K. Takasu et al. / Tetrahedron Letters 51 (2010) 2737–2740
2739
Table 1
Ar
N
Enantioselective addition of cyclohexanone to trans-b-nitrostyrene catalyzed by
S
trifunctional thioureaa
H
O
N
N
Ph
catalyst (10 mol%)
AcOH-H2O
O
Ph
H
O
H
N
N
O
NO2
Me
NO2
+
Ph
AcO
N
toluene, rt, 5 h
N
N
16
Entry
Catalyst
% Yield of 16b
dr (syn/anti)c
% ee of syn-16d
Figure 2. Proposed transition state for asymmetric Michael addition by trifunc-
tional thiourea 13d.
1
2
13d
13e
15d
17
91
93
32
10f
91: 9
91: 9
93: 7
91: 9
92
82 (ent)
87
3
4e
93 (ent)
of HPLC data with the reported ones. The configuration is consis-
tent with a synclinal transition state for pyrrolidine-based chiral
organocatalysis. A suggested transition state model is shown in
Figure 2. Hydrogen bond network among the thiourea moiety, ter-
tiary ammonium, and nitro group would direct the nitrostyrene to
attack the si-face of the enamine.
a
The reaction was conducted with nitrostyrene (0.34 mmol) and cyclohexanone
(3.4 mmol, 10 equiv) in the presence of catalyst (10 mol %), AcOH (15 mol %), and
H2O (1.0 equiv) in toluene (0.5 mL) at ambient temperature.
b
Isolated yield as a mixture of syn/anti isomers.
Determined by HPLC analysis and 1H NMR.
c
Determined by HPLC analysis (Daicel Chiralpak AS-H, hexane–iPrOH = 90:10).
d
In conclusion, we have described the synthesis of several tri-
functional thiourea catalysts bearing a 1,2,3-triazole tether in
which one of the functional group is placed at a considerable dis-
tant position from the thiourea moiety. Regioisomeric catalysts
having 1,5- and 1,4-disubstituted triazole were readily prepared
by using ruthenium- and copper-catalyzed Huisgen cycloaddition,
respectively. To the best of our knowledge, it is the first case for the
preparation of asymmetric catalysts by Ru-catalyzed azide–alkyne
click chemistry.13 Moreover, we demonstrated the catalytic activ-
ity of synthesized thiourea-pyrrolidine-based catalysts in the
enantioselective Michael addition. It was found that thiourea and
pyrrolidine functions would synergistically activate substrates
although they are placed at a sequentially remote position (7
atoms’ tether length) to achieve acceleration of the reaction rate.
Further application of synthetic catalysts and synthesis of a new
class of trifunctional thioureas are currently under investigation
and will be reported in due course.
e
The reaction result was cited from Kilburn’s study (Ref. 4d).
Conversion yield after the reaction was carried out for 720 h.
f
H
N
O
Ph
17
the producible nitroalkanes bearing contiguous stereogenic centers
would be versatile synthetic intermediates. Several pyrrolidine-
based derivatives have been reported to catalyze the reaction with
good to high diastereo- and enantioselectivities. Chiral thiourea-
pyrrolidine-based bifunctional catalysts have also been found to
give excellent enantioselectivities.4 However, some problems such
as the slow reaction rate still remain in most of the pyrrolidine-
based organocatalysts. During the course of our study, Kilburn
et al reported thiourea-pyrrolidine-based bifunctional catalysts,4d
in which both functions are placed at considerably distant posi-
tions tethering with simple alkyl chain. Some of the bifunctional
catalysts demonstrated excellent rate acceleration with good stere-
oselectivity in the reaction of cyclohexanone with trans-b-nitrosty-
rene. They made clear that the tether length between thiourea and
pyrrolidine of the optimized catalyst is 5 atoms.
Acknowledgments
The work was supported by a Grant-in-Aid for Scientific Re-
search and Targeted Proteins Research Program from Ministry of
Education, Culture, Sports, Science, and Technology, Japan and Tak-
eda Science Foundation.
Under the same conditions as Kilburn’s study, catalytic activity
of thiourea-pyrrolidine catalyst 13d, 13e, and 15d was evaluated
(Table 1). The tether lengths between thiourea and pyrrolidine of
13 and 15 are 7 and 8 atoms, respectively. Catalysts 13d and 13e
having 1,5-disubstituted triazole tether gave nitroalkane 16 in high
chemical yield with good diastereo- and enantioselectivities. The
stereochemistry of the major isomer 16 was determined as syn iso-
mer by comparison with reported ones. Chirality of 16 from 13d
was opposite to one from 13e. Thus, the enantioselection in the
reaction would be mainly dominated by the chirality of pyrrolidi-
nyl moiety. Although the difference of a value of enantiomeric ex-
cess is not so significant, it was observed that the chirality of 1,2-
diaminocyclohexyl moiety somewhat effects on the selectivity (en-
tries 1 and 2). In contrast, the rate of reaction with 15d having 1,4-
disubstituted triazole tether was much slower than that with 13d,
e although the enantioselectivity was comparable (entry 3). The re-
sults clearly indicated that relative position of the thiourea and
pyrrolidine moieties would be a critical factor for the rate acceler-
ation in the reaction of the Michael addition. As Kilburn reported
that the reaction rate drastically decreased in the reaction with
monofunctional pyrrolidine catalyst 17 (entry 4), it made clear that
the thiourea function of the catalyst system would positively par-
ticipate in the activation of the substrate.
References and notes
1. Berkessel, A.; Gröger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
2005.
2. For recent reviews, see: (a) Bhadury, P. S.; Song, B.-A.; Yang, S.; Hu, D.-Y.; Xue,
W. Curr. Org. Synth. 2009, 6, 380–399; (b) Shibasaki, M.; Kanai, M.; Matsunaga,
S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117–1127; (c) Kano, T.; Maruoka, K.
Chem. Commun. 2008, 5465–5473; (d) Miyabe, H.; Takenomo, Y. Bull. Chem. Soc.
Jpn. 2008, 81, 785–795; (e) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem.
2006, 4, 393–406.
3. For representative examples of thiourea-based organocatalysis, see: (a) Okino,
T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672–12673; (b)
Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Adv. Synth. Catal. 2005, 347, 1643–
1648; (c) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012–10014;
(d) Inokuma, T.; Takasu, K.; Sakaeda, T.; Takemoto, Y. Org. Lett. 2009, 11, 2425–
2428.
4. Thiourea-pyrrolidine based organocatalysis: (a) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.;
Tang, Y. Org. Lett. 2006, 8, 2901–2904; (b) Cao, Y.-J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.;
Xiao, W.-J. Tetrahedron Lett. 2006, 48, 21–24; (c) Shen, Z.; Zhang, Y.; Jiao, C.; Li,
B.; Ding, J.; Zhang, Y. Chirality 2007, 19, 307–312; (d) Carley, A. P.; Dixon, S.;
Kilburn, J. D. Synthesis 2009, 2509–2516.
5. Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686–6687.
6. Huisgen, R. Pure Appl. Chem. 1989, 61, 613–628.
7. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
2021.
8. (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H.; Williams, I. D.; Sharpless, K. B.; Fokin,
V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998–15999; (b) Rasmussen, L. K.;
Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337–5339; (c) Boren, B. C.; Narayan,
S.; Rasmussen, L. K.; Zhang, L.; Xhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem.
Soc. 2008, 130, 8923–8930.
The absolute configuration of the major enantiomer syn-16 in
the reaction with 13d was determined to be (2R,10S) by comparison