LETTER
Novel 3,3′-Disubstituted 2,2′-Bipyridine-Based Chiral Ligands
1993
At the same time, a set of control reactions were carried chemistry of chiral ligand 1 with metals and carrying out
out under different reaction conditions as shown in Table a series of control reactions. The promising features with
4 for the further clarification of the bifunctional nature of these bifunctional catalysts lie in being easily prepared,
the examined catalysts. It should be pointed out that li- flexibility of metal acids, and tolerating to water and air.
gand 1 can serve as organocatalyst to catalyze the reac- The in-depth investigations of the bifunctional nature of
tion, thus producing the desired products in 76:24 dr these catalysts and the extension of the reaction scope
(anti/syn) and 59% ee (anti). However, the reaction pro- with these catalysts are currently in progress, and will be
ceeded slowly (Table 4, entry 1). With the use of water as reported in due course.
additives, chiral ligand 1 provided the desired product in
increased yield and selectivity (Table 4, entry 1 vs. 4).
Moreover, the sole use of Yb(OTf)3 can hardly catalyze
Acknowledgment
We thank Beijing Municipal Commission of Education (No.
JC015001200902), Beijing Municipal Natural Science Foundation
(No. 7102010), Funding Project for Academic Human Resources
Development in Institutions of Higher Learning Under the Jurisdic-
tion of Beijing Municipality (No. PHR201008025), Doctoral Scien-
tific Research Start-up Foundation of Beijing University of
Technology (No. 52015001200701) for financial support.
the reaction either in the presence or in the absence of wa-
ter (Table 4, entry 2). In the absence of water, chiral ligand
1 in complexation with Yb(OTf)3 delivered the desired
products in 5% yield with 58:42 dr (anti/syn) and 11% ee
(anti). To our delight, the Yb(OTf)3/H2O/ligand 1 cataly-
sis system exhibited the best reactivity and stereoselectiv-
ity, giving rise to the desired products in 80% yield and
95:5 dr (anti/syn) and 85% ee (anti; Table 4, entry 5).
Therefore, based on the above-mentioned experimental
data, we believed that the Yb(OTf)3/H2O/ligand 1 system
should behave as a bifunctional catalyst, and in the aldol
reactions the aldehydes were activated by the coordinated
metal ions, and ketones were activated by the free second-
ary amines.
Supporting Information for this article is available online at
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t
iornat
References and Notes
(1) For a selected review on direct catalytic asymmetric aldol
reaction, see: Trost, B. M.; Brindle, C. S. Chem. Soc. Rev.
2010, 39, 1600.
(2) For selected reviews on bifunctional catalysis, see:
(a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713. (b) Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009,
6145. (c) Ma, J.-A.; Cahard, D. Angew. Chem. Int. Ed. 2004,
43, 4566. (d) Shibasaki, M.; Kanai, M.; Matsunaga, S.;
Kumagai, N. Acc. Chem. Res. 2009, 42, 1117.
Table 4 Control Reactions for Clarification of the Bifunctional Na-
ture of the Examined Catalystsa
O
O
OH
ligand 1,
Yb(OTf)3,
H2O, 0 °C
O2N
+
CHO
NO2
(e) Yamamoto, H.; Futatsugi, K. Angew. Chem. Int. Ed.
2005, 44, 1924.
anti-product
(3) For a selected review on combination transition-metal
catalysis and organocatalysis, see: Zhong, C.; Shi, X. Eur. J.
Org. Chem. 2010, 2999.
Entry
L
Yb
(OTf)3
H2O
–
Yield
(%)b
dr
ee
(%, anti/syn) (%, anti)c
(4) For selected examples on Lewis acid–Lewis base catalysis,
see: (a) Arnold, K.; Batsanov, A. S.; Davies, B.; Grosjean,
C.; Schutz, T.; Whiting, A.; Zawatzky, K. Chem. Commun.
2008, 44, 3879. (b) Daka, P.; Xu, Z.; Alexa, A.; Wang, H.
Chem. Commun. 2011, 47, 224. (c) Paradowska, J.;
Pasternak, M.; Gut, B.; Gryzło, B.; Mlynarski, J. J. Org.
Chem. 2012, 77, 173. (d) Xu, Z.; Daka, P.; Budik, I.; Wang,
H.; Bai, F.-Q.; Zhang, H.-X. Eur. J. Org. Chem. 2009, 4581.
(e) Xu, Z.; Daka, P.; Wang, H. Chem. Commun. 2009, 45,
6825.
1
2
3
4
5
+
–
–
+
+
–
+
10
76:24
–
59
–
+ or – trace
+
+
+
–
+
+
5
40
80
58:42
74:26
95: 5
11
67
85
a Reaction was carried out at 0 °C for 72 h with 0.1 mmol of aldehydes
and 1.0 mL of cyclohexanone in the presence of 5.0 mol% ligand 1,
5.0 mol% Yb(OTf)3, and 25.0 μL of H2O if used.
b The combined yield of syn and anti products.
(5) For selected reviews, see: (a) Kwong, H.-L.; Yeung, H.-L.;
Yeung, C.-T.; Lee, W.-S.; Lee, C.-S.; Wong, W.-L. Coord.
Chem. Rev. 2007, 251, 2188. (b) Malkov, A. V.; Kocovsky,
P. Curr. Org. Chem. 2003, 7, 1737.
c With (2S,1′R) configuration.
(6) For selected examples, see: (a) Assalit, A.; Billard, T.;
Chambert, S.; Langlois, B. R.; Queneau, Y.; Coe, D.
Tetrahedron: Asymmetry 2009, 20, 593. (b) Boyd, D. R.;
Sharma, N. D.; Sbircea, L.; Murphy, D.; Belhocine, T.;
Malone, J. F.; James, S. L.; Allen, C. C. R.; Hamilton, J. T.
G. Chem. Commun. 2008, 44, 5535. (c) Denmark, S. E.; Fan,
Y.; Eastgate, M. D. J. Org. Chem. 2005, 70, 5235.
(d) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S.
J. Am. Chem. Soc. 2004, 126, 12236. (e) Kadlčíková, A.;
Hrdina, R.; Valterová, I.; Kotora, M. Adv. Synth. Catal.
2009, 351, 1279. (f) Kobayashi, S.; Ogino, T.; Shimizu, H.;
Ishikawa, S.; Hamada, T.; Manabe, K. Org. Lett. 2005, 7,
4729. (g) Kokubo, M.; Naito, T.; Kobayashi, S. Chem. Lett.
In conclusion, we have developed a class of novel chiral
ligands based on 2′2-bipyridine skeleton using enantio-
pure α-amino acids as chiral sources. In complexation
with metal Lewis acids, the prepared chiral ligands have
shown moderate to high diastereoselectivities and enanti-
oselectivities in the direct asymmetric aldol reactions of
cyclic or acyclic ketones with a variety of aromatic alde-
hydes. The bifunctional nature of the examined catalysts
was investigated in details by examining coordination
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Synlett 2012, 23, 1990–1994