ethyl acetate. The
organic layer was dried over MgSO4, filtered, and concen-
trated to give pure aldol product after thin layer
chromatographic purification on silica gel (petroleum
ether/ethyl acetate).
calcd for C15H16N2Oþ; M+H+Å; 257.1290, found 257.1291.
2
4.2.6. (S)-N-(2-(4-Methylphenylsulfonamido)phenyl)pyrrol-
idine-2-carboxamide 1f. Yellow-white powder: mp 62.7–
4.3.2.2. Reaction in water. Aldehyde (0.33 mmol) was
added to the mixture of 0.4 mL cyclohexanone, 1.0 mL
water, and 0.067 mmol of catalyst. After being stirred at
room temperature for the indicated time, the mixture was
treated the same as that of the step in neat ketone.
20
64.4 ꢁC; ½aꢀD ¼ ꢁ60:8 (c 0.88, EtOH); IR (KBr, cmꢁ1):
3376, 3243, 3064, 2971, 2875, 1672, 1597, 1525, 1453,
1
1333, 1161, 1092, 815, 760, 661, 565; H NMR (CDCl3)
d: 1.76–1.81 (m, 2H, CH2), 1.95–1.98 (m, 1H, CHHCH),

3356
Y.-Q. Fu et al. / Tetrahedron: Asymmetry 17 (2006) 3351–3357
4.3.2.3.
2-(Hydroxyl(4-nitrophenyl)methyl)cyclohexa-
4.3.2.8. 2-(Hydroxyl(3-chlorophenyl)methyl)cyclohexa-
none. 1H NMR (CDCl3) d: syn-isomer: 1.45–2.11 (m,
6H), 2.32–2.45 (m, 2H), 2.53–2.56 (m, 1H), 3.05 (s, 1H),
5.50 (d, J = 2.0 Hz, 1H), 7.21–7.30 (m, 3H, Ar), 7.37 (s,
1H, Ar); anti-isomer: 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); HPLC (for anti-isomer): Chiralcel
OD-H, UV 220, i-PrOH/hexane = 1/30, flow rate 1.0 mL/
min, tR 14.2 min (major), tR 19.1 min (minor).
none. 1H NMR (CDCl3) d: syn-isomer: 1.50–1.88 (m,
5H), 2.09–2.15 (m, 1H), 2.37–2.52 (m, 2H), 2.62–2.66 (m,
1H), 3.10 (s, 1H), 5.49 (d, J = 1.6 Hz, 1H), 7.49 (d,
J = 8.4 Hz, 2H), 8.22 (d, J = 8.4 Hz, 2H); anti-isomer:
1.36–1.44 (m, 1H), 1.51–1.73 (m, 3H), 1.83 (m, 1H),
2.10–2.15 (m, 1H), 2.33–2.46 (m, 1H), 2.50 (m, 1H),
2.57–2.63 (m, 1H), 3.80 (s, 1H), 4.90 (d, J = 8.4 Hz, 1H),
7.51 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H); HPLC
(for anti-isomer): Chiralcel OD-H, UV 254, i-PrOH/hex-
ane = 5/95, flow rate 1.0 mL/min, tR 33.8 min (major), tR
44.7 min (minor).
4.3.2.9. 2-(Hydroxyl(3-bromophenyl)methyl)cyclohexa-
none. 1H NMR (CDCl3) d: syn-isomer: 1.50–2.08 (m,
6H), 2.31–2.61 (m, 3H), 5.36 (d, J = 2.0 Hz, 1H), 7.20–
7.23 (m, 2H), 7.39–7.50 (m, 2H); anti-isomer: 1.30–2.08
(m, 6H), 2.30–2.45 (m, 3H), 4.74 (d, J = 8.8 Hz, 1H),
7.20–7.23 (m, 2H), 7.39–7.50 (m, 2H). HPLC (for anti-iso-
mer): Chiralcel OD-H, UV 254, i-PrOH/hexane = 5/95,
flow rate 1.0 mL/min, tR 12.3 min (major), tR 16.5 min
(minor).
4.3.2.4.
2-(Hydroxyl(2-nitrophenyl)methyl)cyclohexa-
none. 1H NMR (CDCl3) d: syn-isomer: 1.53–1.87 (m,
5H), 2.10 (m, 1H), 2.42–2.47 (m, 2H), 2.90 (dd, J = 13.2,
4.8 Hz, 1H), 3.15 (s, 1H), 5.96 (d, J = 1.6 Hz, 1H), 7.46
(dt, J = 0.8, 8.0 Hz, 1H), 7.66 (dt, J = 0.8, 8.0 Hz, 1H),
7.84 (dd, J = 8.0, 0.8 Hz, 1H), 8.02 (dd, J = 8.0, 0.8 Hz,
1H); anti-isomer: 1.61–1.87 (m, 5H), 2.10 (m, 1H), 2.34–
2.47 (m, 2H), 2.77 (m, 1H), 3.95 (s, 1H), 5.45 (d,
J = 7.2 Hz, 1H), 7.44 (dt, J = 0.8, 8.0 Hz, 1H), 7.66 (dt,
J = 0.8, 8.0 Hz, 1H), 7.78 (dd, J = 8.0, 0.8 Hz, 1H), 7.86
(dd, J = 8.0, 0.8 Hz, 1H); HPLC (for anti-isomer): Chiral-
cel OD-H, UV 254, i-PrOH/hexane = 5/95, flow rate
0.5 mL/min, tR 38.1 min (major), tR 47.6 min (minor).
4.3.2.10. 2-(Hydroxyl(4-fluorophenyl)methyl)cyclohexa-
none. 1H NMR (CDCl3) d: syn-isomer: 1.50–1.87 (m,
5H), 1.84–1.88 (m, 1H), 2.36–2.56 (m, 3H), 3.05 (br, 1H),
5.36 (d, J = 1.6 Hz, 1H), 7.00–7.05 (m, 2H), 7.25–7.29
(m, 2H); anti-isomer: 1.24–1.33 (m, 1H), 1.53–1.82 (m,
4H), 2.07–2.12 (m, 1H), 2.35–2.59 (m, 3H), 4.01 (s, 1H),
4.77 (d, J = 8.8 Hz, 1H), 7.01–7.05 (m, 2H), 7.27–7.31
(m, 2H); HPLC (for anti-isomer): Chiralcel OD-H, UV
254, i-PrOH/hexane = 5/95, flow rate 0.5 mL/min, tR
23.6 min (major), tR 40.2 min (minor).
4.3.2.5. 2-(Hydroxyl(2-chlorophenyl)methyl)cyclohexa-
none. 1H NMR (CDCl3) d: syn-isomer: 1.53–1.71 (m,
4H), 1.81–1.84 (m, 1H), 2.08 (m, 1H), 2.33–2.42 (m, 1H),
2.48 (m, 1H), 2.81 (m, 1H), 3.95 (s, 1H), 5.72 (d,
J = 2.0 Hz, 1H), 7.20–7.34 (m, 3H), 7.56 (d, J = 8.0 Hz,
1H); anti-isomer: 1.53–1.84 (m, 5H), 2.05–2.13 (m, 1H),
2.31–2.39 (m, 1H), 2.46–2.49 (m, 1H), 2.65–2.71 (m, 1H),
3.88 (s, 1H), 5.35 (d, J = 8.0 Hz, 1H), 7.20–7.34 (m, 3H),
7.56 (d, J = 8.4 Hz, 1H); HPLC (for anti-isomer): Chiralcel
OD-H, UV 220, i-PrOH/hexane = 5/95, flow rate 1.0 mL/
min, tR 10.0 min (major), tR 12.9 min (minor).
4.3.2.11. 2-(Hydroxy(2-nitrophenyl)methyl)cyclopenta-
none. 1H NMR (CDCl3) d: syn-isomer: 1.70–1.78 (m,
2H), 2.03–2.19 (m, 3H), 2.37 (dd, J = 8.0, 1.6 Hz, 1H),
2.60 (br, 1H), 2.74 (m, 1H), 5.92 (d, J = 2.4 Hz, 1H) 7.44
(td, J = 8.0, 0.8 Hz, 1H, Ar–H), 7.66 (t, J = 8.0 Hz, 1H,
Ar–H), 7.89 (d, J = 8.0 Hz, 1H, Ar), 8.02 (d, J = 8.0 Hz,
1H, Ar–H); anti-isomer: 1.70–2.03 (m, 4H), 2.19–2.38 (m,
2H), 2.68 (d, J = 7.6 Hz, 1H), 2.90 (br, 1H), 5.21 (d,
J = 7.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H, Ar–H), 7.66 (t,
J = 8.0 Hz, 1H, Ar–H), 7.89 (d, J = 8.0 Hz, 1H), 8.00
(dd, J = 8.0, 0.8 Hz, 1H); HPLC: syn-isomer: Chiralcel
OD-H, UV 254, i-PrOH/hexane = 5/95, flow rate 1.0 mL/
min, tR 17.5 min (major), tR 13.7 min (minor); anti-isomer:
Chiralcel OD-H, UV 254, i-PrOH/hexane = 5/95, flow rate
1.0 mL/min, tR 22.6 min (major), tR 25.6 min (minor).
4.3.2.6. 2-(Hydroxyl(4-chlorophenyl)methyl)cyclohexa-
none. 1H NMR (CDCl3) d: syn-isomer: 1.42–2.11 (m,
6H), 2.32–2.45 (m, 2H), 2.53–2.56 (m, 1H), 3.05 (s, 1H),
5.36 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.32
(d, J = 8.4 Hz, 2H); anti-isomer: 1.27–1.31 (m, 1H), 1.53–
1.82 (m, 4H), 2.07–2.11 (m, 1H), 2.35–2.56 (m, 3H), 4.76
(d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.32 (d,
J = 8.0 Hz, 2H); HPLC (for anti-isomer): Chiralcel OD-
H, UV 220, i-PrOH/hexane = 5/95, flow rate 1.0 mL/min,
tR 13.9 min (major), tR 21.5 min (minor).
Acknowledgments
4.3.2.7.
2-(Hydroxyl(3-nitrophenyl)methyl)cyclohexa-
We are grateful for the financial support from the National
Natural Science Foundation of China (grants 20372059).
We also thank Jian-Xun Kang and Wei-Guo Zhu for the
determination of NMR, Shao-Min Wang for HRMS and
Jian-Ge Wang for the analysis of the single crystal structure.
none. 1H NMR (CDCl3) d: syn-isomer: 1.48–2.10 (m,
6H), 2.33–2.48 (m, 2H), 2.62–2.66 (m, 1H), 3.16 (s, 1H),
5.48 (d, J = 2.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.66 (d,
J = 1.4 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.20 (d,
J = 8.0 Hz, 1H); anti-isomer: 1.33–2.10 (m, 6H), 2.32–
2.48 (m, 2H,), 2.70 (m, 1H), 3.16 (s, 1H), 4.91 (d,
J = 8.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.68 (d,
J = 0.8 Hz, 1H), 8.15 (m, J = 8.0 Hz, 1H), 8.20 (d,
J = 8.0 Hz, 1H); HPLC (for anti-isomer): Chiralcel OD-
H, UV 254, i-PrOH/hexane = 5/95, flow rate 1.0 mL/min,
tR 22.4 min (major), tR 31.2 min (minor).
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