One-step, efficient synthesis of combined threonine-surfactant organocatalysts for the highly enantioselective direct aldol reactions of cyclic ketones with aromatic aldehydes in the presence of water

Article abstract of DOI:10.1016/j.tetasy.2010.09.006

In this work, a new class of organocatalysts have been designed and synthesized in one step by a rational combination of threonine with acyl chlorides at room temperature in trifluoroacetic acid to make a series of novel combined threonine-surfactant orga

Full text of DOI:10.1016/j.tetasy.2010.09.006

Tetrahedron: Asymmetry 21 (2010) 2465–2470
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
One-step, efficient synthesis of combined threonine–surfactant
organocatalysts for the highly enantioselective direct aldol reactions
of cyclic ketones with aromatic aldehydes in the presence of water
⇑
Chuanlong Wu, Xiangkai Fu , Xuebing Ma, Shi Li
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:
Received 20 July 2010
Accepted 6 September 2010
Available online 8 November 2010
In this work, a new class of organocatalysts have been designed and synthesized in one step by a rational
combination of threonine with acyl chlorides at room temperature in trifluoroacetic acid to make a series
of novel combined threonine-surfactant organocatalysts readily available on a large-scale. No protecting
groups or chromatographic techniques are involved in the procedures, while certain combined threonine-
surfactant organocatalysts mediate the direct aldol reactions of cyclic ketones with aromatic aldehydes to
provide the aldol products in good yields with enantioselectivities of up to 99%.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives are highly efficient organocatalysts for asymmetric
aldol reactions of ketones in the presence of water.8 Although these
Asymmetric organocatalysis has become an important area of
research in organic synthesis.1 The asymmetric aldol reaction is
one of the most powerful methods for constructing carbon–carbon
bonds in organic synthesis.2 The past decade has witnessed the
extraordinary success of amines, especially the use of chiral pri-
mary amino acids and their derivatives which is an important area
of research in enantioselective aldol reactions.3 It has been reported
that primary amino acid catalyzed aldol reactions3k,q,r can only
afford high enantioselectivity in solvents such as dimethylsulfoxide
(DMSO) and N,N-dimethylformamide (DMF); these polar solvents
often create additional hurdles for product isolation. Water is an
ideal solvent for chemical reactions due to its low cost, safety,
and environmentally benign nature. As water offers several
advantages over organic solvents, reactions in aqueous media have
received a great deal of attention in recent years.4 However, the vast
majority of organocatalytic reactions yield racemic products if the
reactions take place in the presence of water.5 Recently, it was
shown by Takabe et al., Barbas et al. and Hayashi et al. that the
direct asymmetric aldol reaction and the Michael reaction could
be catalyzed by the proline-derived hydrophobic catalysts in the
presence of water.3n,o,6 Our group recently reported that the
4-phenoxy substituted and the 4-tert-butyl-dimethylsiloxy-
substituted prolinamides catalyze the direct aldol reactions
between cyclic ketones and aromatic aldehydes in the presence of
water.7 Lu et al. reported that the siloxy theronine and serine
amino acids were not efficient organocatalysts in direct aldol
reactions between cyclohexanone and benzaldehyde in water, their
hydrophobic derivatives (e.g., O-TBS-threonine) proved to be very
efficient catalysts. The desired aldol products were obtained in
excellent yields (up to 99%), with nearly perfect enantiomeric
control (up to 99% ee). However, it should be noted that among
all the reported asymmetric organocatalysts, most of them were
prepared with a laborious procedure, tiresome purification of
chromatography, and/or need some expensive reagents, which
created additional hurdles for industrial production. As a result
these organocatalysts are often only used in research laboratories.
Therefore, the development of a new type of effective asymmetric
organocatalysts from the chiral pool, with simple preparation
procedures, and using inexpensive reagents is urgently needed
and is a significant challenge. Herein, we disclose our findings that
simple, natural L-threonine derivatives are excellent organocata-
lysts for the direct aldol reactions in aqua.
For the design of novel catalysts lꢀHCl, we are particularly inter-
ested in organocatalysts that can be easily derived from the crude
chiral pool. We hypothesized and deduced that the incorporation
of a hydrophobic group into hydrophilic natural amino acids,
which are usually abundant in the chiral pool, which could en-
hance their hydrophobic capability, consequently their interaction
with organic substrates may be favorable in aqueous media.9 With
the properly designed catalysts, water can be sequestered from the
transition state and high stereocontrol may be expected. This ap-
proach is particularly attractive in view of the ready availability
of natural amino acids and the variety of chiral structural scaffolds
that they can offer.
⇑
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 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.006

2466
C. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2465–2470
Threonine seems to be good chiral structural scaffolds, as its hy-
When only with 5 mol % catalyst 1cꢀHCl, the desired aldol product
was obtained in about 97% yield and with 99% ee in the presence of
water (Table 1, entry 9). When the reaction was carried out neat,
both the diastereoselectivity and the enantioselectivity decreased
(Table 1, entry 10). This result provides evidence that the reaction
proceeds in the organic phase, created inside the emulsion when
the reaction is performed in the presence of water.
Having optimized the reaction conditions, the combined threo-
nine–surfactant organocatalyst 1cꢀHCl catalyzed direct aldol reac-
tions in the presence of water that were extended to a series of
aromatic aldehydes to explore the generality of this catalytic sys-
tem. The results are summarized in Table 2.
droxy group allows for the easy attachment of various hydrophobic
groups such as alkyl, acyl, and so on.10a–c,8 In this work we show
how an O-acylation of
L-threonine with acyl chlorides at room
temperature in trifluoroacetic acid in one step makes a series of
novel
L-threonine derivatives readily available on large-scale
(Scheme 1).10d,e No protecting groups or chromatographic tech-
niques are involved in the procedures, and certain combined
threonine-surfactant organocatalysts mediate the direct aldol
reaction of cycloheaxanone with 4-nitrobenzaldehyde in the
presence of water (Table 1).
O
1a.HCl n=2
1b.HCl n=4
In the presence of only 5 mol % of catalyst 1cꢀHCl, most reac-
tions between cyclohexanone and various aromatic aldehydes
afforded the aldol products in excellent yields and nearly perfect
enantioselectivities in water. The more reactive aromatic alde-
hydes underwent the catalytic process to afford the products in
excellent enantioselectivities and with good diastereoselectivities
(Table 2, entries 1–10). In contrast, the enantioselectivities ob-
tained for a representative electron rich aromatic aldehydes gave
excellent enantioselectivity, especially the p-tolualdehyde (Table 2,
entry 11, 85:15 anti/syn ratio and >99% ee), although the yield was
moderate (Table 2, entries 11–13). Moreover, the direct aldol reac-
tion of neutral aromatic aldehydes catalyzed by the catalyst 1cꢀHCl
also afforded the products in high enantioselectivities and diaste-
reoselectivities (Table 2, entries 14–17).
Cyclopentanone and 4-methylclohexanone were also explored
as aldol donors with nitrobenzaldehydes (o-nitrobenzaldehyde,
m-nitrobenzaldehyde, p-nitrobenzaldehyde) under the same con-
ditions. As shown in Table 3, the aldol products were obtained in
high yields (up to 98%) with excellent enantioselectivities (up to
99% ee).
1. acyl chlorides
(1.5 equiv),
HO
CO2H
NH2
O
1c.HCl
1d.HCl
n=6
n=8
CF3CO2H
CO2H
NH3Cl
n
H3C
1e.HCl n=10
2. crystallization
from Et2O
H3C
1f.HCl
n=14
1g.HCl n=16
Scheme 1. Synthetic scheme for acyloxythreonines 1: (1) acyl chlorides, CF3CO2H,
0 °C to room temperature; (2) crystallization from Et2O.
2. Results and discussion
Emulsions may be the ideal reaction medium for achieving
effective mixing, as demonstrated by Kobayashi et al. for several
surfactant-combined organometallic catalysts, which promote or-
ganic reactions in the presence of water.6c,11 Natural threonine
was not an efficient organocatalyst in the presence of water (Ta-
ble 1, entry 1).8 The incorporation of hydrophobic acylation groups
into threonine resulted in effective organocatalysts capable of cat-
alyzing the direct aldol reaction in the presence of water (Table 1,
entries 2–9 and entry 11). From the seven threonine–surfactant
derivatives synthesized obtained by the O-acylation of L-threonine
with acyl chlorides, it was found that the chain length (n) dramat-
ically affected the yields and enantioselectivities. Neither very long
(n = 8, 10, 14, 16) nor very short carbon chains (n = 2, 4) were effec-
tive, whereas catalyst 1cꢀHCl containing the n-octanoic group
(n = 6) gave the best yield (98%), diastereoselectivity (anti/
syn = 92:8), and enantioselectivity (98% ee) (Table 1, entry 4).
3. Conclusion
In conclusion, we have designed and synthesized a new series of
combined threonine–surfactant organocatalysts in one step for the
first time, which were prepared from commercially available and
Table 1
Screening of organocatalystsa
O
O
OH
O
Catalyst 1.HCl
Et3N
H
+
H2O, r.t
NO2
NO2
Yieldb (%)
2
Entry
1e
Catalyst
-Thr
Catalyst loading (%)
10
Time (h)
48
Anti/sync
eed (%)
—
<5
—
L
2
3
4
5
6
1aꢀHCl
1bꢀHCl
1cꢀHCl
1dꢀHCl
1eꢀHCl
1fꢀHCl
1gꢀHCl
1cꢀHCl
1cꢀHCl
1cꢀHCl
10
10
10
10
10
10
10
5
24
24
20
24
24
24
24
24
24
24
92
95
98
96
94
87
80
97
97
90
75:25
80:20
92:8
85:15
89:11
72:28
81:19
92:8
90
97
98
94
93
81
75
99
96
93
7
8
9f
10g
11h
5
2
88:12
89:11
a
The reactions were performed with 4-nitrobenzaldehyde (1 mmol), cyclohexanone (2.5 mmol), Et3N (0.1 mmol), and catalyst 1ꢀHCl (0.1 mmol) in the presence of water
(11 mmol) at room temperature.
b
Isolated yield.
c
The anti to syn ratio was determined by 1H NMR analysis of the crude product and by HPLC.
d
The ee value of the anti-isomer was determined by chiral HPLC analysis.
See Ref. 8.
Aldehyde/cyclohexanone/water/Et3N/catalyst ratio was 1:2.5:11:0.05:0.05.
The reaction was performed neat.
e
f
g
h
Aldehyde/cyclohexanone/water/Et3N/catalyst ratio was 1:2.5:11:0.02:0.02.

C. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2465–2470
2467
Table 2
Table 3
Organocatalyst 1cꢀHCl-catalyzed direct aldol reactions in the presence of watera
Direct asymmetric aldol reactions between cyclic ketones and nitrobenzaldehydes in
the presence of water, catalyzed by 1cꢀHCla
1c.HCl (5 mol%)
Et3N (5 mol%)
O
OH
O
O
1c.HCl (5 mol%)
Et3N (5 mol%)
O
CHO
O
OH
R
+
H
R
+
H2O, rt
R1
R2
H2O, rt
NO2
R1
R2
Entry Product
Time (h) Yieldb (%) Anti/sync eed (%)
NO2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2 (R = p-NO2-C6H4)
3 (R = o-NO2-C6H4)
4 (R = m-NO2-C6H4)
24
20
20
97
99
99
98
97
92
98
92
92
92
63
68
65
76
86
62
96
92:8
96:4
99:1
97:3
84:16
82:18
93:7
85:15
93:7
93:7
85:15
98:2
94:6
86:14
95:5
91:9
90:10
99
>99
99
97
95
96
97
97
98
97
>99
98
96
>99
96
97
98
Entry Product
Time (h) Yieldb (%) anti/sync eed (%)
O
OH
5 (R = 2,4-dinitrophenyl) 20
6 (R = p-CN-C6H4)
7 (R = p-CF3-C6H4)
8 (R = p-Br-C6H4)
9 (R = p-Cl-C6H4)
10 (R = o-Cl-C6H4)
11 (R = p-F-C6H4)
12 (R = p-CH3-C6H4)
13 (R = p-OMe-C6H4)
14 (R = m-OMe-C6H4)
15 (R = 2-naphthyl)
16 (R = 1-naphthyl)
17 (R = C6H5)
24
24
30
30
30
24
36
36
36
30
30
48
24
1
20
98
63:37
95/57
NO2
19
O
OH NO
2
2
20
20
96
98
52:48
75:25
99/81
98/31
20
O
OH
NO2
3
21
18 (R = pyridinthyl)
O
OH
a
The reactions were performed with aldehyde (1 mmol), cyclohexanone
4
24
24
24
95
98
97
93:7
99:1
96:4
96
99
95
(2.5 mmol), Et3N (0.05 mmol), and 1cꢀHCl (0.05 mmol) in the presence of water
(11 mmol) at room temperature.
NO2
b
Isolated yield.
22
c
The anti to syn ratio was determined by 1H NMR analysis of the crude product
O
OH NO2
and by HPLC.
d
The ee value of the anti-isomer was determined by chiral HPLC analysis.
5
23
inexpensive threonine and acyl chlorides. No protecting groups or
chromatographic techniques were involved in the procedures. For
the asymmetric direct aldol reactions of cyclic ketones with aro-
matic aldehydes, high isolated yields (up to 99%) and enantioselec-
tivities (up to 99% ee) were obtained by using catalyst 1cꢀHCl. The
reactions described in this report are highly enantioselective, envi-
ronmentally benign, and operationally simple. Our findings repre-
sent a novel application of primary amino acids derivatives as
asymmetric organocatalysts in aqueous organic reactions. Mecha-
nistic studies, the development of catalytic systems applicable to
a broader range of substrates and the extension of our catalysts
to other organic transformations are currently being investigated,
and will be reported in due course.
O
OH
NO2
6
24
a
The reactions were performed with nitrobenzaldehydes (1 mmol), cyclohexa-
none (2.5 mmol), Et3N (0.05 mmol), and 1cꢀHCl (0.05 mmol) in the presence of
water (11 mmol) at room temperature.
b
Isolated yield.
The anti to syn ratio was determined by 1H NMR analysis of the crude product
c
and by HPLC.
d
The ee value of the anti-isomer was determined by chiral HPLC analysis.
(29.78 g, 250 mmol, dried at 70–75 °C for 24 h) was added in small
portions under vigorous stirring to give a viscous solution (leaving
some small pieces of undissolved material). The reaction mixture
was stirred for 15 min, and then removed from the ice/water bath.
After 5 min of stirring, acyl chloride (375 mmol) was added in one
portion. The reaction flask was fitted with a loose glass stopper,
and the reaction mixture was stirred at room temperature without
any external temperature adjustment for 6 h, to give a clear and
colorless solution. The reaction flask was then cooled in an ice/
water bath, and Et2O (360 mL) was added under vigorous stirring
over a period of 20 min, slowly at first. The resulting white suspen-
sion was stirred at 0–5 °C for 15 min after completed addition, and
then filtered by vacuum. The crystals were washed with two por-
tions of Et2O and dried at room temperature for 23 h in a ventilated
4. Experimental
4.1. General information
All reagents were commercial products. The reactions were mon-
itored by TLC (thin layer chromatography). The column and prepara-
tive TLC purifications were carried out using silica gel. Flash column
chromatography was performed on silica gel (200–300 mesh). NMR
spectra were recorded on a 300 MHz instrument. Chemical shifts (d)
are given in ppm relative to TMS as the internal reference, coupling
constants (J) in hertz. IR spectra were recorded on a spectrometer.
Melting points were measured on a digital melting point apparatus.
Mass spectra (MS) were measured with a spectrometer. Analytical
high performance liquid chromatography (HPLC) was carried out on
Agilent 1200 instrument using Chiralpak AD (4.6 mm ꢁ 250 mm),
Chiralcel OD-H (4.6 mm ꢁ 250 mm) columns. Optical rotations were
measured on a JASCO P-1010 Polarimeter at k = 589 nm.
hood to give O-acyl-L-threonine hydrochloride 1, as a fine white
powder. This essentially pure material was used for the next step
without further purification.
4.2.1. O-(n-Butyl)-
L
-threonine hydrochloride 1aꢀHCl
Yield: 96%; white solid; mp: 120–121 °C; ½a D20
¼ þ16:1 (c 1,
ꢂ
4.2. Typical experimental procedure for the preparation of
MeOH); 1H NMR (300 MHz, DMSO): d 0.84–0.92 (m, 3H), 1.32–
1.34 (d, J = 6.5 Hz, 3H), 1.45–1.60 (m, 2H), 2.26–2.31(m, 2H), 4.13
(d, J = 2.7 Hz, 1H), 5.26–5.29 (dq, J = 3.5 Hz and 6.2 Hz, 1H); 13C
NMR (75 MHz, DMSO): d 13.4, 16.7, 17.9, 35.4, 55.4, 67.7, 168.4,
combined threonine–surfactant 1aꢀHCl–1gꢀHCl (Scheme 1):10d,e
A 500 ml round bottom flask was charged with CF3CO2H
(120 mL) and placed in an ice/water bath. Powdered L-threonine

2468
C. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2465–2470
171.7. MS (ESI) m/z calcd for (C8H15NO4): 189.51 (M+). FT-IRmmax
(neat)/cmꢃ1: 2968, 1754, 1737, 1588, 1493, 1415, 1167, 1124,
1056, 747, 709.
cmꢃ1: 2920, 2851, 1753, 1717, 1412, 1353, 1159, 1141, 1076,
744, 705.
4.3. General procedure for the aldol reaction of cyclohexanone
with aromatic aldehydes
4.2.2. O-(n-Hexanoyl)-
L
-threonine hydrochloride 1bꢀHCl
Yield: 97%; white solid; mp: 126–127 °C; ½a D20
¼ þ15:0 (c 1,
ꢂ
MeOH); 1H NMR (300 MHz, DMSO): d 0.84–0.88 (m, 3H),1.05–
1.26(m, 4H), 1.32–1.34 (d, J = 6.5 Hz, 3H), 1.45–1.60 (m, 2H),
2.27–2.32 (m, 2H), 4.13 (d, J = 2.7 Hz, 1H), 5.25–5.28 (dq,
J = 3.6 Hz and 6.0 Hz, 1H); 13C NMR(75 MHz, DMSO): d 13.9, 16.7,
21.8, 24.0, 30.6, 33.4, 55.4, 67.7, 168.5, 171.9; MS(ESI) m/z calcd
for (C10H19NO4): 217.51 (M+). FT-IRmmax (neat)/cmꢃ1: 2959, 1759,
1737, 1413, 1340, 1166, 1125, 1057, 783, 715.
4.3.1. Reactions in neat cyclohexanone
Cyclohexanone (0.25 mL, 2.5 mmol) was added to a mixture of
p-nitrobenzaldehyde (0.1512 g, 1 mmol), catalyst 1cꢀHCl (14.05
mg, 0.05 mmol) and Et3N (0.05 mmol). After being stirred for the
indicated time, the mixture was treated with saturated ammonium
chloride solution and extracted with ethyl acetate. The organic
layer was dried over MgSO4, filtered, and concentrated to give a
pure aldol product after thin flash column chromatography (silica
gel, petroleum ether/ethyl acetate). The absolute configuration of
aldol products was extrapolated by comparison of the HPLC data
with the known literature values.
4.2.3. O-(n-Octanoyl)-
L
-threonine hydrochloride 1cꢀHCl
Yield: 95%; white solid; mp: 127–128 °C; ½a D20
¼ þ13:2 (c 1,
ꢂ
MeOH); 1H NMR (300 MHz, DMSO): d 0.86–0.90 (m, 3H), 1.27 (br
s, 8H), 1.34–1.36 (d, J = 6.6 Hz, 3H), 1.51–1.55 (m, 2H), 2.29–2.34
(m, 2H), 4.15 (d, J = 2.7 Hz, 1H), 5.27–5.30 (dq, J = 3.6 Hz and
6.0 Hz, 1H); 13C NMR (75 MHz, DMSO): d 13.997, 16.703, 22.102,
24.294, 28.381, 31.147, 33.449, 55.378, 67.629, 168.510, 171.820.
MS (ESI) m/z calcd for (C12H23NO4): 245.56 (M+). FT-IRmmax
(neat)/cmꢃ1: 2957, 1758, 1737, 1413, 1383, 1208, 1164, 1122,
1055, 789, 635.
4.3.2. Reactions in the presence of water
To a mixture of catalyst 1cꢀHCl (14.05 mg, 0.05 mmol), Et3N
(0.05 mmol), and aldehyde in the presence of water (0.2 mL) was
added the ketone under air in a closed system. After being stirred
at room temperature for the indicated time, the mixture was trea-
ted in the same manner as shown above.
4.3.3. (2S,10R)-2-(Hydroxy-(4-nitrophenyl)methyl) cyclohexan-
1-one 2
4.2.4. O-(n-Decanoyl)-
L
-threonine hydrochloride 1dꢀHCl
Yield: 96%; white solid; mp: 128–129 °C; ½a D20
¼ þ13:0 (c 1,
ꢂ
Yield 97%, anti/syn = 92:8, enantiomeric excess: 99% of anti dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 20:80; flow rate 0.5 mL/min, 20 °C, k = 254 nm;
tR = 42.5 min (anti, major), tR = 32.8 min (anti, 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).
MeOH); 1H NMR (300 MHz, DMSO): d 0.84–0.86 (m, 3H), 1.24 (br
s, 12H), 1.32–1.34 (d, J = 6.3 Hz, 3H), 1.40–1.42 (m, 2H), 2.27–
2.31 (m, 2H), 4.15 (d, J = 2.7 Hz, 1H), 5.26–5.27 (dq, J = 3.6 Hz and
6.0 Hz, 1H); 13C NMR (75 MHz, DMSO): d 14.0, 16.7, 22.19, 24.3,
28.5, 28.8, 28.8, 28.9, 31.4, 33.5, 55.4, 67.7, 168.5, 171.8; MS (ESI)
m/z calcd for (C14H27NO4): 273.55 (M+). FT-IRmmax (neat)/cmꢃ1
:
2923, 2854, 1753, 1412, 1353, 1159, 1141, 1076, 744, 705.
4.2.5. O-(n-Dodecanoyl)-
L
-threonine hydrochloride 1eꢀHCl
4.3.4. (2S,10R)-2-(Hydroxy-(2-nitrophenyl)methyl) cyclohexan-
1-one 3
Yield 99%, anti/syn = 96:4, enantiomeric excess: >99% of anti-
diastereomer determined by HPLC (Dicael Chiralpak OD-H column;
i-PrOH/Hexane = 5:95; flow rate 0.5 mL/min, 20 °C, k = 254 nm;
tR = 41.9 min (anti, major), tR = 50.7 min (anti, minor)). 1H NMR
Yield: 94%; white solid; mp: 127–128 °C; ½a D20
¼ þ11:6 (c 1,
ꢂ
MeOH); 1H NMR (300 MHz, DMSO): d 0.84–0.86 (m, 3H), 1.24 (br
s, 16H), 1.31–1.33 (d, J = 6.6 Hz, 3H), 1.39–1.41 (m, 2H), 2.26–
2.31 (m, 2H), 4.13 (d, J = 2.6 Hz, 1H), 5.25–5.28 (dq, J = 3.6 Hz and
6.3 Hz, 1H); 13C NMR (75 MHz, DMSO): d 14.1, 16.8, 22.3, 24.4,
28.5, 28.8, 28.9, 29.0, 29.2, 31.4, 33.5, 55.5, 67.7, 168.6, 171.9; MS
(ESI) m/z calcd for (C16H31NO4): 301.59 (M+). FT-IRmmax (neat)/
cmꢃ1: 2922, 2852, 1753, 1717, 1412, 1353, 1159, 1141, 1076,
744, 705.
(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).
4.2.6. O-(n-Palmitoyl)-
L
-threonine hydrochloride 1fꢀHCl
Yield: 90%; white solid; mp: 129–130 °C; ½a D20
¼ þ7:8 (c 1,
ꢂ
4.3.5. (2S,10R)-2-(Hydroxy-(3-nitrophenyl)methyl) cyclohexan-
1-one 4
MeOH); 1H NMR (300 MHz, DMSO): d 0.82–0.84 (m, 3H), 1.22 (br
s, 24H), 1.30–1.32 (d, J = 6.5 Hz, 3H), 1.49 (m, 2H), 2.25–2.30 (m,
2H), 4.11 (d, J = 2.6 Hz, 1H), 5.23–5.26 (dq, J = 3.5 Hz and 6.2 Hz,
1H); 13C NMR (75 MHz, DMSO): d 13.9, 16.6, 22.1, 22.1, 24.3,
28.4, 28.7, 28.9, 29.0, 29.1, 31.3, 33.4, 55.4, 67.6, 168.4, 171.7. MS
(ESI) m/z calcd for (C20H39NO4): 357.71 (M+). FT-IRmmax (neat)/
cmꢃ1: 2920, 2851, 1753, 1716, 1412, 1353, 1159, 1141, 1076,
744, 705.
Yield 99%, anti/syn = 99:1, enantiomeric excess: 99% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 20:80; flow rate 0.5 mL/min, 20 °C, k = 254 nm;
tR = 41.9 min (anti, major), tR = 32.4 min (anti, 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).
4.2.7. O-(n-Stearoyl)-
L
-threonine hydrochloride 1gꢀHCl
Yield: 85%; white solid; mp: 129–130 °C; ½a D20
¼ þ8:0 (c 1,
ꢂ
4.3.6. (2S,10R)-2-(Hydroxy-(2,4-dinitro-phenyl)methyl) cyclo-
hexan-1-one 5
MeOH); 1H NMR (300 MHz, DMSO): d 0.82–0.86 (m, 3H), 1.22 (br
s, 28H), 1.30–1.32 (d, J = 6.5 Hz, 3H), 1.49 (m, 2H), 2.25–2.30 (m,
2H), 4.12 (d, J = 2.6 Hz, 1H), 5.23–5.26 (dq, J = 3.7 Hz and 5.9 Hz,
1H); 13C NMR (75 MHz, DMSO): d 14.0, 16.7, 22.2, 24.3, 28.5,
28.8, 29.0, 29.0, 29.1, 29.2, 31.4, 33.5, 55.4, 67.6, 168.5, 171.8; MS
(ESI) m/z calcd for (C22H43NO4): 385.72 (M+). FT-IRmmax (neat)/
Yield 98%, anti/syn = 97:3, enantiomeric excess: 97% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column;
i-PrOH/Hexane = 15:85; flow rate 1.0 mL/min, 20 °C, k = 254 nm;
tR = 27.6 min (anti, major), tR = 24.5 min (anti, minor)). 1H NMR
(300 MHz, CDCl3): d 8.75 (d, J = 2.4 Hz, 1H), 8.48 (dd, J = 8.4,

C. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2465–2470
2469
2.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 5.53(s, 1H), 4.31(d, J = 4.0 Hz,
1H) 2.31–2.82 (m, 3H), 2.11–2.16 (m, 1H), 1.63–1.94 (m, 5H).
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).
4.3.7. (2S,10R)-2-(Hydroxy-(4-cyanophenyl)methyl) cyclohexan-
1-one 6
4.3.13. (2S,10R)-2-(Hydroxy-(4-tolyl)methyl)cyclohexan-1-one
12
Yield 97%, anti/syn = 84:16, enantiomeric excess: 95% of anti-
diastereomer determined by HPLC (Dicael Chiralpak AD-H column;
i-PrOH/Hexane = 20:80, flow rate 0.5 mL/min, 20 °C, k = 254 nm;
tR = 22.5 min (anti, major), tR = 18.1 min (anti, minor)). 1H NMR
Yield 63%, anti/syn = 85:15, enantiomeric excess: >99% of anti-
diastereomer determined by HPLC (Dicael Chiralpak AD-H column;
i-PrOH/Hexane = 10:90; flow rate 0.5 mL/min, 20 °C, k = 221 nm;
tR = 32.8 min (anti, major), tR = 44.5 min (anti, 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).
(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).
4.3.8. (2S,10R)-2-(Hydroxy-(4-(trifluoromethyl)methyl) cyclo-
hexan-1-one 7
4.3.14. (2S,10R)-2-(Hydroxy-(4-methoxy-phenyl)methyl) cyclo-
hexan-1-one 13
Yield 92%, anti/syn = 82:18, enantiomeric excess: 96% of anti-
diastereomer determined by HPLC (Dicael Chiralpak AD-H column;
i-PrOH/Hexane = 10:90; flow rate 0.5 mL/min, 20 °C, k = 254 nm;
tR = 34.4 min (anti, major), tR = 26.9 min (anti, minor)). 1H NMR
(300 MHz, CDCl3): d 7.74–7.55 (m, 3H), 7.40 (t, 1H, J = 7.2 Hz),
5.30 (d, 1H, J = 9.3 Hz), 4.03 (t, 1H, J = 3.0 Hz), 2.81–2.69 (m, 1H),
2.55–2.45 (m, 1H), 2.37 (td, 1H, J = 12.9, 4.8 Hz), 2.15–2.03 (m,
1H), 1.81–149 (m, 3H), 1.48–1.23 (m, 1H).
Yield 68%, anti/syn = 98:2, enantiomeric excess: 98% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 10:90; flow rate 0.8 mL/min, 20 °C, k = 221 nm;
tR = 32.5 min (anti, major), tR = 30.8 min (anti, 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).
4.3.15. (2S,10R)-2-(Hydroxy-(3-methoxy-phenyl)methyl) cyclo-
hexan-1-one 14
4.3.9. (2S,10R)-2-(Hydroxy-(4-bromophenyl)methyl) cyclohex-
an-1-one 8
Yield 65%, anti/syn = 96:4, enantiomeric excess: 96% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 10:90; flow rate 0.5 mL/min, 20 °C, k = 221 nm;
tR = 56.3 min (anti, major), tR = 51.1 min (anti, 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).
Yield 98%, anti/syn = 93:7, enantiomeric excess: 97% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 10:90; flow rate 0.8 mL/min, 20 °C, k = 221 nm;
tR = 27.0 min (anti, major), tR = 22.4 min (anti, 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).
4.3.16. (2S,10R)-2-(Hydroxy-(2-naphthyl)methyl) cyclohexan-1-
one 15
4.3.10. (2S,10R)-2-(Hydroxy-(4-chlorophenyl)methyl) cyclohex-
an-1-one 9
Yield 76%, anti/syn = 86:14, enantiomeric excess: >99% of anti-
diastereomer determined by HPLC (Dicael Chiralpak OD-H column;
i-PrOH/Hexane = 10:90; flow rate 1.0 mL/min, 20 °C, k = 221 nm;
tR = 15.7 min (anti, major), tR = 22.2 min (anti, 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).
Yield 92%, anti/syn = 85:15, enantiomeric excess: 97% of anti
diastereomer determined by HPLC (Dicael Chiralpak AD-H column;
i-PrOH/Hexane = 10:90; flow rate 0.5 mL/min, 20 °C, k = 221 nm;
tR = 39.2 min (anti, major), tR = 33.4 min (anti, 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).
4.3.17. (2S,10R)-2-(Hydroxy-(1-naphthyl)methyl) cyclohexan-1-
one 16
Yield 86%, anti/syn = 95:5, enantiomeric excess: 96% of anti-dia-
stereomer 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 = 45.9 min (anti, major), tR = 36.7 min (anti, 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).
4.3.11. (2S,10R)-2-(Hydroxy-(2-chlorophenyl)methyl) cyclo-
hexan-1-one 10
Yield 92%, anti/syn = 93:7, enantiomeric excess: 98% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak OD-H column; i-
PrOH/Hexane = 5:95; flow rate 1.0 mL/min, 20 °C, k = 221 nm;
tR = 9.7 min (anti, major), tR = 12.3 min (anti, 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).
4.3.12. (2S,10R)-2-(Hydroxy-(4-fluor-phenyl)methyl) cyclohex-
an-1-one 11
4.3.18. (2S,10R)-2-(Hydroxy-(phenyl)methyl) cyclohexan-1-one
17
Yield 92%, anti/syn = 93:7, enantiomeric excess: 97% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 5:95; flow rate 1.0 mL/min, 20 °C, k = 221 nm;
tR = 28.3 min (anti, major), tR = 24.7 min (anti, 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,
Yield 62%, anti/syn = 91:9, enantiomeric excess: 97% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak OD-H column; i-
PrOH/Hexane = 10:90; flow rate 0.5 mL/min, 20 °C, k = 220 nm;
tR = 19.6 min (anti, major), tR = 30.6 min (anti, 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,

2470
C. Wu et al. / Tetrahedron: Asymmetry 21 (2010) 2465–2470
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).
tR = 32.5 min (anti, major), tR = 34.7 min (anti, minor)). 1H NMR
(300 MHz, CDCl3): d 7.81–7.84 (m, 1H), 7.72–7.74 (m, 1H), 7.62 (m,
1H), 7.40–7.45 (m, 1H), 5.42 (d, 1H, J = 7.2 Hz), 3.95 (br, 1H),
2.89–2.92 (m, 1H), 2.44–2.46 (m, 1H), 2.33–2.39 (m, 2H), 2.09–
2.11 (m, 1H), 1.74–1.93 (m, 3H), 1.52 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H).
4.3.19. (2S,10R)-2-(Hydroxy-(pyridin-4-yl)methyl) cyclohexan-
1-one 18
Yield 96%, anti/syn = 90:10, enantiomeric excess: 98% of anti-
diastereomer determined by HPLC (Dicael Chiralpak AD-H column;
i-PrOH/Hexane = 10:90; flow rate 1.0 mL/min, 20 °C, k = 254 nm;
tR = 27.5 min (anti, major), tR = 25.0 min (anti, minor)). 1H NMR
(300 MHz, CDCl3): d 8.53–8.55 (d, J = 6.0 Hz, 2H), 7.25–7.28 (d,
J = 6.0 Hz, 2H), 4.80 (d, J = 8.4 Hz, 1H), 4.29 (br, 1H), 2.31–2.63
(m, 3H), 2.07–2.12 (m, 1H), 1.81–1.84 (m, 1H), 1.61–1.71 (m,
4H), 1.30–1.41 (m, 1H).
4.3.25. (2S,4S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)-4-methyl-
cyclohexan-1-one 24
Yield 97%, anti/syn = 96:4, enantiomeric excess: 95% of anti-dia-
stereomer determined by HPLC(Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 10:90; flow rate 0.5 mL/min, 20 °C, k = 254 nm;
tR = 63.4 min (anti, major), tR = 46.5 min (anti, minor)). 1H NMR
(300 MHz, CDCl3): d 8.11 (s, 1H, Ar), 7.53–7.86 (m, 3H, Ar), 5.20
(d, 1H, J = 8.4 Hz), 3.93 (br, 1H), 2.85–2.90 (m, 1H), 2.45–2.47 (m,
1H), 2.35–2.42 (m, 2H), 2.38–2.79 (m, 2H), 1.90–1.93 (m, 1H),
1.64–1.75 (m, 3H), 1.43 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H).
4.3.20. (2S,10R)-2-(Hydroxy-(4-nitrophenyl) methyl)-cyclo-
pentan-1-one 19
Yield 98%, anti/syn = 63:37, enantiomeric excess: 95% of anti-
isomer and 57% 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 = 58.4 min (anti, major), tR = 55.4 min (anti, minor));
tR = 30.8 min (syn, major), tR = 43.9 min (syn, minor)). 1H NMR
Acknowledgment
Authors are grateful to Southwest University of China for finan-
cial support.
(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),
References
2.08–1.95 (m, 1H), 1.81–1.48 (m, 3H).
1. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 116, 5248–5286; (b)
Berkssel, A.; Groger, H. In Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
2005.
2. (a)For reviews on direct aldol reactions, see: Modern Aldol Additions; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, 2004; (b) Palomo, C.; Oiarbide, M.; Garcia, J. M.
Chem. Eur. J. 2002, 8, 36–44; (c) Machajewski, T. D.; Wong, C. H. Angew. Chem.,
Int. Ed. 2000, 39, 1352–1374.
4.3.21. (2S,10R)-2-(Hydroxy-(2-nitrophenyl) methyl)-cyclopen-
tan-1-one 20
Yield 96%, anti/syn = 52:48, enantiomeric excess: 99% of anti-
isomer and 81% syn-isomer determined by HPLC (Dicael Chiralpak
OD-H column; i-PrOH/Hexane = 5:95; flow rate 1.0 mL/min, 20 °C,
k = 254 nm; tR = 39.8 min (anti, major), tR = 43.2 min (anti, minor);
tR = 20.7 min (syn, major), tR = 23.1 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d 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).
3. For reviews, see: (a) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004,
37, 580–591; (b) Mukherjee, S.; Yang, J. W.; Hoffman, S.; List, B. Chem. Rev.
2007, 107, 5471–5569; (c) Liu, X. H.; Lin, L. L.; Feng, X. M. Chem. Commun. 2009,
41, 6145–6158; (d) Raj, M.; Singh, V. K. Chem. Commun. 2009, 42, 6687–6703;
(e) Xu, L. W.; Luo, J.; Lu, Y. X. Chem. Commun. 2009, 1807–1821; (f) Xu, L. W.; Lu,
Y. X. Org. Biomol. Chem. 2008, 6, 2047–2053; (g) Peng, F. Z.; Shao, Z. H. J. Mol.
Catal. A 2008, 285, 1–13; (h) Chen, Y. C. Synlett 2008, 1919–1930; (i) Bartoli, G.;
Melchiorre, P. Synlett 2008, 1759–1771; For selected examples of anti-aldol
reactions, see: (j) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Córdova, A.
Angew. Chem., Int. Ed. 2005, 44, 1343–1345; (k) Córdova, A.; Zou, W.; Ibrahem,
I.; Reyes, E.; Engqvist, M.; Liao, W. W. Chem. Commun. 2005, 3586–3588; (l)
Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2005, 46, 3359–3363; (m) Torii, H.;
Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004,
43, 1983–1986; (n) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka,
F., ; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 734–735; (o) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int.
Ed. 2006, 45, 958–961; (p) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C. G. Org. Lett.
2005, 7, 5321–5323; (q) Córdova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes,
E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383–5397; (r) Hayashi, Y.; Itoh, T.; Nagae, N.;
Ohkubo, M.; Ishikawa, H. Synlett 2008, 1565–1570.
4.3.22. (2S,10R)-2-(Hydroxy-(3-nitrophenyl) methyl)-cyclopen-
tan-1-one 21
Yield 98%, anti/syn = 75:25, enantiomeric excess: 98% of anti-
isomer and 31% syn-isomer determined by HPLC (Dicael Chiralpak
AD-H column; i-PrOH/Hexane = 8:92; flow rate 1.0 mL/min, 20 °C,
k = 254 nm; tR = 29.4 min (anti, major), tR = 43.3 min (anti, minor);
tR = 20.7 min (syn, major), tR = 23.1 min (syn, minor)). 1H NMR
(300 MHz, CDCl3): d 8.17–8.18 (m, 1H), 8.10 (ddd, J = 8.1, 2.3,
1.1 Hz, 1H), 7.62–7.65 (m, 1H), 7.47 (t, J = 7.9 Hz, 1H), 4.77 (d,
1H, J = 9.3 Hz), 4.72 (s, 1H), 2.16–2.47 (m, 3H), 1.92–2.01 (m, 1H),
1.61–1.78 (m, 2H), 1.50–1.55 (m, 1H).
4. (a)Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie: London, 1998; (b)
Lindstrom, U. M. Chem. Rev. 2002, 102, 2751–2772; (c) Li, C. J. Chem. Rev. 2005,
105, 3095–3166; (d) Pirrung, M. C. Chem. Eur. J. 2006, 12, 1312–1317.
5. (a) Córdova, A.; Notz, W.; Barbas, C. F., III Chem. Commun. 2002, 3024–3025; (b)
Akthivel, K. S.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc 2001, 123,
5260–5267.
6. (a) Monika, R.; Vinod, S. K. Chem. Commun. 2009, 44, 6687–6692; (b) Mase, N.;
Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc.
2006, 128, 4966–4967; (c) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.;
Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527–5529.
7. (a) Zhang, S. P.; Fu, X. K.; Fu, S. D.; Pan, J. F. Cat. Commun. 2009, 10, 401–405; (b)
Zhang, S. P.; Fu, X. K.; Fu, S. D. Tetrahedron Lett. 2009, 50, 1172–1173; (c) Fu, S.
D.; Fu, X. K.; Zhang, S. P.; Zou, X. C.; Wu, X. J. Tetrahedron: Asymmetry 2009, 20,
2390–2396.
8. Wu, X. Y.; Jiang, Z. Q.; Shen, H. M.; Lu, Y. X. Adv. Synth. Catal. 2007, 349, 812–
816.
9. For the use of hydrophobicity in organic synthesis, see: (a) Lindstrom, U. M.;
Andersson, F. Angew. Chem., Int. Ed. 2006, 45, 548–551; (b) Otto, S.; Engberts, J.
B. F. N. Org. Biomol. Chem. 2003, 1, 2809–2820; (c) Breslow, R. Acc. Chem. Res.
2004, 37, 471–478.
4.3.23. ((2S,4S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)-4-meth-
ylcyclohexan-1-one 22
Yield 95%, anti/syn = 93:7, enantiomeric excess: 96% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane = 10:90; flow rate 1.0 mL/min, 20 °C, k = 254 nm;
tR = 36.3 min (anti, major), tR = 41.3 min (anti, 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).
10. (a) Siyutkin, D. E.; Kucherenko, A. S.; Zlotin, S. G. Tetrahedron 2009, 65, 1366–
´
1372; (b) Dziedzic, P.; Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2008, 49, 803–
4.3.24. (2S,4S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)-4-methy-
lcyclohexan-1-one 23
Yield 98%, anti/syn = 99:1, enantiomeric excess: 99% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column;
i-PrOH/Hexane = 10:90; flow rate 0.8 mL/min, 20 °C, k = 254 nm;
807; (c) Chen, L. L.; Han, X.; Huang, M. H.; Wong, M. W.; Lu, Y. X. Chem.
Commun. 2007, 40, 4143–4145; (d) Kristensen, T. E.; Hansen, F. K.; Hansen, T.
Eur. J. Org. Chem. 2009, 3, 387–395; (e) Kristensen, T. E.; Vestli, K.; Fredriksen, K.
A.; Hansen, F. K.; Hansen, T. Org. Lett. 2009, 11, 2968–2971.
11. (a) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209–217; (b) Hamada, T.;
Manabe, K.; Kobayashi, S. J. Syn. Org. Chem. Jpn. 2003, 61, 445–448.