Direct asymmetrie aldol reaction with recyclable fluorous organocatalyst

Article abstract of DOI:10.1021/ol1003719

(Figure Presented) Direct asymmetric aldol reactions of aldehydes with ketones In the presence of a catalytic amount of fluorous sulfonamide 4 and trilfluoroacetic acid result in the corresponding aldol products in high yields with up to 96% ee. The fluor

Full text of DOI:10.1021/ol1003719

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1620-1623
Direct Asymmetric Aldol Reaction with
Recyclable Fluorous Organocatalyst
Tsuyoshi Miura,*,† Kie Imai,† Mariko Ina,† Norihiro Tada,† Nobuyuki Imai,‡ and
Akichika Itoh†
Gifu Pharmaceutical UniVersity, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan, and
Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi,
Chiba 288-0025, Japan
miura@gifu-pu.ac.jp
Received February 12, 2010
ABSTRACT
Direct asymmetric aldol reactions of aldehydes with ketones in the presence of a catalytic amount of fluorous sulfonamide 4 and trifluoroacetic
acid result in the corresponding aldol products in high yields with up to 96% ee. The fluorous organocatalyst 4 can be readily recovered from
the reaction mixture by fluorous solid-phase extraction and could be reused without a significant loss of the catalytic activity and
enantioselectivity.
Development of an organocatalytic enantioselective aldol
reaction is an attractive research theme because asymmetric
Scheme 1. Our Previous Work
aldol reactions are one of the most important carbon-carbon
bond-forming procedures in organic chemistry.1 Since List
et al.2 developed the first direct asymmetric aldol reaction
catalyzed by proline, many effective organocatalysts have
been reported.3 Especially, the direct aldol reactions with
water without any organic solvent as a reaction medium have
attracted a great deal of attention because water is a safe
and an environmentally benign solvent from the perception
of green chemistry.4 Although we have recently reported the
direct asymmetric aldol reactions in brine catalyzed by chiral
sulfonamide 1 derived from L-phenylalanine,5 recovery and
reuse of the expensive chiral organocatalysts are usually
difficult (Scheme 1). The recovery of the expensive orga-
nocatalysts from the reaction mixture after completion of
reaction and its recycling are highly desirable. Curran et al.6
elaborated a recycling technique by the fluorous solid-phase
extraction (FSPE) methodology using fluorous silica gel.
Recently, organocatalytic reactions by FSPE concept for
recovery and reuse of the expensive organocatalysts have
also been reported.4n,7 We have also reported the enantiose-
lective Simonth-Smith cyclopropanation using fluorous
chiral ligand 2,8 which can be recyclable by the introduction
of fluorous tag into the original chiral ligand 3 (Figure 1).9
† Gifu Pharmaceutical University.
‡ Chiba Institute of Science.
(1) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2004; Vols. 1 and 2.
(2) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395–2396.
(3) For reviews on organocatalysts, see: (a) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138–5175. (b) Pellissier, H. Tetrahedron
2007, 63, 9267–9331. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. ReV. 2007, 107, 5471–5569. (d) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638–4660.
10.1021/ol1003719  2010 American Chemical Society
Published on Web 03/08/2010

(10 equiv) in the presence of a catalytic amount of the
sulfonamide 4 (0.1 equiv) in brine. Although the higher
enantioselectivities were observed when the reactions were
carried out at 0 °C than that observed at room temperature,
a long reaction time (163 h) was necessary for completion
of the reaction (entries 1 and 2). The addition of trifluoro-
acetic acid (0.05 equiv) improved the enantioselectivity up
to 93% ee (entries 3 and 4). Among our data, optimal results
were obtained when 0.05 equiv of trifluoroacetic acid was
used at rt (entry 3).
Figure 1. Structure of organocatalysts.
Table 2 shows the scope and limitation of the direct
asymmetric aldol reactions with various aldehydes (7b-l)
under the optimized reaction condition mentioned above.10
We selected nitro, trifluoromethyl, cyano, and halogen
substituents as an electron-withdrawing group (entries
1-3, 5-6, and 8-11), and methoxy substituent as a
representative electron-donating group (entry 7), at ben-
zene ring. The aldehydes substituted by an electron-
withdrawing group at the para-position (7b-d) were
converted to the corresponding anti-aldol products in
excellent yields with high enantioselectivities (entries
1-3). The reaction of less reactive benzaldehyde (7e) with
cyclohexanone also gave 8e in 71% yield with 87% ee
(entry 4). The aldehydes substituted by a nitro group at
the ortho- or meta-position (7f and 7g) were also converted
to the corresponding anti-aldol products (8f and 8g) in
excellent yields with 91% ee and 93% ee, respectively
(entries 5 and 6). Although moderate chemical yield (66%
and 41%) was obtained in the reaction of m-anisaldehyde
(7h) and 2,6-dichlorobenzaldehyde (7i), the highest di-
To recover and reuse the valuable organocatalyst 1 for
the direct asymmetric aldol reactions in water, we have
attempted the development of a novel organocatalyst with
a fluorous tag, and designed fluorous sulfonamide 4. In
this paper, we describe a catalytic enantioselective aldol
reaction in brine using reusable fluorous sulfonamide
organocatalyst 4.
Fluorous sulfonamide 4 as a novel recyclable organocata-
lyst was prepared as shown in Scheme 2. 5 as the intermedi-
ate for synthesis of chiral ligands 3 was easily prepared from
phenylalaninol through four steps.9 The treatment of 5 with
perfluorooctanesulfonyl fluoride and triethylamine in dichlo-
romethane resulted in the fluorous compound 6 with 68%
yield. The Boc group of 6 was removed by treatment with
hydrogen chloride in ethyl acetate to provide the desired
fluorous sulfonamide 4 with 87% yield.
We optimized the reaction conditions for the enantiose-
lective direct aldol reactions as shown in Table 1. Aldol
reactions were carried out with aldehydes and cyclohexanone
Scheme 2. Preparation of Fluorous Organocatalyst
Table 1. Optimization of Reaction Conditions
entry
4 (equiv)
additve (equiv)
temp
time (h)
yield (%)a
anti:synb
% eec
1
2
3
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
b
non
non
rt
0 °C
rt
0 °C
rt
rt
24
163
6.5
53
6
47
6
6
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
TFA (0.05)
TFA (0.05)
TFA (0.05)
TFA (0.025)
TFA (0.1)
TFA (0.025)
4
5d
6
7
8
rt
rt
a Isolated yield. Determined by H NMR. c Determined by HPLC analysis with Chiralcel OD-H. d 5 equiv of cyclohexanone was used.
1
Org. Lett., Vol. 12, No. 7, 2010
1621

astereoselectivity (>99:1) was observed in the reaction of
2,6-dichlorobenzaldehyde (7i) with cyclohexanone (entries
7 and 8). The reaction of the pentasubstituted aldehyde
7j was also carried out to afford the corresponding anti-
aldol product 8j in excellent yield with 84% ee (entry 9).
The aldol reaction of cyclopentanone with p-nitrobenzal-
dehyde (7a) gave the expected aldol product 8k in 47%
yield with 96% ee (entry 10). The reaction of acetone as
an acyclic ketone with p-nitirobenzaldehyde (7a) afforded
8l in high yield and lower enantioselectivity (entry 11).
The fluorous organocatalyst 4 makes it possible to
recover itself by using fluorous silica gel based on fluorous
solid-phase extraction.6 Fluorous sulfonamide 4 was
cleanly recovered (89-100%) from the reaction mixture
by using fluorous solid-phase extraction and the organo-
catalyst 4 can be repeatedly reusable. In each reuse, the
recovered 4 without further purification retains its catalytic
activity and same levels of enantioselectivity for five
cycles (Table 3).
Table 2. Direct Asymmetric Aldol Reactions with Fluorous
Organocatalyst
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b
a Isolated yields. Determined by H NMR. c Determined by HPLC
analysis. d The raction was carried out with 30 equiv of acetone in
brine.
1
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Org. Lett., Vol. 12, No. 7, 2010

proceed via a transition state proposed by Co´rdova et al.11
based on the stereochemistry of aldol products 8 (Figure
2). We guess that the acidity of sulfonamide was enhanced
Table 3. Recycling and Reuse of the Fluorous Catalyst by FSPE
yield
(%)a
cat.
recovery
entry
time (h)
5
anti:synb
% eec
85
initial
first
89
86
78
65
75
75
83:17
100
89
94
92
91
90
Figure 2. Proposed transition state model of the aldol reaction.
reuse
second
reuse
third
reuse
fourth
reuse
fifth
5
6
84:16
85:15
83:17
85:15
84:16
91
90
87
90
86
by the powerful electron-withdrawing effect of the long
perfluoroalkyl chain (-C8F17) to strongly coordinate to
aldehydes and stabilize the transition state.
6
In conclusion, fluorous sufonamide 4, a novel fluorous
organocatalyst, efficiently works as a catalyst in the direct
aldol reaction of various aldehydes with ketones in brine
to give the corresponding aldol products with high
enantioselectivities. Fluorous organocatalyst 4 can ef-
ficiently catalyze the aldol reactions in shorter reaction
time at room temperature than the original catalyst 15
without a lowering of enantioselectivity. The organocata-
lyst 4 with the fluorous tag was readily recovered only
by simple solid-phase extraction with fluorous silica gel
after reaction, and can be reused without further purifica-
tion up to five times. The catalytic activity and enanti-
oselectivity of 4 were maintained despite repetitive use.
Further application to the synthesis of bioactive com-
pounds and novel reactions is now in progress.
9
reuse
12
a Isolated yield. b Determined by 1H NMR. c Determined by HPLC
analysis with Chiralcel OD-H.
We suppose that the fluorous sulfonamide 4-catalyzed
direct aldol reactions between aldehydes and ketones
(10) A typical procedure of the aldol condensation with 4 and 7a is as
follows: To a colorless suspension of 7a (90.7 mg, 0.60 mmol) and the
organocatalyst 4 (37.9 mg, 0.060 mmol) in 1.2 mL of brine were added
cyclohexanone (0.620 mL, 6.00 mmol) and trifluoroacetic acid (2.2 mL,
0.030 mmol) at rt. The reaction mixture was stirred at rt 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 4 (37.8 mg,
100%). The 70% methanol fractions were evaporated to one-third original
volume. The residue was extracted 3× with AcOEt. The AcOEt layers were
combined, washed with brine, dried over anhydrous MgSO4, and evaporated.
The residue was purified by frash column chromatography on silica gel
with a 2:1 mixture of hexane and AcOEt to afford the pure 8a (133 mg,
89%) as a colorless crystal.
Acknowledgment. This work was supported in part by
the Suzuken Memorial Foundation.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 4 and 8a-l. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Bassan, A.; Zou, W.; Reues, E.; Himo, F.; Co´rdova, A. Angew.
Chem., Int. Ed. 2005, 44, 7028–7032. (b) Dziedzic, P.; Zou, W.; Ha´fren,
J.; Co´rdova, A. Org. Biomol. Chem. 2006, 4, 38–40.
OL1003719
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