Simple and inexpensive threonine-based organocatalysts as highly active and recoverable catalysts for large-scale asymmetric direct stoichiometric aldol reactions on water

Article abstract of DOI:10.1016/j.tetasy.2012.02.023

Nine O-acylated threonines were screened as catalysts at loadings of 0.5-5 mol % for the direct asymmetric stoichiometric aldol reaction on water by using variable amounts of water. These threonine-based organocatalyst were simple, inexpensive, highly act

Full text of DOI:10.1016/j.tetasy.2012.02.023

Tetrahedron: Asymmetry 23 (2012) 315–328
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Simple and inexpensive threonine-based organocatalysts as highly active
and recoverable catalysts for large-scale asymmetric direct stoichiometric
aldol reactions on water
Chuanlong Wu a,b, Xiaoqin Long b, Shi Li a, Xiangkai Fu a,
⇑
a College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
b Chongqing Unis Chemical Co., Ltd, Chongqing 402161, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 December 2011
Accepted 27 February 2012
Nine O-acylated threonines were screened as catalysts at loadings of 0.5–5 mol % for the direct asymmet-
ric stoichiometric aldol reaction on water by using variable amounts of water. These threonine-based
organocatalyst were simple, inexpensive, highly active and could be synthesized on a large-scale. Among
them, the threonine-based organocatalyst 1a is applicable to the stoichiometric reactions of a wide range
of aromatic and heteroaromatic aldehydes with ketones, with the aldol products being obtained with up
to 99:1 anti/syn ratios and >99% ee. The threonine-based organocatalyst 1a can be easily recovered and
reused, and only a slight decrease in the enantioselectivities was observed after six cycles. This novel
threonine-based organocatalyst 1a can be efficiently used in large-scale reactions with the enantioselec-
tivities being maintained at the same level, which offers great possibility for application in industry.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
reagents; all of these factors are hurdles for industrial applications,
hence these organocatalysts are often only used in research
In spite of the remarkable advancesin asymmetric aldol reactions
for constructing carbon–carbon bonds, providing high ‘atom-econ-
omy’, there continues to be an increasing demand to explore new,
inexpensive, simple, efficient and recoverable organocatalysts.1
However, organocatalysts are usually used at a loading of 5–
30 mol %, and in some cases, higher catalytic loadings have been re-
ported.2–6 This raises a cost concern when large amounts of organo-
catalysts are used for large-scale synthesis in industrial applications.
For synthetic purposes, the design and development of highly active
organocatalysts aimed at lowering the catalytic loading to less than
2 mol % has proven to be a significant challenge and only limited
success has been achieved so far. With regards to the direct asym-
metric aldol reaction, several examplesof organocatalysts have been
employed in low catalytic amounts.7–13 Organocatalysts that are
even more complex have also been reported for aldol reactions. A
laboratories.
Water has many attractive advantages such as being low cost,
safe and environmentally friendly. Many of the reported reactions
were carried out in water.18–20 It has been found that water is able
to promote these reactions with high levels of enantio- and diaste-
reo-selectivity and in high yields. Usually, these reactions are car-
ried out with an excess amount of the ketone, from 2 to 10 equiv
with respect to the aldehyde, and in the presence of variable
amounts of water. It should also be noted that the excess ketone
is not easily recycled.21–24 When an expensive ketone is used in
large excess, it is not reassuring for the direct aldol reaction with
atom economical ‘green’ credentials. This raises a cost concern
when a large amount of the ketone is used for a large-scale synthe-
sis in industrial applications.25 In particular, the use of less volatile
ketones, such as cyclohexanone (bp 155 °C), in large excess compli-
cates the reaction work-up and product purification.25 A highly
efficient, stereoselective, and atom economical reaction in water
is a sought-after goal in synthetic chemistry.26–31 The use of direct
stoichiometric aldol reactions represents an important alternative
approach. Armstrong et al. have developed an asymmetric catalytic
system in water mediated by sulfated b-CD, which can bind an
organocatalyst of tert-butylphenoxyproline and associated hydro-
phobic reactants for direct stoichiometric aldol reactions of cyclo-
hexanone and aryl aldehydes.24
spiro diamine catalyst,14 the tripeptide H-Pro-Pro-Asp-NH2,15
a
biphenyl-based axially chiral amino acid,16 and a very complex den-
drimer catalyst17 were employed in amounts of 0.5–1 mol %.
Although these catalysts work at a loading of 0.5–2 mol % to afford
aldol products with high levels of stereoselectivity, they are expen-
sive, and for their preparation require demanding procedures, tire-
some purification by chromatography and/or use expensive
For these reasons, the development of a new type of effective
asymmetric organocatalysts from a natural chiral pool, with a
⇑
Corresponding author. Tel.: +86 23 8716 1855; fax: +86 23 8716 1874.
E-mail addresses: chuanlong666@yahoo.cn (C. Wu), wcl110@swu. edu.cn (X. Fu).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.02.023

316
C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
simple preparation procedure, inexpensive reagents, a highly
efficient, stereoselective, green, and atom economical reaction is
always desired. An alternative strategy is to design recyclable,
simple and inexpensive organocatalysts that promote stoichiome-
tric reactions. Herein, we report novel, simple, inexpensive, recov-
erable and reusable threonine-based organocatalysts that promote
stoichiometric aldol reactions while achieving excellent enantiose-
lectivities. These catalysts can then be used in large-scale reactions
with the enantioselectivities being maintained at the same level,
thus offering great potential for application on an industrial scale.
activity and stereoselectivity. Barbas et al., Lu et al. and our group
have reported a series of threonine derivative organocatalysts for
the direct asymmetric aldol reactions of various aromatic aldehydes
and ketones, with excellent results being obtained.32–37 At first, we
screened seven new threonine-based derivatives 1a–g and two
known compounds 1h36 and 1i34,35 (Fig. 1).
The organocatalyzed direct stoichiometric aldol reaction was
carried out using cyclohexanone and 4-nitrobenzaldehyde as a
model reaction in order to investigate different parameters, such
as the catalysts, the solvents, and the loading of the catalysts. In
our initial investigations, threonine-based organocatalysts 1a–i
were screened as catalysts. As can be seen from the results in
Table 1, catalysts 1a–i catalyzed the asymmetric direct stoichiom-
etric aldol reaction of 4-nitrobenzaldehyde and cyclohexanone to
give the aldol product 2a in good yields (85–92%) with different
ee values (90–98% ee for anti) on water (Table 1, entries 1–9).
Amongst the nine direct acylated threonine-based derivatives
1a–i, the catalysts containing a phenyl group gave the best yield
(92%) and enantioselectivities (98% ee for anti). The threonine-
2. Results and discussion
Our aim was to find extremely simple and inexpensive organo-
catalysts that could be used in low loadings (2–0.5 mol %), at room
temperature without additives, and that those could catalyze direct
asymmetric stoichiometric aldol reactions between cyclic ketones
and substituted benzaldehydes with high levels of stereoselectivity.
Threonine derivatives have been designed to improve the catalytic
O
O
O
O
O
O
n
CO2H
NH2
CO2H
NH2
CO2H
NH2
1b
: n=1
: n=2
: n=3
1a
1e
1c
1d
O
O
O
O
O
O
O
O
6
CO2H
NH2
CO2H
NH2
CO2H
NH2
CO2H
NH2
1i
1g
1f
1h
Figure 1. Threonine-based organocatalysts.
Table 1
Screening of organocatalysts 1a–i for the direct stoichiometric aldol reaction of cyclohexanone with 4-nitrobenzaldehyde on watera
O
O
O
OH
H
cat.1a-i (5 mol%)
+
H2O, rt
24-36 h
NO2
NO2
1 equiv
1 equiv
2a
c
Entry
Catalyst
Time (h)
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
24
24
24
24
36
24
36
36
36
24
92
89
92
91
87
90
93
85
90
91
91:9
98/10
94/23
94/15
94/34
92/40
96/22
94/12
90/21
95/17
96/41
90:10
87:13
88:12
70:30
91:9
90:10
88:12
91:9
9
10d
1a
90:10
a
b
c
The reactions were carried out using 4-nitrobenzaldehyde (4.0 mmol), cyclohexanone (4.0 mmol) and catalyst (0.2 mmol) on water (2.0 mL).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
d
The reactions were carried out using 4-nitrobenzaldehyde (4.0 mmol), cyclohexanone (4.0 mmol) and catalyst 1a (0.2 mmol) and sulfated b-cyclo-
dextrin (10 mol %) in water (2.0 mL).

C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
317
based organocatalyst 1a turned out to be the most efficient catalyst
(Table 1, entry 1). Armstrong et al. have developed an asymmetric
catalytic system in water mediated by sulfated b-CD which can
bind an organocatalyst of tert-butylphenoxyproline and associated
hydrophobic reactants for direct stoichiometric aldol reactions of
cyclohexanone and aryl aldehydes. We also developed an asym-
metric catalytic system in water mediated by sulfated b-CD;
although catalyst 1a can catalyze the asymmetric direct stoichiom-
etric aldol reaction of 4-nitrobenzaldehyde and cyclohexanone, the
yield and enantioselectivity did not increase (Table 1, entry 10).
We screened several solvents for the stoichiometric reaction be-
tween cyclohexanone and 4-nitrobenzaldehyde (Table 2). Due to its
poor solubility in most solvents, reactions mediated by threonine
itself were restricted to polar organic solvents such as dimethyl
sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N-methyl-
pyrrolidone (NMP), while O-acylated threonine derived organocat-
alysts were more soluble than threonine in organic solvents. For the
catalyst, we used the most hydrophobic one 1a (5 mol %). Both the
enantioselectivities and yields were not good when DMSO, DMF,
NMP, chloroform or toluene were used (Table 2, entries 1–3, 5
and 6). CH3CN, THF and water/chloroform (v/v = 10:1) showed in-
creased yield and enantioselectivities (Table 2, entries 4, 7 and 8),
while water gave the highest stereoselectivity (Table 2, entry 9).
This result indicates that water is indispensable for achieving excel-
lent diastereoselectivities and enantioselectivities. The results sum-
marized in Table 2 suggest that the stoichiometric reaction on
water is different from that in its absence, and that compared to
organic solvents, water has a unique and beneficial effect.
Next, using water as a solvent, and 1a as catalyst, we investi-
gated the effects of catalyst loading on the reactions of cyclohexa-
none with 4-nitrobenzaldehyde (Table 3). When 0.5 mol % of
catalyst was used (Table 3, entry 4), the stoichiometric reaction
was slow and the ee value was slightly lower than that using 5
and 2 mol % of catalyst (Table 3, entries 1 and 2). When using only
1 mol % of catalyst after 36 h, the desired aldol product was ob-
tained in 91% yield and with 99% ee for the anti-enantiomer
(Table 3, entry 3). Thus, the optimized catalyst loading was chosen
as 1 mol % of 1a.
In order to test the substrate generality of this organocatalyzed
direct stoichiometric aldol reaction, the reactions of various
Table 2
Effect of the solvent on the direct stoichiometric aldol reaction catalyzed by 1aa
O
O
O
OH
H
cat. 1a (5 mol%)
+
Solvent, rt
24-36 h
NO2
NO2
1 equiv
1 equiv
2a
c
Entry
Solvent
Time (h)
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
1
2
3
4
5
6
7
8
9
DMSO
DMF
NMP
CH3CN
CHCl3
PhCH3
THF
24
24
24
24
36
36
36
24
24
70
68
86
82
87
75
78
93
92
81:19
93:7
99:1
73:27
73:27
80:20
70:30
90:10
91:9
42/33
25/23
58/34
90/12
53/21
70/34
88/45
95/16
98/10
H2O/CHCl3 = 10:1
H2O
a
The reactions were carried out using 4-nitrobenzaldehyde (4.0 mmol), cyclohexanone (4.0 mmol) and catalyst (0.2 mmol) in a solvent (see Table 2,
2.0 mL).
b
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
c
Table 3
Effect of the catalyst loading on the direct stoichiometric aldol reaction catalyzed by 1aa
O
O
O
OH
H
cat. 1a (x mol%)
+
H2O, rt
24-48 h
NO2
NO2
1 equiv
1 equiv
2a
c
Entry
Catalyst (mol %)
Time (h)
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
1
2
3
4
5
2
1
0.5
24
36
36
48
92
91
91
80
91:9
90:10
99:1
93:7
98/10
98/13
99/44
95/14
a
b
c
The reactions were carried out using 4-nitrobenzaldehyde (4.0 mmol), cyclohexanone (4.0 mmol) and catalyst (see Table 3) on water (2.0 mL).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).

318
C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
Table 4
Organocatalyst 1a-catalyzed direct stoichiometric aldol reactions on watera
O
O
OH
O
cat. 1a (1 mol%)
+
R
H
R
H2O, rt
36-72 h
1 equiv
1 equiv
2a-v
c
Entry
Product
Time (h)
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
1
2
3
4
5
6
7
8
2a (R = p-NO2-C6H4)
2b (R = o-NO2-C6H4)
2c (R = m-NO2-C6H4)
2d (R = p-CF3-C6H4)
2e (R = p-CN-C6H4)
2f (R = p-F-C6H4)
2g (R = p-Cl-C6H4)
2h (R = o-Cl-C6H4)
2i (R = m-Cl-C6H4)
2j (R = 2,6-Cl-C6H4)
2k (R = p-Br-C6H4)
2l (R = o-Br-C6H4)
2m (R = m-Br-C6H4)
2n (R = p-MeO-C6H4)
2o (R = m-MeO-C6H4)
2p (R = p-Me-C6H4)
2q (R = 1-naphthyl)
2r (R = 2-naphthyl)
2s (R = C6H4)
2t (R = pyridinthyl)
2u (R = 2-thiophenaldehyde)
2v (R = 2-furaldehyde)
36
36
36
36
36
48
48
48
48
48
48
48
48
72
72
72
72
72
72
72
36
36
91
98
96
96
95
92
90
86
87
89
92
89
90
68
65
60
89
92
65
90
85
87
99:1
97:3
97:3
90:10
87:13
89:11
96:4
98:2
89:11
88:12
97:3
99:1
85:15
94:6
94:6
95:5
98:2
96:4
90:10
91:9
95:5
80:20
99/44
>99/5
>99/29
97/10
98/23
>99/34
98/67
98/8
>99/15
93/20
98/34
99/0
99/45
98/70
96/21
99/10
99/68
>99/6
97/6
98/23
99/19
>99/67
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
b
c
The reactions were carried out using aldehyde (4.0 mmol), cyclohexanone (4.0 mmol) and catalyst 1a (0.04 mmol) on water (2.0 mL).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H, OD-H and OJ-H).
aromatic aldehydes with cyclohexanone were studied under the
optimized conditions. The results are summarized in Table 4. It
can be seen that a wide range of aromatic and heteroaromatic alde-
hydes can participate in the stoichiometric aldol reaction. From Ta-
ble 4, we were able to access aldol adducts 2a–v derived from their
corresponding aromatic aldehydes, heteroaromatic aldehydes and
cyclohexanone. In the presence of only 1 mol % of catalyst 1a and
0.5 mL of water, most stoichiometric reactions between cyclohexa-
none and various aromatic and heteroaromatic aldehydes afforded
the aldol products in excellent yields and nearly perfect ee values.
In general, the stoichiometric reactions between cyclohexanone
and aromatic aldehydes bearing electron-withdrawing substituents
Table 5
The asymmetric stoichiometric aldol reactions of cyclopentanone with various aryl aldehydes on watera
OH
O
O
O
R
+
cat. 1a (1 mol%)
H
R
H2O, rt
1 equiv
1 equiv
3a-k
c
Entry
Product
Time (h)
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
1
2
3
4
5
6
7
8
3a (R = p-NO2-C6H4)
3b (R = o-NO2-C6H4)
3c (R = m-NO2-C6H4)
3d (R = p-CF3-C6H4)
3e (R = p-Br-C6H4)
3f(R = p-Cl-C6H4)
3g (R = o-Cl-C6H4)
3h (R = m-MeO-C6H4)
3i (R = p-Me-C6H4)
3j (R = 1-naphthyl)
3k (R = C6H4)
36
36
36
36
48
48
48
72
72
72
72
86
96
98
93
89
90
85
70
65
75
65
78:22
85:15
75:15
85:15
74:26
84:16
83:17
74:26
72:28
69:31
75:25
97/43
99/50
98/35
99/33
92/41
99/82
99/96
95/48
92/11
94/68
99/91
9
10
11
a
b
c
The reactions were carried out using aldehyde (4.0 mmol), cyclopentanone (4.0 mmol) and catalyst 1a (0.04 mmol) on water (2.0 mL).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H, OD-H and OJ-H).

C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
319
Table 6
The asymmetric stoichiometric aldol reactions of tetrahydro-4H-pyran-4-one with various aryl aldehydes on watera
O
O
OH
O
O
Catalyst 1a (1 mol%)
H
+
R
R
H2O, rt
O
4a-g
1 equiv
1 equiv
c
Entry
1
Product
Time (h)
48
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
O
OH
90
94:6
98/99
O
O
NO2
4a
OH
NO2
2
3
4
5
6
7
48
48
48
48
48
72
92
90
89
82
80
54
95:5
99/11
>99/53
94/65
91/34
92/23
98/78
O
O
4b
OH
NO2
97:3
O
O
4c
OH
90:10
91:9
O
O
CN
4d
OH
O
O
F
4e
OH
90:10
89:11
O
O
Cl
4f
OH
O
4g
a
The reactions were carried out using aldehyde (4.0 mmol), tetrahydro-4H-pyran-4-one (4.0 mmol) and catalyst 1a (0.04 mmol) on water
(2.0 mL).
b
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H and OD-H).
c
O
O
O
OH
OH
O
O
1 equiv
(1 mol%)
OH
1 equiv
1a
H
OH
1a (1 mol%)
NO2
H2O, rt
36 h
5a
O2N
O2N
6a
H2O, rt
36 h
25% yield,
1 equiv
46% ee for syn-enantiomer
81:19 dr (syn/anti)
34% yield, 41% ee
Figure 2. The stoichiometric aldol reactions between 4-nitrobenzaldehyde and water-soluble ketones.

320
C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
Table 7
Large-scale asymmetric stoichiometric aldol reactionsa
c
Entry
1
Product
Time (h)
24
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
O
OH
NO2
96
98:2
>99/8
2b
O
O
OH
NO2
2
3
24
30
95
89
97:3
94:6
>99/31
97/10
2c
OH
Cl
Br
2g
OH
O
4
5
6
30
30
30
90
85
89
92:8
96:4
99:1
97/30
97/13
99/4
2k
OH
O
O
Cl
2h
OH
2r
OH
O
7
8
36
36
68
85
97:3
95:5
98/75
99/23
OMe
2n
O
O
OH
S
2u
OH
O
9
36
87
74:26
>99/54
2v

C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
321
Table 7 (continued)
c
Entry
Product
Time (h)
48
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
O
OH
10
11
65
91:9
97/10
99/85
99/90
2s
OH
O
O
36
36
90
85
70:30
83:17
Cl
3f
OH
Cl
12
3g
a
The reactions were carried out using aldehyde (400 mmol), ketone (400 mmol) and catalyst 1a (4 mmol) on the water (200 mL).
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
b
c
Table 8
Recycling and reuse of catalyst 1aa
c
Cycle
Time (h)
Yieldb (%)
dr (anti/syn)
ee (anti/syn)c (%)
1
2
3
4
5
6
48
48
48
56
60
60
90
90
89
88
87
80
99:1
93:7
92:8
92:8
93:7
90:10
97/0
97/8
96/15
96/19
96/14
93/33
a
The reactions were carried out using 4-chlorobenzaldehyde (200 mmol) and cyclohexanone (200 mmol) on water (100 mL) at room
temperature.
b
Isolated yield after chromatography on silica gel.
Determined by chiral HPLC analysis (AD-H).
c
furnished b-hydroxy carbonyl aldol products in excellent yields
(86–98%) and enantioselectivities (93 to >99% ee for the anti-enan-
tiomer) within 36–48 h (Table 4, entries 1–13). In contrast, longer
reaction times (72 h) were required for aromatic aldehydes contain-
ing an electron-donating groups to give comparatively lower yields
(60–68%), but without a decrease in enantioselectivity (Table 3, en-
tries 14–16), in particular the p-tolualdehyde (Table 3, entry 16,
95:5 anti/syn ratio and 99% ee). This can be explained in that elec-
tron-withdrawing groups enhance the electrophilicity of the car-
bonyl carbons in aldehydes, which facilitate the reaction, while
electron-donating groups lessen the electrophilicity. Moreover,
the direct stoichiometric aldol reactions of neutral aldehydes cata-
lyzed by the threonine-based organocatalyst 1a also afforded the al-
dol products in high enantioselectivities and diastereoselectivities
(Table 4, entries 17 to 20), especially the 1-naphthyl aldehyde
(Table 4, entry 17, 98:2 anti/syn ratio and 99% ee for the anti-enan-
tiomer). Moreover, the heteroaromatic aldehydes 2-furaldehyde
and 2-thiophenaldehyde both reacted smoothly with cyclohexa-
none under the optimal conditions to give the corresponding aldol
products in good yields (85–87%) and excellent enantioselectivities
(99 to >99%) after 36 h (Table 4, entries 21 and 22). All of the stoichi-
ometric reactions of cyclohexanone with aromatic and heteroaro-
matic aldehydes provided the corresponding products with
excellent enantioselectivities (93 to >99% ee for the anti-enantio-
mer) and excellent diastereoselectivities (anti/syn 80:20–99:1) (Ta-
ble 4, entries 1–22).

322
C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
When aromatic aldehydes and cyclopentanone were employed
catalytic activity or stereoselectivity; (6) this organocatalyzed
direct asymmetric stoichiometric aldol reaction can be performed
on a large-scale with the enantioselectivity being maintained at
the same level, which offers great possibilities for industrial
applications.
interesting results were obtained (Table 5), with excellent enanti-
oselectivities being obtained (92–99% ee for the anti-enantiomer).
We next investigated threonine-based organocatalyst 1a as a
catalyst in the stoichiometric reaction between aromatic aldehydes
and tetrahydro-4H-pyran-4-one (Table 6). It can be seen that a
wide range of aromatic aldehydes can participate in the stoichiom-
etric aldol reaction, with excellent enantioselectivities. The enanti-
oselectivities ranged from 91 to >99% for the anti-enantiomer and
diastereoselectivities ranged from 89:11 to 97:3 (anti/syn).
We also investigated threonine-based organocatalyst 1a as a
catalyst in the stoichiometric aldol reactions between 4-nitrobenz-
aldehyde and water-soluble ketones (acetone and hydroxyacetone)
(Fig. 2). However, when 4-nitrobenzaldehyde and water-ketones
were equivalent, we found that the enantioselectivities of aldol
reactions products were not high.
We performed large-scale asymmetric stoichiometric aldol
reactions with 400 mmol of aromatic aldehydes and 1 equiv of ke-
tones in a 500 mL round bottomed flask. The same catalyst loading
of 1 mol % as employed in the experimental scale was used. The
large-scale experiments can be easily carried out by using the same
procedure as for the experimental scale reactions. As can be seen
from the results summarized in Table 7, the enantioselectivities
were maintained at the same level for the large-scale reactions.
Thus, the threonine-based organocatalyst 1a is not only simple
and easily prepared by a one-step reaction, but the enantioselectiv-
ities are maintained at the same level for the large-scale stoichiom-
etric aldol reactions, which offers great possibilities for industrial
applications.
In order to verify that the threonine-based organocatalyst 1a
could be recovered and reused, we performed a recycling study
of 1a using the stoichiometric aldol reaction between cyclohexa-
none and 4-chlorobenzaldehyde in a 500 mL round bottomed flask
(Table 8). Catalyst 1a could be easily recovered from the reaction
mixture after completion of the reaction by acid treatment; the al-
dol product was extracted with diethyl ether (Et2O), evaporation of
the organic solution to give the aldol product. Catalyst 1a exists in
the acidic aqueous layer; an equivalent amount of triethylamine
(Et3N) was added, which resulted in a white suspension that was
filtered by vacuum. The white crystals were directly used in subse-
quent reaction cycles without adding any new catalyst. In each
reuse, the same amounts of substrates were used. The recovered
catalyst 1a was used without further purification and retained its
catalytic activity; no decrease in enantioselectivity was observed
for six cycles (Table 8).
4. Experimental section
4.1. General information
All reagents were commercial products. The reactions were
monitored by TLC (thin layer chromatography). The column and
preparative TLC purification was 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 (Bru-
ker Avance 300 Spectrometer). Chemical shifts (d) are given in ppm
relative to TMS as the internal reference, with coupling constants
(J) in Hz. IR spectra were recorded on a Bruker Tensor 27 FTIR spec-
trometer. Melting points were measured on a digital melting point
apparatus (TAQ100). Mass spectra (MS) were measured with a Bru-
ker HCT Mass Spectrometer. Analytical high performance liquid
chromatography (HPLC) was carried out on Agilent 1200 instru-
ment using Chiralpak AD (4.6 mm ꢀ 250 mm), Chiralcel OD-H
(4.6 mm ꢀ 250 mm) and Chiralcel OJ-H (4.6 mm ꢀ 250 mm) col-
umns. Optical rotations were measured on a JASCO P-1010 Polar-
imeter at k = 589 nm.
4.2. Typical experimental procedure for the large-scale
preparation of the direct O-acylated threonine organocatalysts
1a–g34–41
A 1000 mL round bottomed flask was charged with CF3CO2H
(240 mL) and placed in an ice/water bath. Powdered threonine
(500 mmol) was added in small portions with vigorous stirring to
give a viscous solution. The reaction mixture was stirred for
40 min, and then the acyl chloride (750 mmol) was added in one
portion. After 60 min of stirring, the reaction mixture was removed
from the ice/water bath. The reaction flask was fitted with a loose
glass stopper, and the reaction mixture was stirred at room tem-
perature 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 (500 mL) was added with
vigorous stirring over a period of 20 min, slowly at first. The result-
ing white suspension was stirred at 0–5 °C for 30 min after the
complete addition, and then filtered by vacuum. The crystals were
washed with two portions of Et2O and dried at room temperature
for 23 h in a ventilated hood to directly give O-acylation threonine
hydrochloride, which was then dissolved in water, and an equiva-
lent amount of triethylamine (Et3N) added. The resulting white
suspension was stirred at room temperature for 10 min after the
complete addition, and then filtered by vacuum. The white crystals
were washed with two portions of H2O and dried to give the
organocatalysts. These essentially pure materials were used for
the next step without further purification.
3. Conclusions
In conclusion, our results demonstrate that the direct threo-
nine catalyst 1a, obtained via a direct O-acylation, is a robust
and effective catalyst for highly enantioselective stoichiometric al-
dol reactions. A wide range of aromatic and heteroaromatic alde-
hydes with cyclic and acyclic ketones can participate in the direct
stoichiometric aldol reactions. Noteworthy features of this cata-
lyst system are; (1) the direct O-acylation of threonine-based
organocatalysts 1a–i that can be prepared easily by a one-step
reaction from commercially available sources, with both enantio-
mers being readily available; (2) the direct aldol reactions proceed
in the presence of water using simple procedures; (3) only 1 mol %
of catalyst 1a was sufficient to furnish the aldol products in excel-
lent yields (up to 99%) and enantioselectivities (up to >99% ee for
the anti-enantiomer); (4) aldehydes and cyclic ketones were
equivalent, which is reassuring for direct stoichiometric aldol
reactions with atom economic ‘green’ credentials; (5) catalyst 1a
can be readily recovered and reused without a significant loss of
4.2.1. (2S,3R)-O-(Benzoyloxy)-L-threonine 1a
White microcrystals, yield 101.56 g (455 mmol, 91%); mp 144–
145 °C; ½a 2D0
ꢁ
¼ ꢂ12:8 (c 1.02, MeOH). 1H NMR (300 MHz, DMSO):
d = 1.46–1.48 (d, 3J = 6.6 Hz, 3H, CH3), 4.35 (br s, 1H, NCH), 5.55–
5.58 (dq, 3J = 3.0 and 6.5 Hz, 1H, 3-H, OCH), 7.52–7.57(m, 2H, Ph-
H), 7.67–7.71 (m, 1H, Ph-H), 8.10–8.13 (m, 2H, Ph-H) ppm. 13C
NMR (75 MHz, DMSO): d = 16.7, 55.6, 68.9, 128.7, 129.0, 129.9,
133.9, 164.6, 168.5 ppm. IR (KBr):
m = 2985, 1759, 1716, 1650,
1602, 1586, 1493, 1415, 1157 cmꢂ1. HRMS (FAB): [M+H] calcd for
[C11H13NO4] 224.2332, found 224.2340. Anal. Calcd for

C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
323
C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.33; H, 5.92; N,
6.30.
found 230.2823. Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35; N,
6.11. Found: C, 57.67; H, 8.38; N, 6.13.
4.2.2. (2S,3R)-O-(2-Phenylacetoxy)-L-threonine 1b
4.2.7. (2S,3R)-O-(1-Adamantylcarbonyl)-L-threonine 1g
White microcrystals, yield 112.7 g (475 mmol, 95%); mp
White microcrystals, yield 126.68 g (450 mmol, 90%); mp
115–116 °C; ½a 2D0
ꢁ
¼ þ28:9 (c 1.26, MeOH). 1H NMR (300 MHz,
97–100 °C; ½a 2D0
ꢁ
¼ þ5:4 (c 1.2, MeOH). 1H NMR (300 MHz, DMSO):
DMSO): d = 1.33–1.35 (d, 3J = 6.6 Hz, 3H, CH3), 3.70–3.76 (d,
3J = 16.2 Hz, 2H, CH2), 4.17 (br s, 1H, NCH), 5.27–5.30 (dq,
d = 1.28–1.30 (d, 3J = 6.6 Hz, 3H, CH3), 1.66 (m, 6H, cyclo-CH2), 1.81
(m, 6H, cyclo-CH2), 1.95 (m, 3H, cyclo-CH), 4.19 (br s, 1H, NCH),
5.24–5.27 (dq, 3J = 2.9 Hz and 6.6 Hz, 1H, 3-H, OCH) ppm. 13C
NMR (75 MHz, DMSO): d = 15.6, 16.6, 27.7, 36.3, 38.2, 40.5, 55.8,
3J = 3.9 Hz and 6.3 Hz, 1H, OCH), 7.28–7.33 (m, 5H, Ph-H) ppm. 13
C
NMR (75 MHz, DMSO): d = 16.7, 41.9, 55.4, 68.2, 126.9, 128.1,
129.4, 134.0, 168.4, 170.1 ppm. IR (KBr):
m
= 2984, 1739, 1621,
65.3, 67.8, 168.8, 175.6 ppm. IR (KBr): m = 3026, 2968, 1758,
1540, 1493, 1415, 1145 cmꢂ1.. HRMS (FAB): [M+H] calcd for
[C12H15NO4] 238.2597, found 238.2587. Anal. Calcd for C12H15NO4:
C, 60.75; H, 6.37; N, 5.90. Found: C, 60.80; H, 6.40; N, 5.93.
1726, 1601, 1575, 1493, 1415, 1157 cmꢂ1. HRMS (FAB): [M+H]
calcd for [C15H23NO4] 282.3554, found 282.3569. Anal. Calcd for
C15H23NO4: C, 64.03; H, 8.24; N, 4.98. Found: C, 64.11; H, 8.28;
N, 5.03.
4.2.3. (2S,3R)-O-(3-Phenylpropanoyloxy)-L-threonine 1c
White microcrystals, yield 120.62 g (280 mmol, 96%); mp
4.3. Representative procedures for the asymmetric
stoichiometric aldol reactions of ketones with aldehydes
112–113 °C; ½a 2D0
ꢁ
¼ þ14:6 (c 1.2, MeOH). 1H NMR (300 MHz,
DMSO): d = 1.30–1.32 (d, 3J = 6.4 Hz, 3H, CH3), 2.61–2.66 (m, 2H,
CH2), 2.61–2.66 (m, 2H, CH2), 2.84 (t, J = 7.0 Hz, 2H, CH2), 4.14 (br s,
1H, NCH), 5.25–5.29 (dq, 3J = 3.8 Hz and 6.3 Hz, 1H, OCH), 7.21–
7.31 (m, 5H, Ph-H) ppm. 13C NMR (75 MHz, DMSO): d = 20.1, 33.4,
38.4, 58.8, 71.2, 129.5, 131.5, 131.7, 143.7, 171.7, 174.4 ppm. IR
On water: To a mixture of catalyst 1a (8.94 mg, 0.04 mmol) and
ketone (4.0 mmol) were added the aldehyde (4.0 mmol) and water
(2.0 mL). The resulting mixture was stirred at room temperature.
The reaction was monitored by TLC. It was then quenched with
8 mL saturated NH4Cl solution, extracted with EtOAc (5 ꢀ 10 mL),
and dried over Na2SO4. Purification by flash chromatography affor-
ded the corresponding pure products.
(KBr):
m .
= 2986, 1757, 1731, 1633, 1575, 1493, 1415, 1164 cmꢂ1
HRMS (FAB): [M+H] calcd for [C13H17NO4] 252.2863, found
252.2875. Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57.
Found: C, 62.20; H, 6.85; N, 5.64.
4.3.1. (2S,10R)-2-(Hydroxy-(4-nitrophenyl)methyl)-cyclohexan-
1-one 2a35–37
4.2.4. (2S,3R)-O-(4-Phenylbutanoyloxy) -L-threonine 1d
White microcrystals, yield 124.16 g (470 mmol, 94%); mp
Yield 91%, anti/syn = 99:1, enantiomeric excess: 99% for the
anti-enantiomer and 44% for the syn-enantiomer 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). HRMS (FAB): [M+Na] calcd for [C13H15NO4Na]
272.2522, found 272.2528.
110–111 °C; ½a 2D0
ꢁ
¼ þ14:7 (c 1.0, MeOH). 1H NMR (300 MHz,
DMSO): d = 1.32–1.34 (d, 3J = 6.5 Hz, 3H, CH3), 1.76–1.86 (m, 2H,
CH2), 2.24–2.35 (m, 2H, CH2), 2.50–2.59 (m, 2H, CH2), 2.61–2.66
(m, 2H, CH2), 4.13 (br s, 1H, NCH), 5.27–5.30 (dq, 3J = 3.6 Hz and
6.3 Hz, 1H, OCH), 7.17–7.19(m, 3H, Ph-H), 7.25–7.30(m, 3H, Ph-H)
ppm. 13C NMR (75 MHz, DMSO): d = 16.7, 26.1, 33.0, 34.3, 55.4,
67.8, 126.0, 128.4, 128.5, 141.4, 168.5, 171.6 ppm. IR
(KBr):m ;
= 2987, 1758, 1733, 1634, 1540, 1500, 1415, 1156 cmꢂ1
HRMS (FAB): [M+H] calcd for [C14H19NO4] 266.3129, found
266.3137. Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.42; H, 7.25; N, 5.32.
4.3.2. (2S,10R)-2-(Hydroxy-(2-nitrophenyl)methyl)-cyclohexan-
1-one 2b35–37
4.2.5. (2S,3R)-O-(2-(Naphthalen-1-yl)-
L
-threonine 1e
Yield 98%, anti/syn = 97:3, enantiomeric excess: >99% for the
anti-diastereomer and 5% for the syn-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 (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). HRMS (FAB): [M+Na] calcd for
[C13H15NO4Na] 272.2522, found 272.2528.
White microcrystals, yield 134.54 g (468 mmol, 94%); mp
110–111 °C; ½a 2D0
ꢁ
¼ þ27:3 (c 1.3, MeOH). 1H NMR (300 MHz,
DMSO): d = 1.37–1.39 (d, 3J = 6.4 Hz, 3H, CH3), 4.20 (br s, 3H, NCH
and CH2), 5.30–5.33 (dq, 3J = 3.6 Hz and 5.9 Hz, 1H, 3-H, OCH),
7.46–7.58 (m, 4H, Ph-H), 7.86–7.96 (m, 3H, Ph-H) ppm. 13C NMR
(75 MHz, DMSO): d = 17.2, 38.1, 55.9, 68.7, 124.4, 125.9, 126.2,
126.8, 128.1, 128.5, 128.9, 131.0, 132.2, 133.7, 168.8, 170.5 ppm.
IR (KBr):
m = 2986, 1755, 1719, 1650, 1602, 1586, 1493, 1415,
1157 cmꢂ1. HRMS (FAB): [M+H] calcd for [C16H17NO4] 288.3184,
found 288.3178. Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N,
4.88. Found: C, 66.90; H, 6.99; N, 4.91.
4.3.3. (2S,10R)-2-(Hydroxy-(3-nitrophenyl)methyl)-cyclohexan-
1-one 2c35–37
4.2.6. (2S,3R)-O-(Cyclohexylcarbonyl)-
L
-threonine 1f
Yield 96%, anti/syn = 97:3, enantiomeric excess: >99% for the
anti-diastereomer and 29% for the syn-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 = 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). HRMS (FAB): [M+Na] calcd for [C13H15NO4Na]
272.2522, found 272.2528.
White microcrystals, yield 103.28 g (450 mmol, 90%); mp
97–100 °C;
½
a 2D0
ꢁ
¼ þ15:7 (c 1.1, MeOH). 1H NMR (300 MHz,
DMSO): d = 1.27–1.38 (m, 8H, cyclo-CH2), 1.42–1.44 (d,
3J = 6.6 Hz, 3H, CH3), 1.84–1.88 (m, 2H, cyclo-CH2), 2.30–2.38 (m,
1H, cyclo-CH2), 4.22 (br s, 1H, NCH), 5.30–5.33 (dq, 3J = 3.2 Hz
and 6.5 Hz, 1H, 3-H, OCH) ppm. 13C NMR (75 MHz, DMSO):
d = 16.9, 25.1, 25.2, 25.7, 28.6, 28.7, 42.4, 55.8, 67.9, 168.8,
174.2 ppm. IR (KBr):
m = 3026, 2947, 2929, 2857, 1735,
1629 cmꢂ1. HRMS (FAB): [M+H] calcd for [C11H19NO4] 230.2808,

324
C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
4.3.4. (2S,10R)-2-(Hydroxy-(4-(trifluoromethyl)methyl)-cyclo-
hexan-1-one 2d35–37
4.3.9. (2S,10R)-2-(Hydroxy-(3-chlorophenyl)methyl)-cyclo-
hexan-1-one 2i35–37
Yield 96%, anti/syn = 90:10, enantiomeric excess: 97% for the
anti-diastereomer and 10% o for the syn-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). HRMS (FAB): [M+Na] calcd for [C14H15F3O2Na] 295.2527,
found 295.2534.
Yield 87%, anti/syn = 89:11, enantiomeric excess: >99% for the
anti-diastereomer and 15% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak OD-H column; i-PrOH/Hexane = 4:96;
flow rate 1.0 mL/min, 20 °C, k = 221 nm; tR = 14.8 min (anti, major),
tR = 21.2 min (anti, minor)). 1H NMR (300 MHz, CDCl3): d = 7.37 (s,
1H, Ar), 7.20–7.29 (m, 3H, Ar), 4.80 (d, 1H, J = 8.8 Hz), 2.30–2.45 (m,
3H), 1.31–2.08 (m, 6H). HRMS (FAB): [M+Na] calcd for [C13H15ClO2-
Na] 261.6997, found 261.6992.
4.3.10. (2S,10R)-2-(Hydroxy-(2,6-dichlorophenyl)methyl)-cyclo-
hexan-1-one 2j37
Yield 89%, anti/syn = 88:12, enantiomeric excess: 93% for the
anti-diastereomer and 20% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak OJ-H column; i-PrOH/Hexane = 5:95;
flow rate 1.0 mL/min, 20 °C, k = 221 nm; tR = 10.2 min (anti, major),
tR = 11.9 min (anti, minor)). 1H NMR (300 MHz, CDCl3): d = 7.33 (d,
2H, J = 8.0 Hz) 7.17 (t, 2H, J = 8.0 Hz), 5.86 (d, 1H, J = 9.6 Hz), 3.69
(br s, 1H), 3.49–3.55 (m, 1H), 2.38–2.55 (m, 2H), 2.07–2.14 (m,
1H), 1.34–1.86 (m, 5H). HRMS (FAB): [M+Na] calcd for
[C13H14Cl2O2Na] 294.1448, found 294.1453.
4.3.5. (2S,10R)-2-(Hydroxy-(4-cyanophenyl)methyl)-cyclo-
hexan-1-one 2e35–37
Yield 95%, anti/syn = 87:13, enantiomeric excess: 98% for the
anti-diastereomer and 23% for the syn-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 (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). HRMS (FAB): [M+Na] calcd for [C14H15NO2Na]
252.2641, found 252.2637.
4.3.11. (2S,10R)-2-(Hydroxy-(4-bromophenyl)methyl)-cyclo-
hexan-1-one 2k35–37
Yield 92%, anti/syn = 97:3, enantiomeric excess: 98% for the
anti-diastereomer and 34% for the syn-diastereomer 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). HRMS (FAB): [M+Na] calcd for [C13H15BrO2Na]
306.1507, found 306.1513.
4.3.6. (2S,10R)-2-(Hydroxy-(4-fluor-phenyl)methyl)-cyclo-
hexan-1-one 2f35–37
Yield 92%, anti/syn = 89:11, enantiomeric excess: >99% for the
anti-diastereomer and 34% for the syn-diastereomer 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, ma-
jor), 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, 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). HRMS (FAB): [M+Na] calcd for [C13H15FO2Na] 245.2441,
found 245.2445.
4.3.12. (2S,10R)-2-(Hydroxy-(2-bromophenyl)methyl)-cyclo-
hexan-1-one 2l36,37
Yield 89%, anti/syn = 99:1, enantiomeric excess: 99% for the
anti-diastereomer determined by HPLC (Dicael Chiralpak OD-H col-
umn; i-PrOH/Hexane = 5:95; flow rate 1.0 mL/min, 20 °C,
k = 221 nm; tR = 18.4 min (anti, major), tR = 15.3 min (anti, minor)).
1H NMR (300 MHz, CDCl3): d = 7.50–7.54 (m, 2H), 7.33 (t, 1H,
J = 24.6 Hz), 7.11–7.16 (m, 1H), 5.30 (d, 1H, J = 9.6 Hz), 4.02 (s,
1H), 2.64–2.72 (m, 1H), 2.29–2,49 (m, 2H), 2.06–2.12 (m, 1H),
1.49–1.84 (m, 5H). HRMS (FAB): [M+Na] calcd for [C13H15BrO2Na]
306.1507, found 306.1513.
4.3.7. (2S,10R)-2-(Hydroxy-(4-chlorophenyl)methyl)-cyclo-
hexan-1-one 2g35–37
Yield 90%, anti/syn = 96:4, enantiomeric excess: 98% for the
anti-diastereomer and 67% for the syn-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 = 37.2 min (anti, major),
tR = 32.4 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). HRMS (FAB): [M+Na] calcd for [C13H15ClO2Na] 261.6997,
found 261.6992.
4.3.13. (2S,10R)-2-(Hydroxy-(3-bromophenyl)methyl)-cyclo-
hexan-1-one 2m37
Yield 90%, anti/syn = 85:15, enantiomeric excess: 99% for the
anti-diastereomer and 45% for the syn-diastereomer 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 = 22.1 min (anti, major),
tR = 27.7 min (anti, minor)). 1H NMR (300 MHz, CDCl3): d = 7.37 (s,
1H, Ar), 7.20–7.29 (m, 3H, Ar), 4.80 (d, 1H, J = 8.8 Hz), 2.30–2.45 (m,
3H), 1.31–2.08 (m, 6H). HRMS (FAB): [M+Na] calcd for [C13H15BrO2-
Na] 306.1507, found 306.1513.
4.3.8. (2S,10R)-2-(Hydroxy-(2-chlorophenyl)methyl)-cyclo-
hexan-1-one 2h37
Yield 86%, anti/syn = 98:2, enantiomeric excess: 98% for the
anti-diastereomer and 8% for the syn-diastereomer 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), 3.88
(s, 1H), 2.65–2.71 (m, 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). HRMS (FAB): [M+Na] calcd
for [C13H15ClO2Na] 261.6997, found 261.6992..
4.3.14. (2S,10R)-2-(Hydroxy-(4-methoxy-phenyl)methyl)-cyclo-
hexan-1-one 2n35–37
Yield 68%, anti/syn = 94:6, enantiomeric excess: 98% for the
anti-diastereomer and 70% for the syn-diastereomer 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),

C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
325
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). HRMS (FAB):
[M+Na] calcd for [C14H18O3Na] 257.2807, found 257.2812.
(m, 1H), 1.87–1.73 (m, 1H), 1.72–1.50 (m, 3H), 1.40–1.22 (m,
1H). HRMS (FAB): [M+Na] calcd for [C13H16O2Na] 227.2547, found
227.2553.
4.3.20. (2S,10R)-2-(Hydroxy-(pyridin-4-yl)methyl)-cyclohexan-
1-one 2t37
4.3.15. (2S,10R)-2-(Hydroxy-(3-methoxy-phenyl)methyl)-cyclo-
hexan-1-one 2o35–37
Yield 90%, anti/syn = 91:9, enantiomeric excess: 98% for the
anti-diastereomer and 23% for the syn-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).
HRMS (FAB): [M+H] calcd for [C12H16NO2] 206.2609, found
206.2635.
Yield 65%, anti/syn = 94:6, enantiomeric excess: 96% for the
anti-diastereomer and 21% for the syn-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 = 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). HRMS (FAB): [M+Na] calcd for [C14H18O3Na]
257.2807, found 257.2812.
4.3.21. (S)-2-((R)-Hydroxy(thiophen-2-yl)methyl)-cyclo-hexan-
one 2u37
4.3.16. (2S,10R)-2-(Hydroxy-(4-tolyl)methyl)-cyclohexan-1-one
2p35–37
Yield 85%, anti/syn = 95:5, enantiomeric excess: 99% for the
anti-diastereomer and 19% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
flow rate 1.0 mL/min, 20 °C, k = 220 nm; tR = 19.6 min (anti, major),
tR = 21.7 min (anti, minor)). 1H NMR (300 MHz, CDCl3): d = 7.30
(dd, J = 4.8, 0.8 Hz, 1H), 7.00–6.96 (m, 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), 1.30–1.40 (m, 1H). HRMS (FAB):
[M+Na] calcd for [C11H14SO2Na] 233.2824, found 233.2829.
Yield 60%, anti/syn = 95:5, enantiomeric excess: 99% for the
anti-diastereomer and 10% for the syn-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). HRMS (FAB): [M+Na]
calcd for [C14H18O2Na] 241.2813, found 241.2808.
4.3.22. (S)-2-((R)-Furan-2-yl(hydroxy)methyl)-cyclo-hexanone
2v37
4.3.17. (2S,10R)-2-(Hydroxy-(1-naphthyl)methyl)-cyclohexan-1-
one 2q35–37
Yield 87%, anti/syn = 80:20, enantiomeric excess: >99% for the
anti-diastereomer and 67% for the syn-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 = 7.39 (s,
1H), 6.34–6.30 (m, 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), 1.33–1.43 (m, 1H). HRMS (FAB): [M+Na] calcd for
[C11H14O3Na] 217.2168, found 217.2172.
Yield 89%, anti/syn = 98:2, enantiomeric excess: 99% for the
anti-diastereomer and 68% for the syn-diastereomer 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 = 43.2 min (anti, major),
tR = 35.3 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). HRMS (FAB): [M+Na] calcd for [C17H18O2Na]
277.3134, found 277.3140.
4.3.23. (S)-2-(R)-Hydroxyl(4-nitrophenyl)methyl)-cyclopentan-
1-one 3a35
Yield 86%, anti/syn = 78:22, enantiomeric excess: 97% for the
anti-diastereomer and 43% for the syn-diastereomer 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 = 63.6 min (anti, major),
tR = 61.6 min (anti, minor)); 1H NMR (300 MHz, CDCl3): d = 8.21 (d,
2H, J = 8.7 Hz), 7.54 (d, 2H, J = 9.0 Hz), 4.85 (d, 1H, J = 9.2 Hz), 4.76
(s, 1H), 2.54–2.18 (m, 3H), 2.08–1.95 (m, 1H), 1.81–1.48 (m, 3H).
HRMS (FAB): [M+Na] calcd for [C12H13NO4Na] 258.2257, found
258.2252.
4.3.18. (2S,10R)-2-(Hydroxy-(2-naphthyl)methyl)-cyclohexan-1-
one 2r36,37
Yield 92%, anti/syn = 96:4, enantiomeric excess: >99% for the
anti-diastereomer and 6% for the syn-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 = 21.9 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). HRMS (FAB): [M+Na] calcd
for [C17H18O2Na] 277.3134, found 277.3140.
4.3.24. (S)-2-(R)-Hydroxyl(2-nitrophenyl)methyl)-cyclopentan-
1-one 3b35
Yield 96%, anti/syn = 85:15, enantiomeric excess: 99% for the
anti-diastereomer and 50% for the syn-diastereomer 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); 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). HRMS (FAB): [M+Na] calcd for [C12H13NO4Na]
258.2257, found 258.2252.
4.3.19. (2S,10R)-2-(Hydroxy-(phenyl)methyl)-cyclohexan-1-one
2s35–37
Yield 65%, anti/syn = 90:10, enantiomeric excess: 97% for the
anti-diastereomer and 6% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak OD-H column; i-PrOH/Hexane = 10:90;
flow rate 0.5 mL/min, 20 °C, k = 221 nm; tR = 19.6 min (anti, major),
tR = 30.6 min (anti, minor)). 1H NMR(300 MHz, CDCl3): d = 7.39–
7.28 (m, 5H), 4.80 (d, J = 9.0 Hz, 1H), 4.00 (m, 1H), 2.70–2.56 (m,
1H), 2.55–2.44 (m, 1H), 2.34 (td, J = 12.3, 5.4 Hz, 1H), 2.16–2.03

326
C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
4.3.25. (S)-2-(R)-Hydroxyl(hydroxy-(3-nitrophenyl)methyl)-
cyclopentan-1-one 3c35
(m, 7.62H); HRMS (FAB): [M+Na] calcd for [C13H16O3Na]
243.2541, found 243.2527.
Yield 98%, anti/syn = 75:25, enantiomeric excess: 98% for the
anti-diastereomer and 35% for the syn-diastereomer 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); 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). HRMS (FAB): [M+Na] calcd for [C12H13NO4Na]
258.2257, found 258.2252.
4.3.31. (S)-2-(R)-Hydroxyl(4-methylphenyl)methyl)-cyclo-
pentanone 3i42
Yield 65%, anti/syn = 72:28, enantiomeric excess: 92% for the
anti-diastereomer and 11% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
flow rate 0.5 mL/min, 20 °C, k = 220 nm; tR = 28.4 min (anti, major),
tR = 32.0 min (anti, minor)); 1H NMR (300 MHz, CDCl3): d = 7.29–
7.13 (m, 4H), 5.24 (d, J = 2.8 Hz, 0.67H), 4.68 (d, J = 9.2 Hz, 0.33H),
2.44–1.66 (m, 10H); HRMS (FAB): [M+Na] calcd for [C13H16O2Na]
227.2547, found 227.2541.
4.3.26. (S)-2-(R)-Hydroxyl(4-(trifluoromethyl)methyl)-cyclo-
pentanone 3d42
4.3.32. (S)-2-(R)-Hydroxyl(1-naphthyl)methyl)-cyclopentanone
3j43
Yield 93%, anti/syn = 85:15, enantiomeric excess: 99% for the
anti-diastereomer and 33% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
flow rate 1.0 mL/min, 20 °C, k = 214 nm; tR = 12.3 min (anti, major),
tR = 16.9 min (anti, minor); 1H NMR (300 MHz, CDCl3): d = 7.66 (d,
J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.37 (d, J = 2.8 Hz, 0.97H),
4.79 (d, J = 9.2 Hz, 0.03H), 2.48–1.69 (m, 8H); HRMS (FAB):
[M+Na] calcd for [C13H13F3O3Na] 274.2357, found 274.2350.
Yield 75%, anti/syn = 69:31, enantiomeric excess: 94% for the
anti-diastereomer and 68% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 5:95;
flow rate 1.0 mL/min, 20 °C, k = 264 nm; tR = 40.0 min (anti, major),
tR = 44.1 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), 5.14 (d, J = 2.8 Hz, 0.67H), 4.76
(d, J = 9.2 Hz, 0.33H), 2.44–1.66 (m, 10H);. HRMS (FAB): [M+Na]
calcd for [C16H16O2Na] 263.2868, found 263.2874.
4.3.27. (S)-2-(R)-Hydroxyl(4-bromophenyl)methyl)-cyclo-
pentanone 3e42
4.3.33. (S)-2-(R)-Hydroxyl-(phenyl-methyl)-cyclopentanone
3k42
Yield 89%, anti/syn = 74:26, enantiomeric excess: 92% for the
anti-diastereomer and 41% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 5:95;
flow rate 1.0 mL/min, 20 °C, k = 220 nm; tR = 27.9 min (anti, major),
tR = 20.7 min (anti, minor); 1H NMR (300 MHz, CDCl3): d = 7.36 (s,
1H), 7.29–7.19 (m, 3H), 5.28 (d, J = 3.2 Hz, 0.7H), 4.69 (d,
J = 7.2 Hz, 0.3H), 2.45–1.70 (m, 7H); HRMS (FAB): [M+Na] calcd
for [C12H13BrO2Na] 292.1242, found 292.1250.
Yield 65%, anti/syn = 75:25, enantiomeric excess: 99% for the
anti-diastereomer and 91% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak OD-H column; i-PrOH/Hexane = 10:90;
flow rate 1.0 mL/min, 20 °C, k = 213 nm; tR = 11.6 min (anti, major),
tR = 14.0 min (anti, minor); 1H NMR (300 MHz, CDCl3): d 7.37–7.25
(m, 5H), 5.31 (d, J = 3.2 Hz, 0.86H), 4.72 (d, J = 9.2 Hz, 0.14H), 2.62–
1.72 (m, 7H); HRMS (FAB): [M+Na] calcd for [C12H14O2Na]
213.2281, found 213.2278.
4.3.28. (S)-2-(R)-Hydroxyl(4-chlorophenyl)methyl)-cyclo-
pentanone 3f42
4.3.34. (S)-3-((R)-Hydroxy(4-nitrophenyl)methyl)-tetrahydro-
pyran-4-one 4a37,43
Yield 90%, anti/syn = 84:16, enantiomeric excess: 99% for the
anti-diastereomer and 82% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 5:95;
flow rate 1.0 mL/min, 20 °C, k = 220 nm; tR = 29.9 min (anti, major),
tR = 36.9 min (anti, minor); 1H NMR (300 MHz, CDCl3): d = 7.33–
7.26 (m, 4H), 5.28 (d, J = 3.2 Hz, 0.73H), 4.70 (d, J = 9.2 Hz, 0.27H),
2.46–1.68 (m, 7H); [M+Na] calcd for [C12H13ClO2Na] 247.6732,
found 247.6737
Yield 90%, anti/syn = 94:6, enantiomeric excess: 98% for the anti
diastereomer and 99% for the syn-diastereomer determined by HPLC
(Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90; 1.0 mL/
min, 20 °C, k = 254 nm) tR = 16.7 min (anti, major) and tR = 39.4 min
(anti, minor)). 1H NMR (300 MHz, CDCl3) d = 8.24 (d, J = 8.8 Hz, 2H,
Ar-H), 7.53 ((d, J = 8.8 Hz, 2H, Ar-H), 4.99 (d, J = 8.0 Hz, 1H), 4.19–
4.25(m, 1H), 3.70–3.85 (m, 3H), 3.42–3.49 (m, 1H), 2.88–2.94 (m,
1H), 2.64–2.70 (m, 1H), 2.50–2.57 (m, 1H) ppm. HRMS (FAB):
[M+Na] calcd for [C12H13NO5 Na] 274.2251, found 274.2244.
4.3.29. (S)-2-(R)-Hydroxyl(2-chlorophenyl)methyl)-cyclo-
pentanone 3g42
Yield 85%, anti/syn = 83:17, enantiomeric excess: 99% for the
anti-diastereomer and 96% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 4:96;
flow rate 1.0 mL/min, 20 °C, k = 220 nm; tR = 17.9 min (anti, major),
tR = 19.6 min (anti, minor); 1H NMR (300 MHz, CDCl3): d = 7.61 (s,
1H), 7.59–7.26 (m, 2H), 7.23–7.18 (m, 1H), 5.69 (d, J = 2.8 Hz,
0.96H), 5.3 (d, J = 7.2 Hz, 0.04H), 2.70–1.67 (m, 8H); [M+Na] calcd
for [C12H13ClO2Na] 247.6732, found 247.6737.
4.3.35. (S)-3-((R)-Hydroxy(2-nitrophenyl)methyl)-tetrahydro-
pyran-4-one 4b43
Yield 92%, anti/syn = 95:5, enantiomeric excess: 99% for the
anti-diastereomer and 11% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
1.0 mL/min, 20 °C, k = 254 nm) tR = 66.3 min (anti, major) and
tR = 63.2 min (anti, minor)). 1H NMR (300 MHz, CDCl3) d = 7.93
(dd, J = 8.4, 0.8 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.70–7.66 (m, 1H),
7.49–7.45 (m, 1H), 5.48 (d, J = 6.8 Hz, 1H), 4.25–4.20 (m, 1H),
4.06 (br s, 1H), 3.95–3.90 (m, 1H), 3.83–3.75 (m, 2H), 3.10–3.04
(m, 1H), 2.72–2.64 (m, 1H), 2.54–2.49 (m, 1H) ppm. HRMS (FAB):
[M+Na] calcd for [C12H13NO5Na] 274.2251, found 274.2244.
4.3.30. (S)-2-(R)-Hydroxyl(3-methoxylphenyl)methyl)-cyclo-
pentanone 3h42
Yield 70%, anti/syn = 74:26, enantiomeric excess: 95% for the
anti-diastereomer and 48% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
flow rate 0.5 mL/min, 20 °C, k = 270 nm; tR = 41.3 min (anti, major),
tR = 44.0 min (anti, minor); 1H NMR (300 MHz, CDCl3): d = 7.27 (dd,
J = 5.2, 5.2 Hz, 2H), 6.89–6.86 (m, 2H), 5.23 (d, J = 3.2 Hz, 0.62H),
4.66 (d, J = 9.2 Hz, 0.38H), 4.50 (br, 0.38H), 3.80 (s, 3H), 2.46–1.26
4.3.36. (S)-3-((R)-Hydroxy(3-nitrophenyl)methyl)-tetrahydro-
pyran-4-one 4c43
Yield 90%, anti/syn = 97:3, enantiomeric excess: 99% for the
anti-diastereomer and 53% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak OD-H column; i-PrOH/Hexane = 10:90;

C. Wu et al. / Tetrahedron: Asymmetry 23 (2012) 315–328
327
1.0 mL/min, 20 °C, k = 254 nm) tR = 54.6 min (anti, major) and
tR = 83.8 min (anti, minor)). 1H NMR (300 MHz, CDCl3) d = 8.23–
8.19 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 4.98
(d, J = 8.4 Hz, 1H), 4.25–4.21 (m, 1H), 3.80–3.71 (m, 2H), 3.46 (t,
J = 8.8 Hz, 1H), 2.97–2.91 (m, 1H), 2.75–2.67 (m, 1H), 2.56–2.52
(m, 1H) ppm. HRMS (FAB): [M+Na] calcd for [C12H13NO5Na]
274.2251, found 274.2244.
1H), 5.20–5.22 (m, 1H), 7.60–7.63 (m, 2H), 8.24–8.27 (m, 2H). HRMS
(FAB): [M+Na] calcd for [C10H11NO5Na] 248.1878, found 248.1883.
4.3.42. 4-Hydroxyl-4-(4-nitrophenyl)-2-butanone 6a37
Yield 34%, enantiomeric excess: 41% ee determined by HPLC (Dic-
ael Chiralpak OJ-H column; i-PrOH/Hexane = 10:90; 1.0 mL/min,
20 °C, k = 220 nm) tR = 21.0 min (major) and tR = 35.2 min (minor)).
1HNMR (300 MHz, CDCl3) d 8.20 (d, J = 8.4 Hz, 2H), 7.56 (d,
J = 8.8 Hz, 2H), 5.27 (t, J = 6.0 Hz, 1H), 3.69 (br, 1H), 2.88 (d,
J = 6.0 Hz, 2H), 2.20 (s, 3H). HRMS (FAB): [M+Na] calcd for
[C10H11NO4Na] 232.1884, found 232.1890.
4.3.37. 4-((R)-Hydroxy((S)-4-oxotetrahydro-2H-pyran-3-yl)meth-
yl)benzonitrile 4d43
Yield 89%, anti/syn = 90:10, enantiomeric excess: 94% for the
anti-diastereomer and 65% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
1.0 mL/min, 20 °C, k = 220 nm) tR = 54.3 min (anti, major) and
tR = 45.7 min (anti, minor)). 1H NMR(300 MHz, CDCl3): d = 7.66 (d,
J = 5.6 Hz, 2H), 7.46 (d, J = 7.6 Hz, 2H), 4.94 (dd, J = 8.0, 3.2 Hz,
1H), 4.16 (s, 1H), 3.87 (s, 1H), 3.80–3.6 8(m, 2H), 3.46–3.41 (m,
1H), 2.85–2.63 (m, 2H), 2.56–2.52 (m, 1H). HRMS (FAB): [M+Na]
calcd for [C13H14NO3Na] 254.2370, found 254.2367.
4.4. General procedure for the large-scale stoichiometric aldol
reactions on water
To a mixture of catalyst 1a (0.893 g, 4 mmol) and ketone
(400 mmol) were added aromatic aldehyde (400 mmol) and water
(200 mL) in a 500 mL round bottomed flask. The resulting mixture
was stirred at room temperature. The stoichiometric reaction was
monitored by TLC. It was then quenched with 100 mL of saturated
NH4Cl solution, extracted with EtOAc (3 ꢀ 150 mL), and dried over
Na2SO4. Purification by flash chromatography afforded the corre-
sponding pure aldol products 2b (95.716 g), 2c (94.719 g), 2g
(84.981 g), 2k (95.716 g), 2b (101.938 g), 2h (81.161 g), 2r
(90.538 g), 2n (63.727 g), 2u (71.498 g), 2v (67.592 g), 2s (53.108 g),
3f (80.885 g), 3g (76.391 g).
4.3.38. (S)-3-((R)-Hydroxy(4-fluorophenyl)methyl)-dihydro-2H-
pyran-4(3H)-one 4e43
Yield 82%, anti/syn = 91:9, enantiomeric excess: 91% of anti- dia-
stereomer and 34% of syn-diastereomer determined by HPLC (Dic-
ael Chiralpak AD-H column; i-PrOH/Hexane = 10:90; 1.0 mL/min,
20 °C, k = 220 nm) tR = 38.0 min (anti, major) and tR = 31.2 min
(anti, minor)). 1H NMR(300 MHz, CDCl3): d = 7.31–7.28 (m, 2H),
7.06–7.02 (m, 2H), 4.86 (dd, J = 8.8, 2.4 Hz, 1H), 4.15–4.10 (m,
1H), 3.80 (br, s, 1H), 3.79–3.73 (m, 1H), 3.65–3.60 (m, 1H), 3.35
(dd, J = 11.6, 9.2 Hz, 1H), 2.85–2.79 (m, 1H), 2.66–2.51 (m, 2H).
HRMS (FAB): [M+Na] calcd for [C12H14FO3Na] 247.2180, found
247.2183.
4.5. Procedure for catalyst recovery
To a mixture of catalyst 1a (0.447 g, 2 mmol) and cyclohexa-
none (200 mmol) were added 4-chlorobenzaldehyde (28.114 g,
200 mmol) and water (100 mL) in a 500 mL round bottomed flask.
The mixture was stirred at room temperature as specified in Ta-
ble 8. The reaction mixture was quenched with aqueous HCl
(2 mmol, 6 mol/L) and then diluted with diethyl ether (200 mL)
and the reaction mixture was stirred vigorously for 5 min. The
reaction mixture was placed in an ethanol bath (ꢂ20 °C) for 1 h.
The organic layer was concentrated in vacuo to afford the crude al-
dol product, which was purified by column chromatography (ethyl
acetate/hexane = 1:10 to 1:5). Since catalyst 1a exists in the acidic
aqueous layer, an equivalent amount of triethylamine (Et3N) was
added, and the resulting white suspension was stirred at room
temperature for 10 min after the complete addition, and then fil-
tered by vacuum. The white crystals 1a can be recycled to catalyze
subsequent aldol reaction cycles without adding any new catalyst.
4.3.39. (S)-3-((R)-Hydroxy(4-chlorophenyl)methyl)-dihydro-2H-
pyran-4(3H)-one 4f43
Yield 80%, anti/syn = 90:10, enantiomeric excess: 92% for the
anti- diastereomer and 23% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
1.0 mL/min, 20 °C, k = 220 nm) tR = 40.6 min (anti, major) and
tR = 31.4 min (anti, minor)). 1H NMR(300 MHz, CDCl3): d = 7.33 (d,
J = 7.6 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.85 (d, J = 7.2 Hz, 1H),
4.16–4.10 (m, 1H), 3.78 (br s, 1H), 3.77–3.73 (m, 1H), 3.67–3.62
(m, 1H), 3.36 (t, J = 9.6 Hz, 1H), 2.84–2.79 (m, 1H), 2.66–2.50 (m,
2H). HRMS (FAB): [M+Na] calcd for [C12H14ClO3Na] 263.6726,
found 263.6726.
4.3.40. (S)-3-((R)-Hydroxy(phenyl)methyl)-tetrahydropyran-4-
one 4g43
Acknowledgement
Yield 54%, anti/syn = 89:11, enantiomeric excess: 98% for the
anti-diastereomer and 78% for the syn-diastereomer determined
by HPLC (Dicael Chiralpak AD-H column; i-PrOH/Hexane = 10:90;
1.0 mL/min, 20 °C, k = 220 nm) tR = 31.7 min (anti, major) and
tR = 35.8 min (anti, minor). 1H NMR(300 MHz, CDCl3): d 7.37–7.30
(m, 5H), 4.87 (dd, J = 8.8, 3.2 Hz, 1H), 4.10–4.07 (m, 1H), 3.80–
3.72 (m, 2H), 3.62 (dd, J = 11.2, 5.6 Hz, 1H), 3.36 (dd, J = 11.2,
8.8 Hz, 1H), 2.87–2.82 (m, 1H), 2.64–2.51 (m, 2H). HRMS (FAB):
[M+Na] calcd for [C12H15O3Na] 229.2287, found 229.2283.
Authors are grateful to Southwest University of China for finan-
cial support.
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