Enantioselective epoxidation of α,β-enones promoted by (1R,3S,4S)-2-azanorbornyl-3-methanol as an organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2008.07.175

(1R,3S,4S)-2-Azanorbornyl-3-methanol was synthesized form (R)-1-phenylethylamine and used as a catalyst for the enantioselective epoxidation of α,β-enones to afford the corresponding epoxides in good yields and high enantioselectivities at room temperature.

Full text of DOI:10.1016/j.tetlet.2008.07.175

Tetrahedron Letters 49 (2008) 6007–6008
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Tetrahedron Letters
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Enantioselective epoxidation of a,b-enones promoted by
(1R,3S,4S)-2-azanorbornyl-3-methanol as an organocatalyst
*
Jun Lu, Yun-He Xu, Feng Liu, Teck-Peng Loh
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
(1R,3S,4S)-2-Azanorbornyl-3-methanol was synthesized form (R)-1-phenylethylamine and used as a
Received 6 June 2008
Revised 19 July 2008
Accepted 31 July 2008
Available online 6 August 2008
catalyst for the enantioselective epoxidation of
yields and high enantioselectivities at room temperature.
a,b-enones to afford the corresponding epoxides in good
Ó 2008 Published by Elsevier Ltd.
Chiral epoxides are very important building blocks for the syn-
thesis of enantiomerically pure complex molecules, in particular, of
biologically active compounds.1 The asymmetric epoxidation of
functionalized and unfunctionalized olefins has emerged as a very
versatile and important synthetic tool in organic synthesis,2 and
many asymmetric synthetic methods have been developed to meet
this purpose.3 Asymmetric catalysis by small organic molecules is a
rapidly growing area, which has led to the development of efficient
metal-free methodologies for many asymmetric organic synthe-
Cl
N
N
Ph
AlCl3 / Et3N
+
N
H
Cl
N
Ph
Scheme 1.
ses.4 Among the most studied organocatalysts,
L-proline and its
derivatives have shown wide applicability and generally good to
presence of 20 mol % of chiral ligand 1, the best result was obtained
when the epoxidation was carried out in hexane (Table 1, entries 1
and 6). The use of toluene and dichloromethane resulted in lower
enantioselectivities and yields (Table 1, entries 4 and 5). When
the reaction was carried out in THF or MeOH, or using hydrogen
peroxide as the oxidant, the reaction failed to afford the corre-
sponding product (Table 1, entries 7–9). Thus, hexane is the solvent
of choice. Performing the epoxidation at 4 °C had no effect on the
level of selectivity (Table 1, entry 3). Higher catalytic loading of 1
(30 mol %) afforded comparable results in terms of conversion
(Table 1, entry 2).
Through this screening process, it was established that the
epoxidation reaction could be carried out smoothly in the presence
of catalyst 1 (20 mol %) in hexane at room temperature, using TBHP
as oxidant. To study the scope and potential of this epoxidation
method, we extended the catalytic asymmetric epoxidation to a
high control of asymmetric induction.5,6
Recently, we have developed methods for the synthesis of aza-
bicyclo[2.2.1]heptene derivatives as analogues of epibatidine
(Scheme 1).7 In connection with our interest in modifying these
analogues as organocatalysts for asymmetric epoxidations, a series
of chiral azabicyclo[2.2.1] heptane derivatives were prepared and
applied in asymmetric reactions.
Herein, we describe a procedure for the synthesis of chiral epox-
ides by the reaction of a,b-enones with tert-butyl hydrogen perox-
ide (TBHP) catalyzed by chiral 2-azabicyclo[2.2.1]heptane-3-exo-
bis(phenyl)methanol 1, which was synthesized with 21% overall
yield from (R)-1-phenylethylamine (Eq. 1).8
O
O
O
Hexane, rt, TBHP
R1
R2
R1
R2
Ph
Ph
ð1Þ
2
3
wide variety of
shown in Table 2.
Under the optimal reaction conditions, various
a,b-unsaturated ketones. The results obtained are
Cat.:
OH
1
N
H
a,b-unsaturated
ketones in the presence of 1 furnished diastereoisomerically pure
trans-(2R,3S)-epoxides in good yields (Table 2, entries 1–12), which
indicates that the reaction is a very efficient enantioselective meth-
od for epoxidation. Even the more hindered 2-naphthyl derivative
could be converted to the corresponding epoxide in moderate yield
and comparable ee (Table 2, entry 8). However, when the methyl-
substitued enone 2 m was used as the substrate, the epoxide was
Our initial studies began with the asymmetric organocatalytic
epoxidation of trans-chalcone with TBHP in different solvents at
room temperature. The results are summarized in Table 1. In the
* Corresponding author. Fax: +65 6791 1961.
E-mail address: teckpeng@ntu.edu.sg (T.-P. Loh).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.07.175

6008
J. Lu et al. / Tetrahedron Letters 49 (2008) 6007–6008
Table 1
In summary, we have disclosed a new catalyst for the asymmet-
ric epoxidation of ,b-enones. The reaction is operationally simple,
Optimization of the reaction conditions for the asymmetric epoxidation of trans-
chalcone 2a
a
and could afford the corresponding epoxides in good yields and
high enantioselectivities. Although the asymmetric epoxidation
catalyzed by this azabicyclo catalyst afforded the products in lower
or comparable enantioselectivities as compared to proline deriva-
tives, it opens up a novel avenue for the design of chiral azabi-
cyclo[2.2.1]heptane analogues as organocatalysts. Further work is
focused on modifying the chiral 2-azanorbornyl-3-methanol for
the epoxidation as well as for other organic transformations.
Ph
Ph
OH
N
H
O
O
O
Ph
Ph
Ph
Ph
3a
Yielda
2a
Entry
Cat.
Solvent
Oxidant
T (°C)
Time
(h)
eeb (%)
(mol %)
(%)
1
2
3
4
5
6
7
8
9
20
30
20
20
20
20
20
20
20
Hexane
Hexane
Hexane
Toluene
DCM
Hexane
THF
MeOH
Hexane
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
rt
rt
4
rt
rt
rt
rt
rt
rt
60
48
82
70
62
65
81
Trace
Trace
Trace
88 (2R,3S)
88 (2R,3S)
87 (2R,3S)
80 (2R,3S)
64 (2R,3S)
88 (2R,3S)
nd
Acknowledgement
144
144
144
144
144
144
144
144
*
We gratefully acknowledge A STAR (Grant No. 072101 0024)
for funding of this research
Supplementary data
nd
nd
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.175.
The reaction was carried out with a,b-enone (1 equiv) and TBHP (1.3 equiv) in the
presence of 20 mol %of catalyst 1 at rt.
a
Yield of isolated product.
Enantiomeric excess was determined by HPLC analysis using a chiral column.
b
References and notes
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Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem. Soc.
1996, 118, 11311–11312.
Table 2
Enantioselective epoxidation of
a
,b-unsaturated ketones catalyzed by chiral ligand 1
3. (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1997, 119, 2329–2330; (b) Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang,
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(d) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001,
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Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544–14545; (f)
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Ph
Ph
OH
N
H
O
O
O
(20 mol%)
R1
R2
R1
R2
Hexane, rt, TBHP
6 d
2a-n
R1
3a-n
Yielda (%)
Entry
Enone
R2
Product
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
81
84
84
80
78
81
76
62
88
76
80
88
25
0
88 (2R,3S)
82 (2R,3S)
80 (2R,3S)
86 (2R,3S)
82 (2R,3S)
87 (2R,3S)
80 (2R,3S)
86 (2R,3S)
87 (2R,3S)
84 (2R,3S)
83 (2R,3S)
84 (2R,3S)
69 (3R,4S)
—
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-O2NC6H,
C6H5
2-Naphthyl
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
Me
C6H5
C6H5
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2000, 122, 9336–9337; (e) Gu, L. Q.; Zhao, G. Adv. Synth. Catal. 2007, 349, 1629–
1632; (f) Gu, L. Q.; Yu, M. L.; Wu, X. Y.; Zhang, Y. Z.; Zhao, G. Adv. Synth. Catal.
2006, 348, 2223–2228; (g) Liu, D.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 8160–8161; (h) List, B. Chem. Commun. 2006, 819–824.
4-ClC6H4
C6H5
C6H5
C6H5
t-Bu
The reaction was carried out with a,b-enone (1 equiv) and TBHP (1.3 equiv) in the
6. (a) Lattanzi, A. Org. Lett. 2005, 7, 2579–2582; (b) Lattanzi, A. Adv. Synth. Catal.
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12269; (e) Liu, X. Y.; Li, Y. W.; Wang, G. Y.; Chai, Z.; Wu, Y. Y.; Zhao, G.
Tetrahedron: Asymmetry 2006, 17, 750–755; (f) Zhao, G. L.; Ibrahem, I.; Sunden,
H.; Cordova, A. Adv. Synth. Catal. 2007, 349, 1210–1224; (g) Marigo, M.; Franzen,
J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964–
6965.
presence of 20 mol % of catalyst 1 at rt in hexane.
a
Yield of isolated product.
Enantiomeric excess was determined by HPLC analysis using a chiral column,
b
the absolute configuration was determined by comparison of the HPLC retention
times or optical rotation with those in the literature.
7. Loh, T. P.; Koh, K. S. V.; Sim, K. Y.; Leong, W. K. Tetrahedron Lett. 1999, 40, 8447–
8451.
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obtained in poor yield with moderate enantioselectivity (Table 2,
entry 13). The reaction failed when the t-butyl derivative 2n was
tested.