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
1. Modern Aldol Reactions; Mahrwald, R., Ed.2004; Wiley: Weinheim; Vols. 1 and
2.
2. For reviews on organocatalysts, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138; (b) Pellisier, H. Tetrahedron 2007, 63, 9267; (c) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (d) Dondoni,
A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
3. (a)For reviews on organic synthesis in water, see: Organic Synthesis in Water;
Grieco, P. A., Ed.; Blackie A&P: London, 1994; (b) Kobayashi, S.; Manabe, K. Acc.
Chem. Res. 2002, 35, 209; (c) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (d) Li,
C. J. Chem. Rev. 2005, 105, 3095.
O
O
O
OH
96
77:23
71:29
—
N
8l
OH
4. For review on stereoselective organocatalytic reaction in water, see:
Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33; For
examples of organocatalyzed aldol reactions in water without any organic
solvent using pyrrolidine derivatives, see: (a) Mase, N.; Nakai, Y.; Ohara, N.;
Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 734; (b)
Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 958; (c) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.;
Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527; (d) Font, D.; Jimeno,
C.; Pericàs, M. A. Org. Lett. 2006, 8, 4653; (e) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.;
Wang, S. Org. Lett. 2006, 8, 4417; (f) Font, D.; Jimeno, C.; Pericàs, M. A. Org. Lett.
2006, 8, 4653; (g) Huang, W.-P.; Chen, J.-R.; Li, X.-Y.; Cao, Y.-J.; Xiao, W.-J. Can. J.
Chem. 2007, 85, 208; (h) Giacalone, F.; Gruttadauria, M.; Marculescu, A. M.;
Noto, R. Tetrahedron Lett. 2007, 48, 255; (i) Aratake, S.; Itoh, T.; Okano, T.; Usui,
T.; Shoji, M.; Hayashi, Y. Chem. Commun. 2007, 2524; (j) Maya, V.; Raj, M.;
Singh, V. K. Org. Lett. 2007, 9, 2593; (k) Gruttadauria, M.; Giacalone, F.;
Marculescu, A. M.; Meo, P. L.; Riela, S.; Noto, R. Eur. J. Org. Chem. 2007, 4688; (l)
Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2008, 10,
337; (m) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Org. Lett. 2008, 10, 1211; (n)
Lombardo, M.; Pasi, F.; Easwar, S.; Trombini, C. Synlett 2008, 2471.
5. 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) Peng, F.-Z.; Shao, Z.-H.; Pu, X.-W.; Zhang, H.-B. Adv. Synth.
Catal. 2008, 350, 2199.
6. For examples of organocatalyzed aldol reactions in organic solvents using
organocatalysts with primary amine group, see: (a) Córdova, A.; Zou, W.;
Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem. Commun. 2005, 3586; (b)
Zou, W.; Ibrahem, I.; Dziedzic, P.; Sundén, H.; Córdova, A. Chem. Commun. 2005,
4946; (c) Dziedzic, P.; Zou, W.; Háfren, J.; Córdova, A. Org. Biomol. Chem. 2006,
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