Synthesis of chiral dihydrofuran compounds by thiourea derivatives-catalyzed "interrupted" Feist-Bénary reaction

Article abstract of DOI:10.1016/j.cclet.2009.10.012

In this study, six thiourea derivatives of cinchona alkaloids with 9-nat or 9-epi-configuration were synthesized. After characterized the structures, we adopted them to the asymmetric "interrupted" Feist-Bénary (IFB) reaction of α-haloketones with β-dicar

Full text of DOI:10.1016/j.cclet.2009.10.012

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Chinese Chemical Letters 21 (2010) 167–170
www.elsevier.com/locate/cclet
Synthesis of chiral dihydrofuran compounds by thiourea
´
derivatives-catalyzed ‘‘interrupted’’ Feist-Benary reaction
Hui Chen a, Ru Jiang a, Qiao Feng Wang a, Xiao Li Sun a,
Jing Luo b, Sheng Yong Zhang a,
*
a Department of Chemistry, Fourth Military Medical University, Xi’an 710032, China
b Department of Shannxi Institute for Food and Drug Control, Xi’an 710061, China
Received 25 June 2009
Abstract
In this study, six thiourea derivatives of cinchona alkaloids with 9-nat or 9-epi-configuration were synthesized. After
´
characterized the structures, we adopted them to the asymmetric ‘‘interrupted’’ Feist-Benary (IFB) reaction of a-haloketones
with b-dicarbonyl compounds, to give optically active dihydrofurans. Various thiourea derivatives as organocatalysts were
examined. The corresponding chiral hydroxyl dihydrofurans have been obtained in excellent yields and moderate ees. To the acyclic
substrate, we obtained exciting and promising result.
# 2009 Sheng Yong Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
´
Keywords: ‘‘Interrupted’’ Feist-Benary (IFB) reaction; Chiral; Thiourea; Dihydrofuran
The preparation of 2,3-dihydrofuran-containing molecules has been promising in organic synthesis as a result of
´
their broad application to organic and medicinal chemistry [1]. The ‘‘interrupted’’ Feist-Benary (IFB) reaction of a-
haloketones with b-dicarbonyl compounds serves as a powerful synthetic method in this area of dihydrofuran
chemistry [2,3]. To date reports of this reaction are sparse [4], while an asymmetric version of this reaction would
furnish enantiomerically enriched adducts. A great deal of effort has been directed toward the research of this reaction
(Scheme 1).
Recently, we have disclosed an organo-catalytic enantioselective approach for the IFB reaction in high yields (91–
98%) with up to 96% ee [5–7]. The ester derivatives of cinchona alkaloids were found to present good asymmetrically
catalytic activities. However, they had poor chiral induce to acyclic substrates (2–21% ee). Enantiomerically products
from acyclic b-dicarbonyl compounds are more valuable chemicals in their own right. They serve as starting materials
in the preparation of a wealth of enantiomerically pure pharmaceuticals, and many other types of chiral compounds
[2,3].
In our continuing effort, we wish to describe our investigation which has led to the development of an efficient
method for carrying out enantioselective IFB reactions by using cinchona alkaloid thiourea derivatives. In addition, a
family of chiral thiourea catalysts had been previously identified to catalyze enantioselective reactions [8,9]. Intrigued
* Corresponding author.
E-mail address: syzhang@fmmu.edu.cn (S.Y. Zhang).
1001-8417/$ – see front matter # 2009 Sheng Yong Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.10.012

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H. Chen et al. / Chinese Chemical Letters 21 (2010) 167–170
Scheme 1. IFB reaction.
Fig. 1. Structures of T1–T6.
by the possibility that these compounds might constitute an emerging class of privileged enantioselective catalysts, we
investigated their activity in the asymmetric IFB reaction. The structures of the organocatalysts are listed below
(Fig. 1).
1. Results and discussion
To test their catalytic ability to promote asymmetric IFB reaction, a reaction between ethyl bromopyruvate
1(R = H) and 1,3-cyclohexadione 2 in the presence of 10 mol% catalyst in THF at ꢀ78 8C was carried out. The results
reveal that the organocatalyzed processes proceeded smoothly (10 min) in high yields (>90%). Among the
organocatalysts probed, natural configuration derivatives of T5–T6 displayed lower enantioselectivity than that of epi-
configuration T1–T4 (Table 1, entries 5, 6 vs. entries 1–4). The change of 9-configuration did not enhance the
asymmetric induce, but decreased it (Scheme 2).
The catalytic activities of the b-substituted substrates were tested. Two stereogenic centers formed in these
reactions, leading to two pairs of enantiomers. With b-phenyl ethyl bromopyruvate (R = Ph) as the substrate, the two
pairs of enantiomers (R,S)ꢀ/(S,R)ꢀ and (R,R)ꢀ/(S,S)ꢀ were obtained, and the (R,S)ꢀ/(S,R)ꢀconfiguration was the
main product (Table 1, entries 7–12). In case of natural configuration derivatives T5–T6, a drop in the ee was noticed
(entries 11, 12), which is similar to the previous IFB reaction result in entries 1–6 (R = H).
Table 1
IFB reaction results of 1 and 2 using different catalystsa.
Entry
Cat*
R
syn:antib
Yield (%)c
%ee (syn)c
Entry
Cat*
R
syn:antib
Yield (%)c
%ee (syn)c
1
2
3
4
5
6
7
8
9
T1
T2
T3
T4
T5
T6
T1
T2
T3
H
–
91
92
94
94
92
94
89
92
93
58 (S)
65 (S)
55 (S)
45 (R)
36 (S)
7 (S)
56
10
11
12
13
14
15
16
17
18
T4
T5
T6
T1
T2
T3
T4
T5
T6
Ph
Ph
Ph
Pr
Pr
Pr
Pr
Pr
Pr
64:36
84:16
78:22
93:7
96:4
94:6
95:5
95:5
97:3
93
89
90
92
92
91
90
91
90
55
5
H
–
–
H
26
48
53
47
70
10
4
H
–
H
–
H
–
Ph
Ph
Ph
81:19
79:21
85:15
59
55
Cat*: thiourea catalyst.
a
The reactions were carried out using 10 mol% catalysts at ꢀ78 8C in THF.
Isolated yield.
b
c
Determined by HPLC analysis.

H. Chen et al. / Chinese Chemical Letters 21 (2010) 167–170
169
Scheme 2. IFB reaction of 1 with 2.
Table 2
Yields and enantioselectivities of compound 5 and 6 using different catalystsa.
Entry
Starting material
Cat*
Yieldb (%)
%ee (5)c
Entry
Starting material
Cat*
Yieldb (%)
5:6c
%ee (5)c
1
2
3
4
5
6
4a
4a
4a
4a
4a
4a
T1
T2
T3
T4
T5
T6
87
85
87
92
83
87
64
54
57
47
36
51
5
8
4b
4b
4b
4b
4b
4b
T1
T2
T3
T4
T5
T6
90
89
78
84
82
91
87:13
89:11
94:6
61
70
54
19
38
41
9
10
11
12
90:10
87:13
93:7
Cat*: thiourea catalyst.
a
The reactions were carried out using 10 mol% catalysts at ꢀ78 8C in THF.
Isolated yield.
b
c
Determined by HPLC analysis.
Scheme 3. IFB reaction of ethyl bromopyruvate with 4.
Not bearing any oxygen-based substituent at position 60 in the quinoline ring, cinchona alkaloids CND thiourea T3
(Table 1, entry 9) was not found to afford the desired adduct with lower enantioselectivities than those bearing a 60-
methoxyquinoline moiety, which showed the 60-substitution is not important to the asymmetric induction.
Encouraged by the results, we next investigated b-propyl ethyl bromopyruvate (R = Pr). In this case, the IFB
reaction gave good yields; however, the obtained ees were moderate. Especially, 9-(R)-DHQ thiourea derivative T6
obtained almost racemic product, the ee value was only 4% (entry 18); and the results are summarized in entries 13–18.
Compared with the results in Table 1, entries 7–12, a significant enhancement in diastereoselectivity (more than 93:7)
was observed. 9-Natural configuration derivatives of T1–T4 obtained similar enantioselectivities, which demonstrated
the vinyl or ethyl substitution had no influence on the asymmetric induce.
As a whole, the asymmetric induction of the b-substituted substrate was no better than that of the unsubstituted
substrate.
To establish the generality of this reaction in substrate scope, we finally examined the IFB reaction with alicyclic b-
dicarbonyl compounds 4 under catalysis by T1–T6. The results are shown in Table 2. The desired adduct was isolated
in satisfactory to good yield. Surprisingly, an enhancement in the ee was obtained (Scheme 3).
In summary, we have performed the catalytic asymmetric IFB reaction by a series of easily available cinchona
alkaloid thiourea derivatives. The reaction gave good results for several substrates furnishing the chiral dihydrofuran
products in good yield with satisfying enantioselectivities. The influence of different cinchona alkaloids, 9-
configuration and substrates were investigated. It is noticeable that, to acyclic substrate, the enantioselectivities of the
thiourea organocatalysts were superior to that of previously reported ether and ester derivatives. Therefore, our method
should intrigue generation of other potential catalyst.
The catalyst derived from different cinchona alkaloids exhibited differently asymmetric induction patterns
according to their respective substrates. Further work to explore the scope of this and related catalysts is ongoing in our
group and the results will be reported in due course.

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H. Chen et al. / Chinese Chemical Letters 21 (2010) 167–170
Acknowledgment
We thank the National Natural Science Foundation of China (Nos. 20572131, 20372083, 20972189, 20672141,
30901883).
References
[1] K.C. Nicolaou, K.R. Reddy, G.F. Skokotas, J. Am. Chem. Soc. 115 (1993) 3558.
[2] M.A. Calter, C. Zhu, R.J. Lachicotte, Org. Lett. 4 (2002) 209.
[3] M.A. Calter, C. Zhu, Org. Lett. 4 (2002) 205.
[4] M.A. Calter, R.M. Phillips, C. Flaschenriem, J. Am. Chem. Soc. 127 (2005) 14566.
[5] Y. Jin, X.Y. Liu, L.L. Jing, Chirality 19 (2007) 386.
[6] Y. Jin, Z.J. Yao, P. Liu, Chin. J. Org. Chem. 28 (2008) 94.
[7] H. Chen, Y. Jin, R. Jiang, Catal. Commun. 9 (2008) 1858.
[8] B. Vakulya, S. Varga, A. Csampai, Org. Lett. 7 (2005) 1967.
[9] L. Bernardi, F. Fini, R.P. Herrer, Tetrahedron 62 (2006) 375.