Direct asymmetric aldol reactions in water with a β-aminosulfonamide organocatalyst

Article abstract of DOI:10.1016/j.tetasy.2011.05.014

Organocatalyst 4 promoted the direct asymmetric aldol reactions of aldehydes with ketones in brine or in the presence of water to afford the corresponding anti-aldol products in moderate to excellent yields with up to 97% ee.

Full text of DOI:10.1016/j.tetasy.2011.05.014

Tetrahedron: Asymmetry 22 (2011) 1028–1034
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Direct asymmetric aldol reactions in water with a b-aminosulfonamide
organocatalyst
Tsuyoshi Miura a, , Mariko Ina a, Kie Imai a, Kosuke Nakashima a, Yumi Yasaku b, Naka Koyata b,
⇑
Yasuoki Murakami b, Nobuyuki Imai b, Norihiro Tada a, Akichika Itoh a
a Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
b Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 April 2011
Accepted 18 May 2011
Organocatalyst 4 promoted the direct asymmetric aldol reactions of aldehydes with ketones in brine or in
the presence of water to afford the corresponding anti-aldol products in moderate to excellent yields with
up to 97% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
been reported in a
preliminary communication.9 Herein, we
would like to describe the full details of the direct aldol reactions
in brine and in the presence of water using bifunctional organo-
catalysts 4.
The development of organocatalyzed direct aldol reactions for
the stereoselective construction of carbon–carbon bonds has been
intensively investigated over the past decade because of the desir-
able properties of many organocatalysts, such as stability, low tox-
icity, and convenient handling.1 Most organocatalysts that have
successfully promoted these reactions have used proline deriva-
tives, because proline, with its cyclic secondary amino group,
was expected to be suitable for aldol reaction because of the ease
in enamine formation. However, type I aldolases, which are natural
enzymes, employ the primary amine of a lysine residue under
aqueous conditions for enamine formation and aldol reactions.2
In this context, other chiral primary amines have recently been re-
ported as viable enamine organocatalysts that have achieved a new
level of catalytic performance beyond that of secondary amine cat-
alysts such as proline derivatives.3,4Also significant from the stand-
point of green chemistry, the use of water as a reaction medium in
the absence of organic solvents has attracted a great deal of atten-
tion because water is inexpensive, safe, and environmentally be-
nign.5,6 Therefore, the development of a direct asymmetric aldol
reaction using an organocatalyst in water is of considerable inter-
est, and several groups have reported organocatalytic direct asym-
metric aldol reactions under neat aqueous conditions.3,7
R1
R2HN
NHR3
: R1 = H, R2 = Ms , R3 = SO2C6H4-p-NO2
1
2: R1 = H, R2 = Ms , R3 = Ts
3: R1 = OCH2CH2CH2C8F17, R2 = Ms , R3 = Ts
4
: R1 = H, R2 = H, R3 = Tf
2. Results and discussion
b-Aminosulfonamide 4, an organocatalyst for the direct aldol
reactions, was prepared as shown in Scheme 1. Treatment of com-
pound 5,10 which is an intermediate for the synthesis of chiral
ligands 1 and 2, with trifluoromethanesulfonic anhydride (Tf2O)
Previously, we have reported an enantioselective Simmons–
Smith cyclopropanation using chiral disulfonamide ligands 1–3
Ph
Ph
Tf2O, Et3N
derived from the natural amino acids L-phenylalanine or L-tyro-
BocHN
NHTf
BocHN
NH2
CH2Cl2, rt, 16 h
74%
sine.8 Our efforts to expand the utility of disulfonamide 1–3 ana-
logues to other reactions and conditions led to the application of
organocatalyst 4 as a derivative of disulfonamides 1–3 to direct
stereoselective aldol reactions in brine, and early results have
5
6
Ph
HCl
H2N
NHTf
AcOEt, rt, 4 h
94%
4
⇑
Corresponding author.
E-mail address: miura@gifu-pu.ac.jp (T. Miura).
Scheme 1. Preparation of organocatalyst 4.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.014

T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1028–1034
1029
Table 1
Optimization of reaction conditions (part 1)
O
Ph
O
H
O
OH
H2N
NHTf
4 (0.1 equiv)
(10 equiv)
NO2
NO2
7a
8a
Entry
Solvent
Additive (equiv)
Temp (°C)
Time (h)
Yielda (%)
anti:synb
%eec
1
2
3
4
5
6
7
8
MeOH
MeCN
NMP
DMSO
1,4-Dioxane
neatd
H20
Brine
Brine
Brine
Brine
Brine
Brine
Brine
Brine
Brine
Non
Non
Non
Non
Non
Non
Non
Non
CF3CO2H (0.1)
CF3CO2H (0.1)
CF3CO2H (0.2)
CF3CO2H (0.05)
CF3CO2H (0.05)
CH3CO2H (0.05)
PhCO2H (0.05)
CF3SO3H (0.05)
CF3CO2H (0.05)
CF3CO2H (0.05)
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
0
0
0
0
0
0
0
0
95
94
94
70
168
48
47
48
48
120
120
48
48
48
48
118
48
79
94
83
83
89
85
85
92
81
89
31
92
85
77
89
85
88
89
55:45
53:47
56:44
60:40
55:45
56:44
55:45
61:39
76:24
77:23
78:22
82:18
86:14
85:15
64:36
82:18
79:21
79:21
12
23
50
60
55
62
55
69
85
87
81
90
89
90
69
90
86
88
9
10
11
12
13e
14
15
16
17
18
Sea water
Brinef
48
a
b
c
d
e
f
Isolated yield.
Determined by 1H NMR.
Determined by HPLC analysis using a Chiralcel OD-H column.
Solvent was not employed.
The reaction was carried out with 5 equiv of cyclohexanone.
Brine prepared from sea water was used.
Table 2
Optimization of reaction conditions (part 2)
O
Ph
H2N
O
H
O
OH
TFA
(0.05 equiv)
NHTf
4
(0.1 equiv)
H2O, 0oC, 48 h
NO2
NO2
7a
8a
Entry
Cyclohexanone (equiv)
H2O (equiv)
Yielda (%)
anti:synb
%eec
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
5
3
3
0
0.5
1
2
3
10
1
0.5
0.5
0.3
68
80
89
98
99
34
84
93
91
89
76:24
83:17
85:15
86:14
85:15
89:11
85:15
87:13
81:19
87:13
87
90
92
91
90
87
89
92
88
89
a
b
c
Isolated yield.
Determined by 1H NMR.
Determined by HPLC analysis using a Chiralcel OD-H column.
in the presence of triethylamine in CH2Cl2 afforded sulfonamide 6
in 74% yield. The Boc group of 6 was removed by treatment with
HCl in ethyl acetate to afford the desired b-aminosulfonamide 4
in 94% yield.
We investigated the optimal reaction conditions for an enantio-
selective aldol reaction using various solvents and additives, as
shown in Table 1. Aldol reactions were carried out with p-nitro-
benzaldehyde and cyclohexanone (10 equiv) as test reactants in
the presence of a catalytic amount of b-aminosulfonamide 4. Meth-
anol and acetonitrile are generally poor solvents for aldol reactions
and provided low enantioselectivities (entries 1 and 2). Moderate
enantioselectivities were observed when NMP, DMSO, and 1,4-
dioxane were used as the solvent (entries 3–5). Under neat condi-
tions, the anti-aldol product was obtained with 62% ee (entry 6).

1030
T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1028–1034
Table 3
Aldol condensation of various aldehyde in the presence of 4
Ph
H2N
NHTf
Ketone
4
TFA
(0.1 equiv)
0 oC
(0.05 eq.)
Aldehyde 7
Product 8
Entry
Product 8
Methoda
Time (h)
Yieldb (%)
anti:sync
%eed
1
2
A
B
73
90
88
70
86:14
87:13
91
91
O
O
O
OH
CF3
CN
Br
8b
OH
3
4
A
B
73
72
93
86
80:20
84:16
88
92
8c
OH
5
6
Ae
B
120
120
87
70
81:19
84:16
92
93
8d
7
8
A
B
119
120
12
10
87:13
>99:1
92
89
O
O
OH
OMe
8e
OH
9
10
A
B
118
120
23
29
84:16
86:14
89
94
8f
11
12
A
B
120
120
84
76
88:12
92:8
91
93
O
O
OH NO2
8g
OH
13
14
A
B
72
72
92
84
82:18
86:14
91
94
NO2
8h
OH
15
16
Ae
B
120
120
77
60
84:16
86:14
93
93
O
O
OMe
8i
17
18
OH Cl
A
B
72
72
93
79
>99:1
97:3
86
97
Cl
8j
19
20
A
B
72
74
88
99
93:7
>99:1
85
85
O
OH
F
F
F
F
F
8k
21
22
O
O
A
B
72
72
71
61
71:29
65:35
88
72
OH
NO2
NO2
8l
OH
23f
24f
A
B
120
120
61
37
—
—
29
77
8m
a
b
c
d
e
f
Method A: The reactions were carried out with 10 equiv of ketone; Method B: The reactions were carried out with 5 equiv of ketone and 0.5 equiv of H2O.
Isolated yield.
Determined by 1H NMR.
Determined by HPLC analysis.
The reactions were carried out with 0.2 equiv of catalyst 4, 20 equiv of cyclohexanone, and 0.1 equiv of TFA in brine.
The reaction was carried out with 30 equiv of acetone in brine.

T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1028–1034
1031
Although the aldol reaction in water, an environmentally benign
solvent, occurred with 55% ee, the related conversion in brine
afforded the product with 69% ee (entries 7 and 8). Therefore, brine
proved to be the best medium for direct aldol reactions. Next, we
examined the effects associated with the presence of an acid. Addi-
tion of trifluoroacetic acid (TFA, 0.1 equiv) to the reaction in brine
significantly increased the enantioselectivity to 85% ee (entry 9).
Although a longer reaction time was needed, the reaction at 0 °C
under similar conditions yielded the same results (up to 87% ee,
entry 10). Addition of more TFA (0.2 equiv) resulted in a reduction
in both yield and stereoselectivity (entry 11). More suitable reac-
tion conditions were obtained when 0.05 equiv of TFA was used
at 0 °C (entry 12). Furthermore, we also examined other protic
acids, including acetic acid, benzoic acid, and trifluoromethanesul-
fonic acid; however, TFA was found to be the most suitable addi-
tive (entries 14–16). In addition, both sea water taken directly
from the Pacific Ocean and brine prepared by addition of sodium
chloride to sea water, which is available more easily than pure
water, were examined as reaction solvents. It was found that both
the yield and enantioselectivity of the aldol reactions in sea water
and brine prepared from sea water were nearly equal to those in
brine prepared from pure water (entries 17 and 18).
We hypothesized that the amount of water from brine dissolved
in cyclohexanone might play an important role in achieving
enantioselectivity because the results obtained from the reactions
in brine were better than those in water or run under neat condi-
tions. Therefore, the amount of water added in comparison to the
quantity of cyclohexanone was examined as shown in Table 2.
The most suitable amount of water was 1 equiv when 10 equiv of
cyclohexanone was used in the reaction (entries 1–6). High enanti-
oselectivity was also achieved by the addition of 0.5 equiv of water
when the level of cyclohexanone was reduced to 5 equiv (entries 7
and 8), suggesting the optimal ratio of water to cyclohexanone is
1:10 in comparison with the reactions in brine. Lowering the
amount of cyclohexanone to 3 equiv resulted in slightly lower
enantioselectivities (entries 9 and 10).
with various aldehydes were evaluated in the presence of 4
(0.1 equiv) and TFA (0.05 equiv) using two sets of conditions. In
the first set, reactions were carried out in the presence of 10 equiv
of ketone in brine (method A). Alternative conditions utilized
5 equiv of ketone and 0.5 equiv of water (method B). We chose ni-
tro, trifluoromethyl, cyano, and halogen substituents as represen-
tative electron-withdrawing groups (entries 1–6 and 11–14), and
a methoxy substituent as an electron-donating group on the ben-
zene ring (entries 7, 8, 15, and 16). The reactions of cyclohexanone
with aromatic aldehydes bearing electron-withdrawing groups at
the para-position 7b–d proceeded smoothly to afford the corre-
sponding anti-aldol products 8b–d in excellent yields with high
enantioselectivities (88–93% ee). p-Anisaldehyde 7e and benzalde-
hyde 7f were poor substrates for the aldol reaction giving low
yields (10–29%) despite the longer reaction time; however, high
enantioselectivities were observed (entries 7–10). The aldehydes
substituted by a nitro group at the ortho or meta position 7g and
7h were converted into the corresponding anti-aldol products 8g
and 8h in excellent yields with high enantioselectivities (entries
11–14). The reaction of less reactive m-anisaldehyde 7i with cyclo-
hexanone also gave 8i in good yields with 93% ee (entries 15 and
16). The highest diastereoselectivity (>99:1) and enantioselectivity
(97% ee) were observed in the reactions of 2,6-dichlorobenzalde-
hyde with cyclohexanone (entries 17 and 18). The reactions of
the penta-substituted aldehyde 7k were also carried out to afford
the corresponding anti-aldol product 8k in excellent diastereose-
lectivity with 85% ee (entries 19 and 20). We also examined reac-
tions between other ketones and p-nitrobenzaldehyde 7a. The
aldol reaction of cyclopentanone with 7a gave the expected aldol
products 8l in good yields and enantioselectivities (entries 21
and 22). The reaction of acetone as an acyclic ketone with 7a in
brine (method A) afforded 8m in moderate yield and with low
enantioselectivity (entriy 23), and while the aldol reaction in the
presence of water (method B) resulted in low yield, the enantiose-
lectivity improved substantially (up to 77% ee, entry 24). Aliphatic
aldehydes phenylpropionaldehyde and isobutyraldehyde were also
examined as reactants with cyclohexanone, but the corresponding
aldol products could not be obtained under these reaction condi-
tions. Results from these experiments have demonstrated excellent
setereoselectivities for Method B, which was found to be superior
With the optimal conditions in hand, we next investigated sub-
stituent effects of the aromatic aldehydes on the aldol reactions in
order to identify the scope and limitations of the aldehyde sub-
strate, as shown in Table 3. The direct asymmetric aldol reactions
O
F
F
F
Ph
H2N HN
O
S
F
O
O
9
O
OH
(5 equiv)
F
TFA
H
(0.1 equiv)
(0.05 equiv)
H2O (0.5 equiv), 0 oC, 48 h
71%
NO2
NO2
7a
8a
anti:syn = 76:24
84% ee
Scheme 2.
O
TFA
O
H2N
NHTf
O
OH
(0.05 equiv)
10
(10 equiv)
H
(0.1 equiv)
brine, 0 oC, 69 h
99%
NO2
NO2
7a
8a
anti:syn = 87:13
88% ee
Scheme 3.

1032
T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1028–1034
to method A in many cases. Most significantly, the reaction of 7j
with cyclohexanone using method B showed enhanced enantiose-
lectivity (up to 97% ee) as compared to the same reaction using
method A (86% ee, entries 17 and 18).
4.2. Preparation of organocatalyst
4.2.1. (S)-tert-Butyl 1-phenyl-3-(trifluoromethylsulfonamido)
propan-2-ylcarbamate 6
We also examined other types of organocatalysts (9 and 10) for
the direct asymmetric aldol reactions (Schemes 2 and 3). Both
organocatalysts 9 and 10 catalyzed the reaction of 7a with cyclo-
hexanone under similar reaction conditions to afford aldol adduct
8a in 71% and 99% yields, respectively; however, the enantioselec-
tivities were slightly reduced as compared to organocatalyst 4.
The stereochemistry of all anti-aldol products obtained with
organocatalyst 4 was determined by chiral-phase HPLC analysis
and NMR spectroscopy. We infer that the b-aminosulfonamide 4-
catalyzed direct aldol reactions between aldehydes and ketones pro-
ceed via a transition state similar to that proposed by Córdova
etal.,4c,11 whichis basedonthestereochemistryofthealdolproducts
8 (Fig. 1). A plausible transition state proposed for the aldol reaction
is shown in Figure 1. From this hypothesis, the primary amino group
of 4 condenses with the ketone to afford an enamine intermediate.
Then, it is reasonable to expect that the sulfonamide proton of 4
coordinates to the aldehyde oxygen to control the approach direc-
tion of the aldehyde to the enamine intermediate affording the cor-
responding anti-aldol products with remarkable stereo control.
Moreover, the addition of TFA to the aldol reactions might accelerate
the formation of the enamine intermediate,12 as well as reinforce the
rigid transition state of the aldol reaction shown in Figure 1.
To a solution of (S)-tert-butyl 1-amino-3-phenylpropan-2-ylcar-
bamate 510 (375 mg, 1.50 mmol) in dry CH2Cl2 (10 mL) was added
triethylamine (251
sphere. After stirring for 5 min, trifluoromethanesulfonic anhy-
dride (277 L, 1.65 mmol) was added to the reaction mixture at
lL, 1.80 mmol) at rt under an argon atmo-
l
0 °C. After stirring for 1 h at 0 °C, the reaction mixture was addi-
tionally stirred for 16 h at rt. The reaction mixture was added to
saturated aqueous NaHCO3 and extracted three times with AcOEt.
The AcOEt layers were combined, washed with brine, dried over
anhydrous MgSO4, and evaporated. The residue was purified by
flash column chromatography on silica gel with a 4:1 mixture of
hexane and AcOEt to give pure 6 (425 mg, 74%) as a colorless pow-
der. Mp = 114–116 °C; ½a D25
ꢀ
¼ ꢁ13:6 (c 1.35, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 1.40 (s, 9H), 2.81 (m, 2H), 3.23 (m, 1H),
3.43 (d, J = 11.4 Hz, 1H), 3.98 (m, 1H), 4.67 (br s, 1H), 6.82 (br s,
1H), 7.16–7.34 (m, 5H); 13C NMR (100 MHz, CDCl3): d = 28.2,
1
38.4, 49.0, 51.7, 80.9, 119.8 (q, JC-F = 321 Hz), 127.2, 128.9, 129.1,
136.2, 157.0; HRMS (ESI-TOF): calcd for
C15H21F3N2O4SNa
(M+Na)+: 405.1066, found: 405.1045.
4.2.2. (S)-N-(2-Amino-3-phenylpropyl)-1,1,1-trifluoromethane
sulfonamide 4
To a solution of 6 (404 mg, 1.06 mmol) in AcOEt (5 mL) was
added 5 mL of a 4 M solution of hydrochloric acid in AcOEt at 0 °C.
After stirring for 3.5 h at rt, the reaction mixture was evaporated.
The residue was added to saturated aqueous NaHCO3 and extracted
three times with AcOEt. The AcOEt layers were combined, washed
with brine, dried over anhydrous MgSO4, and evaporated. The resi-
due was purified by flash column chromatography on silica gel with
a 9:1:0.08 mixture of CHCl3, MeOH, and H2O to give pure 4 (281 mg,
H
N
R2
Ph
O
Ar
N
H
Tf
R1
H
94%) as a colorless powder. Mp 164–166 °C; ½a D25
ꢀ
¼ þ10:7 (c 2.01,
Figure 1. Proposed transition state model for the aldol reaction.
MeOH); 1H NMR (400 MHz, CD3OD): d = 2.81 (dd, J = 6.9, 13.8 Hz,
1H), 2.93 (dd, J = 7.2, 13.8 Hz, 1H), 3.10 (dd, J = 7.2, 13.0 Hz, 1H),
3.23–3.35 (m, 2H), 7.24–7.35 (m, 5H); 13C NMR (100 MHz, CD3OD):
3. Conclusion
1
d = 38.5, 48.7, 55.8, 123.0 (q, JC-F = 326 Hz), 128.2, 129.9, 130.4,
In conclusion, organocatalyst 4 can be easily prepared from
phenylalanine, commercially available, inexpensive natural
L-
137.9; HRMS (ESI-TOF): calcd for
C
10H14F3N2O2S (M+H)+:
a
283.0723, found: 283.0691. Anal. Calcd for C10H13F3N2O2S: C,
42.55; H, 4.64; N, 9.92. Found: C, 42.47; H, 4.57; N, 9.90.
amino acid. The simple b-aminosulfonamide 4, with only one stere-
ogenic center, functions efficiently as a catalyst in the direct aldol
reaction of various aldehydes with ketones to give the correspond-
ing anti-aldol products 8 with high enantioselectivities. Further-
more, we have demonstrated that the reaction conditions using a
1:10 ratio of water to cyclohexanone are superior to the reactions
in brine. Further application of this process to the synthesis of bio-
active compounds is currently in progress in our laboratory.
4.2.3. (S)-N-(2-Amino-3-phenylpropyl)-2,3,4,5,6-pentafluoro
benzenesulfonamide 9
To a solution of (S)-tert-butyl 1-amino-3-phenylpropan-2-ylcar-
bamate 5 (423 mg, 1.69 mmol) in dry CH2Cl2 (10 mL) was added
triethylamine (703
pentafluorobenzoyl chloride (373
l
L, 5.07 mmol) at rt. After stirring for 5 min,
L, 2.54 mmol) was added to
l
the reaction mixture at rt. After stirring for 20 h at rt, the reaction
mixture was added to saturated aqueous NaHCO3 and extracted
three times with AcOEt. The AcOEt layers were combined, washed
with brine, dried over anhydrous MgSO4, and evaporated. The res-
idue was purified by flash column chromatography on silica gel
with a 4:1 mixture of hexane and AcOEt to give (S)-tert-butyl 1-
(perfluorophenylsulfonamido)-3-phenylpropan-2-ylcarbamate
(171 mg, 21%). Then, to a solution of (S)-tert-butyl 1-(perflu-
orophenylsulfonamido)-3-phenylpropan-2-ylcarbamate (161 mg,
0.335 mmol) in AcOEt (1.7 mL) was added 1.7 mL of a 4 M solution
of hydrochloric acid in AcOEt at 0 °C. After stirring for 3.5 h at rt,
the reaction mixture was evaporated. The residue was added to
saturated aqueous NaHCO3 and extracted three times with AcOEt.
The AcOEt layers were combined, washed with brine, dried over
anhydrous MgSO4, and evaporated. The residue was purified by
flash column chromatography on silica gel with a 20:1 mixture
of CHCl3 and MeOH to give pure 9 (110 mg, 86%) as a colorless
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were measured with a Bruker
Ultrashield™ 400 Plus spectrometer, a JEOL AL 400 spectrometer
(400 MHz for 1H NMR and 100 MHz for 13C NMR), or JEOL ECA-
500 spectrometer (500 MHz for 1H NMR and 125 MHz for 13C
NMR). The chemical shifts are expressed in ppm downfield from
tetramethylsilane (d = 0.00) as an internal standard. The high-reso-
lution Mass spectra (HRMS) of the compounds were recorded using
a Waters LCT Premier (ESI-TOF-MS) spectrometer. For thin layer
chromatographic (TLC) analyses, Merck precoated TLC plates (Silica
Gel 60 F254, Art 5715) were used. The products were isolated by
flash column chromatography on silica gel (Kanto Chemical, Silica
Gel 60 N, spherical, neutral, 40–50 lm).

T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1028–1034
1033
powder. Mp = 129 °C;
½
a 2D2
ꢀ
¼ þ8:7 (c 1.00, MeOH); 1H NMR
All the aldol products in the paper are known compounds that
exhibited spectroscopic data identical to those reported in the
literature.
(500 MHz, CD3OD): d = 2.62 (dd, J = 7.4, 13.8 Hz, 1H), 2.80 (dd,
J = 6.3, 13.2 Hz, 1H), 2.97 (dd, J = 7.4, 13.2 Hz, 1H), 3.08 (dd,
J = 4.6, 13.2 Hz, 1H), 3.12–3.17 (m, 1H), 7.19–7.23 (m, 3H), 7.27–
7.30 (m, 2H); 13C NMR (125 MHz, CD3OD): d = 41.1, 53.9, 127.7,
129.7, 130.3, 139.2. Anal. Calcd for C15H13F5N2O2S: C, 47.37; H,
3.45; N, 7.37. Found: C, 47.11; H, 3.48; N, 7.22.
4.3.3. (2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-
one 8a7b,e,13
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (hexane/2-propanol = 80:20), flow rate = 0.5
mL/min; k = 254 nm; tmajor = 17.8 min, tminor = 22.8 min.
4.2.4. (S)-N-(2-Amino-3-methylbutyl)-1,1,1-trifluoromethane
sulfonamide 10
To a solution of (S)-tert-butyl 1-amino-3-methylbutan-2-ylcar-
4.3.4. (2S,10R)-2-[(4-Trifluoromethylphenyl)hydroxymethyl]
cyclohexan-1-one 8b7e
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (hexane/2-propanol = 80:20), flow rate = 0.5
mL/min; k = 216 nm; tmajor = 10.0 min, tminor = 11.2 min.
bamate 510 (441 mg, 2.19 mmol) in dry CH2Cl2 (10 mL) was added
triethylamine (458
After stirring for 5 min, trifluoromethanesulfonic anhydride
(395 L, 1.65 mmol) was added to the reaction mixture at 0 °C. After
lL, 3.29 mmol) at rt under an argon atmosphere.
l
stirring for 1 h at 0 °C, the reaction mixture was additionally stirred
for 16 h at rt. The reaction mixture was added to saturated aqueous
NaHCO3 and extracted three times with AcOEt. The AcOEt layers
were combined, washed with brine, dried over anhydrous MgSO4,
and evaporated. The residue was purified by flash column chroma-
tography on silica gel with a 4:1 mixture of hexane and AcOEt to
give (S)-tert-butyl 3-methyl-1-(trifluoromethylsulfonamido)butan
-2-ylcarbamate (439 mg, 61%). Then, to a solution of (S)-tert-butyl
3-methyl-1-(trifluoromethylsulfonamido)butan-2-ylcarbamate
(439 mg, 1.36 mmol) in AcOEt (5 mL) was added 5 mL of a 4 M solu-
tion of hydrochloric acid in AcOEt at 0 °C. After stirring for 8 h at rt,
the reaction mixture was evaporated. The residue was added to sat-
urated aqueous NaHCO3 and extracted three times with AcOEt. The
AcOEt layers were combined, washed with brine, dried over anhy-
drous MgSO4, and evaporated. The residue was purified by flash col-
umn chromatography on silica gel with a 9:1:0.08 mixture of CHCl3,
MeOH, and H2O to give pure 10 (126 mg, 39%) as a colorless powder.
4.3.5. 4-[Hydroxy(2-oxocyclohexyl)methyl]benzonitrile 8c7b
Enantiomeric excess was determined by HPLC with Chiralcel OD-
H column (hexane/2-propanol = 70:30), flow rate = 0.5 mL/min;
k = 234 nm; tmajor = 12.9 min, tminor = 16.2 min.
4.3.6. (2S,10R)-2-[(4-Bromophenyl)hydroxymethyl] cyclohexan-
1-one 8d7b,e
Enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (hexane/2-propanol = 90:10), flow rate = 0.5 mL/min;
k = 217 nm; tmajor = 28.0 min, tminor = 29.5 min.
4.3.7. (2S,10R)-2-[Hydroxy(4-methoxyphenyl)methyl]
cyclohexan-1-one 8e7b,e
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (hexane/2-propanol = 90:10), flow rate = 0.5
mL/min; k = 225 nm; tmajor = 21.0 min, tminor = 29.1 min.
Mp = 146–148 °C; ½a D24
ꢀ
¼ þ15:1 (c 0.87, MeOH); 1H NMR (500 MHz,
CD3OD): d = 1.00 (d, J = 7.5 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.88–1.95
(m, 1H), 2.81–2.85 (m, 1H), 3.09 (dd, J = 8.6, 13.2 Hz, 1H), 3.35 (dd,
J = 3.5, 13.2 Hz, 1H); 13C NMR (125 MHz, CD3OD): d = 18.8, 19.0,
4.3.8. (2S,10R)-2-(1-Hydroxy-1-phenylmethyl)cyclohexan-1-one
8f7b,e,13
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (hexane/2-propanol = 95:5), flow rate = 1.0
mL/min; k = 210 nm; tmajor = 11.7 min, tminor = 17.3 min.
1
30.1, 47.2, 60.4, 123.2 (q, JC-F = 326 Hz). Anal. Calcd for
C6H13F3N2O2S: C, 30.77; H, 5.59; N, 11.96. Found: C, 30.93; H,
5.43; N, 11.83.
4.3. Typical procedure for direct aldol reactions using
organocatalyst 4 (Table 3)
4.3.9. (2S,10R)-2-[Hydroxy(2-nitrophenyl)methyl]cyclohexan-1-
one 8g7b,13
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (hexane/2-propanol = 80:20), flow rate = 0.5 mL/
min; k = 250 nm; tmajor = 13.4 min, tminor = 15.0 min.
4.3.1. Method A
To a colorless suspension of 7a (90.7 mg, 0.60 mmol) and organ-
ocatalyst 4 (16.9 mg, 0.060 mmol) in 1.2 mL of brine were added
cyclohexanone (0.62 mL, 6.00 mmol) and trifluoroacetic acid
(2.2 lL, 0.030 mmol) at 0 °C. After stirring for 48 h at 0 °C, the reac-
4.3.10. (2S,10R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclohexan-
1-one 8h7b
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (hexane/2-propanol = 80:20), flow rate = 0.5 mL/
min; k = 254 nm; tmajor = 15.2 min, tminor = 19.2 min.
tion mixture was added to water and extracted three times with
AcOEt. The AcOEt layers were combined, washed with brine, dried
over anhydrous MgSO4, and evaporated. The residue was purified
by flash column chromatography on silica gel with a 2:1 mixture
of hexane and AcOEt to give the pure 8a (137 mg, 92%) as a color-
less powder.
4.3.11. (2S,10R)-2-[Hydroxy(3-methoxyphenyl)methyl]
cyclohexan-1-one 8i3a
Enantiomeric excess was determined by HPLC with a Chiralpak
AS column (hexane/2-propanol = 90:10), flow rate = 1.0 mL/min;
k = 220 nm; tmajor = 13.1 min, tminor = 16.7 min.
4.3.2. Method B
To a solution 7a (90.7 mg, 0.60 mmol) and the organocatalyst 4
(16.9 mg, 0.060 mmol) in cyclohexanone(0.62 mL, 6.00 mmol) were
added H2O (5.4 lL, 0.30 mmol) and trifluoroacetic acid (2.2 lL,
0.030 mmol) at 0 °C. After stirring for 48 h at 0 °C, the reaction mix-
ture was added to water and extracted three times with AcOEt. The
AcOEt layers were combined, washed with brine, dried over anhy-
drous MgSO4, and evaporated. The residue was purified by flash col-
umn chromatography on silica gel with a 2:1 mixture of hexane and
AcOEt to give pure 8a (139 mg, 93%) as a colorless powder.
4.3.12. (2S,10R)-2-[(2,6-Dichlorophenyl)hydroxymethyl]
cyclohexan-1-one 8j13
Enantiomeric excess was determined by HPLC with a Chiralcel
OJ-H column (hexane/2-propanol = 95:5), flow rate = 1.0 mL/min;
k = 210 nm; tmajor = 9.9 min, tminor = 11.6 min.

1034
T. Miura et al. / Tetrahedron: Asymmetry 22 (2011) 1028–1034
Ramasastry, S. S. V.; Barbas, C. F. Org. Lett. 2007, 9, 3445; (h) Xu, X.-Y.; Wang,
4.3.13. (2S,10R)-2-[(2,3,4,5,6-
Y.-Z.; Gong, L.-Z. Org. Lett. 2007, 9, 4247; (i) Luo, S.; Xu, H.; Zhang, L.; Li, J.;
Cheng, J.-P. Org. Lett. 2008, 10, 653; (j) Luo, S.; Li, J.; Zhang, L.; Xu, H.; Cheng, J.-P.
Chem. Eur. J. 2008, 14, 1273; (k) Luo, S.; Xu, H.; Chen, L.; Cheng, J.-P. Org. Lett.
2008, 10, 1775; (l) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130,
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P.; Li, J.; Cheng, J.-P. Chem. Eur. J. 2010, 16, 4457.
Pentafluorophenyl)hydroxymethyl]cyclohexan-1-one 8k13
Enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (hexane/2-propanol = 90:10), flow rate = 0.5 mL/min;
k = 210 nm; tmajor = 14.8 min, tminor = 18.8 min.
4.3.14. (2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclopentan-
1-one 8n7b,13
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (hexane/2-propanol = 95:5), flow rate = 1.0 mL/min;
k = 265 nm; tmajor = 50.7 min, tminor = 48.4 min.
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4.3.15. (4R)-4-Hydroxy-p-nitrophenylbutan-2-one 8m7b,e,13
Enantiomeric excess was determined by HPLC with a Chiralcel
OJ column (hexane/2-propanol = 90:10), flow rate = 1.0 mL/min;
k = 266 nm; tmajor = 34.3 min, tminor = 38.8 min.
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Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific
Research (C) (No. 22590007) from the Japan Society for the Promo-
tion of Science.
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