Highly enantioselective direct vinylogous Michael addition of γ-substituted deconjugated butenolides to maleimides catalyzed by chiral squaramides

Article abstract of DOI:10.1039/c3ra43344g

Highly enantioselective direct vinylogous Michael reactions of γ-aryl-substituted deconjugated butenolides with maleimides, catalyzed by only 1 mol% bifunctional squaramides derived from cinchona alkaloids, were achieved with excellent yields (up to 96%) and enantioselectivities (up to 97% ee). This protocol features a very low catalyst loading, mild reaction conditions and provides a potential and effective method for the construction of optically active chiral butenolides with adjacent quaternary and tertiary stereocenters.

Full text of DOI:10.1039/c3ra43344g

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Highly enantioselective direct vinylogous Michael
addition of c-substituted deconjugated butenolides to
maleimides catalyzed by chiral squaramides3
Yun-Long Guo,ab Li-Na Jia,ab Lin Peng,a Liang-Wen Qi,ab Jing Zhou,ab Fang Tian,a Xiao-
Ying Xu*a and Li-Xin Wang*a
Cite this: RSC Advances, 2013, 3, 16973
Received 1st July 2013,
Accepted 23rd July 2013
DOI: 10.1039/c3ra43344g
www.rsc.org/advances
Highly enantioselective direct vinylogous Michael reactions of
c-aryl-substituted deconjugated butenolides with maleimides,
catalyzed by only 1 mol% bifunctional squaramides derived from
cinchona alkaloids, were achieved with excellent yields (up to
96%) and enantioselectivities (up to 97% ee). This protocol
features a very low catalyst loading, mild reaction conditions
and provides a potential and effective method for the construc-
tion of optically active chiral butenolides with adjacent quatern-
ary and tertiary stereocenters.
Over the past few years, chiral thioureas have been proved to be
effective tools for asymmetric catalysis.9 However, it was dis-
covered that chiral squaramide catalysts were superior in activity
and stereoinduction and have been successfully implemented in
various important asymmetric transformations.10 Based on this
background, we recognized that tertiary amine squaramides could
be efficient catalysts in the reaction of c-substituted butenolides
with maleimides, in which the tertiary amine group would activate
the c-substituted butenolides and the H-bond of the squaramide
would activate the maleimides. Thus the synergistic interactions
would ensure high stereoselectivity in such a transformation,
affording the corresponding optically active products via a
postulated transition state (TS) as shown in Scheme 1. As part of
our continuing interests in asymmetric syntheses,11 herein, we
wish to report the highly effective direct vinylogous Michael
reaction of c-substituted butenolides with maleimides, which was
catalyzed by only 1 mol% of bifunctional squaramides derived
from cinchona alkaloids under mild conditions.
Introduction
Chiral butenolides, bearing quaternary stereocenters,1 are the core
structural motifs in a number of natural compounds2 (Fig. 1)
which exhibit biological activities. There are two generally applied
and feasible strategies used for the construction of these
interesting molecules: the reaction of c-substituted butenolides
or substituted silyloxy furans with various acceptors.3 Among
them, the direct asymmetric vinylogous Michael reaction of
Results and discussion
c-substituted butenolides provides
a straightforward route.
Initial investigations were carried out using a series of squaramide
catalysts (Fig. 2) for the model reaction of N-phenyl maleimide 1a
Recently, the reactions of c-substituted butenolides with enals,4
nitroolefins5 and (E)-4-oxo-4-arylbutenamides6 have been studied,
while similar additions of c-substituted butenolides to maleimides
(which are extensively used to construct chiral succinimides7) have
not been documented. Very recently, and during the preparation
of this manuscript, Mukherjee and Manna have reported the first
catalytic asymmetric direct vinylogous Michael addition of
deconjugated butenolides to maleimides.8 However, only aliphatic
substituents of butenolides were investigated. To expand and gain
deeper understanding of this useful and asymmetric transforma-
tion, it is still desirable to develop new efficient catalytic systems.
aKey Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, People’s Republic of China. E-mail: wlxioc@cioc.ac.cn; xuxy@cioc.ac.cn;
Fax: +86-028-8525-5208
bUniversity of Chinese Academy of Sciences, Beijing 10039, People’s Republic of
China
Fig. 1 Several natural compounds containing butenolides.
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Table 1 Screening of conditions for the asymmetric vinylogous Michael addition
of 1a to 2aa
Scheme 1 Strategy for the direct vinylogous Michael reaction.
Entry Cat.
x
Solvent
t (h) Yieldb (%) drc
eed (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
4b
4b
4b
4b
4b
4b
10 DCE
10 DCE
10 DCE
10 DCE
10 DCE
10 DCE
12
12
12
12
12
12
65
5
85
90
93
92
94
90
96
97
96
95
95
96
77/23 95f
75/25 95
80/20 95
80/20 94f
with c-phenyl-substituted butenolide 2a in 1,2-dichloroethane at
30 uC. As shown in Table 1, when 10 mol% catalyst 4a was used,
the reaction afforded 3a in 85% yield and 95% ee (Table 1, entry
1). Bifunctional squaramides 4b–f were then screened and good
yields, moderate diastereoselectivities and excellent enantioselec-
tivities were obtained (90–94% yield, 75/25–91/9 dr and 86–95% ee,
Table 1, entries 2–6). Cinchona alkaloid derived squaramides 4a–d
gave better enantioselectivities than cyclohexane-1,2-diamine
derived squaramides 4e and 4f (Table 1, entries 1–4 vs. entries
5–6). Through the catalyst screening, catalyst 4b was the better
catalyst and was chosen for further optimization. When the
catalyst loading was decreased to 1 mol%, the desired product 3a
was obtained in excellent yield and enantioselectivity (96% yield,
83/17 dr and 97% ee, Table 1, entry 7) over a longer reaction time
(65 h). By increasing the concentration of the substrates, the
reaction time was reduced to 5 h with almost the same yield and
enantioselectivity (Table 1, entry 8 vs. entry 7). Solvents slightly
affected the enantioselectivities and yields. In terms of reaction
time and results, DCM was chosen as the suitable solvent (Table 1,
entry 9). Based on the above results, 0.22 mmol 1a and 0.2 mmol
2a in 0.3 mL DCM with 1 mol% catalyst 4b at 30 uC were
established as the optimal reaction conditions.
91/9
86f
87/13 90f
83/17 97
81/19 96
82/18 97
79/21 97
67/33 92
78/22 96
1
1
1
1
1
1
DCE
DCE
DCM
CHCl3
THF
8e
9e
10e
11e
12e
5
7
24
m-Xylene 24
a
Reactions carried out using 0.11 mmol 1a and 0.1mmol 2a in 1.0
b
mL DCM at 30 uC. Isolated yield of the products after column
chromatography. Determined by HPLC analysis. Enantiomeric
excess of the major diastereoisomer determined by HPLC on a chiral
stationary phase. Reactions carried out using 0.22 mmol 1a and 0.2
mmol 2a in 0.3 mL DCM. Contrary configuration.
c
d
e
f
Under the optimized reaction conditions, the scope of the
asymmetric vinylogous Michael reaction was surveyed with respect
to both maleimides and c-substituted butenolides. The results are
summarized in Table 2. For all cases, high yields (up to 96%),
excellent enantioselectivities (up to 97%) and acceptable diaster-
eoselectivities were obtained. The effects of N-aryl maleimides
were screened first. It was found that the reaction worked well
with various N-aryl maleimides bearing either electron-donating or
electron-withdrawing substituents in the aromatic ring, regardless
of the substituents at ortho- (Table 2, entry 12), meta- (Table 2,
entries 8–11) or para-positions (Table 2, entries 2–7), and excellent
yields and enantioselectivities were obtained (88%–96% yield,
94%–97% ee, Table 2, entries 2–12). N-Methyl maleimide was also
studied and 3m was obtained in 82% yield and 95% ee (Table 2,
entry 13). c-Aryl-substituted butenolides were evaluated and
afforded products 3n–s with good yields and excellent enantios-
electivities (80–96% yield, 94–97% ee, Table 2, entries 14–19).
c-Methyl-substituted butenolide was used and led to 3t with 83%
ee because of the smaller steric interaction of the methyl group
compared with aryl substitutes.
Conclusions
In conclusion, a highly effective direct vinylogous Michael addition
of c-aryl-substituted butenolides to maleimides, catalyzed by
cinchona alkaloid derived squaramides, with a low catalyst
loading (1 mol%) has been reported. This protocol features a very
Fig. 2 Squaramide catalysts used for the asymmetric vinylogous Michael addition
reactions.
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Table 2 The scope of the asymmetric vinylogous Michael additiona
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Yieldb
t (h) Product (%)
eed
(%)
Entry R1
R2
drc
1
2
3
Ph
4-F-C6H4
4-Cl-C6H4
Ph
Ph
Ph
5
5
7
3a
3b
3c
96
95
96
94
96
93
95
93
95
91
93
88
82
80
86
83
87
96
95
92
82/18 97
74/26 96
78/22 96
81/19 95
77/23 96
77/23 96
81/19 97
82/18 92
81/19 96
78/22 94
80/20 97
79/21 95
44/56 95/70
75/25 95
77/23 94
78/22 95
79/21 97
77/23 97
78/22 97
68/32 83e
4
5
4-NO2-C6H4 Ph
4-OMe-C6H4 Ph
10 3d
5
5
5
4
4
4
3e
3f
3g
3h
3i
6
7
8
4-Br-C6H4
4-Me-C6H4 Ph
3-NO2-C6H4 Ph
Ph
9
3-F-C6H4
3-Br-C6H4
3-Me-C6H4 Ph
2-F-C6H4
Me
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
3j
20 3k
4
96 3m
30 3n
6
6
3
Ph
Ph
3l
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4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
2,5-(Me)2-C6H3 24 3r
2-naphthyl 3s
12 3t
3o
3p
3q
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Ph
Ph
4
3-Me-C6H4 Me
a
Reactions carried out using 0.22 mmol 1 and 0.2 mmol 2 in 0.3
b
mL DCM. Isolated yield of the products after column
c
d
chromatography. Determined by HPLC analysis. Enantiomeric
excess of the major diastereoisomer determined by HPLC on a chiral
e
stationary phase. determined by comparing the retention times of
the two enantiomers on a chiral HPLC with the literature.8
low catalyst loading, mild conditions and excellent results (up to
96% yield, 97% ee), which provides a potential and effective
method for the construction of optically active chiral butenolides
with adjacent quaternary and tertiary stereocenters.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21272230) and Western Light Talent
Culture Project.
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