lective Michael addition reactions using 1,3-dioxo com-
pounds as donors.6b,7,8 Furthermore, in this preliminary study,
we have demonstrated that the Michael adducts can be
readily converted to synthetically and biologically useful
building blocks, R-substituted-â-amino acids.
Table 1. Results of Organocatalyst Screening for Asymmetric
Michael Addition Reactions of 2,4-Pentanedione (1a) and
trans-â-Nitrostyrene (2a)a
In the past few years, the utilization of chiral ureas/
thioureas has emerged as a viable strategy in the design of
efficient organocatalysts for asymmetric organic transfor-
mations.6,9-12 Notable examples include Jacobsen’s ureas/
thioureas for a variety of reactions10 and Takemoto’s amine
thioureas for Michael addition and aza-Henry reactions.6a,b,11
It is noted that both catalyst systems are built upon the trans-
cyclohexane diamine scaffold. More recently, cinchona
alkaloids-based thioureas have been employed for the
Michael addition reaction as well.12 However, thioureas
derived from another important “privileged” structure, bi-
naphthyl, have not been reported yet.13 We envisioned that
including a thiourea and an amine moiety on that scaffold
could lead to a new class of bifunctional organocatalysts,
which would provide high catalytic activity and high
enantioselectivity toward organic reactions. The results from
this investigation disclosed that the newly designed orga-
nocatalyst VI displayed remarkably catalytic activity (1 mol
% catalyst loading) in bond-forming processes while achiev-
ing excellent levels of enantioselectivities (up to 97% ee)
by its dual functional activations of substrates (Figure 1).
entry
catalyst
solvent
t (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
I
II
THF
THF
THF
THF
THF
THF
toluene
Et2O
Et2O
Et2O
DMSO
60
30
48
48
8
3.5
7
5
<10
<10
52 (90)g
47 (95)g
92
93
89
95
92
n.d.d
n.d.d
17
96
84
95
91
97
95
III
IV
V
VI
VI
VI
VI
VI
VI
9e
10f
11
15
28
2
95
96
95
5
a Unless otherwise specified, the reaction was carried out with 2 equiv
of 1a and 1 equiv of 2a in the presence of 10 mol % of catalyst at room
temperature on a scale of 0.17 mmol of 2a. b Isolated yields. c Enantiomeric
excess (ee) determined by chiral HPLC analysis (Chiralpak AS-H). d Not
determined. e 2 mol % of catalyst used. f 1 mol % of catalyst used. g Yields
based on recovered starting materials.
I-V, which have been used for catalyzing various reactions9-12
and the newly designed VI.14 A reaction between 2,4-
pentandione 1a and trans-â-nitrostyrene 2a in THF at room
temperature in the presence of one of the six catalysts (10
mol %) was used to evaluate their catalytic activities. The
results showed that catalysts I-III exhibited poor activities
(Table 1, entries 1-3). In contrast, thioureas IV-VI afforded
promising results (entries 4-6). Under the same reaction
conditions, catalyst IV gave the product 3a in high enan-
(7) For organocatalytic asymmetric Michael addition of ketoesters to
nitroolefins, see: Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.;
Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105.
(8) Catalyst V (10 mol %) also tested for the reaction in toluene, see ref
6b: 80% yield and 89% ee and cinchona alkaloids have been employed
for the process, but very low enantioselectivities (26-29% ee) were
obtained: Brunner, H.; Kimel, B. Monatsh. Chem. 1996, 127, 1063.
(9) For reviews related to ureas/thioureas catalysis, see: (a) Pihko, P.
M. Angew. Chem., Int. Ed. 2004, 43, 2062. (b) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719. (c) Schreiner, P. R. Chem. Soc. ReV. 2003,
32, 289.
(10) For Jacobsen’s urea and thiourea catalysis, see: (a) Sigman, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (b) Sigman, M. S.;
Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279. (c)
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. (d) Yoon,
T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 466. (e) Joly, G.
D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102. (f) Taylor, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.
(11) For Takemoto’s amine thioureas for catalysis, see: (a) Okino, T.;
Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625. (b)
Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44,
4032 and refs 6a and 6b. (c) Berkessel, A.; Cleemann, F.; Mukherjee, S.;
Mu¨ller, T. N.; Lex, J. Angew. Chem., Int. Ed. 2005, 44, 807. (d) Berkessel,
A.; Mukherjee, S.; Cleemann, F.; Mu¨ller, T. N.; Lex, J. Chem. Commun.
2005, 1898.
Figure 1. Screened organocatalysts.
In the initial study, six organocatalysts were screened for
the process (Figure 1 and Table 1). They include compounds
(6) For organocatalytic asymmetric Michael addition of malonates to
nitroolefins, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (c) Li, H.; Wang, Y.;
Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906.
(12) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7,
1967.
(13) For a review of “privileged” structures in catalysis, see: Yoon, T.
P.; Jacobsen, E. N. Science 2003, 299, 1691.
(14) For preparation of the catalyst, see the Supporting Information.
4714
Org. Lett., Vol. 7, No. 21, 2005