A highly efficient large-scale asymmetric Michael addition of isobutyraldehyde to maleimides promoted by a novel multifunctional thiourea

Article abstract of DOI:10.1016/j.tetasy.2011.10.002

A novel class of chiral multifunctional thioureas bearing a chiral lipophilic beyerane scaffold and a primary amino group were designed and prepared. The thioureas were proven to be effective for catalyzing the asymmetric Michael addition between isobutyr

Full text of DOI:10.1016/j.tetasy.2011.10.002

Tetrahedron: Asymmetry 22 (2011) 1740–1748
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A highly efficient large-scale asymmetric Michael addition of
isobutyraldehyde to maleimides promoted by a novel multifunctional thiourea
Zhi-wei Ma a, Yu-xia Liu a,b, Pan-li Li a, Hang Ren a, Yu Zhu a, Jing-chao Tao a,
⇑
a Department of Chemistry, New Drug Research and Development Center, Zhengzhou University, Zhengzhou 450052, China
b Department of Material and Chemistry Engineering, Henan Institute of Engineering, Zhengzhou 450007, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of chiral multifunctional thioureas bearing a chiral lipophilic beyerane scaffold and a pri-
mary amino group were designed and prepared. The thioureas were proven to be effective for catalyzing
the asymmetric Michael addition between isobutyraldehyde and maleimides with only 0.5 mol % catalyst
loading, and exhibited double asymmetric induction. Both of the catalysts afforded the corresponding
adduct with high to excellent yields (up to 98%) and excellent enantioselectivities (up to 99%). Further-
more, this catalytic system can be used efficiently in large-scale reactions with the yields and enantiose-
lectivities being maintained at the same level.
Received 27 August 2011
Accepted 12 October 2011
Available online 19 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
thesis.5 However, the efficient preparation of both enantiomers of a
chiral compound still represents a daunting task, and to the best of
Substituted succinimides are valuable synthetic targets as
important structural scaffolds or precursors of biologically inter-
esting substances.1 The Michael addition is one of the most effi-
cient and powerful atom-economic carbon–carbon bond-forming
reactions in synthetic chemistry.2 In particular, the asymmetric
Michael addition of maleimide represents a potentially attractive
our knowledge, effective double asymmetric inductions on metal-
free organocatalytic reactions have rarely been reported.6 Thus,
developing an effective organocatalytic method to prepare both
enantiomers of substituted succinimides is a highly desirable goal.
In the past few years, a series of thioureas have been designed,
synthesized, and emerged as efficient catalysts for various types of
asymmetric reaction.7,8 Motivated by these works, we envisioned
that a bulky chiral scaffold may play an important and positive
role, especially with regards to the enantioselectivity (Fig. 1). In
the plausible transition state, the primary amine can activate iso-
butyraldehyde via enamine intermediate formation, while the
maleimide may be attracted and activated by the thiourea moiety
approach.3,4 With regards to sterically hindered
aldehydes such as isobutyraldehyde, the first attempt at using
them as a Michael donor to construct -substituted succinimides
a,a-disubstituted
a
was made in 2007 by Córdova by employing chiral diphenylprolin-
ol silyl ether as a catalyst.4a However, such a catalytic system was
ineffective for isobutyraldehyde, and only low yield and poor
enantioselectivity were observed. In 2010, Duan,4b Wang4c, and
Liang4d reported highly enantioselective Michael additions of
activation of N-phenylmaleimide
a,a-disubstitued aldehydes to maleimides catalyzed by a primary
S
amine-thiourea. In each of these cases, high to excellent yields
and enantioselectivities were obtained. Recently, a recyclable flu-
orous thiourea organocatalyst used to promote the asymmetric
Michael addition of aldehydes to maleimides was reported by
Miura.4e However, all of these reactions have only been investi-
gated on an analytical scale and the substrates remained limited.
Clearly, there still remains much room for improvement regarding
a novel catalytic system with regards to practicality and substrate
scope.
N
H
N
H
HN
activation of aldehyde
O
N
Both enantiomers of a chiral compound are often useful and
versatile in terms of the pharmaceutical industry and organic syn-
O
shielding one face of N-phenylmaleimide
⇑
Corresponding author. Tel./fax: +86 371 67767200.
E-mail address: jctao@zzu.edu.cn (J. Tao).
Figure 1. Proposed transition state of the Michael addition between isobutyralde-
hyde and N-phenylmaleimide.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.002

Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
1741
S
S
N
H
N
H
N
H
N
H
NH2
NH2
COOEt
COOEt
1b
1a
Figure 2. Novel multifunctional thiourea catalysts.
through H-bonding interactions. Furthermore, the lipophilicity and
chiral environment of the bulky group should have chance to direct
the approach of the Michael acceptor through a lipophilic interac-
tion. The maleimide can be attacked by the enamine only from the
re-face or si-face. As a result, a high enantioselectivity is expected.
As a part of our continuing interests in natural product9 and
asymmetric catalysis,10 we herein report a highly efficient asym-
metric Michael addition of isobutyraldehyde to maleimides pro-
moted by the primary amine thioureas 1a and 1b (Fig. 2) with
high to excellent yields (up to 98%) and enantioselectivities (up
to 99%); this catalyst can be used in large-scale reactions with
the enantioselectivity being maintained at the same level.
Figure 3. ORTEP diagram of isothiocyanate 4.
2. Results and discussion
An initial screen revealed that the catalysts 1a and 1b can effi-
ciently catalyze this transformation with high levels of reaction
efficiency and enantioselectivity. As expected, the catalysts 1a
and 1b exhibited a reversed sense of asymmetric induction, pro-
viding the adduct as the (S)-enriched enantiomer of 1a with a
98% yield and a 97% ee and the (R)-enriched enantiomer of 1b with
a 97% yield and a 96% ee (Table 1, entry 1 vs 2).
We next examined the effects of other solvents in the reaction
with 1a as the catalyst. The results showed that both the yield
and enantioselectivity were highly dependent on the solvent.
Aprotic solvents, such as n-hexane, toluene, CH2Cl2, THF, and CHCl3
gave high to excellent yields (92–98%) and enantioselectivities
(86–97%, Table 1, entries 1–6). When we tested protic solvents
such as i-PrOH, both the yield and enantioselectivity were greatly
decreased (Table 1, entry 7). In addition, when an aqueous medium
such as H2O or brine was employed, a lower yield and enantiose-
lectivity were obtained (Table 1, entries 8 and 9). This was proba-
bly due to the hydrogen bonding interactions between the
substrates and the protic solvents, which disturbed the efficient
A detailed description of our multifunctional thiourea catalysts
is presented in Scheme 1 with the synthesis of 1a as a representa-
tive example. Starting from the commercially available natural
compound stevioside, compound 2 was readily obtained.9b Treat-
ment of compound 2 with NaBH4/MoO3 gave the corresponding
amine 3 stereoselectively.11 The reaction of compound 3 with
CS2, Boc2O, DMAP, and TEA afforded the isothiocyanate 4,12 which
was then reacted directly with (S,S)-1,2-cyclohexyldiamines in
CH2Cl2 to give organocatalyst 1a in a 72% yield. The structures of
compound 1–4 were fully characterized and the structure of the
isothiocyanate 4 was further confirmed by single crystal X-ray
crystallography (Fig. 3). Thiourea 1b was synthesized according
to this procedure without incident. It is noteworthy that due to
the simple manipulation procedures, these catalysts could be eas-
ily prepared on gram scales.
With the novel multifunctional thioureas 1a and 1b in hand, we
began to investigate their catalytic activities for asymmetric Mi-
chael additions with isobutyraldehyde 5a as the donor aldehyde
and N-phenylmaleimide 6a as the acceptor substrate (Table 1).
NOH
NH2
NaBH4/MoO3
CS2, Boc2O, DMAP, TEA
EtOH, rt, 2 h, 89%
CH3OH, rt ,6 h, 77%
3
2
COOEt
COOEt
H2N
S
NCS
N
H
N
H
H2N
NH2
CH2Cl2, rt, 12 h, 72%
COOEt
4
1a
COOEt
Scheme 1. Synthesis of thiourea-amine multifunctional catalyst 1a.

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Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
Table 1
Optimization of the asymmetric Michael addition of isobutyraldehyde 5a to N-phenylmaleimide 6a catalyzed by 1a
O
O
O
O
1 10mol%
N
Ph
N
Ph
H
Solvent, 2 h
H
ambient temperature
O
O
7a
5a
6a
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
CHCl3
CHCl3
n-Hexane
Toluene
CH2Cl2
THF
i-PrOH
H2O
Brine
98
97
92
93
97
94
27
88
84
92
98
97
ꢀ96
96
92
93
86
65
81
72
9
10
Neat
CHCl3
82
99
11d,e
a
Unless otherwise specified, all reactions were carried out using isobutyraldehyde 5a (0.40 mmol), N-phenylmaleimide 6a (0.20 mmol), and
10 mol % catalyst 1 in 0.5 mL solvent at ambient temperature.
b
Isolated yield.
Determined by chiral HPLC analysis.
0.20 mmol PhCOOH (100 mol %, 1.0 equiv) was used.
Reaction time was 0.25 h.
c
d
e
Table 2
Screening of the catalyst loadinga
O
O
1a X mol%
O
PhCOOH 10X mol%
O
N
Ph
N
Ph
H
CHCl3
H
ambient temperature
O
O
7a
6a
5a
Entry
X (mol %)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
10
5
2
1
0.5
0.1
0.25
0.5
1.0
3.0
6.0
98
98
97
97
97
90
99
99
99
99
99
98
48
a
Unless otherwise specified, all reactions were carried out using isobutyraldehyde 5a (0.40 mmol), N-phenylmaleimide 6a (0.20 mmol), X
mol % catalyst 1a, and 10X mol % PhCOOH in 0.5 mL CHCl3 at ambient temperature.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
aggregation surrounding the multifunctional catalyst. The Michael
reaction, when performed without a solvent also furnished the
product in high yield, but the enantioselectivity was lower (Table 1,
entry 10). A screen of solvents revealed that CHCl3 was the most
suitable solvent.
In order to make an organocatalyst more effective, the role of a
suitable additive, or co-catalyst, can be crucial in enhancing the
reactivity and stereoselectivity of the catalytic system. For exam-
ple, it has been shown that PhCOOH was often an efficient pro-
enantioselectivity were also improved upon (Table 1, entry 11 vs
1).
Using CHCl3 as the solvent and PhCOOH as a co-catalyst, we
evaluated the effect of the catalyst loading (Table 2). It was found
that lowering the catalyst loading from 10 mol % to 0.5 mol % did
not affect the yield or enantioselectivity. When the catalyst was
used as low as 0.1 mol %, the enantioselectivity was slightly lower,
but the yield decreased significantly, despite a prolonged reaction
time of 48 h. Thus, the optimized catalyst loading was chosen as
0.5 mol %.
moter for the chiral thiourea catalyzed asymmetric Michael
8k
reaction.6a,6b,8g–j,
When PhCOOH was used as an additive for
Based on all of the above results, a set of acceptable reaction
conditions, 0.40 mmol 5a (2.0 equiv) and 0.20 mmol 6a (1.0 equiv)
in 0.5 mL CHCl3 with 0.5 mol % catalyst 1a or 1b and 5 mol %
the asymmetric Michael addition of isobutyraldehyde to N-phenyl-
maleimide, the reaction rate greatly increased; the yield and

Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
1743
Table 3
Substrate studies of the Michael addition between isobutyraldehyde and maleimidesa
O
O
1 0.5 mol%
O
O
PhCOOH 5 mol%
N
R
N
R
H
CHCl3
H
ambient temperature
O
O
6a-l
7a-l
5a
Entry
R
Catalyst
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5 6a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
7a
7b
7c
7d
7e
7f
7g
7h
7i
97
91
77
79
72
66
59
75
94
80
94
95
98
88
77
81
75
64
62
70
92
82
93
96
99
98
94
96
97
94
95
95
98
4-F-C6H4 6b
3-Cl-C6H4 6c
4-Cl-C6H4 6d
3-Br-C6H4 6e
4-Br-C6H4 6f
3-NO2-C6H4 6g
4-NO2-C6H4 6h
4-CH3-C6H4 6i
2,6-(CH3)2-C6H3 6j
2-CH3O-C6H4 6k
Bn 6l
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
7j
7k
7l
95
98
99
C6H5 6a
7a0
7b0
7c0
7d0
7e0
7f0
7g0
7h0
7i0
7j0
7k0
7l0
ꢀ96
ꢀ93
ꢀ95
ꢀ95
ꢀ94
ꢀ90
ꢀ93
ꢀ97
ꢀ97
ꢀ98
ꢀ98
ꢀ98
4-F-C6H4 6b
3-Cl-C6H4 6c
4-Cl-C6H4 6d
3-Br-C6H4 6e
4-Br-C6H4 6f
3-NO2-C6H4 6g
4-NO2-C6H4 6h
4-CH3-C6H4 6i
2,6-(CH3)2-C6H3 6j
2-CH3O-C6H4 6k
Bn 6l
a
Unless otherwise specified, all reactions were carried out using aldehyde (5a or 5b, 0.40 mmol), maleimide (6, 0.20 mmol), 0.5 mol % catalyst 1a/1b
and, 5 mol % PhCOOH in 0.5 mL CHCl3 at ambient temperature for 6-36 h.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
PhCOOH at ambient temperature were established. A representa-
tive selection of maleimides was investigated to determine the
scope of this Michael addition. As shown in Table 3, the reaction
displayed obvious generality and functional-group tolerance. The
yield varied as the substituent on the N-phenyl moiety of the
maleimides, but the enantioselectivity was to some degree inde-
pendent of the substituent. All of the maleimides gave the desired
Michael adducts in good to high yields (59–98%) and excellent
enantioselectivities (90–99%) regardless of the electronic and steric
properties of the substituents (Table 3, entries 1–11 and 13–23).
For the N-alkyl substituted maleimide 6l, the conjugate addition
also produced excellent results both in terms of yield and enanti-
oselectivity (Table 3, entries 12 and 24). Moreover, the results also
indicated that the yields and enantioselectivities furnished by the
non-polar group substituted N-phenylmaleimide were higher than
substrates with polar substituted group. This was probably due to
the more effective lipophilic interactions between the non-polar
group of the maleimide and the chiral skeleton of the catalyst
(Table 3, entries 1, 9, 11, 12 vs 3–8).
We performed further large-scale asymmetric Michael reac-
tions with 100 mmol of maleimide and 2 equiv of isobutyralde-
hyde. The same catalyst loading of 0.5 mol % as in the
experimental scale was used. The large-scale experiments can be
easily carried out using the same procedure as for the experimental
scale reactions. As can be seen from the results summarized in
Table 5, both the yield and enantioselectivity were maintained at
the same level for the large-scale reactions, which offers a great
possibility for application in industry.
Although the precise reaction mechanism needs further study, a
possible transition state was proposed based on the observed ste-
reoselectivities of the asymmetric Michael addition of isobutyral-
dehyde to N-phenylmaleimide (Fig. 4). Mechanistically, the
in situ formed enamine intermediate between isobutyraldehyde
5a and catalyst 1a attacked the si-face of N-phenylmaleimide 6a
to give the corresponding product (S)-7a.
3. Conclusion
Encouraged by the above results, we next selected cyclohexane-
carboxaldehyde 5b as another donor to react with various malei-
mides (Table 4, entries 1–12). These reactions proceeded
smoothly and the corresponding Michael adducts were obtained
with high yields (70–97%) and enantioselectivities (90–97%). We
next investigated the aldehydes 5c and 5d as donors; two stereo-
genic carbon centers were formed in these reactions. As summa-
rized in Table 4, the diastereoselectivities were low, but both
diastereomers were formed in excellent ee values (entries 13–16).
In conclusion, we have developed a novel class of chiral multi-
functional primary amine-thiourea catalysts 1a and 1b, which have
been successfully applied to the asymmetric Michael addition of
isobutyraldehyde and maleimides. The most important result is
that chiral thiourea 1a preferentially furnishes the (S)-enantiomer,
while 1b selectively produces the (R)-enantiomer. With only
0.5 mol % catalyst loading, the adducts were obtained in high to
excellent yield (up to 98%) and enantioselectivity (up to 99%). Fur-
thermore, this novel catalytic system can be used efficiently in

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Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
Table 4
Substrate studies of the Michael addition between aldehydes and maleimidesa
O
O
1 0.5 mol%
O
O
PhCOOH 5 mol%
R1
N
R
N
R
H
*
CHCl3
*
H
ambient temperature
R2
R2 R1
O
O
6a-l
5b-d
8-10
Entry
R1
R2
R
Catalyst
Product
Yieldb (%)
drc
eed (%)
95
1
2
3
4
5
6
7
8
CH2(CH2)3CH2- 5b
-CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
–CH2(CH2)3CH2- 5b
C6H5 6a
4-F-C6H4 6b
4-CH3-C6H4 6i
2,6-(CH3)2-C6H3 6j
2-CH3O-C6H4 6k
Bn 6l
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1a
1b
1a
1b
8a
8b
8i
92
96
85
70
97
96
93
96
80
75
97
95
96
97
66
71
—
—
—
—
—
—
—
—
—
—
—
—
97
92
92
93
90
8j
8k
8l
C6H5 6a
8a0
8b0
8i0
ꢀ90
4-F-C6H4 6b
4-CH3-C6H4 6i
2,6-(CH3)2-C6H3 6j
2-CH3O-C6H4 6k
Bn 6l
C6H5 6a
C6H5 6a
C6H5 6a
C6H5 6a
ꢀ97
9
ꢀ90
10
11
12
13
14
15
16
8j0
ꢀ90
8k0
8l0
ꢀ96
ꢀ90
H
H
H
H
CH3 5c
CH3 5c
n-C4H10 5d
n-C4H10 5d
9a
9a0
10a
10a0
2.4/1
2.1/1
1.9/1
1.7/1
99/97
ꢀ99/ꢀ99
97/94
ꢀ95/ꢀ96
a
Unless otherwise specified, all reactions were carried out using aldehyde 5b - 5d (0.40 mmol), maleimide 6 (0.20 mmol), 0.5 mol % catalyst 1a/1b and, 5 mol % PhCOOH in
0.5 mL CHCl3 at ambient temperature for 6-36 h.
b
Isolated yield.
c
Determined by 1H NMR analysis.
d
Determined by chiral HPLC analysis.
Table 5
Large-scale asymmetric Michael additiona
O
O
1a 0.5 mol%
O
H
O
PhCOOH 5 mol%
N
R
N
R
H
CHCl3
O
ambient temperature
O
5a
7
6
Entry
R
Yieldb (%)
eec (%)
1
2
3
4
C6H5 6a
98
88
94
90
98
98
92
98
4-F-C6H4 6b
4-CH3-C6H4 6i
Bn 6l
a
Unless otherwise specified, all reactions were carried out using isobutyraldehyde 5a (200 mmol), maleimide 6 (100 mmol), 0.5 mol % catalyst 1a and, 5 mol % PhCOOH in
250 mL CHCl3 at ambient temperature for 6–24 h.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
large-scale reactions with the enantioselectivity being maintained
at the same level, which offers a great possibility for application in
industry. Further investigations of these organocatalysts in other
asymmetric reactions as well as more detailed mechanistic insight
are ongoing in our laboratory.
purified by standard procedures. Chemicals were used as received
unless otherwise noted. Reagent grade solvents were redistilled
prior to use. 1H NMR and 13C NMR spectra were collected on a Bru-
ker DPX 400 NMR spectrometer with TMS as internal reference. IR
spectra were determined on a Thermo Nicolet IR200 unit. High res-
olution mass spectra (HRMS) were obtained on a Waters Micro-
mass Q-Tof Micro™ instrument using the ESI technique.
Chromatography was performed on silica gel (200–300 mesh).
Melting points were determined using an XT5 apparatus and are
uncorrected. Optical rotations were determined on a Perkin Elmer
341 polarimeter. Enantiomeric excess was determined by chiral
HPLC at room temperature using Labtech 2006 pump equipped
4. Experimental
4.1. General
All reagents were obtained from commercial supplier without
further purification. Commercial grade solvents were dried and

Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
1745
S
O
N
H
N
H
O
HN
N
Ph
H
O
COOEt
O
Ph
N
(S)-7a
si-face attack
O
Figure 4. Proposed transition state.
with Labtech UV600 ultra detector with Chiral columns (Chiralcel
OD-H, Chiralpak AD-H and AE.LICHROM-AM2–5).
Single crystals of compound 4 suitable for X-ray analysis were
obtained by recrystallization from EtOH at room temperature. Crys-
tal data for 4: C23H35O2NS (389.58), monoclinic, space group: P21,
4.2. General procedures for the preparation of catalysts 1a and
1b
a = 7.2618(7) Å, b = 12.1436(15) Å, c = 12.6476(19) Å, a
= 90.00o,
b = 96.170(11)o,
c
= 90.00o, Volume = 1108.9(2) Å3, Z = 2, Crystal si-
ze = 0.30 ꢂ 0.20 ꢂ 0.20 mm3, T = 293(2) K, absorption coefficient:
1.414 mmꢀ1, reflections collected: 8245, independent reflections:
3838[R(int) = 0.0326], data/restraints/parameters 3838/1/248,
4.2.1. Ethyl ent-16b-aminobeyeran-19-oate 3
To a mixture of compound 2 (3.61 g, 10 mmol) and MoO3
(2.19 g, 15 mmol) in methanol (100 mL) was carefully added
NaBH4 (1.90 g, 50 mmol) at room temperature. The resulting dark
colored mixture was stirred at ambient temperature for 6 h and
then filtered. The resultant mixture was concentrated under re-
duced pressure. The residue was treated with aqueous KOH (20%)
and extracted several times with dichloromethane. The combined
organic layer was washed with water and brine, and then dried
over MgSO4. After filtration and evaporation of the solvent, the
crude product 3 was obtained and used directly for the next step
without further purification. Yield: 77%; mp: 186–188 °C;
goodness-of-fit on F2 = 1.046, final R indices [I>2r(I)] R1 = 0.0502,
wR2 = 0.1283, final R indices (all data) R1 = 0.0632, wR2 = 0.1431,
Largest diff. peak/hole/e Åꢀ3 0.184/ꢀ0.193.
CCDC-830982 (for 4) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
4.2.3. Catalyst 1
The isothiocyanate 4 (1.20 g, 3 mmol) was added over a period
of 0.5 h to a stirred solution of (S,S)- or (R,R)-1,2-diaminocyclohex-
ane (0.41 g, 3.6 mmol) in dry dichloromethane (25 mL). The reac-
tion mixture was stirred for a further 12 h at room temperature.
The solvent was removed under reduced pressure and the crude
product was purified using column chromatography eluting with
CHCl3/MeOH = 50:1.
½
a 2D0
ꢁ
¼ ꢀ47:4 (c 0.56, EtOH); 1H NMR (400 MHz, CDCl3, TMS) d
0.73 (s, 3H), 0.84 (s, 3H), 0.97–1.05 (m, 4H), 1.16 (s, 3H), 1.25 (t,
J = 7.2 Hz, 3H), 1.31–1.36 (m, 6H), 1.56–1.81 (m, 9H), 2.14–2.17
(m, 1H), 2.87–2.91 (m, 1H), 4.06–4.11 (m, 2H); 13C NMR
(100 MHz, CDCl3, TMS) d:13.3, 14.0, 18.9, 20.5, 21.7, 24.9, 28.9,
33.3, 38.0, 40.0, 41.5, 41.7, 41.8, 42.9, 43.6, 55.7, 56.5, 57.1, 59.8,
61.1, 177.5, 178.0; HRMS (m/z): 348.2904, calcd for C22H38NO2
[M+H]+ 348.2903.
4.2.3.1. 1-((1S,2S)-2-Aminocyclohexyl)-3-(ethyl ent-beyeran-19-
oate-16-yl)thiourea 1a. White solid: yield: 72%; mp: 130–
132 °C; ½a 2D0
ꢁ
¼ ꢀ108:0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3,
4.2.2. Ethyl ent-16b-isothiocyanobeyeran-19-oate 4
TMS): d 0.75 (s, 3H), 0.82–0.89 (m, 2H), 0.95 (s, 3H), 0.96–1.08
(m, 4H), 1.15 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.24–1.45 (m, 10H),
1.56–1.60 (m, 3H), 1.64–1.70 (m, 3H), 1.75–1.82 (m, 3H), 1.95–
2.02 (m, 2H), 2.05 (m, 1H), 2.13–2.16 (m, 1H), 2.80 (s, 1H), 4.07
(m, 2H), 4.34 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d 13.4,
14.1, 14.2, 18.8, 20.4, 21.0, 21.6, 24.6, 24.7, 25.1, 28.9, 32.1, 33.8,
34.5, 37.9, 38.0, 39.8, 40.7, 41.3, 42.2, 43.6, 55.8, 55.9, 57.0, 59.8,
Ethanol (5 mL) was added to compound 3 (1.53 g, 4.4 mmol).
Next, CS2 (3.34 g, 44 mmol) and Et3N (0.44 g, 4.4 mmol) were
added while stirring, resulting in the precipitation of the dithiocar-
bamate. The reaction mixture was stirred for 30 min at room tem-
perature and then cooled on an ice bath. Next, Boc2O (0.95 g,
4.4 mmol), dissolved in ethanol (1 mL), was added followed by
the immediate addition of a catalytic amount of DMAP (2 mol %)
in ethanol (1 mL). The reaction mixture was kept in the ice bath
for 5 min, and then allowed to reach room temperature. After evo-
lution of gas from the reaction mixture had ceased (approximately
10 min), the reaction mixture was stirred for a further 5 min at
room temperature and evaporated thoroughly in vacuo. After
recrystallization from EtOH, the isothiocyanate 4 was obtained as
60.4, 77.2, 177.5, 183.3; IR (KBr, cmꢀ1):
1096, 1151, 1179, 1237, 1369, 1450, 1543, 1721, 2848, 2937,
m 732, 974, 1025, 1043,
3060, 3264; HRMS (m/z): 504.3631, calcd. for
C29H49N3O2S
[M+H]+ 504.3525.
4.2.3.2. 1-((1R,2R)-2-Aminocyclohexyl)-3-(ethyl ent-beyeran-
19-oate-16-yl)thiourea 1b. White solid: yield: 72%; mp: 142–
a white solid. Yield: 89%; mp: 85–87 °C; ½a D20
¼ ꢀ26:5 (c 1.0,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d 0.76 (s, 3H), 0.83–0.99
(m, 2H), 1.00 (s, 3H), 1.01–1.16 (m, 3H), 1.24 (s, 3H), 1.26 (t,
J = 7.2 Hz, 3H), 1.31–1.52 (m, 5H), 1.53–1.83 (m, 8H), 2.05–2.11
(m, 1H), 2.15–2.18 (m, 1H), 3.69–3.73 (dd, J = 4.9, 11.5 Hz, 1H),
4.05–4.13 (m, 1H); 13C NMR (100 MHz, CDCl3, TMS): d 13.2, 14.1,
18.8, 20.0, 21.6, 24.8, 28.9, 34.7, 37.9, 38.0, 39.8, 40.8, 41.0, 43.1,
144 °C; ½a 2D0
ꢁ
¼ þ5:5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3,
TMS): d 0.69 (s, 3H, -CH3), 0.82–0.89 (m, 2H), 0.95 (s, 3H), 0.96–
1.08 (m, 4H), 1.15 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.24–1.45 (m,
10H), 1.56–1.60 (m, 3H), 1.64–1.70 (m, 3H), 1.75–1.82 (m, 3H),
1.95–2.02 (m, 2H), 2.05 (m, 1H), 2.13–2.16 (m, 1H), 2.80 (s, 1H),
4.07 (m, 2H), 4.34 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d
13.3, 14.1, 18.8, 20.3, 21.0, 21.7, 24.4, 24.7, 25.2, 28.9, 32.0, 33.4,
34.6, 38.0, 39.9, 40.8, 41.4, 41.9, 42.2, 43.6, 55.8, 55.9, 57.0, 59.9,
43.6, 44.0, 54.5, 55.4, 56.9, 60.0, 64.3, 177.3; IR (KBr, cmꢀ1):
m
616, 719, 796, 853, 974, 1028, 1095, 1151, 1181, 1243, 1326,
1453, 1720, 2113, 2843, 2952.
60.4, 62.9, 77.2, 177.6, 183.3; IR (KBr, cmꢀ1):
m 733, 975, 1029,

1746
Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
1096, 1149, 1180, 1236, 1368, 1450, 1541, 1720, 2848, 2938, 3058,
3261; HRMS (m/z): calcd. for C29H49N3O2S (M+H)+ 504.3624, found
504.3521.
ralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min,
k = 220 nm): tR = 25.2 min (major), 45.9 min (minor).
4.3.5. 2-(1-(3-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-meth
ylpropanal 7e
4.3. Typical procedure for the Michael addition
White solid; ½a 2D0
ꢁ
¼ ꢀ4:4 (c 1.0, CHCl3); 1H NMR (400 MHz,
The aldehyde 5a or 5b (0.40 mmol) was added to a mixture of
catalyst 1 (0.5 mg, 0.5 mol %), PhCOOH (1.2 mg, 5 mol %) and the
corresponding maleimide 6 (0.20 mmol) in CHCl3 (0.5 mL). The
reaction mixture was stirred at ambient temperature for the re-
quired time. After the maleimide was consumed (TLC analysis),
the reaction mixture was subjected to thin layer chromatography
on silica gel (ethyl acetate/petroleum ether) to afford the pure Mi-
chael product. The enantiomeric excess of the products was deter-
mined by chiral HPLC analysis using chiral columns.
CDCl3, TMS): d 1.29 (s, 3H), 1.36(s, 3H), 2.62 (dd, J = 5.6, 18.4 Hz,
1H), 2.98 (dd, J = 9.6, 18.4 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H),
7.24–7.27 (m, 1H), 7.32–7.36 (t, J = 8.0 Hz, 1H), 7.47–7.48 (t,
J = 2.0 Hz, 1H), 7.52–7.55 (m, 1H), 9.49 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS): d 19.9, 20.5, 32.0, 45.0, 48.7, 122.5,
125.3, 129.6, 130.4, 131.8, 133.0, 174.7, 176.6, 202.7; IR (KBr,
cmꢀ1):
m 621, 661, 681, 721, 785, 814, 886, 1066, 1180, 1383,
1425, 1475, 1573, 1706, 1778, 2850, 2919, 2963, 3466; HPLC: Chi-
ralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min,
k = 220 nm): tR = 24.5 min (major), 30.2 min (minor).
4.3.1. 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropanal
7a4
4.3.6. 2-(1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-meth
ylpropanal 7f4
White solid; ½a 2D0
ꢁ
¼ ꢀ5:6 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.27 (s, 3H), 1.31(s, 3H), 2.61 (dd, J = 5.6, 18.2 Hz,
1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.14 (dd, J = 5.6, 9.6 Hz, 1H),
7.27 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.2 Hz,
2H), 9.50 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d 19.6, 20.3,
31.8, 45.0, 48.5, 126.5, 128.7, 129.2, 131.8, 174.8, 176.9, 202.8; IR
White solid; ½a 2D0
ꢁ
¼ ꢀ3:2 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.28 (s, 3H), 1.36 (s, 3H), 2.61 (dd, J = 5.6, 18.0 Hz,
1H), 2.97 (dd, J = 9.6, 18.4 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H),
7.17–7.21 (m, 2H), 7.58–7.61 (m, 2H), 9.48 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS): d 19.9, 20.5, 32.0, 45.0, 48.7, 122.6,
(KBr, cmꢀ1):
m
499, 563, 627, 666, 703, 755, 814, 885, 1164,
128.1, 130.8, 132.4, 174.4, 176.6, 202.7; IR (KBr, cmꢀ1):
m 570,
1189, 1395, 1454,1471, 1490, 1500, 1705, 1773, 2730, 2822,
2932, 2989, 3459; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/
25, flow rate = 0.6 mL/min, k = 220 nm): tR = 25.1 min (major),
31.8 min (minor).
720, 769, 828, 887, 1015, 1067, 1168, 1200, 1399, 1489, 1698,
1719, 1770, 2849, 2922, 2966, 3093, 3450; HPLC: Chiralcel OD-H
(Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, k = 220 nm):
tR = 32.4 min (major), 55.3 min (minor).
4.3.2. 2-(1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl
propanal 7b4
4.3.7. 2-Methyl-2-(1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)
propanal 7g4
White solid; ½a 2D0
ꢁ
¼ ꢀ2:0 (c 1.0, CHCl3); 1H NMR (400 MHz,
White solid; ½a 2D0
ꢁ
¼ ꢀ3:4 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.29 (s, 3H), 1.36(s, 3H), 2.61 (dd, J = 5.6, 18.4 Hz,
1H), 2.98 (dd, J = 9.6, 18.4 Hz, 1H), 3.12 (dd, J = 5.6, 9.6 Hz, 1H),
7.16 (m, 2H), 7.27 (m, 2H), 9.49 (s, 1H); 13C NMR (100 MHz, CDCl3,
TMS): d 19.9, 20.5, 31.9, 44.9, 48.7, 116.2, 127.7, 128.4, 163.5,
CDCl3, TMS): d 1.32 (s, 3H), 1.42(s, 3H), 2.67 (dd, J = 5.6, 18.4 Hz,
1H), 2.03 (dd, J = 9.6, 18.4 Hz, 1H), 3.13 (dd, J = 5.6, 9.6 Hz, 1H),
7.66 (t, J = 8.0 Hz, 1H), 7.71 (dt, J = 1.6, 8.0 Hz, 1H), 8.25–8.28 (m,
2H), 9.48 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d 20.3, 20.7,
32.1, 45.0, 49.0, 121.9, 123.3, 129.9, 132.5, 132.9, 148.5, 174.0,
174.7, 176.9, 202.8; IR (KBr, cmꢀ1):
m 468, 532, 669, 760, 841,
1198, 1222, 1392, 1508, 1703, 1728, 1780, 2977, 3081, 3121,
3464; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow
rate = 0.6 mL/min, k = 220 nm): tR = 24.2 min (major), 41.0 min
(minor).
176.4, 202.7; IR (KBr, cmꢀ1):
m 581, 679, 731, 782, 820, 1193,
1350, 1395, 1481, 1529, 1587, 1712, 1780, 2733, 2833, 2874,
2937, 2970, 3097, 3473; HPLC: Chiralcel OD-H (Hexanes/i-
PrOH = 75/25, flow rate = 0.6 mL/min, k = 220 nm): tR = 31.7 min
(major), 38.3 min (minor).
4.3.3. 2-(1-(3-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl
propanal 7c
4.3.8. 2-Methyl-2-(1-(4-nitrophenyl)-2,5-dioxopyrrolidin-3-
yl)propanal 7h4
White solid; ½a 2D0
ꢁ
¼ ꢀ6:0 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.26 (s, 3H), 1.33(s, 3H), 2.60 (dd, J = 5.6, 18.4 Hz,
1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.12 (dd, J = 5.6, 9.6 Hz, 1H),
7.21 (d, J = 6.8 Hz, 1H), 7.33–7.42 (m, 3H), 9.48 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS): d 19.7, 20.4, 31.8, 44.9, 48.6, 124.8,
126.8, 128.8, 130.1, 133.0, 134.5, 174.4, 176.6, 202.8; IR (KBr,
White solid; ½a 2D0
ꢁ
¼ ꢀ6:9 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.32 (s, 3H), 1.43(s, 3H), 2.67 (dd, J = 5.6, 18.0 Hz,
1H), 3.02 (dd, J = 9.6, 18.0 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H),
7.58 (dt, J = 2.4, 9.2 Hz, 2H), 8.34 (dt, J = 1.6, 9.2 Hz, 2H), 9.47 (s,
1H); 13C NMR (100 MHz, CDCl3, TMS): d 20.4, 20.8, 32.2, 45.0,
49.0, 124.4, 127.1, 137.4, 147.1, 173.9, 176.2, 202.7; IR (KBr,
cmꢀ1):
m 481, 582, 624, 683, 731, 791, 808, 873, 964, 1073, 1155,
1193, 1386, 1430, 1477, 1585, 1705, 1778, 2850, 2919, 2969,
3467; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow
rate = 0.6 mL/min, k = 220 nm): tR = 22.5 min (major), 27.5 min
(minor).
cmꢀ1):
m 585, 644, 689, 718, 752, 782, 852, 1171, 1200, 1292,
1347, 1396, 1494, 1524, 1593, 1611, 1709, 1778, 2860, 2968,
3116, 3473; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = i-
PrOH = 75/25, flow rate = 0.6 mL/min, k = 220 nm): tR = 50.5 min
(major), 64.8 min (minor).
4.3.4. 2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methyl
propanal 7d4
4.3.9. 2-(2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-methylprop
White solid; ½a 2D0
ꢁ
¼ ꢀ2:5 (c 1.0, CHCl3); 1H NMR (400 MHz,
anal 7i4
CDCl3, TMS): d 1.28 (s, 3H), 1.35(s, 3H), 2.61 (dd, J = 5.2, 18.4 Hz,
1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H),
7.24 (m, 2H), 7.43 (m, 2H), 9.49 (s, 1H); 13C NMR (100 MHz, CDCl3,
TMS): d 19.9, 20.5, 32.0, 45.0, 48.7, 127.8, 129.4, 130.3, 134.5,
White solid; ½a 2D0
ꢁ
¼ ꢀ7:5 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.28 (s, 3H), 1.31(s, 3H), 2.38 (s, 3H), 2.60 (dd,
J = 5.2, 18.4 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.16 (dd,
J = 5.6, 9.6 Hz, 1H), 7.14 (m, 2H), 7.26 (m, 2H), 9.52 (s, 1H); 13C
NMR (100 MHz, CDCl3, TMS): d 19.6, 20.3, 21.2, 31.8, 45.0, 48.5,
174.5, 176.7, 202.7; IR (KBr, cmꢀ1):
m
510, 730, 773, 838, 1090,
1167, 1200, 1398, 1493, 1702, 1720, 1773, 2969, 3456; HPLC: Chi-
126.3, 129.1, 129.9, 138.8, 174.9, 177.0, 202.8; IR (KBr, cmꢀ1):
m

Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
1747
510, 669, 754, 782, 822, 1167, 1202, 1397, 1512, 1708, 1732, 1779,
2929, 2964, 3465; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25,
flow rate = 0.6 mL/min, k = 220 nm): tR = 24.9 min (major),
30.3 min (minor).
TMS) d 21.1, 21.3, 25.1, 28.2, 28.5, 31.6, 42.2, 52.4, 116.1, 116.3,
127.8, 127.9, 128.5, 174.7, 177.1, 204.5; IR (KBr, cmꢀ1):
528,
594, 654, 754, 772, 843, 878, 948, 1095, 1181, 1220, 1296, 1394,
1449, 1511, 1600, 1704, 1775, 2854, 2945, 3076, 3465; HPLC: Chi-
ralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min,
k = 220 nm): tR = 33.7 min (major), 58.2 min (minor).
m
4.3.10. 2-(1-(2,6-Dimethylphenyl)-2,5-dioxopyrrolidin-3-yl)-2-
methylpropanal 7j
White solid; ½a 2D0
ꢁ
¼ ꢀ3:0 (c 1.0, CHCl3); 1H NMR (400 MHz,
4.3.15. 1-(2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)cyclohexane
carbaldehyde 8i
CDCl3, TMS): d 1.30 (s, 3H), 1.35(s, 3H), 2.08 (s, 3H), 2.18 (s, 3H),
2.70 (dd, J = 6.4, 18.4 Hz, 1H), 3.01 (dd, J = 9.6, 18.4 Hz, 1H), 3.23
(dd, J = 6.4, 9.6 Hz, 1H), 7.12–7.15 (m, 2H), 7.21–7.26 (m, 1H),
9.53 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d 17.8, 18.0, 19.8,
20.5, 32.0, 45.5, 48.1, 128.5, 128.7, 129.5, 130.2, 135.5, 136.1,
White solid;
½
a 2D0
ꢁ
¼ ꢀ4:7 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) d 1.49–1.63 (m, 7H), 1.83–1.89 (m, 1H), 1.94–1.95 (m,
2H), 2.37 (s, 3H), 2.66 (dd, J = 6.0, 18.4 Hz, 1H), 2.86 (dd, J = 9.6,
18.0 Hz, 1H), 3.20 (dd, J = 6.0, 9.6 Hz, 1H), 7.12–7.16 (m, 2H),
7.25–7.27 (m, 2H), 9.55 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS)
d 21.2, 21.3, 21.5, 25.1, 28.1, 28.7, 31.5, 52.1, 126.3, 126.4, 129.2,
174.5, 176.6, 202.7; IR (KBr, cmꢀ1):
m 492, 665, 724, 746, 784,
864, 909, 1028, 1070, 1193, 1284, 1381, 1474, 1704, 1732, 1780,
2710, 2809, 2926, 2979, 3469; HPLC: Chiralcel OD-H (Hexanes/i-
PrOH = 75/25, flow rate = 0.6 mL/min, k = 220 nm): tR = 20.0 min
(major), 26.8 min (minor).
129.8, 138.7, 175.0, 177.1, 204.6; IR (KBr, cmꢀ1):
m 510, 671, 744,
818, 934, 1103, 1204, 1397, 1447, 1512, 1708, 1773, 2860, 2930,
3455; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow
rate = 0.6 mL/min, k = 220 nm): tR = 31.9 min (major), 36.7 min
(minor).
4.3.11. 2-(1-(2-Methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-
methylpropanal 7k
White solid; ½a 2D0
ꢁ
¼ þ4:0 (c 1.0, CHCl3); 1H NMR (400 MHz,
4.3.16. 1-(1-(2,6-Dimethylphenyl)-2,5-dioxopyrrolidin-3-yl)
cyclohexanecarbaldehyde 8j
CDCl3, TMS): d 1.28 (s, 3H), 1.30(s, 3H), 2.60 (dd, J = 5.6, 18.4 Hz,
1H), 2.98 (dd, J = 8.0, 18.0 Hz, 1H), 3.21 (dd, J = 5.2, 9.6 Hz, 1H),
3.78 (s, 3H), 6.99–7.05 (m, 2H), 7.12 (q, J = 8.0 Hz, 1H), 7.39 (t,
J = 8.0 Hz, 1H), 9.59 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d
19.5, 20.3, 31.6, 45.2, 48.1, 55.7, 112.1, 120.6, 120.9, 129.1, 130.9,
White solid;
½
a 2D0
ꢁ
¼ ꢀ2:0 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) d 1.43–1.65 (m, 7H), 1.74–1.78 (m, 1H), 1.86–2.00 (m,
2H), 2.08 (s, 3H), 2.06 (s, 3H), 2.77 (dd, J = 6.8, 18.0 Hz, 1H), 2.88
(dd, J = 9.2, 18.0 Hz, 1H), 3.27 (dd, J = 6.8, 9.2 Hz, 1H), 7.12 (t,
J = 8.0 Hz, 2H), 7.19–7.26 (m, 1H), 9.58 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS) d 17.8, 18.0, 21.3, 21.5, 25.3, 28.1, 28.8,
31.6, 42.8, 51.4, 128.4, 128.7, 129.4, 130.2, 135.5, 136.3, 174.6,
154.6, 174.8, 176.7, 202.9; IR (KBr, cmꢀ1):
m 472, 567, 623, 669,
756, 865, 1023, 1044, 1114, 1191, 1254, 1284, 1303, 1389, 1465,
1505, 1601, 1709, 1781, 2847, 2930, 2975, 3475; HPLC: AE.LI-
CHROM-AM2–5 (Hexanes/i-PrOH = 80/20, flow rate = 0.6 mL/min,
k = 220 nm): tR = 59.8 min (major), 74.2 min (minor).
176.7, 204.7; IR (KBr, cmꢀ1):
m 529, 658, 720, 747, 769, 814,
1189, 1208, 1378, 1474, 1700, 1774, 2858, 2930, 3462; HPLC: Chi-
ralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min,
k = 220 nm): tR = 17.0 min (major), 33.8 min (minor).
4.3.12. 2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
7l4
White solid; ½a 2D0
ꢁ
¼ þ7:3 (c 1.0, CHCl3); 1H NMR (400 MHz,
4.3.17. 1-(1-(2-Methoxyphenyl)-2,5-dioxo-pyrrolidin-3-yl)
cyclohexanecarbaldehyde 8k
CDCl3, TMS): d 1.15 (d, 6H), 2.45 (dd, J = 5.6, 18.4 Hz, 1H), 2.81
(dd, J = 9.2, 18.4 Hz, 1H), 3.03 (dd, J = 5.6, 9.2 Hz, 1H), 7.24–7.37
(m, 5H), 9.48 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS): d 19.0,
21.0, 31.4, 42.4, 44.9, 48.0, 128.0, 128.6, 128.7, 135.7, 175.4,
White solid;
½
a 2D0
ꢁ
¼ ꢀ6:0 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) d 1.45–1.70 (m, 7H), 1.85–2.01 (m, 3H), 2.66 (dd,
J = 5.6, 18.0 Hz, 1H), 2.85 (dd, J = 9.6, 18.0 Hz, 1H), 3.18 (dd,
J = 5.6, 9.2 Hz, 1H), 3.78 (s, 3H), 6.99–7.05 (m, 2H), 7.13 (dd,
J = 8.0, 29.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 9.55 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS) d 21.3, 22.3, 25.2, 28.1, 28.6, 29.7, 31.7,
52.0, 55.8, 112.0, 120.6, 120.9, 129.1, 130.8, 154.6, 174.8, 176.3,
177.5, 202.7; IR (KBr, cmꢀ1):
m
668, 708, 895, 1084, 1171, 1345,
1400, 1431, 1456, 1497, 1701, 1729, 1774, 2932, 2968, 3446;
HPLC: Chiralpak AD-H (Hexanes/i-PrOH = 80/20, flow
rate = 0.6 mL/min, k = 220 nm): tR = 13.2 min (major), 28.1 min
(minor).
204.7; IR (KBr, cmꢀ1):
1286, 1394, 1461, 1509, 1602, 1704, 1775, 2853, 2927, 3402;
HPLC: AE.LICHROM-AM2–5 (Hexanes/i-PrOH = 75/25, flow
m 471, 623, 675, 755, 1020, 1195, 1256,
4.3.13. 1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexanecarb
aldehyde 8a44
rate = 0.6 mL/min, k = 220 nm): tR = 58.4 min (major), 79.3 min
(minor).
White solid;
½
a 2D0
ꢁ
¼ ꢀ6:7 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) d 1.54–1.63 (m, 7H), 1.85 (d, J = 8.8 Hz, 1H), 1.96 (s,
2H), 2.64–2.68 (m, 1H), 2.86 (dd, J = 9.6, 16.0 Hz, 1H), 3.21 (m,
1H), 7.27–7.29 (m, 2H), 7.39–7.48 (m, 3H), 9.53 (s, 1H); 13C NMR
(100 MHz, CDCl3, TMS) d 21.2, 21.4, 25.1, 28.1, 28.6, 31.6, 42.7,
52.2, 126.6, 128.7, 129.2, 131.9, 174.8, 177.1, 204.6; IR (KBr,
4.3.18. 1-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)cyclohexanecarbal
dehyde 8l
White solid;
½
a 2D0
ꢁ
¼ þ1:7 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) d 1.38–1.53 (m, 7H), 1.73–1.76 (m, 2H), 1.87–1.92 (m,
1H), 2.50 (dd, J = 5.6, 18.0 Hz, 1H), 2.68 (dd, J = 9.2, 18.0 Hz, 1H),
3.03 (dd, J = 6.0, 8.8 Hz, 1H), 4.62 (dd, J = 14.4, 24.0 Hz, 2H), 7.24–
7.36 (m, 5H), 9.49 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS) d
21.3, 21.5, 25.0, 27.7, 28.7, 31.1, 42.3, 51.4, 127.8, 128.5, 135.7,
cmꢀ1):
m 627, 658, 699, 762, 1159, 1186, 1214, 1397, 1499, 1705,
1772, 2857, 2933, 3447; HPLC: Chiralcel OD-H (Hexanes/i-
PrOH = 75/25, flow rate = 0.6 mL/min, k = 220 nm): tR = 30.2 min
(major), 38.9 min (minor).
175.4, 177.5, 204.6; IR (KBr, cmꢀ1):
m
706, 927, 1083, 1169, 1343,
1399, 1431, 1454, 1697, 1773, 2854, 2934, 3450; HPLC: Chiralpak
AD-H (Hexanes/i-PrOH = 80/20, flow rate = 0.6 mL/min,
4.3.14. 1-(1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)cyclo
hexanecarbaldehyde 8b
White solid;
½
a 2D0
ꢁ
¼ ꢀ4:4 (c 1.0, CHCl3); 1H NMR (CDCl3,
k = 220 nm): tR = 14.1 min (major), 22.6 min (minor).
400 MHz) d 1.54–1.68 (m, 7H), 1.83–1.86 (m, 1H), 1.90–1.97 (m,
2H), 2.01–2.08 (m, 1H), 2.66 (dd, J = 6.0, 18.0 Hz, 1H), 2.87 (dd,
J = 9.6, 18.0 Hz, 1H), 3.22 (dd, J = 6.0, 9.6 Hz, 1H), 7.12–7.18 (m,
2H), 7.25–7.31 (m, 2H), 9.51 (s, 1H); 13C NMR (100 MHz, CDCl3,
4.3.19. 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)propanal 9a4
White solid; ½a 2D0
ꢁ
¼ ꢀ23:5 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.26 (d, J = 7.6 Hz, 3H), 2.58 (dd, J = 6.0, 18.0 Hz,

1748
Z.-w. Ma et al. / Tetrahedron: Asymmetry 22 (2011) 1740–1748
Nell, P. G.; Pernerstorfer, J.; Svenstrup, N.; Brunner, N. A.; Schiffer, G.; Freiberg,
C. Bioorg. Med. Chem. Lett. 2005, 15, 1189–1192.
1H), 2.86 (dd, J = 9.6, 17.6 Hz, 1H), 2.96–3.00 (m, 1H), 3.21–3.26 (m,
1H), 7.26–7.50 (m, 5H), 9.62 (s, 1H); 13C NMR (100 MHz, CDCl3,
TMS): d 13.9, 31.5, 39.0, 51.7, 126.7, 128.7, 129.2, 132.2, 175.1,
2. For reviews, see: (a) Berner, A. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem.
2002, 67, 1877–1894; (b) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
1688–1690; (c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 72, 1701–1716; (d)
Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007, 43, 3123–3135.
3. (a) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.;
Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem., Int. Ed. 2006, 45, 4966–4970;
(b) Ye, W.; Jiang, Z.; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh, Y. T.; Tan, C. H. Adv.
Synth. Catal. 2007, 349, 2454–2458; (c) Jiang, Z.; Ye, W.; Yang, Y.; Tan, C. H. Adv.
Synth. Catal. 2008, 350, 2345–2351; (d) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee,
R.; Yang, Y.; Huang, K. W.; Wong, M. W.; Tan, C. H. Angew. Chem., Int. Ed. 2009,
48, 3627–3631.
4. (a) Zhao, G.-L.; Xu, Y.-M.; Sundén, H.; Eriksson, L.; Sayah, M.; Córdova, A. Chem.
Commun. 2007, 43, 734–735; (b) Xue, F.; Liu, L.; Zhang, S.-L.; Duan, W.-H.;
Wang, W. Chem. Eur. J. 2010, 27, 7979–7982; (c) Bai, J.-F.; Peng, L.; Wang, L.-L.;
Wang, L.-X.; Xu, X.-Y. Tetrahedron 2010, 66, 8928–8932; (d) Yu, F.; Jin, Z.-C.;
Huang, H.-C.; Ye, T.-T.; Liang, X.-M.; Ye, J.-X. Org. Biomol. Chem. 2010, 8, 4767–
4774; (e) Miura, T.; Nishida, S.; Masuda, A.; Tada, N.; Itoh, A. Tetrahedron Lett.
2011, 52, 4158–4160.
177.7, 201.6; IR (KBr, cmꢀ1):
m 700, 1191, 1386, 1459, 1500,
1596, 1711, 1772, 2854, 2826, 2854, 3413; HPLC: Chiralpak AD-H
(Hexanes/i-PrOH = 80/20, flow rate = 0.5 mL/min, k = 210 nm): ma-
jor diastereomer: tR = 24.8 min (major), 26.2 min (minor); minor
diastereomer: tR = 21.8 min (minor), 42.4 min (major).
4.3.20. 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)hexanal 10a4
White solid; ½a 2D0
ꢁ
¼ ꢀ20:4 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d 1.30 (t, J = 5.6 Hz, 3H), 1.26–1.34 (m, 4H), 1.60–
1.66 (m, 2H), 2.63 (dd, J = 5.6, 18.4 Hz, 1H), 2.99 (dd, J = 9.6,
18.4 Hz, 1H), 3.16 (dd, J = 5.6, 9.6 Hz, 1H), 3.34 (dd, J =8.8,
18.4 Hz, 1H), 7.27–7.33 (m, 2H), 7.38–7.51 (m, 3H), 9.52 (s, 1H);
13C NMR (100 MHz, CDCl3, TMS): d 14.1, 22.7, 29.3, 29.7, 31.9,
37.1, 48.6, 126.4, 126.5, 128.8, 129.0, 129.2, 129.3, 172.2, 174.8,
5. For reviews, see: (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46–58; (b) Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E. Chem.
Soc. Rev. 2003, 32, 115–129.
202.7; IR (KBr, cmꢀ1):
m 753, 1199, 1229, 1379, 1401, 1459, 1501,
6. For some selected examples: (a) Jiang, X.-X.; Zhang, Y.-F.; Chan, A. S. C.; Wang,
R. Org. Lett. 2009, 11, 153–156; (b) Chen, J.-R.; Cao, Y.-J.; Zou, Y.-Q.; Tan, F.; Fu,
L.; Zhu, X.-Y.; Xiao, W.-J. Org. Biomol. Chem. 2010, 8, 1275–1279; (c) Chen, J.-R.;
Zou, Y.-Q.; Fu, L.; Ren, F.; Tan, F.; Xiao, W.-J. Tetrahedron 2010, 66, 5367–5372.
7. For reviews concerning thiourea catalysis, see: (a) Takemoto, Y. Org. Biomol.
Chem. 2005, 3, 4299–4306; (b) Connon, S. J. Chem. Eur. J. 2006, 12, 5419–5427;
(c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543; (d)
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743; (e) Connon, S. J.
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Soc. Rev. 2009, 38, 1187–1198.
1719, 1746, 2853, 2923, 2956, 3489; HPLC: Chiralpak AD-H (Hex-
anes/i-PrOH = 80/20, flow rate = 0.5 mL/min, k = 210 nm): major
diastereomer: tR = 31.6 min (minor), 47.0 min (major); minor dia-
stereomer: tR = 38.6 min (major), 45.1 min (minor).
4.4. General procedure for large-scale Michael additions
The isobutyraldehyde 5a (0.2 mol) was added to a mixture of
catalyst 1 (250 mg, 0.5 mol %), PhCOOH (600 mg, 5 mol %) and
the corresponding maleimide 6 (0.1 mol) in CHCl3 (250 mL). The
reaction mixture was stirred at ambient temperature for the re-
quired time as indicated in Tables 5. After the maleimide was con-
sumed by TLC analysis, the solvent was removed under reduced
pressure and the crude product was purified using column chro-
matography eluting with ethyl acetate. The enantiomeric excess
of the products was determined by chiral HPLC analysis using chi-
ral columns.
8. For some selected examples of primary thiourea catalysis in organocatalytic
asymmetric Michael reactions, see: (a) Tsogoeva, S. B.; Wei, S. Chem. Commun.
2006, 29, 1451–1453; (b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 6366–6370; (c) Cao, Y.-J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.; Xiao,
W.-J. Tetrahedron Lett. 2007, 48, 21–24; (d) Li, P.-F.; Wang, Y.-C.; Liang, X.-M.;
Ye, J.-X. Chem. Commun. 2008, 44, 3302–3304; (e) Gu, Q.; Guo, X.-T.; Wu, X.-Y.
Tetrahedron 2009, 65, 5265–5270; (f) Kokotos, C. G.; Kokotos, G. Adv. Synth.
Catal. 2009, 351, 1355–1362; (g) Ma, H.; Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.;
Ma, J.-A. J. Org. Chem. 2010, 75, 1402–1409; (h) Zhou, Y.-F.; Li, X.; Li, W.-J.; Wu,
C.-L.; Liang, X.-M.; Ye, J.-X. Synlett 2010, 15, 2357–2360; (i) Wen, S.-G.; Li, P.-F.;
Wu, H.-B.; Yu, F.; Liang, X.-M.; Ye, J.-X. Chem. Commun. 2010, 46, 4806–4808; (j)
Li, B.-L.; Wang, Y.-F.; Luo, S.-P.; Zhong, A.-G.; Li, Z.-B.; Du, X.-H.; Xu, D.-Q. Eur. J.
Org. Chem. 2010, 656–662; (k) Li, B.-L.; Wang, Y.-F.; Luo, S.-P.; Zhong, A.-G.; Li,
Z.-B.; Du, X.-H.; Xu, D.-Q. Eur. J. Org. Chem. 2010, 656–662.
9. (a) Wu, Y.; Dai, G.-F.; Yang, J.-H.; Zhang, Y.-X.; Zhu, Y.; Tao, J.-C. Bioorg. Med.
Chem. Lett. 2009, 19, 1818–1821; (b) Wu, Y.; Yang, J.-H.; Dai, G.-F.; Liu, C.-J.;
Tian, G.-Q.; Ma, W.-Y.; Tao, J.-C. Bioorg. Med. Chem. 2009, 17, 1464–1473; (c)
Wu, Y.; Liu, C.-J.; Liu, X.; Dai, G.-F.; Du, J.-Y.; Tao, J.-C. Helv. Chim. Acta. 2010, 93,
2052–2069.
10. For selected studies: (a) Fu, Y.-Q.; Li, Z.-C.; Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.;
Tang, M.-S. Tetrahedron: Asymmetry 2006, 17, 3351–3357; (b) Fu, Y.-Q.; An, Y.-
J.; Liu, W.-M.; Li, Z.-C.; Zhang, G.; Tao, J.-C. Catal. Lett. 2008, 124, 397–404; (c)
An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu, Z.-M.; Pi, C.; Tao, J.-C. Tetrahedron:
Asymmetry 2010, 21, 688–694; (d) An, Y.-J.; Wang, C.-C.; Xu, Y.-Z.; Wang, W.-
J.; Tao, J.-C. Catal. Lett. 2011, 141, 1123–1129.
Acknowledgments
We are grateful for the financial support of the National Natural
Science Foundation of China (NSFC 20772113) and the Doctoral
Foundation of Henan Institute of Engineering (D09002).
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