Table 3 The aldol reaction of different ketone donorsa
Entry
R1
R2, R3
Product
Yield (%)c
Anti/synb
ee (%)d
1e
2
3
4
5
6
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
4-CNC6H4
2-Naphthyl
C6H5
–CH2CH2–
–CH2OCH2–
–CH2SCH2–
–CH2SCH2–
–CH2SCH2–
–CH2SCH2–
–CH2SCH2–
H, H
6a
6b
6c
6d
6e
6f
66
97
82
76
86
57
68
84
3/1
86
87
94
94
91
87
94
72
10/1
22/1
25/1
46/1
34/1
25/1
—
7
6g
6h
8e
4-NO2C6H4
a
b
The reactions were performed with 0.2 mmol of aldehyde and 0.5 mmol of ketone at room temperature in 1 mL of THF for 12–48 h. Determined
by 1H NMR. Combined yield. Determined by chiral HPLC. The reaction was performed with 0.2 mmol of aldehyde with 1 mL of ketone (neat).
c
d
e
Notes and references
1 (a) Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming
and C.-H. Heathcock, Pergamon, Oxford, 1991, vol. 2;
(b) T. Mukaiyama, Angew. Chem., Int. Ed., 2004, 43, 5590;
(c) K. C. Nicolaou, D. Vourloumis, N. Winssinger and
P. S. Baran, Angew. Chem., Int. Ed., 2000, 39, 44.
2 (a) T. D. Machajewski and C.-H. Wang, Angew. Chem., Int. Ed.,
2000, 39, 1352; (b) H. J. M. Gijsen, L. Qiao, W. Fitz and
C.-H. Wang, Chem. Rev., 1996, 96, 443.
3 (a) B. List, R. A. Lerner and C. F. Barbas, III, J. Am. Chem. Soc.,
2000, 122, 2395; (b) W. Notz and B. List, J. Am. Chem. Soc., 2000, 122,
7386; (c) K. S. Sakthivel, W. Notz, T. Bui and C. F. Barbas, III, J. Am.
Chem. Soc., 2001, 123, 5260; For reviews, see: (d) P. Melchiorre,
M. Marigo, A. Carlone and G. Bartoli, Angew. Chem., Int. Ed.,
2008, 47, 6138; (e) S. Mukherjee, J. W. Yang, S. Hoffmann and
B. List, Chem. Rev., 2007, 107, 5471; (f) A. Erkkila, I. Majander and
P. M. Pihko, Chem. Rev., 2007, 107, 5416.
Scheme 1 Cooperative nature of the bifunctional enamine-metal
Lewis acid catalyst.
4 (a) Y. M. A. Yamada, N. Yoshikawa, H. Sasai and M. Shibasaki,
Angew. Chem., Int. Ed. Engl., 1997, 36, 1871; (b) N. Yoshikawa, Y.
M. A. Yamada, J. Das, H. Sasai and M. Shibasaki, J. Am. Chem.
Soc., 1999, 121, 4168; (c) B. M. Trost and H. Ito, J. Am. Chem. Soc.,
2000, 122, 12003; (d) B. M. Trost, H. Ito and E. R. Silcoff, J. Am.
Chem. Soc., 2001, 123, 3367; (e) J. Paradowska, M. Stodulski and
J. Mlynarski, Adv. Synth. Catal., 2007, 349, 1041.
Fig. 2 Proposed transition state.
5 For reviews on primary amine catalysis, see: (a) L.-W. Xu and
Y. Lu, Org. Biomol. Chem., 2008, 6, 2047; (b) L.-W. Xu, J. Luo and
Y. Lu, Chem. Commun., 2009, 1807.
In summary, we have developed a novel class of primary
amine-based enamine-metal Lewis acid cooperative bifunc-
tional catalysts, and successfully applied them to asymmetric
direct aldol reactions. These catalysts are highly efficient in
catalyzing the aldol reaction of cyclic ketones with both
electron-rich and electron-poor aldehydes in very good to
excellent stereoselectivity. It is found that the coexistence of
the primary amine and metal Lewis acid is critical for the
reaction to occur. This catalytic system has the following
features: (1) it is the first example of bifunctional catalyst
combining metal Lewis-acid catalysis and primary amine
catalysis; (2) the catalysts’ structure can be easily tuned by
introducing different metals and/or different acyclic amino
acids; (3) the ligands are very simple and can be readily
prepared in large scales; (4) the reaction does not need an
inert atmosphere as required by most metal catalysis. Applica-
tion of these catalysts to Mannich reactions and Michael
reactions is underway.
6 (a) M. Amedjkouh, Tetrahedron: Asymmetry, 2005, 16, 1411;
(b) A. Cordova, W.-B. Zou, I. Ibrahem, E. Reyes, M. Engqvist and
W.-W. Liao, Chem. Commun., 2005, 3586; (c) Z. Jiang, Z. Liang,
X. Xu and Y. Lu, Chem. Commun., 2006, 2801; (d) X. Wu, Z. Jiang,
H.-M. Shen and Y. Lu, Adv. Synth. Catal., 2007, 349, 812; (e) S. Luo,
H. Xu, J. Li, L. Zhang and J.-P. Cheng, J. Am. Chem. Soc., 2007, 129,
3074; (f) X.-Y. Xu, Y.-Z. Wang and L.-Z. Gong, Org. Lett., 2007, 9,
4247; (g) K. Nakayama and K. Maruoka, J. Am. Chem. Soc., 2008,
130, 17666; (h) I. Ibrahem, W. Zou, M. Engqvist, Y. Xu and
A. Cordova, Chem.–Eur. J., 2005, 11, 7024; (i) S. S.
V. Ramasastry, H. L. Zhang, F. Tanaka and C. F. Barbas III,
J. Am. Chem. Soc., 2007, 129, 288; (j) L. Cheng, X. Han, H. Huang,
M. W. Wong and Y. Lu, Chem. Commun., 2007, 4143.
7 (a) D. H. Paull, C. J. Abraham, M. T. Scerba, E. Alden-Danforth
and T. Lectka, Acc. Chem. Res., 2008, 41, 655–663; (b) J.-A. Ma and
D. Cahard, Angew. Chem., Int. Ed., 2004, 43, 4566–4583;
(c) M. Kanai, N. Kato, E. Ichikawa and M. Shibasaki, Synlett,
2005, 1491–1508.
8 Z. Xu, P. Daka, I. Budik, H. Wang, F. Bai and H. Zhang, Eur. J.
Org. Chem., 2009, 4581.
9 (a) A. Heine, G. DeSantis, J. G. Luz, M. Mitchell, C.-H. Wong and
I. A. Wilson, Science, 2001, 294, 369; (b) F. Tanaka,
R. Thayumanavan, N. Mase and C. F. Barbas, III, Tetrahedron
Lett., 2004, 45, 325.
We thank Professor Mike Novak for useful discussions.
Financial support was provided by Miami University.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6825–6827 | 6827