Simple amphiphilic isosteviol-proline conjugates as chiral catalysts for the direct asymmetric aldol reaction in the presence of water

Article abstract of DOI:10.1016/j.tetasy.2010.04.019

Two novel amphiphilic catalysts 3 and 4 were synthesized by the condensation of isosteviol with l-proline in a one-pot process. With only 1 mol % loading, the catalyst 3 showed excellent activity (up to >99% yield) and stereoselectivity (up to 99:1 dr, >9

Full text of DOI:10.1016/j.tetasy.2010.04.019

Tetrahedron: Asymmetry 21 (2010) 688–694
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Simple amphiphilic isosteviol–proline conjugates as chiral catalysts for the
direct asymmetric aldol reaction in the presence of water
Ya-Jie An a, Yun-Xiao Zhang a, Ya Wu a,b, Zhao-Min Liu a, Chao Pi a, Jing-Chao Tao a,
*
a Department of Chemistry, New Drug Research and Development Center, Zhengzhou University, Zhengzhou 450052, PR China
b School of Pharmacy, Henan College of Traditional Chinese Medicine, Zhengzhou 450008, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two novel amphiphilic catalysts 3 and 4 were synthesized by the condensation of isosteviol with L-pro-
Received 4 February 2010
Accepted 5 April 2010
Available online 17 May 2010
line in a one-pot process. With only 1 mol % loading, the catalyst 3 showed excellent activity (up to >99%
yield) and stereoselectivity (up to 99:1 dr, >99% ee) for the direct aldol reaction of cyclohexanone and
substituted benzaldehydes at room temperature in the presence of water. In addition, solvent effects, cat-
alyst loading, substrate scope, temperature, and the influence of water on the reactions were investi-
gated. These results demonstrate that the catalysts with a chiral concave and hydrophobic substituent
in the 4-position of
L
-proline furnished high activity and stereoselectivity for the reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
proline-derived small peptides,11 diamine/acid,12 and others all per-
formed better than the native proline, and are summarized by the
following general formulae1b I, II, and III (Fig. 1).
Enantioselective reactions using water as the reaction media
have received much attention in recent years,1 because water has
unique properties to alter the reactivity of catalyst and assist the for-
mation of intermediate transition states during catalytic processes.2
Natural products have drawn great attention as efficient organ-
ocatalyst in the asymmetric synthesis in the past few years, be-
cause of their unique structural characteristics. In 2005, Kokotos
et al.13a employed (2S,4R)-4-camphorsulfonyloxy-proline as an
organocatalyst for the aldol reaction between aldehyde and ace-
tone. The new catalyst with the special backbone and chiral struc-
ture demonstrated higher enantiomeric selectivity than proline
itself though the reactions time was longer. Chen et al.13b recently
developed water-compatible pyrrolidinyl-camphor for aldol reac-
tion with highly diastereo- and enantioselectivities, though high
catalyst loading, additive, and longer reaction time were required.
Iuliano et al.14 then reported their work on proline and bile acids,
which gave poor results for direct aldol reactions in water.
Taking into account our longstanding research into isosteviol,15
Since the discovery of L-proline as a useful organocatalyst for the
direct asymmetric aldol reaction,3 the search for high effective cata-
lysts has been very important. Considering the special effect of
water, much work has been focused on developing efficient catalysts
for water-based synthetic organic reactions,4 especially for the di-
rect asymmetric aldol reactions.5 Barbas III5a reported that the
cross-aldol reaction could be carried out in phosphate buffer, but
only poor enantioselectivity was achieved using native L-proline.
An improved result was achieved by Córdova5b for the cross-aldol
reactions with aqueous formaldehyde for the preparation of
a
-hydroxymethylated cyclohexanone in higher enantioselectivity
in the presence of DMSO, when using 10 mol % -proline as the cat-
alyst. The literature results indicated that the native -proline and
L
we were interested in developing isosteviol-modified L-proline
L
derivatives as new catalysts. Isosteviol (ent-16-ketobeyeran-19-
oic acid, Fig. 2) is a tetracyclic diterpenoid with a beyerane skele-
ton, obtained by acid hydrolysis of stevioside. This natural product
has two special features for the current research: the hydrophobic
polycyclic skeleton and the chiral concave structure because of the
cis-junction of the 19-carboxyl group and D cyclopentane rings.
Herein, we designed and synthesized a novel class of conjugates
substrates may scatter across two phases in neat water, which led
to the unsatisfactory performance. Therefore, a number of hydro-
phobic proline derivatives have been developed as organocatalysts
for the aldol reaction in aqueous solution. Under such reaction
conditions, the catalysts were used to promote the reaction taking
place in a hydrophobic cavity, away from water molecules, there-
fore, giving better results than
L
-proline. For example, the long chain
by coupling L-proline with isosteviol in a one-pot process (Fig. 3).
alkyloxy-substituted proline6 and acyloxyproline7 analogues, poly-
mer-supported prolines,8 prolinamides,9 prolinamide phenols,10
We expected that the special structural features of these new cat-
alysts would facilitate the aldol reaction in the presence of water.
First, the hydrophobic effect of isosteviol allows the proline moiety
away from the water phase, which could cluster the catalyst with
reactants in neat water. Second, the concave space constructed by
isosteviol and (2S,4R)-4-hydroxyproline would facilitate the
* Corresponding author. Tel./fax: +86 371 67767200.
E-mail address: jctao@zzu.edu.cn (J.-C. Tao).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.019

Y.-J. An et al. / Tetrahedron: Asymmetry 21 (2010) 688–694
689
O
O
O
O
O
N
N
N
OH
HN
HN
H
H
H
Figure 1. General formula for proline derivatives.
hydroxyl group. The structures of these catalysts were fully charac-
terized by IR, 1H NMR, 13C NMR, and HR-MS analyses.
16
C
O
D
2.2. Aldol condensations
A
B
cis
With the novel catalysts in hand, we began to evaluate their
catalytic behavior for the C–C bond formation reaction. The aldol
reaction of 2-nitrobenzaldehyde and cyclohexanone was selected
as a model, and the influence of solvents on the reaction catalyzed
by 3 was studied at room temperature with 5 mol % catalyst load-
ing. Encouraging results were obtained and are summarized in
Table 1. When the reaction proceeded under neat conditions, the
anti-isomer was obtained with moderate diastereoselectivity and
excellent enantioselectivity (entry 1). Common organic solvents,
such as chloroform, n-hexane, tetrahydrofuran, toluene, and aceto-
nitrile, were unsuitable for catalyst 3, only trace amount of product
being detected within 24 h when these solvents were used (entries
2–6). Surprisingly, 95% EtOH was found to be a good organic sol-
vent for diastereoselectivity, but the yield and enantioselctivity
were lower (entry 7). As expected, when a small amount of water
was added to the water-immiscible solvents, good diastereoselec-
tivities and enantioselctivities were observed (entries 8 and 9). The
results demonstrated that water is indispensable in the direct aldol
reactions mediated by catalyst 3.
COOH
19
Figure 2. Structure of isosteviol.
lipophilic
Isosteviol
skeleton
hydrophilic
catalytic group
O
O
O
N
H
OH
X
assistant functional
group
Figure 3. Proposed structure of catalyst in the presence of water.
The influence of water on the direct aldol reaction was then
investigated. Interestingly, when catalyst 3 was used in the pres-
ence of water, the reaction mixture appeared to be a two-phase sys-
tem and some solid suspension was observed, with this
phenomenon being maintained throughout the reaction process.
When 2 mL water was used as a solvent, good result was obtained
with 96% yield and 99% ee, however, the dr value was moderate (Ta-
ble 2, entry 1). When brine was used as a solvent with salting-out
effect, the diastereoselectivity was further improved, though the
yield was low (entry 2). It was further found that the concentration
of reactants showed an obvious effect on the yield and stereoselec-
tivity (entries 2, 3, and 4). Five equivalents of water resulted in
excellent yield (98%), high dr (99:1), and up to 99% ee (entry 5).
From the synthetic point of view, it is desirable to use as little water
as possible. However, the reaction yield decreased sharply when an
equivalent amount of water was used (entry 6). Tolerable results
were also observed when the amount of water and cyclohexanone
enantioselection of transition states; in addition, the presence of a
16-carbonyl group provides further advantage by controlling the
position of substrate in the cavity of the organocatalyst via hydro-
gen bonds.
2. Results and discussion
2.1. Synthesis of catalysts 3 and 4
Amphiphilic conjugate 3 was synthesized in high yield by con-
densation of isosteviol 1 with L-proline 2 via a one-pot process
(Scheme 1). In order to understand the efficiency of the 16-func-
tional group in the isosteviol skeleton, the 16-carbonyl group of
3 was selectively reduced to a hydroxyl group with NaBH4 in
C2H5OH. As previously reported,16 the R-configuration was
obtained when the 16-carbonyl of isosteciol was reduced to a
O
OH
O
1) SOCl2, rt, 1h
2) HO
3) NABH4, C2H5OH
0ºC, 1h
COOH
O
O
N
COOH
H
TFA
O
2
O
1
COOH
COOH
N
N
H
H
4
3
Scheme 1. Synthetic routes for the preparation of catalysts 3 and 4.

690
Y.-J. An et al. / Tetrahedron: Asymmetry 21 (2010) 688–694
Table 1
Table 3
Organocatalyst 3 catalyzed direct aldol reactions in different organic solventsa
The influence of catalyst loading on the catalyst 3 catalyzed direct aldol reactionsa
O
O
OH
O
NO2
OH
O
NO2
CHO
CHO
cat. 3 (X mol%)
cat. 3 (5 mol%)
+
+
5eq. H2O, 25oC
solvent, 25oC
O2N
O2N
7
6c
5
7
6a
5
Entry
Cat. (mol %)
Time (h)
Yieldb (%)
(anti:syn)c
eec (%)
Entry
Solvent
Time (h)
Yieldb (%)
(anti:syn)b
eec (%)
1
5
5
2
1
0.5
0.2
0.1
0.1
1
8
8
9
>99
>99
>99
>99
84
38
20
30
87
81:19
83:17
89:11
91:9
89:11
87:13
89:11
92:8
99
98
99
99
98
97
97
99
97
1
2
3
4
5
6
7
8
9
—
14
24
24
24
24
24
24
36
36
49
80:20
—
—
—
—
98
—
—
—
—
2d
3
CHCl3
Hexane
THF
CH3CN
Toluene
95% EtOH
Trace
Trace
Trace
Trace
Trace
48
4
5
6
7
9
10
10
10
24
10
—
—
92:8
82:18
89:11
95
92
98
8
Toluene/H2O = 1/1
CHCl3/H2O = 1/1
20
41
9e
86:14
a
Reaction conditions: aldehyde (50 mg, 0.33 mmol), cyclohexanone (163 mg,
1.65 mmol), solvent 5 equiv H2O (30 mg, 1.65 mmol).
Isolated yield after thin layer chromatography on silica gel.
The dr value and the ee value of anti-isomer was determined by chiral HPLC on
Chiralcel OD-H, AD-H, OJ-H column.
a
Reaction conditions: aldehyde (50 mg, 0.33 mmol), cyclohexanone (163 mg,
1.65 mmol), catalyst 3 (0.0165 mmol), solvent 2 mL.
Isolated yield after thin layer chromatography on silica gel.
The ee of the anti-isomer was determined by chiral HPLC on a chiralcel OD-H
column.
b
b
c
c
d
3-Nitrobenzaldehyde as aldol receptor.
Using 1 mol % 4 as catalyst.
e
Table 2
The influence of water on the direct aldol reactiona
and cyclohexanone was selected as a model. When the catalyst
loading was reduced to 2 mol %, the diastereoselectivity was im-
proved remarkably with high ee value (entry 3). When the catalyst
loading was decreased to 1 mol %, we observed the best result with
the yield up to 99%, dr and ee values up to 91:9 and 99%, respec-
tively (entry 4). However, with further reduction of the catalyst
loading, the product yield decreased sharply (entries 5–7), even
with extended reaction times (entry 8). Therefore, 1 mol % was
found to be the best catalyst loading. Catalyst 4 was also evaluated
by using the best catalyst loading (entry 9), but only poor diastere-
oselectivity was obtained under the same conditions, indicating
that polar functional group at the 16 position of the isosteviol skel-
eton is unfavorable for its catalytic effect.
The substrate scope was then investigated under the optimal
conditions and the results are listed in Table 4. The electronic nat-
ure of substituents did not show much influence on the enantiose-
lectivity. Electron-poor aromatic aldehydes offered the best
reactivity in 9 h when catalyst 3 was used (entries 1, 3, and 5).
Compared to 3, catalyst 4 showed a slightly lower catalytic perfor-
mance under the same condition (entries 2, 4, and 6). Moreover,
the halogenated aromatic aldehydes and electron-rich aromatic
aldehydes could be employed even though longer reaction times
were generally required (entries 7–11). The reaction conditions
discovered were also found to be suitable for pyridylaldehyde
(entry 12).
O
NO2
OH
O
NO2
CHO
cat. 3 (5 mol%)
+
solvent, 25oC
7
6a
5
Entry
Solvent
Time (h)
Yieldb (%)
(anti:syn)b
eec (%)
1
H2O
24
24
22
22
14
14
14
14
14
96
88
95
90
98
85
93
96
95
81:19
92:8
92:8
92:8
99:1
99:1
91:9
91:9
96:4
99
98
99
2
Brined
Brined
Brined
H2O
3e
4f
>99
>99
98
5g
6h
7i
H2O
H2O
H2O
Brine
97
98
97
8g,j
9d,j
a
Reaction conditions: aldehyde (50 mg, 0.33 mmol), cyclohexanone (163 mg,
1.65 mmol), catalyst 3 (0.0165 mmol), solvent 2 mL.
b
Isolated yield after thin layer chromatography on silica gel.
The ee of the anti-isomer was determined by chiral HPLC on a chiralcel OD-H
c
column.
d
Saturated sodium chloride solution.
Using 1 mL brine as solvent.
Using 0.5 mL brine as solvent.
5 equiv H2O (30 mg, 1.65 mmol).
1 equiv H2O (6 mg, 0.33 mmol).
2 equiv cyclohexanone (65 mg, 0.66 mmol), 2 equiv H2O (12 mg, 0.66 mmol).
Using 5 mol % catalyst 4.
e
f
g
h
i
j
NO2
NO2
OH
O
O
CHO
+
cat. 3 (1 mol%)
used were decreased synchronously (entry 7). Last, we compared
the catalytic efficiency of 3 and 4 using brine and 5 equiv of water
as solvent, respectively (entries 8 and 9). It was found that catalyst
4 showed lower enantioselctivity with slightly higher dr value in
brine, while demonstrated lower diastereoselectivity and enanti-
oselectivity 5 equiv of water than catalyst 3.
5eq. H2O, 25oC
6a
8
Yield: >99%
anti: syn: 82: 18
ee: syn 68%
anti 96%
Next, we checked the reactions using 3- and 4-nitrobenzalde-
hyde as the acceptor, with 5 mol % catalyst loading. Although the
ee values were excellent, the diastereoselectivities were barely
satisfactory (Table 3, entries 1 and 2). We achieved higher dr
values when the catalyst loading was reduced, and the results
are summarized in Table 3. The reaction of 4-nitrobenzaldehyde
ð1Þ
Catalyst 3 was also employed successfully on cyclopentanone
with 1 mol % catalyst loading (Eq. 1). The desired anti-aldol product
was obtained in excellent enantioselectivity, although the diastere-
oselectivity was moderate.

Y.-J. An et al. / Tetrahedron: Asymmetry 21 (2010) 688–694
691
Table 4
Table 5
Catalytic aldol reactions using 1 mol % catalyst loadinga
The effect of catalyst on reaction of acetone with aromatic aldehydesa
OH
O
OH
O
O
CHO
CHO
O
cat. 3 or 4 (5 mol%)
cat. 3 (5 mol%)
R
R
+
+
R
R
0oC
5eq. H2O, 25oC
7
11
6
5
6
10
Entry
R
Cat. Time (h) Yieldb (%) (anti:syn)c
eec (%)
Entry
R
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-NO2
3
4
3
4
3
4
3
3
3
3
3
3
9
10
7
7
8
12
36
36
36
36
36
30
>99
87
99
99
82
90
93
78
78
58
53
66
91:9
86:14
92:8
82:18
99:1
92:8
99
97
>99
96
99
97
1d
2e
3
2-NO2
12
9
9
20
6
6
12
12
12
12
12
12
12
14.5
91
93
77
91
99
93
82
48
94
91
83
80
90
89
93
93
89
94
79
81
80
81
82
75
79
3-NO2
2-NO2
4f
5
3-NO2
4-NO2
2-Cl
4-Cl
4-F
2-CH3O
4-Br
—
6
7
8
9
10
11
12g
13
2-Cl
4-Cl
4-F
98:2
94:6
98
99
9
95:5 (97:3)d
98:2
95 (>99)d
10
11
12e
H
93
96
>99
2-CH3O
—
99:1
85:15
H
a
Reaction conditions: aldehyde (50 mg, 0.33 mmol), cyclohexanone (163 mg,
1.65 mmol), solvent 5 equiv H2O (30 mg, 1.65 mmol).
Isolated yield after thin layer chromatography on silica gel.
The dr value and the ee value of anti-isomer was determined by chiral HPLC on
chiralcel OD-H, AD-H, OJ-H column.
a
Reaction conditions: 5 mol % catalyst 3, aldehyde (50 mg, 0.33 mmol), acetone
1 mL.
b
c
b
Isolated yield after thin layer chromatography on silica gel.
c
The ee was determined by chiral HPLC on Chiralcel OD-H, AD-H, OJ-H column
and the major enantiomer was assigned to be (R) according to ½a D20
ꢀ
and Ref. 3.
d
Using 5 mol % catalyst 3.
Pyridylaldehyde as aldol receptor.
e
d
e
f
25 °C, 5 equiv acetone and 5 equiv H2O.
25 °C, 1 mL acetone as solvent.
Using 2 mol % catalyst 3.
g
Pyridylaldehyde as aldol receptor.
In order to extend the range of substrates, we investigated the
reaction between acetone and aromatic aldehydes (Table 5). Using
2-nitrobenzaldehyde and acetone as a model, however only a poor
yield was obtained in the presence of water, even though the ee va-
lue is satisfactory (entry 1). However, the reaction proceeded
favorably in neat acetone at room temperature, and the desired
R-configuration product was obtained in high yield (91%) and
enantioselectivity (89%) within 9 h (entry 2). Surprisingly, when
the reaction temperature was decreased to 0 °C, both yield and
enantioselectivity increased (entry 3). However, the reaction slo-
wed down when the catalyst loading was decreased to 2 mol % (en-
try 4). Therefore, we chose 5 mol % catalyst loading, 1 mL acetone,
and 0 °C as the optimal conditions, and extended the reaction
scope. Both electron-withdrawing and electron-donating group-
substituted aromatic aldehydes were appropriate to the optimum
conditions (entries 5–11). When 4-nitrobenzaldehyde was used
as the aldol receptor, we observed the best results with 99% yield
and 94% ee value within 6 h (entry 6). But 4-fluorobenzaldehyde
showed low yield, even though the enantioselectivity could be tol-
erated (entry 9); pyridylaldehyde gave 75% ee value in this condi-
tion (entry 12).
Hydrophilic
region
O
H
H2O
O
O
O
O
O
O
N
H
O
H
O
H
Hydrophobic
region
O
O
O
H
O
proline
H
isosteviol skeleton
The prepared transition state of the 3 catalyzed aldol reaction is
shown in Figure 4. Water plays a crucial role in the transition state.
Firstly, due to the hydrophobic isosteviol unit and the hydrophilic
proline moiety of catalyst 3, a hydrophobic chiral pocket itself
assembled on the surface of water phase through hydrogen bond
and hydrophobic–hydrophobic interaction. Meanwhile, free OH
groups on the surface of the water could link the proline moiety
through hydrogen bonds, which led to the improvement of the
activity and diastereoselectivity. In fact, the satisfactory results ob-
tained from the reaction between cyclohexanone and benzalde-
hyde in water and neat condition (Table 1, entry 1, and Table 2,
entries 1 and 6), showed that water surely enhanced the catalyst
activity by increasing the yield from 49% to 98%, and it also
improved diastereoselectivity from 82:18 to 99:1. Secondly, the
isosteviol moiety coupled with the catalytic group [(2S,4R)-4-
hydroxyproline] to form a suitable chiral space for the reaction
substrates, which shields the Re face of anti-enamine to provide
the high stereoselectivities of products.
Figure 4. The proposed transition state.
3. Conclusion
A novel and simple amphiphilic isosteviol–proline conjugated
organocatalyst 3 was developed, which could be easily prepared
via a one-pot process and successfully used in the direct asymmet-
ric aldol reaction in the presence of water. With 1 mol % of catalyst
loading, the desired anti-aldol products of cyclohexanone and aro-
matic aldehydes were obtained with good to excellent yields in a
reasonable reaction time, and the enantioselectivities and diastere-
oselectivities were excellent in almost all cases. When acetone was
employed as the aldol donor, good yields and enantioselectivities
were obtained in neat acetone; however, the presence of water
did not facilitate the reaction. A transition state of 3 catalyzed
aqueous aldol reactions was proposed. It was found that due to

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Y.-J. An et al. / Tetrahedron: Asymmetry 21 (2010) 688–694
the amphiphilic property of catalyst 3, a hydrophobic chiral pocket
could be formed via self-assembly on the surface of water through
hydrogen bond and hydrophobic–hydrophobic interaction, which
leads to the improvement of the activity and diastereoselectivity
of the catalyst. Further studies on the reaction mechanism and
broad scope of application of the novel catalyst are in progress.
50.2, 43.8, 42.5, 42.0, 41.9, 41.6, 40.3, 39.7, 38.1, 37.7, 35.0, 33.7,
28.9, 24.9, 21.7, 20.4, 18.8, 13.8; HR-MS (ESI, m/z) calcd for
C
25H39NNaO5 [M+Na]+ 456.2726. Found: 456.2726.
4.3. General procedure for the aldol condensations
4.3.1. General procedure for condensations of acetone and
aromatic aldehydes in neat acetone
4. Experimental
0.33 mmol of an aldehyde was added to a mixture of 5 mol %
catalyst and 1.0 mL acetone at 0 °C. The reaction mixture was stir-
red for the indicated time, purified by thin layer chromatography
on silica gel (petroleum ether/ethyl acetate).
4.1. General
All chemicals were used as received unless otherwise noted. Re-
agent grade solvents were re-distilled prior to use. 1H NMR and 13
C
4.3.1.1. 4-Hydroxyl-4-(2-nitrophenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.24 (s, 3H), 2.74 (dd, J = 17.8, 9.4 Hz, 1H), 3.13 (dd,
J = 17.8, 1.8 Hz, 1H), 3.89 (s, 1H), 5.68 (dd, J = 9.4, 1.8 Hz, 1H),
7.44 (t, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz,
NMR spectra were collected on a Bruker DPX 400 NMR spectrometer
with TMS as internalreference. IR spectrawere determined on a Ther-
mo Nicolet IR200 unit. High resolution mass spectra (HR-MS) were
obtained on a Waters Micromass Q-Tof Micro™ instrument using
the ESI technique. Chromatography was performed on silica gel
(200–300mesh). Melting pointsweredetermined using a XT5A appa-
ratus and are uncorrected. Optical rotations were determined on a
Perkin Elmer 341 polarimeter. Enantiomeric excess was measured
by chiral HPLC at room temperature using Labtech 2006 pump
equipped with Labtech UV600 ultra detector with Chiralpak AD-H
(4.6 mm ꢁ 250 mm), Chiralcel OD-H (4.6 mm ꢁ 250 mm) columns
and Chiralcel OJ-H (4.6 mm ꢁ 250 mm) columns.
1H), 7.96 (d, J = 8.0 Hz, 1H); ½a D20
¼ ꢂ138:6 (c 0.52); Enantiomeric
ꢀ
excess: 93%, determined by HPLC: Chiralcel OD-H, UV 254 nm,
i-PrOH/hexane = 1/15, flow rate 0.5 mL/min, (S)-isomer, tR
26.7 min, (R)-isomer, tR 29.6 min.
4.3.1.2. 4-Hydroxyl-4-(3-nitrophenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.24 (s, 3H, CH3), 2.89 (dd, J = 7.2, 2.0 Hz, 2H, CH2),
3.46 (br, 1H, OH), 5.27 (t, J = 7.2 Hz, CH), 7.54 (t, J = 8.0 Hz, 1H,
Ar), 7.72 (d, J = 8.0 Hz, 1H, Ar-H), 8.14 (dd, J = 8.0, 2.0 Hz, 1H, Ar-
H), 8.24 (s, 1H, Ar-H); ½a D20
¼ þ60:3 (c 0.60); Enantiomeric excess:
ꢀ
4.2. Synthesis of catalysts
89%, determined by HPLC: Chiralcel OJ-H, i-PrOH/hexane = 1/15;
flow rate 1.0 mL/min; (S)-isomer, tR 43.6 min, (R)-isomer, tR
49.2 min.
4.2.1. Synthesis of catalyst 3
Isosteviol 1 (318 mg, 1 mmol) was dissolved in SOCl2 (2 mL) by
stirring at room temperature for 1 h. After evaporating the solvent
4.3.1.3. 4-Hydroxyl-4-(4-nitrophenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.24 (s, 3H), 2.87 (d, J = 6.0 Hz, 2H), 3.61 (s, 1H), 5.28
(t, J = 6.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 8.20 (dd, J = 8.8, 2.0 Hz,
under vacuum, trans-4-hydroxy-L-proline 2 (131 mg, 1 mmol) and
CF3COOH (5 mL) were added, the reaction mixture was continue
stirred at room temperature for 2 h. After reaction, Et2O (10 mL)
was added carefully under ice bath, and the resulted white precip-
itate was filtered, washed with Et2O (5 mL ꢁ 2), and dried under
vacuum. Thus obtained white powder was dissolved in 15 mL of
warm 95% EtOH, and propylene oxide (2 mL) was then added.
The solution was kept at room temperature for 7 h give the crystal
3 (345 mg, 80%) as transparent flat needles; mp: 176–178 °C,
2H); ½a 2D0
¼ þ65:5 (c 0.50); Enantiomeric excess: 94%, determined
ꢀ
by HPLC: Chiralcel OJ-H, UV 254, i-PrOH/hexane = 10/90; flow rate
1.0 mL/min, (R)-isomer, tR 27.4 min, (S)-isomer, tR 30.9 min.
4.3.1.4. 4-Hydroxyl-4-(2-chlorophenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.20 (s, 3H, CH3), 2.68 (dd, J = 17.6, 9.6 Hz, 1H, CHH),
2.96 (dd, J = 17.6, 2.0 Hz, 1H, CHH), 3.30 (br, 1H, OH), 5.50 (dd,
J = 9.6, 2.0 Hz, 1H, CHOH), 7.20 (td, J = 8.0, 1.6 Hz, 1H, Ar-H), 7.29
(td, J = 8.0, 1.6 Hz, 1H, Ar-H), 7.32 (dd, J = 8.0, 1.6 Hz, 1H, Ar-H),
½
a 2D0
ꢀ
¼ ꢂ56:7 (c 0.13, CHCl3), IR (KBr, cmꢂ1): 3601, 3448, 2955,
2849, 1733, 1654, 1149, 1130; 1H NMR (400 MHz , CDCl3) d: 5.23
(s, 1H), 4.13 (d, J = 1.68 Hz, 1H), 3.60 (s, 1H), 3.38 (s, 1H), 2.64–
2.59 (d, J = 20 Hz, 1H), 2.44 (s, 1H), 2.29 (s, 1H), 2.20–2.16 (d,
J = 12 Hz, 3H), 1.88–1.78 (m, 2H), 1.66–1.38 (m, 10H), 1.18 (s,
3H), 1.12–1.09 (m, 2H), 0.95 (s, 3H), 0.98–0.85 (m, 2H), 0.69 (s,
3H); 13C NMR (100 MHz, CDCl3) d: 222.5, 176.5, 173.1, 72.3, 59.7,
57.0, 54.5, 54.1, 49.8, 48.6, 48.4, 43.8, 41.4, 39.6, 39.4, 38.0, 37.5,
37.2, 35.4, 28.9, 21.5, 20.3, 19.8, 19.0, 13.8; HR-MS (ESI, m/z) calcd
for C25H37NNaO5 [M+Na]+ 454.2569. Found: 454.2570.
7.61 (dd, J = 8.0, 1.6 Hz, 1H, Ar-H); ½a D20
¼ þ86:0 (c 1.40); Enantio-
ꢀ
meric excess: 79%, determined by HPLC: Chiralpak AD-H, UV
220 nm, i-PrOH/hexane = 1/30; flow rate 1.0 mL/min; (R)-isomer,
tR 16.5 min, (S)-isomer, tR 18.9 min.
4.3.1.5. 4-Hydroxyl-4-(4-chlorophenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.19 (s, 3H, CH3), 2.79–2.83 (m, 2H, CH2), 3.42 (br, 1H,
OH), 5.12 (dd, J = 8.8, 3.6 Hz, CH), 7.29 (q, J = 8.8 Hz, 4H, Ar-H);
½
a 2D0
ꢀ
¼ þ63:8 (c 0.54); Enantiomeric excess: 81%, determined by
4.2.2. Synthesis of catalyst 4
HPLC: Chiralpak AD-H, UV 220 nm, i-PrOH/hexane = 1/15; flow
A solution of catalyst 3 (431 mg, 1 mmol) and sodium borohy-
dride (57 mg, 1.5 mmol) in dry ethanol (10 mL) was stirred at
0 °C for 1 h. The reaction mixture was concentrated under vacuum,
and extracted with CHCl3. The organic layer was washed with sat-
urated NaCl aqueous solution, dried with MgSO4, and concentrated
under vacuum to give white powder 4 (424 mg, 98%), mp: 167–
rate 0.5 mL/min; (R)-isomer, tR 24.2 min, (S)-isomer, tR 26.0 min.
4.3.1.6. 4-Hydroxyl-4-(4-fluorophenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.20 (s, 3H, CH3), 2.82 (m, 2H, CH2), 3.13 (br, 1H, OH),
5.13 (dd, J = 8.8, 3.6 Hz, 1H, CH), 7.03 (m, 2H, Ar-H), 7.32 (m, 2H,
Ar-H); ½a 2D0
¼ þ57:7 (c 0.36); Enantiomeric excess: 80%, deter-
ꢀ
170 °C, ½a 2D0
ꢀ
¼ ꢂ50:0 (c 0.12, CH3OH); IR (KBr, cmꢂ1): 3422, 2926,
mined by HPLC: Chiralcel AD-H, UV 257 nm, i-PrOH/hexane = 1/
15; flow rate 0.5 mL/min, (R)-isomer, tR 22.8 min, (S)-isomer, tR
24.3 min.
2847, 1719, 1596, 1438, 1384, 1176, 1150; 1H NMR (400 MHz,
CDCl3): d: 5.26 (s, 1H), 4.20 (s, 1H), 3.81–3.80 (d, J = 5.6 Hz, 2H),
3.32–3.27 (d, J = 16.4 Hz, 1H), 2.39–2.30 (m, 2H), 2.16–2.12 (d, J =
16.4 Hz, 1H), 1.74–1.70 (m, 6H), 1.53–1.38 (m, 5H), 1.29–1.23 (m,
2H), 1.17 (s, 3H), 1.07–0.73 (m, 9H), 0.89 (s, 3H), 0.73 (s, 3H); 13C
NMR (100 MHz, CDCl3): d: 177.0, 80.1, 72.7, 60.6, 57.0, 55.7, 55.0,
4.3.1.7. 4-Hydroxyl-4-(2-methoxyphenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.18 (s, 3H, CH3), 2.28 (dd, J = 17.2, 9.2 Hz, 1H, CHH), 2.91
(dd, J = 17.2, 2.8 Hz, 1H, CHH), 3.82 (s, 3H, CH3), 5.41 (dd, J = 9.2,

Y.-J. An et al. / Tetrahedron: Asymmetry 21 (2010) 688–694
693
2.8 Hz, CH), 6.85 (d, J = 8.0 Hz, 1H, Ar-H), 6.97 (t, J = 8.0 Hz, 1H, Ar-
H), 7.24 (t, J = 8.0 Hz, 1H, Ar-H), 7.43 (d, J = 8.0 Hz, 1H, Ar-H);
1H), 7.49 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 8.4 Hz, 2H); anti: 1.36–
1.44 (m, 1H), 1.51–1.73 (m, 3H), 1.83 (m, 1H), 2.10–2.15 (m, 1H),
2.33–2.46 (m, 1H), 2.50 (m, 1H), 2.57–2.63 (m, 1H), 3.80 (br, 1H),
4.90 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz,
2H); HPLC (for anti): Chiralcel OD-H, UV 254 nm, i-PrOH/hex-
ane = 5/95, flow rate 1.0 mL/min, tR 32.3 min (major), tR 50.8 min
(minor).
½
a 2D0
ꢀ
¼ þ76:8 (c 0.54); Enantiomeric excess: 81%, determined by
HPLC: Chiralpak AD-H, UV 220 nm, i-PrOH/hexane = 10/90, flow
rate 1.0 mL/min, (R)-isomer, tR 11.1 min, (S)-isomer, tR 12.6 min.
4.3.1.8. 4-Hydroxyl-4-(4-bromophenyl)butan-2-one. 1H NMR
(CDCl3) d: 2.18 (s, 3H, CH3), 2.73–2.86 (m, 2H, CH2), 3.36 (br, 1H,
OH), 5.08 (dd, J = 8.8, 3.6 Hz, 1H, CH), 7.21 (d, J = 8.4 Hz, 2H, Ar-
4.3.2.4. 2-[Hydroxy-(2-chlorophenyl)methyl]cyclohexanone.
1H NMR (CDCl3) d: syn: 1.53–1.71 (m, 4H), 1.81–1.84 (m, 1H),
2.08 (m, 1H), 2.33–2.42 (m, 1H), 2.48 (m, 1H), 2.81 (m, 1H), 3.95
(s, 1H), 5.72 (d, J = 2.0 Hz, 1H), 7.20–7.34 (m, 3H), 7.56 (d,
J = 8.0 Hz, 1H); anti: 1.53–1.84 (m, 5H), 2.05–2.13 (m, 1H), 2.31–
2.39 (m, 1H), 2.46–2.49 (m, 1H), 2.65–2.71 (m, 1H), 3.88 (s, 1H),
5.35 (d, J = 8.0 Hz, 1H), 7.20–7.34 (m, 3H), 7.56 (d, J = 8.4 Hz, 1H);
HPLC (for anti): Chiralcel OD-H, UV 220 nm, i-PrOH/hexane = 5/
95, flow rate 1.0 mL/min, tR 10.0 min (major), tR 13.7 min (minor).
H), 7.45 (d, J = 8.4 Hz, 2H, Ar-H); ½a D20
¼ þ50:7 (c 0.70); Enantio-
ꢀ
meric excess: 82%, determined by HPLC: Chiralpak AD-H, UV
220 nm, i-PrOH/hexane = 10/90, flow rate 0.8 mL/min, (R)-isomer,
tR 12.7 min, (S)-isomer, tR 14.0 min.
4.3.1.9. 4-Hydroxyl-4-pyridylbutan-2-one. 1H NMR (CDCl3) d:
2.21 (s, 2H, CH3), 2.87–2.94 (dd, J = 17.2, 8.8 Hz, 1H), 3.02–3.07
(dd, J = 17.2, 3.6 Hz, 1H), 4.35 (bra, 1H), 5.18–5.21 (dd, J = 8.4,
3.6 Hz, 1H), 7.18–7.21 (dd, J = 6.8, 5.6 Hz, 1H), 7.45–7.47 (d,
J = 8.0 Hz, 1H), 7.68–7.72 (m, 1H), 8.51–8.52 (d, J = 4.4 Hz, 1H).
4.3.2.5. 2-[Hydroxy-(4-chlorophenyl)methyl]cyclohexanone.
1H NMR (CDCl3) d: syn: 1.42–2.11 (m, 6H), 2.32–2.45 (m, 2H),
2.53–2.56 (m, 1H), 3.05 (s, 1H), 5.36 (d, J = 2.0 Hz, 1H), 7.24 (d,
J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H); anti: 1.27–1.31 (m, 1H),
1.53–1.82 (m, 4H), 2.07–2.11 (m, 1H), 2.35–2.56 (m, 3H), 4.76
(d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz,
2H); HPLC (for anti): Chiralcel OD-H, UV 220 nm, i-PrOH/hex-
ane = 5/95, flow rate 1.0 mL/min, tR 13.6 min (major), tR
23.3 min (minor).
½
a 2D0
ꢀ
¼ þ44:0 (c 0.40); Enantiomeric excess: 75%, determined by
HPLC: Chiralpak AD-H, UV 254 nm, i-PrOH/hexane = 10/90, flow
rate 0.5 mL/min, (R)-isomer, tR 24.5 min, (S)-isomer, tR 28.0 min.
4.3.1.10. 4-Hydroxyl-4-phenylbutan-2-one. 1H NMR (CDCl3) d:
2.13 (s, 3H, CH3), 2.74 (dd, J = 17.2, 3.2 Hz, 1H), 2.85 (dd, J = 17.2,
9.6 Hz, 1H), 3.63 (br, 1H, OH), 5.10 (dd, J = 9.6, 3.2 Hz, 1H, CH),
7.24–7.32 (m, 5H, Ar-H); ½a D20
¼ þ63:1 (c 0.66); Enantiomeric
ꢀ
excess: 79%, determined by HPLC: Chiralpak AD-H, UV 254 nm,
i-PrOH/hexane = 10/90, flow rate 0.6 mL/min, (R)-isomer, tR
25.2 min, (S)-isomer, tR 28.6 min.
4.3.2.6. 2-[Hydroxy-(4-bromophenyl)methyl]cyclohexanone.
1H NMR (400 MHz, CDCl3) d: syn: 1.55–1.86 (series of m, 5H,
CH2), 2.08 (m, 1H, CH2), 2.44–2.46 (m, 3H, CH), 3.06 (br s, 1H,
OH), 5.33 (s, 1H, CH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 7.48 (d,
J = 8.4 Hz, 2H, ArH); anti: 1.20–1.35 (m, 1H, CH2), 1.40–1.85 (m,
4H, CH2), 2.07 (m, 1H, CH2), 2.36–2.37 (m, 2H, CH2), 2.53–2.55
(m, 1H, CH), 3.98 (br s, 1H, OH), 4.73–4.76 (d, J = 8.8 Hz, 1H,
CH), 7.17 (d, J = 8.4 Hz, 2H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH);
HPLC (for anti): Chiralcel AD-H, UV 220 nm, i-PrOH/hex-
ane = 10/90, flow rate 0.8 mL/min, tR 20.4 min (major), tR
23.2 min (minor).
4.3.2. General procedure for condensations of cyclohexanone
and aromatic aldehydes
Aldehyde (0.33 mmol) was added to the mixture of 5 equiv
cyclohexanone, 5 equiv water, and 1 mol % of catalyst under
25 °C. Then the reaction mixture was stirred for the indicated time,
purified by thin layer chromatography on silica gel (petroleum
ether/ethyl acetate).
4.3.2.1. 2-[Hydroxy-(2-nitrophenyl)methyl]cyclohexanone. 1H
NMR (CDCl3) d: syn: 1.53–1.87 (m, 6H, 3CH2), 2.10 (m, 1H), 2.42–
2.47 (m, 2H), 2.87–2.91 (dd, J = 13.2, 4.8 Hz, 1H, CH), 3.15 (br, 1H,
OH), 5.96 (d, J = 1.6 Hz, 1H, CHOH), 7.46 (td, J = 8.0, 0.8 Hz, 1H,
Ar-H), 7.66 (td, J = 8.0, 0.8 Hz, 1H, Ar-H), 7.84 (dd, J = 8.0, 0.8 Hz,
1H, Ar), 8.02 (dd, J = 8.0, 0.8 Hz, 1H, Ar-H); anti: 1.61–1.87 (m,
6H), 2.10 (m, 1H), 2.34–2.47 (m, 2H), 2.77 (m, 1H), 3.95 (br, 1H),
5.45 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 8.0, 0.8 Hz, 1H, Ar-H), 7.66 (d,
J = 8.0, 0.8 Hz, 1H, Ar-H), 7.78 (dd, J = 8.0, 0.8 Hz, 1H), 7.86 (dd,
J = 8.0, 0.8 Hz, 1H); HPLC (for anti): Chiralcel OD-H, UV 254 nm, i-
PrOH/hexane = 5/95, flow rate 0.5 mL/min, tR 36.6 min (major), tR
45.5 min (minor).
4.3.2.7. 2-[Hydroxy-(4-flurophenyl)methyl]cyclohexanone. 1H
NMR (CDCl3) d: syn: 1.50–1.87 (m, 5H), 1.84–1.88 (m, 1H), 2.36–
2.56 (m, 3H), 3.05 (br, 1H), 5.36 (d, J = 1.6 Hz, 1H), 7.00–7.05 (m,
2H), 7.25–7.29 (m, 2H); anti: 1.24–1.33 (m, 1H), 1.53–1.82 (m,
4H), 2.07–2.12 (m, 1H), 2.35–2.59 (m, 3H), 4.01 (s, 1H), 4.77 (d,
J = 8.8 Hz, 1H), 7.01–7.05 (m, 2H), 7.27–7.31 (m, 2H); HPLC (for
anti): Chiralcel OD-H, UV 254 nm, i-PrOH/hexane = 5/95, flow rate
1.0 mL/min, tR 12.7 min (major), tR 28.5 min (minor).
4.3.2.8. 2-[Hydroxy-phenylmethyl]cyclohexanone. 1H NMR
(400 MHz, CDCl3): d: syn: 1H NMR (400 MHz, CDCl3): d: 1.61–
1.78 (m, 4H, CH2), 2.08–2.09 (m, 1H, CH2), 2.38–2.48 (m, 2H, CH),
2.62 (m, 1H, CH), 5.41 (s, 1H, CH), 7.31–7.36 (m, 5H, ArH); anti:
1.30–1.33 (m, 1H, CH2), 1.57–1.78 (m, 4H, CH2), 2.08–2.09 (m,
1H, CH2), 2.37–2.48 (m, 2H, CH), 2.62–2.64 (m, 1H, CH), 4.79–
4.82 (d, J = 8.8 Hz, 1H, CH), 7.28–7.36 (m, 5H, ArH); HPLC (for anti):
Chiralcel OD-H, UV 254 nm, i-PrOH/hexane = 5/95, flow rate
1.0 mL/min, tR 13.4 min (major), tR 24.0 min (minor).
4.3.2.2. 2-[Hydroxy-(3-nitrophenyl)methyl]cyclohexanone. 1H
NMR (CDCl3) d: syn: 1.48–2.10 (m, 6H), 2.33–2.48 (m, 2H), 2.62–
2.66 (m, 1H), 3.16 (s, 1H), 5.48 (d, J = 2.0 Hz, 1H), 7.52 (t,
J = 8.0 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H),
8.20 (d, J = 8.0 Hz, 1H); anti: 1.33–2.10 (m, 6H), 2.32–2.48 (m,
2H), 2.70 (m, 1H), 3.16 (s, 1H), 4.91 (d, J = 8.4 Hz, 1H), 7.54 (t,
J = 8.0 Hz, 1H), 7.68 (d, J = 0.8 Hz, 1H), 8.15 (m, J = 8.0 Hz, 1H),
8.20 (d, J = 8.0 Hz, 1H); HPLC (for anti): Chiralcel OD-H, UV
254 nm, i-PrOH/hexane = 5/95, flow rate 1.0 mL/min, tR 26.5 min
(major), tR 41.9 min (minor).
4.3.2.9. 2-[Hydroxy-(2-methoxyphenyl)methyl]cyclohexanone.
1H NMR (CDCl3) d: syn: 1.49–1.87 (m, 5H), 1.84–1.89 (m, 1H),
2.36–2.56 (m, 3H), 3.05 (br, 1H), 5.39 (d, J = 1.6 Hz, 1H), 6.85 (d,
J = 8.0 Hz, 1H, Ar-H), 6.97 (t, J = 8.0 Hz, 1H, Ar-H), 7.24 (t,
J = 8.0 Hz, 1H, Ar-H), 7.43 (d, J = 8.0 Hz, 1H, Ar-H) anti: 1.30–1.98
(m, 6H), 2.30–2.46 (m, 3H), 3.00 (br, 1H), 4.78 (d, J = 1.6 Hz, 1H),
6.88 (d, J = 8.0 Hz, 1H, Ar-H), 6.97 (t, J = 8.0 Hz, 1H, Ar-H), 7.25 (t,
4.3.2.3. 2-[Hydroxy-(4-nitrophenyl)methyl]cyclohexanone. 1H
NMR (CDCl3) d: syn: 1.50–1.88 (m, 5H), 2.09–2.15 (m, 1H), 2.37–
2.52 (m, 2H), 2.62–2.66 (m, 1H), 3.10 (br, 1H), 5.49 (d, J = 1.6 Hz,

694
Y.-J. An et al. / Tetrahedron: Asymmetry 21 (2010) 688–694
Adv. Synth. Catal. 2007, 349, 441–447; (e) Phukan, M.; Borah, K. J.; Borah, R.
Synth. Commun. 2008, 38, 3068–3073.
J = 8.0 Hz, 1H, Ar-H), 7.46 (d, J = 8.0 Hz, 1H, Ar-H) HPLC (for anti):
Chiralcel OD-H, UV 254 nm, i-PrOH/hexane = 5/95 flow rate
0.5 mL/min, tR 30.5 min (major), tR 51.7 min (minor).
5. (a) Córdova, A.; Notz, W.; Barbas, C. F., III Chem. Commun. 2002, 3024–3025; (b)
Casas, J.; Sundén, H.; Córdova, A. Tetrahedron Lett. 2004, 45, 6117–6119.
6. (a) Hayashi, J.; Sumiya, T.; akahashi, T.; Gotoh, H.; Urushima, T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 958–961; (b) Fu, Y. Q.; An, Y. J.; Liu, W. M.; Li, Z.
C.; Zhang, G.; Tao, J. C. Catal. Lett. 2008, 124, 397–404.
7. (a) Hayashi, J.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 5527–5529; (b) Giacalone, F.; Gruttadauria, M.; Meo, P.
L.; Riela, S.; Noto, R. Adv. Synth. Catal. 2008, 350, 2747–2760.
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Sayalero, S.; Bastero, A.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2008, 10, 337–340;
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9. (a) Raj, M.; Maya, V.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097–4099;
(b) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595; (c) Wang, C.;
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4.3.2.10. 2-[Hydroxy-2-pyridylmethyl]cyclohexanone. 1H NMR
(400 MHz, CDCl3): d: syn: 1.58–2.44 (m, 9H, CH2); 3.73 (s, 1H,
OH); 5.40 (s, 1H, CHOH); 7.15–7.18 (m, 1H, Ar); 7.46–7.48 (d, 1H,
Ar, J = 8.0 Hz); 7.67–7.70 (t, 1H, Ar); 8.51–8.52 (m, 1H, Ar);13C
NMR d: 24.79, 26.26, 27.77, 42.68, 56.20, 71.02, 121.65, 122.42,
136.59, 148.51, 160.94, 213.83; anti: 1.59–1.84 (m, 6H, CH2);
2.36–2.38 (m, 2H, CH2); 2.96–3.00 (m, 1H, CH); 3.04–3.09 (m,
1H, OH); 4.91 (s, 1H); 7.15–7.17 (m, 1H, Ar); 7.46–7.48 (d, 1H,
Ar, J = 8.0 Hz); 7.67–7.70 (t, 1H, Ar); 8.51–8.52 (m, 1H, Ar); 13C
NMR d: 24.71, 26.26, 27.69, 42.48, 55.95, 71.02, 120.84, 122.01,
136.52, 148.44, 160.63, 213.83; HPLC (for anti): Chiralcel OJ-H,
UV 254 nm, i-PrOH/hexane/Et3N = 1/100/0.05, flow rate 1.0 mL/
min, tR 39.1 min (major), tR 41.6 min (minor).
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Asymmetry 2006, 17, 3351–3357.
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2285–2287.
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