Direct asymmetric aldol reactions in brine using novel sulfonamide catalyst

Article abstract of DOI:10.1016/j.tetlet.2009.03.053

Direct asymmetric aldol reactions of aldehydes with ketones in the presence of a catalytic amount of sulfonamide 4 and trifluoroacetic acid afforded the corresponding anti-aldol products in moderate to excellent yields with 85-93% ee.

Full text of DOI:10.1016/j.tetlet.2009.03.053

Tetrahedron Letters 50 (2009) 2632–2635
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Direct asymmetric aldol reactions in brine using novel sulfonamide catalyst
*
*
Tsuyoshi Miura , Yumi Yasaku, Naka Koyata, Yasuoki Murakami, Nobuyuki Imai
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:
Direct asymmetric aldol reactions of aldehydes with ketones in the presence of a catalytic amount of sul-
fonamide 4 and trifluoroacetic acid afforded the corresponding anti-aldol products in moderate to excel-
lent yields with 85–93% ee.
Received 4 February 2009
Revised 3 March 2009
Accepted 10 March 2009
Available online 14 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The aldol reaction is one of the most popular carbon–carbon
bond-forming procedures and plays an important role in organic
synthesis.1 The development of organocatalyst, which promotes
the direct asymmetric aldol reaction, is an attractive research field.2
On the other hand, the exploration of the reaction using water with-
out any organic solvent as a reaction medium has attracted a great
deal of attention because water is a safe and an environmentally
friendly solvent from perception of green chemistry.3 Therefore,
the development of a direct asymmetric aldol reaction using organ-
ocatalyst in water has received considerable interest, and some
groups have reported organocatalytic direct asymmetric aldol reac-
tions in water without using any organic co-solvent.4,5 Most of the
studies for organocatalytic direct asymmetric aldol reactions have
been done with proline-derived chiral catalysts because proline
and its derivatives with a secondary amino group were believed to
be the best catalyst for direct asymmetric aldol condensation due
to the ease of enamine formation.2,4 However, chiral primary amines
recently have been reported to be viable enamine organocatalysts
that attain a new level of catalyst beyond secondary amino catalysts
such as proline derivatives.5,6
group of 6 was removed by treatment with hydrogen chloride in
ethyl acetate to afford the desired sulfonamide 49 in 94% yield.
R1
R2HN
1: R1 = H, R2 = Ms , R3 = SO C H - -NO
2
NHR3
4 p
2
6
1
2
3
2
3
: R = H, R = Ms , R = Ts
: R = OCH2CH2CH2C8F17, R2 = Ms , R3 = Ts
1
4: R1 = H, R2 = H, R3 = Tf
Aldol reactions were carried out between aldehydes and cyclo-
hexanone (10 equiv) using the sulfonamide 4 (0.1 equiv). We opti-
mized the reaction conditions for enantioselective aldol reaction as
shown in Table 1. The various reaction solvents were examined in
the presence of the organocatalyst 4 at room temperature (entries
1–8). It was found that the more suitable reaction solvent was
brine (entry 8).4g,j The addition of trifluoroacetic acid (0.1 equiv)
significantly improved the enantioselectivity up to 85% ee (entry
9).4a,10 The more suitable reaction temperature was 0 °C as indi-
cated in entry 10. A better result on the amount of trifluoroacetic
We have reported the enantioselective Simons–Smith cyclo-
propanation catalyzed by chiral disulfonamides (1–3) derived from
L
-phenylalanine or L
-tyrosine as a primary amino acid.7 We
searched further application of disulfonamide (1–3) analogs to an
another reaction field. In this Letter, we describe a catalytic enan-
tioselective aldol reaction between ketones and aldehydes in brine
using novel sulfonamide 4 as an analog of disulfonamide (1–3).
The novel organocatalyst 4 was prepared as shown in Scheme 1.
The compound 5 as the intermediate for synthesis of chiral ligands
1 and 2 was easily prepared from phenylalaninol in four steps.8 The
reaction of 5 with trifluoromethanesulfonyl anhydride (Tf2O) in
dichloromethane afforded the compound 6 in 74% yield. The Boc
Ph
Ph
Tf2O, Et3N
BocHN
NHTf
BocHN
NH2
CH2Cl2, rt, 16h
74%
5
6
Ph
HCl
H2N
NHTf
AcOEt, rt, 4h
94%
4
* Corresponding authors. Tel.: +81 479 30 4612; fax: +81 479 30 4610 (T.M.);
tel./fax: +81 479 30 4610 (N.I.).
Scheme 1. Preparation of organocatalyst.
E-mail addresses: tmiura@cis.ac.jp (T. Miura), nimai@cis.ac.jp (N. Imai).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.053

T. Miura et al. / Tetrahedron Letters 50 (2009) 2632–2635
2633
Table 1
Optimization of reaction conditions
O
Ph
O
O
OH
H2N
NHTf
H
4
(0.1 equiv)
(10 equiv)
NO2
NO2
7a
8a
Entry
Solvent
Additive (equiv)
Temperature
Time (h)
Yield (%)a
anti: synb
% eec
1
2
3
4
5
6
7
8
9
10
11
12
13
14
MeOH
CH3CN
NMP
DMSO
1,4-Dioxane
Neatd
H2O
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)
CF3CO2H (0.05)
rt
rt
rt
rt
rt
rt
rt
rt
95
94
94
70
168
48
47
48
48
120
120
48
48
48
79
94
83
83
89
85
85
92
81
89
31
92
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
79:21
79:21
12
23
50
60
55
62
55
69
85
87
81
90
86
88
rt
0 °C
0 °C
0 °C
0 °C
0 °C
Brine
Brine
Sea water
Brinee
a
Isolated yield.
b
c
Determined by 1H NMR.
Determined by HPLC analysis using Chiralcel OD-H.
Solvent was not employed.
Brine prepared from sea water was used.
d
e
acid (TFA) was observed in the reaction with the 0.05 equiv at 0 °C
(entries 10–12). In addition, both the sea water taken directly from
the Pacific Ocean and the brine prepared by addition of sodium
chloride into the sea water were examined as a reaction solvent.
It was observed that the yield and the enantioselectivity of the al-
dol reaction in the brine prepared from the sea water were nearly
equal to those with the brine prepared from pure water (entries 13
and 14).
Table 2
Aldol condensation of various aldehyde in the presence of 4
Ph
H2N
O
O
OH
NHTf
Ketone
4
TFA
H
(0.1 equiv)
(10 equiv)
(0.05 equiv)
R
R
brine, 0 ºC
aldehyde 7
Next, the direct asymmetric aldol reactions of various aldehydes
(7b–l) in the presence of 4 (0.1 equiv) and TFA (0.05 equiv) were
examined as shown in Table 2.11 We selected methoxy substituent
as a representative electron-donating group (entries 4 and 8), nitro,
trifluoromethyl, cyano, and halogen substituents as an electron-
withdrawing group (entries 1–3 and 6–7) on the benzene ring.
The aldehydes substituted by electron-withdrawing groups at p-
position (7b–d) were converted to the corresponding anti-aldol
products in excellent yields with high enantioselectivities (88–
92% ee). Low chemical yields (12% and 23%) were obtained in the
reaction of p-anisaldehyde (7e) and benzaldehyde (7f), respec-
tively (entries 4 and 5). The aldehydes substituted by nitro group
at o- and m-position (7g and 7h) were converted to the corre-
sponding anti-aldol products (8g and 8h) in excellent yields with
91% ee, respectively (entries 6 and 7). The reaction of the com-
pound 7i substituted by methoxyl group at m-position afforded
the highest enantioselectivity (93% ee) than those of the other
aldehydes (entry 8). The highest diastereoselectivity (>99:1) was
observed in the reaction of 2,6-dichlorobenzaldehyde (7j) with
cyclohexanone (entry 9). The reactions of the penta-substituted
aldehyde 7k and the pyridine-ring containing aldehyde 7l were
also carried out to afford the corresponding anti-aldol products in
excellent yields with 85% and 87% ee, respectively (entries 10 and
11). We examined the reactions between various ketones and alde-
hydes. The aldol reaction of cyclopentanone with p-nitrobenzalde-
hyde gave the expected aldol product 8m in 71% yield with 88% ee
(entry 12). The reaction of acetone as a linear ketone with p-nitro-
Product 8
anti:synb
Entry
Product 8
Time (h)
Yielda (%)
% eec
91
O
OH
1
73
88
93
86:14
CF3
8b
O
O
O
OH
2
73
80:20
88
CN
Br
8c
OH
3d
120
119
87
12
81:19
87:13
92
92
8d
OH
4
OMe
8e
(continued on next page)

2634
T. Miura et al. / Tetrahedron Letters 50 (2009) 2632–2635
Table 2 (continued)
H
N
Entry
Product 8
Time (h)
118
Yielda (%)
anti:synb
% eec
89
R2
Ph
O
OH
O
Ar
H
5
23
84:16
R1
N
H
8f
Tf
O
O
OH NO2
Figure 1. Proposed transition state model of aldol reaction.
6
120
72
84
92
77
93
88
81
71
61
88:12
82:18
84:16
>99:1
93:7
91
91
93
86
85
87
88
29
8g
stereochemistry of the aldol products 8, we suppose that the sul-
fonamide 4-catalyzed direct aldol reactions between ketones and
aldehydes occurred via a transition state proposed by Córdova
et al. (Fig. 1).6c,12
In summary, the sulfonamide 4, which is readily prepared from
phenylalaninol, efficiently works as a catalyst in the direct asym-
metric aldol reactions of various aldehydes with ketones in brine
to give the corresponding anti-aldol products in moderate to excel-
lent yields with excellent enantioselectivities. Further application
to the synthesis of bioactive compounds and to novel reactions is
now in progress.
OH
NO2
7
8h
O
O
OH
OMe
8d
120
72
8i
Acknowledgments
OH Cl
This work was supported in part by Ajinomoto Award in Syn-
thetic Organic Chemistry, Japan and by Grants-in-Aid for Scientific
Research (C) (No. 18590014) from the Japan Society for the Promo-
tion of Science. This work was performed through the Scientific Re-
search Project by CIS (Chiba Institute of Science).
9
Cl
8j
O
OH
F
F
F
F
References and notes
10
11
12
72
F
8k
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O
O
O
OH
96
77:23
71:29
—
N
8l
OH
4. For review on stereoselective organocatalytic reaction in water, see:
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5. For examples of organocatalyzed aldol reactions in water using organocatalysts
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Commun. 2006, 2801; (b) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv. Synth. Catal.
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Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem. Commun. 2005, 3586; (b)
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4, 38; (d) Córdova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem.
72
NO2
8m
OH
13e
120
NO2
8n
a
Isolated yield.
Determined by 1H NMR.
Determined by HPLC analysis.
b
c
d
The reactions were carried out with 0.2 equiv of catalyst 4, 20 equiv of cyclo-
hexanone, and 0.1 equiv of TFA in brine.
e
The reaction was carried out with 30 equiv of acetone in brine.
benzaldehyde afforded a moderate yield and a low enantioselectiv-
ity (entry 13). Then, the reactions of phenylpropionaldehyde and
isobutyraldehyde as an aliphatic aldehyde with cyclohexanone
did not give the corresponding aldol products under the similar
reaction conditions.
The stereochemistry of the aldol products 8 was determined by
chiral-phase HPLC analysis and NMR spectroscopy.4 Based on the

T. Miura et al. / Tetrahedron Letters 50 (2009) 2632–2635
2635
Eur. J. 2006, 12, 5383; (e) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F.
J. Am. Chem. Soc. 2007, 129, 288; (f) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J.
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158.
9. Organocatalyst 4: Colorless powder; Mp = 164–166 °C; ½a D25
ꢀ
+10.7 (c 2.01 in
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 H, 1H), 3.23–3.35 (m, 2H), 7.24–7.35
(m, 5H); 13C NMR (100 MHz, CD3OD): d = 38.5, 48.7, 55.8, 123.0 (q, JC–F
= 326 Hz), 128.2, 129.9, 130.4, 137.9; HRMS (ESI-TOF): calcd for C10H14F3N2O2S
1
(M+H)+: 283.0723, found: 283.0691.
10. Mase, N.; Tanaka, F.; Barbas, C. F. Angew. Chem., Int. Ed. 2004, 43, 2420.
11. A typical procedure of the aldol condensation using 4 and 7a is as follows: To a
colorless suspension of 7a (90.7 mg, 0.600 mmol) and the catalyst 4 (16.9 mg,
0.060 mmol) in 1.2 mL of brine were added cyclohexanone (0.62 mL,
7. (a) Imai, N.; Sakamoto, K.; Maeda, M.; Kouge, K.; Yoshizane, K.; Nokami, J.
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Murakami, Y.; Imai, N. Tetrahedron: Asymmetry 2006, 17, 3067; (d) Miura, T.;
Itoh, K.; Yasaku, Y.; Koyata, N.; Murakami, Y.; Imai, N. Tetrahedron Lett. 2008,
49, 5813.
6.00 mmol) and trifluoroacetic acid (2.2 lL, 0.030 mmol) at 0 °C. The reaction
mixture was stirred at 0 °C for 48 h. The reaction mixture 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 8a (137 mg, 92%).
8. Imai, N.; Nokami, J.; Nomura, T.; Ninomiya, Y.; Shinobe, A.; Matsushiro, S. Bull.
Okayama Univ. Sci. 2002, 47.
12. Bassan, A.; Zou, W.; Reues, E.; Himo, F.; Córdova, A. Angew. Chem., Int. Ed. 2005,
44, 7028.