Direct asymmetric aldol reactions in brine with recyclable fluorous β-aminosulfonamide organocatalysts

Article abstract of DOI:10.1016/j.tet.2011.06.004

Fluorous organocatalyst 3 promotes direct asymmetric aldol reactions of ketones with aldehydes in brine, leading to the synthesis of the corresponding anti-aldol products in high yields with up to 96% ee. Fluorous organocatalyst 3 is easily recovered by s

Full text of DOI:10.1016/j.tet.2011.06.004

Tetrahedron 67 (2011) 6340e6346
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Direct asymmetric aldol reactions in brine with recyclable fluorous
b-aminosulfonamide organocatalysts
,
a
a
a
a
b
Tsuyoshi Miura a , Kie Imai , Hikaru Kasuga , Mariko Ina , Norihiro Tada , Nobuyuki Imai ,
*
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:
Fluorous organocatalyst 3 promotes direct asymmetric aldol reactions of ketones with aldehydes in
brine, leading to the synthesis of the corresponding anti-aldol products in high yields with up to 96% ee.
Fluorous organocatalyst 3 is easily recovered by solid-phase extraction using fluorous silica gel and can
be reused up to five times without purification.
Received 28 April 2011
Received in revised form 2 June 2011
Accepted 3 June 2011
Available online 16 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Fluorous
Organocatalyst
Aldol
Water
Recycle
1. Introduction
direct asymmetric aldol reaction in water. Several excellent primary
amine organocatalysts for the aldol reactions under aqueous con-
The development of an organocatalytic enantioselective aldol
reaction has become a major area of research during the past de-
cade as a result of its ability to yield stereoselective carbonecarbon
ditions have been reported.4 In this context, we have recently
reported direct asymmetric aldol reactions in brine catalyzed by
chiral
b-aminosulfonamide
1
derived from
L-phenylalanine
bonds, generating chiral
b
-hydroxycarbonyl compounds as syn-
(Scheme 1);8 unfortunately the organocatalyst was discarded after
the reaction because of the difficulty in recovering and reusing it.
Ultimately, the ability to recover and recycle expensive organo-
catalysts from the reaction mixture after completion of the reaction
is highly desirable. Fluorous chemistry can be used as a recycling
method to overcome this problem.9 Fluorous chemistry has been
thetic building blocks.1 In addition, the properties of organo-
catalysts, such as low toxicity, high stability, and convenient
handling, make them appealing candidates for synthetic chemistry.
Since List et al. reported the first direct asymmetric aldol reaction
catalyzed by proline in 2000,2 many other aldol reactions using
proline analogues as the main organocatalyst have been reported.1
As an alternative approach to asymmetric aldol reactions, several
groups have worked with primary amine catalysts, exchanging the
cyclic secondary amine of proline derivatives.3,4 Moreover, the use
of water as a reaction medium that replaces organic solvents has
attracted a great deal of attention because of its affordability, safety,
and environmentally benign nature, all of which are important
requirements of sustainable green chemistry.4e6 Because type I
aldolases, which are natural enzymes, employ the primary amino
group of a lysine residue to catalyze aldol reactions via the enamine
intermediate under aqueous conditions,7 it was suggested that an
organocatalyst with a primary amino group may be suitable for the
ꢀ
ꢀ
developed extensively since Horvath and Rabai first reported the
concept of the fluorous biphasic system in 1994.10 Further, Curran
et al. elaborated on its use as a recycling technique by the fluorous
solid-phase extraction (FSPE) methodology using fluorous silica
gel.9,11 Subsequently, fluorous recycling techniques have been ap-
plied in organocatalytic chemistry.12 Fluorous organocatalysts were
applied to asymmetric DielseAlder reactions,13 aldol reactions,6n,14
Michael reactions,15 reductions,16 epoxidations,17 and
a-chlorina-
tions of aldehydes18 and could be recovered and reused by their
fluorous characteristics. To recover and reuse valuable organo-
catalyst 1,8 we developed a recyclable organocatalyst 3 with a flu-
orous tag that promotes asymmetric direct aldol reactions in brine,
as discussed in our preliminary communication.4i Herein, we de-
scribe in detail asymmetric direct aldol reactions in brine using
fluorous organocatalysts 3 (Fig. 1).
* Corresponding author. E-mail address: miura@gifu-pu.ac.jp (T. Miura).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.004

T. Miura et al. / Tetrahedron 67 (2011) 6340e6346
6341
reaction time compared to the original organocatalyst 1 (entry 13).
Unfortunately, despite our attempts to recover the catalyst by FSPE
using fluorous silica gel, oraganocatalyst 2 could not be adsorbed by
fluorous silica gel even at 40 wt % of fluorine content and was
eluted with 70% methanol.
O
TFA
Ph
H2N
(0.05 equiv)
O
OH
O
NHTf
(0.1 equiv)
H
1
(10 equiv)
brine, 0oC, 48h
92%
NO2
NO2
5a
4a
Table 1
anti:syn = 82:18
Optimization of reaction solvents
90 % ee
O
Ph
Scheme 1. Our previous work.
O
O
OH
H2N
NHSO2C4F9
(0.1 equiv)
H
(10 equiv)
Ph
2
NO2
solvent
NO2
5a
4a
H2N
NHSO2R
1: R = CF3
Entry
Solvent
Temp
Time (h)
Yielda (%)
anti/synb
eec (%)
2: R = C4F9
3: R = C8F17
1
2
3
4
5
6
7
8
MeOH
i-PrOH
CH3CN
THF
1,4-Dioxane
DMF
DMSO
NMP
Neat
H2O
H2O
Brine
Brine
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
48
96
78
77
83
81
79
75
65
81
81
84
78
81
82
57:43
51:49
55:45
57:43
56:44
57:43
67:33
73:27
54:46
73:27
79:21
79:21
80:20
39
42
39
64
61
54
71
75
56
85
89
91
92
100
120
120
120
23
45
48
24
Fig. 1. Structure of organocatalysts.
2. Results and discussion
To recover and reuse valuable organocatalyst 1, we initially
attempted the preparation of fluorous organocatalyst 2, which at-
tached a perfluorobutyl group as a fluorous tag to 1 instead of tri-
fluoromethyl group (Scheme 2). Treatment of compound 6,19 which
is an intermediate in the preparation of organocatalyst 1, with
perfluorobutanesulfonyl fluoride in the presence of triethylamine
in CH2Cl2 resulted in sulfonamide 7 with 89% yield. The Boc group
of 7 was removed by treatment with HCl in ethyl acetate to afford
9
10
11
12
13
0
0
ꢀC
ꢀC
120
168
20
rt
a
Isolated yield.
Determined by 1H NMR.
Determined by HPLC analysis using Chiralcel OD-H.
b
c
the desired fluorous
b-aminosulfonamide 2 with 92% yield.
We next attempted to prepare fluorous organocatalyst 3 con-
Ph
taining 51 wt % of fluorine, hoping to improve its recoverability
with the FSPE technique (Scheme 3). Compound 6 reacts with
perfluorooctanesulfonyl fluoride in the presence of triethylamine in
CH2Cl2 to give fluorous compound 8 with 68% yield. Treatment of 8
Ph
C4F9SO2F, Et3N
BocHN
NHSO2C4F9
CH2Cl2, rt, 43 h
89%
BocHN
NH2
7
6
with HCl in ethyl acetate results in the desired fluorous
sulfonamide 3 with 87% yield.
b-amino-
Ph
HCl
Ph
AcOEt, rt 3 h
92%
H2N
NHSO2C4F9
F-SO2C8F17, Et3N
Ph
2
CH2Cl2, rt, 24 h
68%
BocHN
NH2
BocHN
NHSO2C8F17
Scheme 2. Preparation of fluorous organocatalyst 2.
6
8
HCl
Ph
The reaction conditions were optimized for enantioselective
direct aldol reactions using fluorous organocatalyst 2, as shown in
Table 1. Aldol reactions were carried out with p-nitrobenzaldehyde
(4a) and cyclohexanone (10 equiv) as test reactants in the presence
of a catalytic amount of 2 (0.1 equiv). Methanol, 2-propanol, and
acetonitrile are poor solvents for aldol reactions and provided low
enantioselectivities (entries 1e3). Moderate enantioselectivities
were observed when THF, 1,4-dioxane, DMF, DMSO, and NMP were
used as the other polar solvents (entries 4e8). The neat conditions
without reaction solvent caused lowering of stereoselectivity to
yield the anti-aldol product with 56% ee (entry 9). The aldol re-
action in water, an environmentally benign solvent, enhances the
enantioselectivity up to 85% ee. This demonstrated that water is
a more suitable solvent for the aldol reactions than commonly used
organic solvents (entry 10). Furthermore, although longer reaction
times (120 h) were needed in water, performing the reaction at 0 ꢀC
enhanced enantioselectivity. Moreover, brine proved to be the best
solvent for direct aldol reaction catalyzed by organocatalyst 2
(entry 12). Overall, organocatalyst 2 is an excellent catalyst and
shows higher stereoselectivity at room temperature for shorter
AcOEt, rt, 4 h
87%
H2N
NHSO2C8F17
3
Scheme 3. Preparation of fluorous organocatalyst 3.
Based on the optimal conditions for aldol reactions using
organocatalyst 2, the reaction conditions were optimized for the
enantioselective direct aldol reactions using fluorous organo-
catalyst 3, as shown in Table 2. Aldol reactions were carried out
with p-nitrobenzaldehyde (4a) and cyclohexanone (10 equiv) as
test reactants in the presence of a catalytic amount of 3 (0.1 equiv)
in brine. A lowering of stereoselectivity was observed when the
aldol reaction using organocatalyst 3 was performed under the
optimal conditions with 2 (Table 2, entry 1 vs Table 1, entry 13).
Although the reaction at 0 ꢀC enhanced stereoselectivity, a long
reaction time (163 h) was necessary for completion of the reaction
(entry 2). The addition of trifluoroacetic acid (TFA, 0.05 equiv) im-
proved the enantioselectivity under both room temperature and
0 ꢀC conditions (entries 3 and 4). The enantioselectivities reduced

6342
T. Miura et al. / Tetrahedron 67 (2011) 6340e6346
Table 2
on the benzene ring. The reactions of cyclohexanone with aromatic
Optimization of reaction conditions
aldehydes bearing electron-withdrawing groups at the para posi-
tion (4bed) proceeded smoothly to afford the corresponding anti-
aldol products (5bed) with excellent yields and high enantiose-
lectivities (88e93% ee). p-Anisaldehyde (4e) was a poor substrate
for the aldol reaction and provided a low chemical yield (34%) with
poor stereoselectivity despite the longer reaction time (entry 4).
Benzaldehyde (4f) was also less reactive, with poor efficiency, and
low yield; ultimately the aldol product 5f was obtained in only 23%
yield using organocatalyst 1.8 Alternatively, fluorous sulfonamide 3
effectively catalyzed the aldol reaction to afford 5f with 71% yield
and 87% ee (entry 5). The aldehydes substituted with nitro groups
at ortho and meta positions (4g and 4h) were converted to the
corresponding anti-aldol products (5g and 5h) in excellent yields
with 91% and 93% ee, respectively (entries 6 and 7). The reaction of
less reactive m-anisaldehyde (4i) with cyclohexanone also gave 5i
in good yield with 75% ee (entry 8). The highest diastereoselectivity
(>99:1) was observed in the reaction of 2,6-dichlorobenzaldehyde
(4j) with cyclohexanone (entry 9). Reaction of the penta-
substituted aldehyde 4k was also carried out, affording the corre-
sponding anti-aldol product 5k with excellent diastereoselectivity
and 84% ee (entry 10). The pyridine ring containing aldehyde 4l was
also converted to the corresponding anti-aldol product 5l in ex-
cellent yield with 85% ee (entry 11). We also examined the reactions
between other types of ketones and p-nitrobenzaldehyde (4a). The
aldol reaction of cyclopentanone with 4a resulted in the expected
aldol product 5m in moderate yield with highest enantioselectivity
(96% ee) (entry 12). Although the reaction of cycloheptanone with
4a gave excellent product yield, low stereoselectivity was observed
(entry 13). 4-Oxotetrahydropyran reacted with 4a to afford the
product 5o with 86% yield and 77% ee (entry 14). The reaction of
acetone as an acyclic ketone with 4a afforded 5n in good yield with
low enantioselectivities (entry 15). Then, the reaction of di-
hydroxyacetone with 4a did not give the corresponding aldol
product 5q under the similar reaction conditions (entry 16).
O
Ph
H2N
O
O
OH
NHSO2C8F17
H
3
NO2
NO2
brine
4a
5a
Entry 3 (equiv) Additive (equiv) Temp Time (h) Yielda (%) anti/synb eec (%)
1
2
3
4
5d
6
7
8
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
None
None
rt
0
24
85
85
87
81
86
86
42
84
74:26
81:19
83:17
89:11
80:20
84:16
80:19
83:17
86
91
91
93
85
89
90
88
ꢀC 163
TFA (0.05)
TFA (0.05)
TFA (0.05)
TFA (0.025)
TFA (0.1)
TFA (0.025)
rt
6.5
53
6
47
6
0 ꢀ
rt
C
rt
rt
rt
6
a
Isolated yield.
Determined by 1H NMR.
Determined by HPLC analysis using Chiralcel OD-H.
Cyclohexanone (5 equiv) was used.
b
c
d
when the amount of cyclohexanone or TFA was decreased (entries 5
and 6). The reaction in the presence of 0.1 equiv amount of TFA
results in a reduction of yield (entry 7). The lowering of the catalyst
loading to 0.05 equiv also slightly decreased the enantioselectivity
(entry 8). Ultimately, the most suitable conditions were found
when the reaction was performed in the presence of TFA
(0.05 equiv) and catalyst 3 (0.1 equiv) at room temperature.
To address the limitations of the reaction substrate and extend
the scope of our investigation, we next examined the substitution
effect of aromatic aldehydes on aldol reactions under the optimal
conditions (Table 3). We selected nitro, trifluoromethyl, cyano, and
halogen substituents as representative electron-withdrawing
groups and methoxy substituent as an electron-donating group
Table 3
Asymmetric aldol reactions with fluorous organocatalyst 3
TFA
Ph
(0.05 equiv.)
O
O
OH
Ketone
H2N
(10equiv.)
NHSO2C8F17
3 (0.1equiv.)
H
R
R
brine, rt,
4
aldehyde
Product 5
Entry
1
Product
Time (h)
Yielda (%)
anti/synb
eec (%)
90
O
OH
8
100
87:13
CF3
5b
O
O
OH
2
3
73
45
93
81
80:20
80:20
88
93
30
5c
CN
Br
OH
5d
O
OH
4
120
34
52:48
OMe
5e

T. Miura et al. / Tetrahedron 67 (2011) 6340e6346
6343
Table 3 (continued )
Entry
Product
Time (h)
121
Yielda (%)
anti/synb
eec (%)
O
O
OH
5
6
7
8
71
94
93
66
78:22
87
91
93
75
5f
OH NO2
24
7
87:13
87:13
64:36
5g
OH
O
O
NO2
5h
OH
OMe
122
5i
O
OH Cl
9
16
91
90
>99:1
91
84
Cl
5j
O
OH
F
F
F
F
10
3
95:5
F
5k
O
OH
11
12
11
8
90
47
74:26
60:40
85
96
N
5l
OH
O
O
5m
NO2
NO2
OH
13
120
96
50:50
25
77
5n
O
OH
14
15
17
24
86
79
77:23
O
O
NO2
NO2
NO2
5o
OH
d
39d
5p
O
OH
d
16
120
0
d
HO
OH
5q
a
Isolated yields.
b
Determined by 1H NMR.
c
Detemined by HPLC analysis.
The reaction was carried out with 30 equiv of acetone in brine.
d

6344
T. Miura et al. / Tetrahedron 67 (2011) 6340e6346
The major objective of our project is to recover and reuse fluo-
with only one chiral center, function efficiently as a catalyst in the
direct aldol reaction of various aldehydes with ketones in brine to
give the corresponding anti-aldol products 5 with high enantiose-
lectivity. Fluorous organocatalysts 2 and 3 can efficiently catalyze
the aldol reactions in mild reaction conditions at room temperature
over shorter reaction times than the original organocatalyst 1,8
without lowering enantioselectivity. Although recycling and reuse
of organocatalyst 2 was unsuccessful, organocatalyst 3 was readily
recovered by simple solid-phase extraction using fluorous silica gel
and was immediately reusable up to five times without purification
providing the same activity and enantioselectivity. Further appli-
cation of this catalyst in the synthesis of bioactive compounds is
currently in progress in our laboratory.
rous organocatalyst 3. After use in the aldol reactions of aldehyde
4a with cyclohexanone under the optimal conditions, fluorous
organocatalyst 3 was readily recovered using fluorous silica gel
based on FSPE.9 Fluorous
b-aminosulfonamide 3 was easily re-
covered in high yields (89e100%) from the reaction mixture by
using FSPE. Moreover, recovered 3 can be reused for five cycles. In
each reuse, recovered 3 retained its catalytic activity and enantio-
selectivity without further purification, although longer reaction
times were necessary for the fourth and fifth reuse (Table 4).
Table 4
Recycling and reuse of the fluorous catalyst by FSPE
O
TFA
Ph
4. Experimental section
4.1. General
(0.05equiv.)
O
O
OH
H2N
NHSO2C8F17
3 (0.1equiv.)
H
(10equiv.)
1H NMR and 13C NMR spectra were measured with a Bruker
UltrashieldÔ 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 parts per million downfield
brine,rt
NO2
NO2
5a
4a
Entry
Initial
First reuse
Second reuse
Third reuse
Fourth reuse
Fifth reuse
Time (h)
Yielda (%)
anti/synb
eec (%)
Cat. recovery
5
5
6
6
9
89
86
78
65
75
75
83:17
84:16
85:15
83:17
85:15
84:16
85
91
90
87
90
86
100
89
94
92
91
90
from tetramethylsilane (
d
¼0.00) as an internal standard. The high-
resolution 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,
12
a
Isolated yield.
Determined by 1H NMR.
b
c
silica gel 60 N, spherical, neutral, 40e50 mm).
Determined by HPLC analysis using Chiralcel OD-H.
4.2. Preparation of organocatalyst
The stereochemistry of all anti-aldol products obtained with
fluorous organocatalyst 3 was determined by chiral-phase HPLC
analysis and NMR spectroscopy. We infer that the direct aldol re-
actions of aldehydes with ketones using fluorous organocatalyst 3
4.2.1. (S)-tert-Butyl 1-phenyl-3-(perfluorobutylsulfonamido) propan-
2-ylcarbamate (7). To
a solution of (S)-tert-butyl 1-amino-3-
phenylpropan-2-ylcarbamate (6)19 (255 mg, 1.02 mmol) in dry
CH2Cl2 (5 mL) was added triethylamine (0.46 mL, 3.06 mmol) at
room temperature. After stirring for 5 min, perfluorobutanesulfonyl
fluoride (0.58 mL, 3.06 mmol) was added to the reaction mixture at
ꢀ
proceed via a transition state similar to that proposed by Cordova’s
group,3c,20 which is based on the stereochemistry of anti-aldol
products 5. A plausible reaction mechanism for the aldol reaction is
proposed as shown in Fig. 2. From this hypothesis, the primary
amino group of 3 condenses with ketones to generate the enamine
intermediates. Then, the acidic proton of sulfonamide group, which
formed intramolecular coordination to nitrogen of the enamine
transition state, successfully interacts with the oxygen of aldehydes
to control the approach direction of aldehyde to the enamine in-
termediates. This ultimately affords the corresponding anti-aldol
products with high stereoselectivity. We believe that the acidity of
sulfonamide is enhanced by the powerful electron-withdrawing
effect of the long perfluoroalkyl chains, such as eC4F9 and eC8F17
to strongly coordinate to aldehyde and stabilize the rigid transition
states during aldol reactions.
0
ꢀC. After stirring for 3 h at 0 ꢀC, the reaction mixture was addi-
tionally stirred for 43 h at room temperature. The reaction mixture
was added to waterand 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 the pure 7 (471 mg, 87%) as a colorless powder.
24
Mp¼117e119 ꢀC; [
a
]
ꢁ10.4 (c 1.05, CHCl3); 1H NMR (400 MHz,
D
CDCl3):
d
¼1.38 (s, 9H), 2.80 (d, J¼5.9 Hz, 2H), 3.26 (m, 1H), 3.43 (d,
J¼12.2 Hz, 1H), 3.98 (m, 1H), 4.75 (d, J¼7.2 Hz, 1H), 7.16 (d, J¼7.2 Hz,
2H), 7.19e7.32 (m, 3H), 7.40 (br s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼28.2, 38.4, 49.5, 51.8, 81.0,107.5e119.0 (complex signals of eCF2e
or eCF3), 127.2, 128.9, 129.0, 136.1, 157.0; HRMS (ESI-TOF): calcd for
C18H21F9N2O4SNa (MþNa)þ: 555.0971, found: 555.0959.
H
H
N
Bn
N
Bn
R2
R2
4.2.2. (S)-N-(2-Amino-3-phenylpropyl)-perfluorobutanesulfon amide
(2). To a solution of 7 (453 mg, 0.851 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 h at room temperature, 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 chromatog-
raphy on silica gel with a 9:1:0.08 mixture of CHCl3, MeOH and H2O
O
Ar
N
O
Ar
N
H
H
SO2C8F17
SO2C8F17
R1
H
R1
H
Fig. 2. Proposed transition state model of aldol reaction.
3. Conclusion
In conclusion, fluorous organocatalysts 2 and 3 can be easily
prepared from -phenylalanine, an inexpensive and commercially
available amino acid. The simple -aminosulfonamides 2 and 3,
to give the pure
2
(339 mg, 92%) as a colorless powder.
þ10.6 (c 1.03, MeOH); 1H NMR (400 MHz,
25
D
Mp¼172e174 ꢀC; [
a
]
L
b
CD3OD):
d
¼2.83 (dd, J¼6.6, 13.9 Hz, 1H), 2.96 (dd, J¼7.0, 13.9 Hz,

T. Miura et al. / Tetrahedron 67 (2011) 6340e6346
6345
1H), 3.16 (dd, J¼8.3, 14.2 Hz, 1H), 3.29e3.35 (m, 2H, overlap with
solvent peaks), 7.24e7.36 (m, 5H); 13C NMR (100 MHz, CD3OD):
All the aldol products in the paper are known compounds that
exhibited spectroscopic data identical to those reported in the
literature.
d¼38.3, 56.1, 107.5e120.7 (complex signals of eCF2e or eCF3),
128.2, 129.9, 130.4, 137.7; HRMS (ESI-TOF): calcd for C13H14F9N2O2S
(MþH)þ:433.0627, found: 433.0667. Anal. Calcd for C13H13F9N2O2S:
C, 36.12; H, 3.03; N, 6.48. Found: C, 36.05; H, 2.99; N, 6.50.
4.3.1. (2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one
(5a)6d,e,21. [
a]
25 þ11.8 (c 1.00, CHCl3); 92% ee; enantiomeric excess was
D
determined by HPLC with Chiralcel OD-H column (hexane/2-
4.2.3. (S)-tert-Butyl 1-phenyl-3-(perfluorooctylsulfonamido) propan-
propanol¼80:20), flow rate¼0.5 mL/min;
l
¼254 nm; tmajor¼17.8 min,
2-ylcarbamate (8). To
a solution of (S)-tert-butyl 1-amino-3-
tminor¼22.8 min.
phenylpropan-2-ylcarbamate (6)19 (1.36 g, 5.43 mmol) in dry
CH2Cl2 (25 mL) was added triethylamine (2.30 mL, 16.3 mmol) at
room temperature. After stirring for 5 min, perfluorooctanesulfonyl
fluoride (4.50 mL, 16.3 mmol) was added to the reaction mixture at
4.3.2. (2S,10R)-2-[(4-Trifluoromethylphenyl)hydroxymethyl]
cyclo-
25
hexan-1-one (5b)6e. [
a
]
ꢁ17.3 (c 1.00, CHCl3); 90% ee; enantio-
D
meric excess was determined by HPLC with Chiralcel OD-H column
0
ꢀC. After stirring for 3 h at 0 ꢀC, the reaction mixture was addi-
(hexane/2-propanol¼80:20), flow rate¼0.5 mL/min;
l¼216 nm;
tionally stirred for 48 h at room temperature. The reaction mixture
was added to water and extracted three times with AcOEt. The
AcOEt layers were combined, washed with brine, dried over an-
hydrous MgSO4, and evaporated. The residue was purified by flash
column chromatography on silica gel with a 4:1 mixture of hexane
tmajor¼10.0 min, tminor¼11.2 min.
4.3.3. 4-[Hydroxy(2-oxocyclohexyl)methyl]benzonitrile (5c)6b. [
a]
D
24
þ15.4 (c 1.00, CHCl3); 88% ee; enantiomeric excess was determined
by HPLC with Chiralcel OD-H column (hexane/2-propanol¼70:30),
and AcOEt to give the pure 8 (2.72 g, 68%) as a colorless powder. Mp
flow rate¼0.5 mL/min; ¼234 nm; tmajor¼12.9 min, tminor¼16.2 min.
l
23
95e97 ꢀC; [
d
a
]
ꢁ8.0 (c 2.13, CHCl3); 1H NMR (400 MHz, CDCl3):
D
¼1.39 (s, 9H), 2.82 (d, J¼6.4 Hz, 2H), 3.28 (m, 1H), 4.47 (br d,
4.3.4. (2S,10R)-2-[(4-Bromophenyl)hydroxymethyl] cyclohexan-1-
26
J¼11.7 Hz, 1H), 3.98 (m, 1H), 4.68 (br s, 1H), 7.09 (br s, 1H), 7.16e7.34
one (5d)6d,e. [
a
]
þ18.3 (c 1.00, CHCl3); 93% ee; enantiomeric ex-
D
(m, 5H); 13C NMR (100 MHz, CDCl3):
d
¼28.2, 38.4, 49.4, 51.8, 80.9,
cess was determined by HPLC with Chiralpak AS-H column (hex-
105.0e121.5 (complex signals of eCF2e or eCF3), 127.2, 128.9, 129.1,
136.3, 157.0; HRMS (ESI-TOF): calcd for C17H14F17N2O2S (MþNa)þ:
755.0843, found: 755.0837.
ane/2-propanol¼90:10), flow rate¼0.5 mL/min;
l¼217 nm;
tmajor¼28.0 min, tminor¼29.5 min.
4.3.5. (2S,10R)-2-(Hydroxyphenylmethyl)cyclohexan-1-one
4.2.4. (S)-N-(2-Amino-3-phenylpropyl)-perfluorooctanesulfon amide
(3). To a solution of 8 (2.69 g, 3.67 mmol) in AcOEt (20 mL) was
added 20 mL of a 4 M solution of hydrochloric acid in AcOEt at 0 ꢀC.
After stirring for 4 h at room temperature, the reaction mixture was
evaporated. The residue was added to saturated aqueous NaHCO3
and extracted three times with AcOEt. The AcOEt layers were com-
bined, washed with brine, dried over anhydrous MgSO4, and evap-
orated. The residue was purified by flash column chromatography
on silica gel with a 20:1 mixture of CHCl3 and MeOH to give the pure
(5e)6d,e. [
a
]
24 þ4.8 (c 1.00, CHCl3); 30% ee; enantiomeric excess was
D
determined by HPLC with Chiralcel OD-H column (hexane/2-
propanol¼90:10), flow rate¼0.5 mL/min;
l¼225 nm; tmajor¼20.2 -
min, tminor¼27.1 min.
4.3.6. (2S,10R)-2-(1-Hydroxy-1-phenylmethyl)cyclohexan-1-one
(5f)6d,e,21. [
a
]
25 þ20.7 (c 1.00, CHCl3); 87% ee; enantiomeric excess
D
was determined by HPLC with Chiralcel OD-H column (hexane/2-
propanol¼95:5), flow rate¼1.0 mL/min;
l¼210 nm; tmajor¼11.7 -
3 (1.67 g, 72%) as a colorless powder. Mp 185e186 ꢀC; [
a
]
19 þ7.8 (c
min, tminor¼17.3 min.
D
0.50, MeOH);1HNMR (400 MHz, CD3OD):
d
¼2.83 (dd, J¼6.6,13.9 Hz,
1H), 2.96 (dd, J¼7.0, 13.9 Hz, 1H), 3.16 (dd, J¼8.3, 14.2 Hz, 1H),
4.3.7. (2S,10R)-2-[Hydroxy(2-nitrophenyl)methyl]cyclohexan-1-one
22
3.29e3.32 (m, 2H, overlap with solvent peaks), 7.24e7.36 (m, 5H);
(5g)6b,21. [
a
]
þ14.3 (c 1.00, CHCl3); 91% ee; enantiomeric excess
D
13C NMR (100 MHz, CD3OD):
d
¼38.3, 49.3, 56.1, 105.0e120.2 (com-
was determined by HPLC with Chiralcel OD-H column (hexane/2-
plex signals of eCF2e or eCF3),128.3,130.0,130.4,137.8; HRMS (ESI-
TOF): calcd for C17H14F17N2O2S (MþH)þ:633.0499, found: 633.0531.
Anal. Calcd for C17H13F17N2O2S: C, 32.29; H, 2.07; N, 4.43. Found: C,
32.08; H, 2.23; N, 4.45.
propanol¼80:20), flow rate¼0.5 mL/min;
l¼250 nm; tmajor¼13.4 -
min, tminor¼15.0 min.
4.3.8. (2S,10R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclohexan-1-one
(5h)6b. [
a
]
23 þ30.1 (c 1.00, CHCl3); 93% ee; enantiomeric excess was
D
4.3. Typical procedure for recycling and reusing fluorous
determined by HPLC with Chiralcel OD-H column (hexane/2-
organocatalyst 3 (Table 4)
propanol¼80:20), flow rate¼0.5 mL/min;
l
¼254 nm; tmajor¼15.2 -
min, tminor¼19.2 min.
A typical procedure of the aldol condensation using 3 and 5a is
as follows: to a colorless suspension of 5a (90.7 mg, 0.60 mmol) and
the organocatalyst 3 (37.9 mg, 0.060 mmol) in 1.2 mL of brine were
added cyclohexanone (0.62 mL, 6.00 mmol) and trifluoroacetic acid
4.3.9. (2S,10R)-2-[Hydroxy(3-methoxyphenyl)methyl] cyclohexan-1-
one (5i)4a. [
a]
þ4.4 (c 1.00, CHCl3); 75% ee; enantiomeric excess
22
D
was determined by HPLC with Chiralpak AS column (hexane/2-
(2.2
m
L, 0.030 mmol) at room temperature. The reaction mixture
propanol¼90:10), flow rate¼1.0 mL/min;
l
¼220 nm; tmajor¼13.1 -
was stirred at room temperature for 5 h. The reaction mixture was
chromatographed on fluorous silica gel with 70% methanol. Next,
the fluorous silica gel was eluted with methanol, and the methanol
fraction was evaporated to recover the fluorous organocatalyst 3
(37.8 mg, 100%). The 70% methanol fractions were evaporated to
a one-third to original volume. The residue was 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 afford the pure 6a (133 mg,
89%) as a colorless oil.
min, tminor¼16.7 min.
4.3.10. (2S,10R)-2-[(2,6-Dichlorophenyl)hydroxymethyl] cyclohexan-
1-one (5j)21. [
a]
ꢁ39.1 (c 1.00, CHCl3); 91% ee; enantiomeric ex-
20
D
cess was determined by HPLC with Chiralcel OJ-H column (hexane/
2-propanol¼95:5), flow rate¼1.0 mL/min;
l¼210 nm; tma-
¼9.5 min, tminor¼11.0 min.
jor
4.3.11. (2S,10R)-2-[(2,3,4,5,6-Pentafluorophenyl)hydroxy methyl]cy-
clohexan-1-one (5k)21. [
a]
ꢁ16.4 (c 1.00, CHCl3); 84% ee; enan-
23
D
tiomeric excess was determined by HPLC with Chiralpak AD-H

6346
T. Miura et al. / Tetrahedron 67 (2011) 6340e6346
4. For examples of organocatalyzed aldol reactions in water using organocatalysts
with primary amino group, see: (a) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem.
Commun. 2006, 2801; (b) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv. Synth. Catal.
2007, 349, 812; (c) Zhu, M.-K.; Xu, X.-Y.; Gong, L.-Z. Adv. Synth. Catal. 2008, 350,
1390; (d) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas, C. F. Org. Lett.
2008, 10, 1621; (e) Tea, Y.-C.; Lee, P. P. Synth. Commun. 2009, 39, 3081; (f) Peng,
F.-Z.; Shao, Z.-H.; Pu, X.-W.; Zhang, H.-B. Adv. Synth. Catal. 2008, 350, 2199; (g)
Ma, X.; Da, C.-S.; Yi, L.; Jia, Y.-N.; Guo, Q.-P.; Che, L.-P.; Wu, F.-C.; Wang, J.-R.; Li,
W.-P. Tetrahedron: Asymmetry 2009, 20, 1419; (h) Zhou, H.; Xie, Y.; Ren, L.;
Wang, K. Adv. Synth. Catal. 2009, 351, 1284; (i) Miura, T.; Imai, K.; Ina, M.; Tada,
N.; Imai, N.; Itoh, A. Org. Lett. 2010, 12, 1620; (j) Li, J.; Fu, N.; Li, X.; Luo, S.; Cheng,
J.-P. J. Org. Chem. 2010, 75, 4501; (k) Ricci, A.; Bernardi, L.; Gioia, C.; Vierucci, S.;
Robitzer, M.; Quignard, F. Chem. Commun. 2010, 6288.
column (hexane/2-propanol¼90:10), flow rate¼0.5 mL/min;
¼210 nm; tmajor¼14.8 min, tminor¼18.8 min.
l
4.3.12. (2S,10R)-2-[Hydroxy(pyridine-4-yl)methyl] cyclohexan-1-one
(5l)21. Enantiomeric excess was determined by HPLC with Chir-
alpak AD-H column (hexane/2-propanol¼90:10), flow rate¼1.0 mL/
min;
l¼254 nm; tminor¼21.7 min, tmajor¼24.2 min.
4.3.13. (2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl] cyclopentan-1-
one (5m)6b,21. Enantiomeric excess was determined by HPLC
with Chiralpak AD-H column (hexane/2-propanol¼95:5), flow
5. For review on stereoselective organocatalytic reaction in water, see: (a) Grut-
tadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33; (b) Para-
dowska, J.; Stodulski, M.; Mlynarski, J. Angew. Chem., Int. Ed. 2009, 48, 4288; (c)
Raj, M.; Singh, K. Chem. Commun. 2009, 6687; (d) Mase, N.; Barbas, C. F., III. Org.
Biomol. Chem. 2010, 8, 4043.
rate¼1.0 mL/min; ¼265 nm; tmajor¼50.7 min, tminor¼48.4 min.
l
4.3.14. (2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl] cycloheptan-1-
6. For examples of organocatalyzed aldol reactions in water without any organic
solvent using pyrrolidine derivatives, see: (a) Chimni, S. S.; Mahajan, D.; Babu,
V. V. S. Tetrahedron Lett. 2005, 46, 5617; (b) Mase, N.; Nakai, Y.; Ohara, N.; Yoda,
H.; Takabe, K.; Tanaka, F.; Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 734; (c)
Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 958; (d) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.;
Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527; (e) Font, D.; Jimeno,
one (5n)6b. [
a
]
ꢁ4.1 (c 1.00, CHCl3); 25% ee; enantiomeric ex-
22
D
cess was determined by HPLC with Chiralpak AD-H column (hex-
ane/2-propanol¼90:10), flow rate¼1.0 mL/min;
l¼254 nm; tmajor¼
50.0 min, tminor¼20.7 min.
4.3.15. (3S,10R)-3-[(10-Hydroxy-10-(400-nitrophenyl))methyl] tetrahy-
dropyran-4-one (5o)21. Enantiomeric excess was determined by
HPLC with Chiralpak AD-H column (hexane/2-propanol¼80:20),
ꢁ
C.; Pericas, M. A. Org. Lett. 2006, 8, 4653; (f) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.;
Wang, S. Org. Lett. 2006, 8, 4417; (g) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45,
8103; (h) Huang, W.-P.; Chen, J.-R.; Li, X.-Y.; Cao, Y.-J.; Xiao, W.-J. Can. J. Chem.
2007, 85, 208; (i) Giacalone, F.; Gruttadauria, M.; Marculescu, A. M.; Noto, R.
Tetrahedron Lett. 2007, 48, 255; (j) Aratake, S.; Itoh, T.; Okano, T.; Usui, T.; Shoji,
M.; Hayashi, Y. Chem. Commun. 2007, 2524; (k) Maya, V.; Raj, M.; Singh, V. K.
Org. Lett. 2007, 9, 2593; (l) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.;
Meo, P. L.; Riela, S.; Noto, R. Eur. J. Org. Chem. 2007, 4688; (m) Font, D.; Sayalero,
flow rate¼1.0 mL/min;
l¼254 nm; tminor¼20.7 min, tmajor¼23.9 min.
24
4.3.16. (4R)-4-Hydroxy-p-nitrophenylbutan-2-one (5p)6d,e,21. [
a]
D
ꢁ
þ24.5 (c 1.00, CHCl3); 39% ee; enantiomeric excess was determined
by HPLC with Chiralcel OJ column (hexane/2-propanol¼90:10), flow
S.; Bastero, A.; Jimeno, C.; Pericas, M. A. Org. Lett. 2008, 10, 337; (n) Zu, L.; Xie,
H.; Li, H.; Wang, J.; Wang, W. Org. Lett. 2008, 10, 1211; (o) Lombardo, M.; Pasi, F.;
Easwar, S.; Trombini, C. Synlett 2008, 2471; (p) Chimni, S. S.; Singh, S.; Mahajan,
D. Tetrahedron: Asymmetry 2008, 19, 2276; (q) Chimni, S. S.; Singh, S.; Kumar, A.
Tetrahedron: Asymmetry 2009, 20, 1722; (r) Zhang, S.-P.; Fu, X.-K.; Fu, S.-D.
Tetrahedron Lett. 2009, 50, 1173; (s) Fu, S.-D.; Fu, X.-K.; Zhang, S.-P.; Zou, X.-C.;
Wu, X.-J. Tetrahedron: Asymmetry 2009, 20, 2390; (t) Nisco, M. D.; Pedatella, S.;
Ullah, H.; Zaidi, J. H.; Naviglio, D.; Ozdamar, O.; Caputo, R. J. Org. Chem. 2009, 74,
9562; (u) Vishnumaya, M. R.; Singh, V. K. J. Org. Chem. 2009, 74, 4289; (v) Mase,
N.; Noshiro, N.; Mokuya, A.; Takabe, K. Adv. Synth. Catal. 2009, 351, 2791; (w) Jia,
Y.-N.; Wu, F.-C.; Ma, X.; Zhu, G.-J.; Da, C.-S. Tetrahedron Lett. 2009, 50, 3059; (x)
An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu, Z.-M.; Pi, C.; Tao, J.-C. Tetrahedron: Asymmetry
rate¼1.0 mL/min; ¼266 nm; tmajor¼34.3 min, tminor¼38.8 min.
l
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific
Research (C) (No. 22590007) from the Japan Society for the Pro-
motion of Science.
ꢀ
ꢀ
ꢀ
2010, 21, 688; (y) Pedrosa, B.; Andres, J. M.; Manzano, R.; Roman, D.; Tellez, S.
Org. Biomol. Chem. 2011, 9, 935.
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