Organocatalyzed asymmetric vinylogous Michael addition of α,β-unsaturated γ-butyrolactam

Article abstract of DOI:10.1039/c3cc44059a

Highly efficient asymmetric vinylogous 1,6-Michael addition of α,β-unsaturated γ-butyrolactam to 3-methyl-4-nitro-5-alkenyl- isoxazoles and Michael addition to trichloromethyl ketones by using a chiral quinine-derived squaramide organocatalyst were described, giving products with high diastereo- and enantioselectivities (up to >25:1 dr and 96% ee).

Full text of DOI:10.1039/c3cc44059a

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ARTICLE TYPE
Organocatalyzed asymmetric vinylogous Michael addition of α,β-
unsaturated γ-butyrolactam
Jinlong Zhang, Xihong Liu, Xiaojuan Ma and Rui Wang*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
Highly efficient asymmetric vinylogous 1,6-Michael addition
of α,β-unsaturated γ-butyrolactam with 3-methyl-4-nitro-5-
alkenyl-isoxazoles and Michael addition to trichloromethyl
ketones by using
a chiral quinine-derived squaramide
10 organocatalyst were described, giving products with high
diastereo- and enantioselectivities (up to >25:1 dr and 96% ee).
The optically active chiral butyrolactams are present in a
variety of pharmaceuticals, natural products and versatile building
blocks that can undergo synthetically useful transformations.1
15 Owing to their synthetic significance, intense efforts have been
made on the development of various elegant methods to access the
structurally diverse family of 5-substituted butyrolactam
derivatives.2 Not surprisingly, the direct vinylogous additon of
α,β-unsaturated γ-butyrolactam is still highly valuable from the
20 standpoint of atom economy which has attracted much research
interest.3 The Shibasaki group has employed their dinuclear nickel
catalytic system for the efficient asymmetric vinylogous Mannich
reaction and Michael reaction.4a Later, asymmetric vinylogous
Michael and Aldol reactions were well developed, which use
25 metal-based chiral complex catalysts or organocatalysts.4
However, to the best of our knowledge, electrophiles have
generally been limited to nitroolefins, α,β-unsaturated aldehydes,
α,β-unsaturated ketones, alkylidene malonates, imines and aryl α-
ketoesters, no reports on catalytic asymmetric Michael reaction to
30 α,β-unsaturated esters. Moreover, there is no example of direct
catalytic asymmetric reactions of α,β-unsaturated γ-butyrolactam
to the δ-position of electro-deficient olefins. Thus, the
development of catalytic asymmetric vinylogous reactions of α,β-
unsaturated γ-butyrolactam to a new 1,6-Michael acceptors and a
35 suitably activated carboxylic acid derivatives is highly desirable
and particularly attractive. 3-methyl-4-nitro-5-alkenyl-isoxazoles,
developed by Adamo and coworkers, are able to be regarded as
1,6-Michael acceptors that show high reactivities toward stabilized
nucleophiles.5 Trichloromethyl ketones not only serve as attractive
40 ester and amide synthetic equivalents, but also enable unique
transformations due to trichloromethyl group is a good leaving
group with strong inductive effect.6 Herein, we describe our
efforts devoted to the direct asymmetric vinylogous 1,6-Michael
addition of α,β-unsaturated γ-butyrolactam with 3-methyl-4-nitro-
45 5-alkenyl-isoxazoles and Michael addition to trichloromethyl
50
Figure 1: The structures of screened organocatalysts.
The utilization of hydrogen bonding as an activation force is
widespread in organocatalysis. Chiral thioureas and, more recently,
squaramides are good hydrogen-bonding donor organocatalysts.
Accordingly, Our initial studies were focused on the reaction of
55 α,β-unsaturated γ-butyrolactam
2
and 3-methyl-4-nitro-5-
styrylisoxazole 3a (Table 1), catalyzed by quinine 1a, thioureas
1b-f or squaramide catalyst 1g (Figure 1). Preliminary screening
of the catalysts was conducted in CH2Cl2 at 50oC using 10 mol%
of quinine 1a (Table 1, entry 1). Pleasingly, the reaction
60 proceeded smoothly to afford the desired product 4a in good yield
albeit with poor diastereo- and enantioselectivity. Considering that
chiral amine thioureas have previously been utilized as effective
bifunctional organocatalysts for conjugate addition via acid–base
cooperative activation. We switched catalysts from quinine to
65 thioureas 1b-f and led to much better enantioselectivity, though
diastereoselectivity was yet satisfactory (Table 1, entry 2-6).
Compared with thioureas 1b-e, quinine derivatived catalyst 1f
gave better result. Encouraged by these results, quinine-derived
squaramide catalyst 1g was then tested (Table 1, entry 7).
70 Improved results in terms of reactivity and selectivity were
obtained and catalyst 1g was identified as the best catalyst.
Subsequent screening of solvents displayed that the reaction media
had a significant effect on the reaction (Table 1, entries 8-12), and
the use of THF was superior to others (Table 1, entry 12).
75 Lowering the reaction temperature to 40oC caused a sharp
decrease of the reaction yield (Table 1, entry 13).
Having established the optimal reaction conditions, we
explored the scope of the 1,6-Michael additon of α,β-unsaturated
γ-butyrolactam. The results are presented in Table 2. Generally, a
80 wide array of 3-methyl-4-nitro-5-alkenyl-isoxazoles compounds
containing electron-withdrawing or electron-donating groups were
ketones by using
organocatalyst.7,8
a
chiral quinine-derived squaramide

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DOI: 10.1039/C3CC44P05a9gAe 2 of 3
Table1: Screening of the reaction conditionsa
unsaturated γ-butyrolactam 2 to α,β-unsaturated trichloromethyl
ketones proceeded nicely to afford the 1,4-addition products with
high diastereo- and enantioselectivities (up to >25:1 dr and 94% ee)
o
under quinine-derived squaramide catalyst in toluene at 30 C (for
25 the details, see SI). As summarized in Table 3, trichloromethyl
ketones 5a-f, regardless of their electronic and steric properties,
underwent efficient reactions affording corresponding adducts in
high enantioselectivities and excellent diastereoselectivities (Table
3, entries 1-6). Meanwhile, chalcone 5g smoothly give rise to the
30 desired 1,4-adduct in high yield, and the ee value of product
improved to 99% on the established optimal conditions. Inert
aliphatic enone 5h can also be utilized as a suitable reaction
partner to afford the product 6h. The absolute configuration of 6a
was determined by X-ray crystallographic analysis,9b and the
35 relative configuration of 6g-h was confirmed by comparation with
the literature.4d
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
Catal.
1a
1b
1c
1d
1e
1f
1g
1g
1g
1g
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Toluene
CH3CN
CHCl3
THF
T (oC) Yield (%) d.r.b
ee (%)b
19
59
73
55
67
79
91
67
93
—-
87
96
50
50
50
50
50
50
50
50
50
50
70
23
78
75
71
75
82
87
85
3:1
5:1
6:1
9:1
9:1
6:1
13:1
10:1
18:1
—
trace
50
50
40
89
88
63
11:1
19:1
19:1
1g
1g
1g
THF
96
Table 3: Substrate scope for the asymmetric vinylogous Michael addition
of α,β-unsaturated γ-butyrolactam to α,β-unsaturated ketonesa
a
Reaction were carried out with 2 (0.1 mmol) , 3a (0.13 mmol), catalyst
(0.01 mmol) in solvent (0.2 mL) for 36 h. b dr was determined by 1H NMR,
and ee by chiral HPLC analysis.
equally good substrates (up to 19:1 dr and 96% ee) (Table 2,
entries 1-7). In the cases of 3h-k as substrates, the corresponding
products were obtained in good yields with excellent
enantioselectivities and lower diastereoselectivities (Table 2,
entries 8-11). In addition, heteroaromatic 3-methyl-4-nitro-5-
alkenyl-isoxazoles 3l-m were readily accommodated to the
standard reaction conditions (Table 2, entries 12-13). When 3-
10 methyl-4-nitro-5-(phenylbuta-1,3-dien-1-yl)isoxazole 3n served as
an Michael acceptor, moderate yield and a significant decrease in
both enantioselectivity and diastereoselectivity (1.3:1 dr, 84% ee)
were observed (Table 2, entry 14). The absolute configuration of
the stereogenic centers of 4i was unambiguously determined by X-
15 ray crystallographic analysis (Figure 1).9a
5
Entry
Ar2, R3
C6H5, CCl3
Product Yield (%)b
d.r.c
ee (%)c
93
93
90
91
93
86
99
93
1
2
3
4
5
6
7
8
91
93
85
79
82
80
88
73
>25:1
>25:1
>25:1
>25:1
>25:1
15:1
6a
6b
6c
6d
6e
6f
4-MeC6H4, CCl3
4-ClC6H4, CCl3
4-BrC6H4, CCl3
4-FC6H4, CCl3
4-MeOC6H4, CCl3
C6H5, C6H5
>25:1
>25:1
6g
6h
C6H5, CH3
a
Reaction conditions: 0.2 mmol (1.0 equiv) of 2, 0.26 mmol (1.3 equiv) of
5, and 0.02 mmol (10 mol %) of catalyst 1g were stirred at 30 oC in toluene
b
c
(0.5 mL); the reaction was monitored by TLC. Isolated yields. dr was
determined by 1H NMR, and ee by chiral HPLC analysis.
Table 2: Substrate scope for the asymmetric vinylogous 1,6-Michael
addition of α,β-unsaturated γ-butyrolactam to 3-methyl-4-nitro-5-alkenyl-
isoxazolesa
40
The synthetic utility of the current reaction was demonstrated
by the transformation shown in Scheme 1. The highly
enantiomerically enriched compound 4a can be easily converted
into 5-substituted pyrrolidin-2-one derivative 4ac. The ester
derivative 7a was smoothly prepared from 6a without
45 epimerization, by treatment with NaHCO3 in MeOH for 30 min.
Entry
1
2
3
4
5
6
7
8
Ar1
C6H5
Product Yield (%)b
d.r.c
19:1
16:1
13:1
19:1
16:1
16:1
13:1
7:1
7:1
7:1
4:1
13:1
16:1
1.3:1
ee (%)c
96
95
94
94
96
96
95
95
92
96
91
95
92
84
88
90
72
75
84
79
86
85
87
82
77
75
71
57
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4-MeC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-CF3C6H4
4-CNC6H4
3,4-Cl2C6H4
4-NO2C6H4
2-furanyl
2-thiopenyl
C6H5CH=CH
9
10
11
12
13
14
Scheme 1: Transformations of the corresponding Michael products.
In summary, we have developed an efficient quinine-derived
squaramide catalyzed direct asymmetric vinylogous 1,6-Michael
50 addition of α,β-unsaturated γ-butyrolactam with 3-methyl-4-nitro-
5-alkenyl-isoxazoles and Michael addition to trichloromethyl
ketones. The reactions with 10 mol% of squaramide 1g proceeded
well to furnish the corresponding adducts in high yields with high
diastereoselectivities and enantioselectivities (up to >25:1 dr and
a Reaction conditions: 0.2 mmol (1.0 equiv) of 2, 0.26 mmol (1.3 equiv) of
3, and 0.02 mmol (10 mol %) of catalyst 1g were stirred at 50 oC in THF
(0.5 mL); the reaction was monitored by TLC. b Isolated yields. c dr was
determined by 1H NMR, and ee by chiral HPLC analysis.
20
Further substrate scope was investigated. The reaction of α,β-

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underway in our laboratory.
50
55
5
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70
Figure 1. X-ray structure of enantiopure 4i.
75
We are grateful for the grants from the National Natural
10 Science Foundation of China (Nos. 91213302, 20932003 and
21272102), the Key National S&T Program “Major New Drug
Development” of the Ministry of Science and Technology of
China (2012ZX09504001-003) and the Program for Changjiang
Scholars and Innovative Research Team in University (PCSIRT:
15 IRT1137 ).
80
6
7
85
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9
45