Asymmetric michael addition of α-substituted isocyanoacetates with maleimides catalyzed by chiral tertiary amine thiourea

Article abstract of DOI:10.1021/jo2025288

A highly diastereoselective and enantioselective Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by bifunctional tertiary amine thioureas has been developed. Various chiral succinimide derivatives bearing adjacent quaternary and tertiary stereocenters were prepared in excellent yields (up to 98%), diastereoselectivities (up to 99:1), and enantioselectivities (up to 98% ee). The synthetic utility of chiral succinimide derivatives is also demonstrated in the preparation of h5-HT_1d receptor agonist motifs.

Full text of DOI:10.1021/jo2025288

Note
pubs.acs.org/joc
Asymmetric Michael Addition of α-Substituted Isocyanoacetates
with Maleimides Catalyzed by Chiral Tertiary Amine Thiourea
Jian-Fei Bai,†,‡ Liang-Liang Wang,†,‡ Lin Peng,† Yun-Long Guo,†,‡ Li-Na Jia,†,‡ Fang Tian,†
Guang-Yun He,† Xiao-Ying Xu,*,† and Li-Xin Wang*,†
†Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China
‡Graduate School of Chinese Academy of Sciences, Beijing, China
S
* Supporting Information
ABSTRACT: A highly diastereoselective and enantioselective
Michael addition of α-substituted isocyanoacetates with
maleimides catalyzed by bifunctional tertiary amine thioureas
has been developed. Various chiral succinimide derivatives
bearing adjacent quaternary and tertiary stereocenters were
prepared in excellent yields (up to 98%), diastereoselectivities
(up to 99:1), and enantioselectivities (up to 98% ee). The
synthetic utility of chiral succinimide derivatives is also
demonstrated in the preparation of h5-HT1d receptor agonist
motifs.
he enantioselective construction of adjacent quaternary
and tertiary stereocenters is one of the most demanding
basis of the concept of bifunctional catalysis, we envisioned that
the addition of α-isocyanoacetates to maleimides may be
realized in the presence of chiral tertiary amine thiourea
catalysts. α-Isocyanoacetates with two electron-withdrawing
substituents at the α-position (an isocyanide group and a
carboxylic group) can be easily deprotonated by tertiary amine,
and the maleimide may be activated by the thiourea moiety
through double H-bondings (Scheme 1). Thus the synergistic
T
key steps in the stereocontrolled synthesis of complex natural
compounds and pharmaceuticals.1 To date, numerous strategies
have been developed.2 A generally applied and feasible way is
the conjugate addition of a prochiral trisubstituted nucleophile
with α,β-substituted acceptor. Among them, α-substituted
isocyanoacetate participated conjugate addition has shown a
promising strategy. Isocyanoacetate derivatives are versatile and
useful building blocks for the synthesis of nitrogen-containing
compounds such as branched amino acids and various
peptides.3 Therefore, the development of effective catalytic
systems for the asymmetric addition of α-substituted
isocyanoacetate to construct adjacent quaternary and tertiary
stereocenters is needed. Up to now, isocyanoacetates react with
many acceptors, such as aldehydes, imines, nitroalkenes,
azodicarboxylates, and α,β-unsaturated carbonyl compounds,
and afford cyclic compounds in most reported cases.4 To the
best of our knowledge, the use of maleimide as an acceptor has
not been reported.5 Interestingly, both Michael addition and [3
+ 2] cycloaddition reactions are possible in the reaction of
isocyanoacetates and maleimides. Both reactions are straightfor-
ward methods to synthesize chiral substituted succinimides,
valuable structural motifs in molecules with interesting
biological activities such as branched chiral amino acids and
natural products.6 Therefore, it is highly desirable to develop
catalytic asymmetric protocols using isocyanoacetates and
maleimides.
Scheme 1. Proposed Organocatalytic Reaction of α-
Substituted Isocyanoacetate and Maleimides
interactions of bifunctional catalysis would ensure high
stereoselectivity in the Michael addition or the [3 + 2]
cycloaddition. As a part of our continuing interest in
asymmetric synthesis,8 herein we wish to report the first
asymmetric Michael addition of α-substituted isocyanoacetates
to maleimides catalyzed by chiral tertiary amine thioureas.
Noteworthy is that the reaction affords multifunctionalized
succinimides bearing both a quaternary and a tertiary
Over the past years, bifunctional thiourea catalysts, powerful
tools to simultaneously activate both donors and acceptors to
induce high enantioselectivity and diastereoselectivity, have
been investigated extensively in asymmetric catalysis.7 On the
Received: December 13, 2011
Published: February 27, 2012
© 2012 American Chemical Society
2947
dx.doi.org/10.1021/jo2025288 | J. Org. Chem. 2012, 77, 2947−2953

The Journal of Organic Chemistry
Note
Scheme 2. Evaluated Bifunctional Catalysts 4a−4i
a
Table 1. Catalyst Screening
b
c
d
entry
catalyst
time (h)
yield (%)
d.r.
ee (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
54
10
10
10
10
10
72
20
20
55
64
99:1
99:1
99:1
99:1
99:1
99:1
n.d.
25
65
78
58
79
82
73
45
80
66
4g
4h
4i
trace
65
n.d.
70
99:1
99:1
48
57
a
Unless noted, all reactions were carried out with 1a (17.5 mg, 0.10 mmol), 2a (17.3 mg, 0.10 mmol), and 4 (10 mol %) in CH2Cl2 (0.5 mL) at 30
b
c
d
1
°C. Isolated yield. Determined by chiral HPLC and H NMR. Enantiomeric excesses were determined by chiral HPLC analysis.
a
Table 2. Optimization of Reaction Conditions
b
c
entry
solvent
CH2Cl2
temp (°C)
time (h)
yield (%)
ee (%)
1
30
30
17
17
17
17
17
17
17
17
18
20
18
20
24
60
72
79
78
76
76
84
87
84
83
88
93
88
89
88
87
81
82
76
71
78
84
80
81
84
92
94
86
89
91
93
92
2
CHCl3
3
ClCH2CH2Cl
toluene
30
4
30
5
p-xylene
30
6
m-xylene
30
7
mesitylene
chlorobenzene
p-xylene
30
8
30
9
26
10
11
12
13
14
15
p-xylene
15
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
26
0
−10
−20
−30
a
Unless noted, all reactions were carried out with 1a (17.5 mg, 0.10 mmol), 2a (17.3 mg, 0.10 mmol), and 4d (10 mol %) in 0.5 mL of anhydrous
b
c
solvent. Isolated yield. Generally, 99:1 d.r. was observed. Enantiomeric excesses were determined by chiral HPLC analysis.
2948
dx.doi.org/10.1021/jo2025288 | J. Org. Chem. 2012, 77, 2947−2953

The Journal of Organic Chemistry
Note
a
Table 3. Scope of N-Substituted Maleimides
b
c
de
,
entry
R3
product
yield (%)
d.r.
ee (%)
1
2
3
4
5
6
7
8
9
Ph
3a
3b
3c
3d
3e
3f
93
98
93
95
98
98
97
96
91
74
95
63
95
99:1
99:1
99:1
99:1
99:1
97:3
99:1
98:2
80:20
85:15
85:15
95:5
90:10
94
91
92
90
90
90
90
98
96
60
85
74
61
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
4-CH3-C6H4
4-CH3O-C6H4
3-F-C6H4
3-OH-C6H4
CH3
3g
3h
3i
f
10
3j
f
11
Bn
3k
3l
f
12
cyclohexyl-
allyl-
f
13
3m
a
Unless noted, all reactions were carried out with 1a (0.20 mmol), 2 (0.2 mmol), and 4d (10 mol %) in 1.0 mL of p-xylene at 15 °C for 18 h.
b
c
d
e
1
Isolated yield. Determined by chiral HPLC and H NMR. Enantiomeric excesses were determined by chiral HPLC analysis. The absolute
f
configuration was determined by single crystal X-ray analysis of 3q. The reaction time was 30 h.
a
Table 4. Scope of Isocyanoacetates
b
c
d
entry
1
1
R3
3
time (h)
yield (%)
d.r.
ee (%)
1a
1b
1c
1d
1d
1d
1d
1d
Ph
Ph
Ph
Ph
3a
3n
3o
3p
3q
3r
3s
3t
18
72
72
18
18
30
30
18
93
71
65
98
92
76
79
94
99:1
94
f
e
2
55:45
55:45
99:1
58/10
e
f
3
54/16
4
5
6
7
92
86
4-Br-C6H4
CH3
93:7
75:25
70:30
96:4
72
Bn
77
g
8
4-Br-C6H4
−90
a
Unless noted, all reactions were carried out with 1 (0.20 mmol), 2 (0.20 mmol), and 4d (10 mol %) in 1.0 mL of p-xylene at 15 °C for 18 h.
b
c
d
e
Isolated yield. Determined by chiral HPLC and 1HNMR. Enantiomeric excesses were determined by chiral HPLC analysis. 20 mol % of catalyst
f
g
was used. ee of minor diastereomer. In this case, catalyst (R,R)-4d was used.
stereocenter that can be easily transformed to chiral bicyclic aza
compounds.
To validate our hypothesis, we selected the reaction between
α-phenylisocyano acetate (1a) and N-phenylmaleimide (2a) in
the presence of various tertiary amine-thioureas 4a−4i (Scheme
2).
As shown in Table 1, catalyst 4b with a chiral cyclohexane-
1,2-diamine skeleton gave better yield and enantioselectivity
than catalyst 4a with chiral 1,2-diphenylethylene-diamine
skeleton (Table 1, entry 1 vs 2). So other thiourea catalysts
derived from 4b skeleton were then synthesized and evaluated
(Table 1, entries 3−7). The effect of substituents on nitrogen
atoms of the catalyst was examined first. Higher enantiose-
lectivities were observed for the cyclic substituted amines 4c−4f
except benzocyclic substituted 4g (Table 1, entries 2 vs 4, 6, 7).
A pyrrolidine substituted catalyst 4d gave 3a in 82% ee, and the
corresponding piperidine substituted catalyst 4f gave 66% ee
(Table 1, entries 4 and 6). Catalyst 4g did not give the desired
adduct (Table 1, entry 7). The substitution on the thiourea
moiety was also studied. A bis(trifluoromethyl)phenyl group
afforded better enantioselectivity (Table 1, entries 3 vs 4, 5 vs
6), possibly because of the acidity of the N−H in the thiourea
group. The use of cinchona alkaloid derived thioureas 4h and 4i
did not provide better results in catalytic activity and
enantioselectivity (Table 1, entries 8 and 9). Thus, catalyst
4d was chosen for further optimization of solvents and reaction
temperature (Table 2).
Most commonly used solvents are compatible with our
asymmetric conditions and afforded good yields (65−87%)
with excellent diastereoselectivities (up to 99:1) and varied
enantioselectivities (Table 2, entries 1−8). When the reaction
was carried out in chlorinated solvents, product 3a was isolated
in almost unchanged yields and slightly decreased enantiose-
lectivities (Table 2, entries 1−3). Aromatic hydrocarbon
2949
dx.doi.org/10.1021/jo2025288 | J. Org. Chem. 2012, 77, 2947−2953

The Journal of Organic Chemistry
Note
solvents afforded good yields and enantioselectivities (76−87%
yields; 78−84% ee; Table 2, entries 4−8). p-Xylene and
chlorobenzene gave almost same results and were chosen as
candidate solvents for further screening of temperature. At a
lower temperature (15 °C), p-xylene gave the best result (93%
yield and 94% ee; Table 2, entry 10) and was chosen as a
suitable reaction media. On the basis of the above screening,
the optimal reaction conditions, 1.0 equiv of 1a and 1.0 equiv of
2a in p-xylene with 10 mol % catalyst 4d at 15 °C, were
established.
transformed to the corresponding α-amino acid derivatives 5a
and 5b with concentrated HCl in EtOH in good yields (86 and
Scheme 3. Synthetic Utility of Adducts 3
To broaden the substrate scope, a variety of N-substituted
maleimides were further examined, and the results were shown
in Table 3, Generally, most substrates provided excellent yields
and high stereoselectivities. The substitution position on the
maleimides had a minor influence on the enantioselectivity.
Either electron-withdrawing or electron-donating groups at
para- or meta-positions afforded the desired products with
excellent yields (up to 98%), diastereoselectivities (up to 99:1),
and enantioselectivities (up to 98% ee) (Table 3, entries 1−9).
Less reactive N-alkyl substitued maleimides gave moderate to
good diasteroselectivites and enantioselectivities (Table 3,
entries 10−13).
The substrate scope of various α-substituted isocyanoacetates
was also evaluated (Table 4). It was found that the α-
substituted group of isocyanoacetate was critical. When R2 was
changed from phenyl to benzyl or methyl, only moderate yields,
diastereoselectivities, and enantioselectivities were obtained
(Table 4, entries 2 and 3). Variation on the ester moiety was
then considered. Ethyl isocyanoacetate 1d reacted well with N-
arylmaleimides and gave excellent results (Table 4, entries 4
and 5), whereas N-alkyl substituted maleimides gave only
moderate yields, disastereoselectivities, and enantioselectivities
(Table 4, entries 6 and 7). When the catalyst was changed from
(S,S)-4d to (R,R)-4d, the corresponding (S,S)-enantiomer of
3q was obtained with a comparable yield and selectivity (Table
4, entry 8).
87%).11 Ring-opening reaction with DMAP/CH3OH followed
by cyclization led to chiral bicyclic γ-lactam derivative 6a and
6b in 77 and 79% yield.12 After reduction with LiAlH4 and
protection using TsCl, octahydropyrrolo[3,4-b]pyrroles 7a and
7b, the basic unit of h5-HT1d receptor agonists, were isolated in
55−61% yields and 90−92% ee.9,13
In conclusion, we have developed a highly diastereoselective
and enantioselective Michael addition of α-substituted
isocyanoacetate to maleimides catalyzed by a chiral tertiary
amine thiourea. The construction of adjacent quaternary and
tertiary stereocenters was possible in excellent yields (up to
98%), diastereoselectivities (up to 99:1), and enantioselectiv-
ities (up to 98% ee). After simple synthetic transformations,
chiral octahydropyrrolo[3,4-b]pyrroles were successfully pre-
pared. Further application of this reaction to other substrates
and to the preparation of biologically relevant compounds are
currently underway.
To determine the absolute configuration of the products, X-
ray analysis was performed on a single crystal of compound 3q.
The absolute configuration was assigned as (6R,7R).9 On the
basis of the above results and commonly accepted mechanism,
we proposed a plausible transition state model as shown in
Figure 1. α-Phenylisocyanoacetate (1a) and N-phenylmalei-
mide (2a) would be activated by tertiary amine and thiourea
simultaneously, enolized isocyanoester attacked maleimide
EXPERIMENTAL SECTION
■
General Procedure for Asymmetric Michael Addition of α-
Substituted Isocyanoacetate and Maleimides. A mixture of α-
substituted isocyanoacetate (0.20 mmol), N-arylmaleimides (0.20
mmol), and catalyst 4d (0.02 mmol) was stirred in p-xylene (1.0 mL)
at 15 °C for 18 h (monitored by TLC). After evaporation under the
reduced pressure, the residue was purified through column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate
= 3/1) to yield pure products.
(R)-Methyl 2-((R)-2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-isocyano-
2-phenylacetate (3a). Yield 93%; white solid: [α]20 = −52.0 (c
D
1
0.56, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.64−7.61 (m, 2H),
7.48−7.41 (m, 6H), 7.29 (d, J = 6.93 Hz, 2H), 4.41 (dd, J = 6.0 Hz,
9.41 Hz, 1H), 3.85 (s, 3H), 2.78 (dd, J = 9.45 Hz, 18.57 Hz, 1H), 2.49
(dd, J = 5.97 Hz, 18.57 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 174.4,
172.9, 166.5, 164.5, 131.9, 131.2, 129.9, 129.5, 129.2, 129.0, 126.5,
125.4, 71.1, 54.4, 48.3, 30.6; HRMS (ESI) for C20H16N2NaO4 [M +
Na]+ calcd 371.1002, found 371.0992; IR (KBr) ν = 3480, 2135, 1783,
1750, 1716, 1267, 1041 cm−1. Enantiomeric excess: 94%, determined
by HPLC (Chiralpak AD-H column, hexane/2-propanol = 50/50, 0.6
mL/min, 220 nm), tR (minor) = 16.37 min, tR (major) = 26.42 min.
(R)-Methyl 2-((R)-1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
Figure 1. Proposed transition state model.
from si-face and the corresponding product with (R,R)-
configuration was obtained.10
Michael adducts 3 are valuable building blocks for
asymmetric synthesis, especially for the synthesis of chiral
unnatural α-amino acids with a quaternary stereocenter as well
as nitrogen-containing bicyclic compounds. As shown in
Scheme 3, two enantiomers of compound 3q were readily
isocyano-2-phenylacetate (3b). Yield 98%; white solid: [α]20
=
D
1
−43.9 (c 0.58, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.65−7.62
(m, 2H), 7.49−7.47 (dd, J = 2.78 Hz, 5.0 Hz, 3H), 7.32−7.26 (m,
2950
dx.doi.org/10.1021/jo2025288 | J. Org. Chem. 2012, 77, 2947−2953

The Journal of Organic Chemistry
Note
2H), 7.19−7.13 (m, 2H), 4.43 (dd, J = 5.93 Hz, 9.42 Hz, 1H), 3.87 (s,
3H), 2.80 (dd, J = 9.45 Hz, 18.64 Hz, 1H), 2.51 (dd, J = 5.92 Hz,
18.62 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 173.4, 172.9, 166.5,
164.5, 162.5 (JC−F = 247.8 Hz), 131.8, 130.0, 129.3, 128.4, 127.0,
125.4, 116.4 (JC−F = 23.0 Hz), 71.1, 54.4, 48.2, 30.6; HRMS (ESI) for
C20H15FN2NaO4 [M + Na]+ calcd 389.0908, found 389.0897; IR
(KBr) ν = 3483, 2134, 1785, 1754, 1715, 1197, 1030 cm−1.
Enantiomeric excess: 90%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 50/50, 0.6 mL/min, 220 nm), tR
(minor) = 15.58 min, tR (major) = 27.79 min.
(R)-Methyl 2-((R)-1-(3-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (3h). Yield 96%; white solid: [α]20
=
D
1
(KBr) ν = 3487, 2134, 1787, 1754, 1720, 1246, 1068 cm−1
.
−50.1 (c 0.63, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.65−7.62
(m, 2H), 7.49−7.43 (m, 4H), 7.13−7.08 (m, 3H), 4.43 (dd, J = 6.0
Hz, 9.39 Hz, 1H), 3.88 (s, 3H), 2.81 (dd, J = 9.48 Hz, 18.62 Hz, 1H),
2.52 (dd, J = 6.0 Hz, 18.63 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
173.0, 172.5, 166.5, 164.5, 162.6 (JC−F = 246 Hz), 132.4, 131.8, 130.4
(JC−F = 8.8 Hz), 129.9, 129.5, 125.4, 122.1(3.3), 116.1 (JC−F = 20.7
Hz), 114.1 (JC−F = 24.3 Hz), 71.1, 54.5, 48.2, 30.6; HRMS (ESI) for
C20H15FN2NaO4 [M + Na]+ calcd 389.0908, found 389.0893; IR
(KBr) ν = 3482, 2135, 1787, 1748, 1716, 1268, 1042 cm−1.
Enantiomeric excess: 98%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 50/50, 0.6 mL/min, 220 nm), tR
(minor) = 17.71 min, tR (major) = 21.31 min.
Enantiomeric excess: 91%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 50/50, 0.6 mL/min, 220 nm), tR
(minor) = 17.45 min, tR (major) = 24.82 min.
(R)-Methyl 2-((R)-1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (3c). Yield 93%; white solid: [α]20
=
D
−55.0 (c 0.64, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.63 (dd, J =
2.37 Hz, 7.67 Hz, 2H), 7.49−7.43 (m, 5H), 7.28−7.25 (m, 2H), 4.43
(dd, J = 6.0 Hz, 9.42 Hz, 1H), 3.87 (s, 3H), 2.79 (dd, J = 9.45 Hz,
18.63 Hz, 1H), 2.50 (dd, J = 5.97 Hz, 18.63 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 173.2, 172.6, 166.5, 164.5, 134.9, 131.8, 130.0,
129.6, 129.5, 129.4, 127.7, 125.3, 71.0, 54.5, 48.2, 30.6; HRMS (ESI)
for C20H15ClN2NaO4 [M + Na]+ calcd 405.0613, found 405.0603; IR
(KBr) ν = 3473, 2132, 1744, 1715, 1210, 1018 cm−1. Enantiomeric
excess: 92%, determined by HPLC (Chiralpak AD-H column, hexane/
2-propanol = 50/50, 0.6 mL/min, 220 nm), tR (minor) = 19.19 min, tR
(major) = 26.66 min.
(R)-Methyl 2-Isocyano-2-((R)-1-methyl-2,5-dioxopyrrolidin-3-yl)-
2-phenylacetate (3j). Yield 74%; colorless oil: [α]20 = −10.6 (c
D
1
0.60, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.60−7.56 (m, 2H),
7.49−7.44 (m, 3H), 4.25 (dd, J = 5.97 Hz, 9.07 Hz, 1H), 3.88 (s, 3H),
3.05 (s, 3H), 2.61 (dd, J = 9.18 Hz, 18.39 Hz, 1H), 2.33 (dd, J = 5.97
Hz, 18.39 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 174.2, 173.9, 166.5,
164.1, 132.0, 129.8, 129.4, 125.3, 70.5, 54.4, 48.3, 30.5, 25.1; HRMS
(ESI) for C15H14N2NaO4 [M + Na]+ calcd 309.0846, found 309.0845;
IR (KBr) ν = 3473, 2136, 1781, 1749, 1706, 1258, 1052 cm−1.
Enantiomeric excess: 60%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 30/70, 0.4 mL/min, 220 nm), tR
(major) = 13.63 min, tR (minor) = 14.26 min.
(R)-Methyl 2-((R)-1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (3d). Yield 95%; white solid: [α]20D = −49
(c 0.20, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.64−7.58 (m, 4H),
7.52−7.47 (m, 3H), 7.26−7.19 (m, 2H), 4.43 (dd, J = 6.05 Hz, 9.38
Hz, 1H), 3.87 (s, 3H), 2.79 (dd, J = 9.44 Hz, 18.62 Hz, 1H), 2.51 (dd,
J = 5.95 Hz, 18.61 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 173.1,
172.6, 166.4, 164.5, 132.4, 131.8, 130.1, 130.0, 129.5, 128.0, 125.3,
122.9, 71.1, 54.5, 48.3, 30.6; HRMS (ESI) for C20H15BrN2NaO4 [M +
Na]+ calcd 449.0107, found 449.0091; IR (KBr) ν = 3473, 2132, 1744,
1715, 1210, 1016 cm−1. Enantiomeric excess: 90%, determined by
HPLC (Chiralpak AD-H column, hexane/2-propanol = 50/50, 0.6
mL/min, 220 nm), tR (minor) = 19.59 min, tR (major) = 26.16 min.
(R)-Methyl 2-Isocyano-2-((R)-1-(4-nitrophenyl)-2,5-dioxopyrroli-
(R)-Methyl 2-((R)-1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-isocyano-
2-phenylacetate (3k). Yield 95%; colorless oil: [α]20 = −9.6 (c
D
1
0.52, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.92 (m, 2H), 7.59−
7.56 (m, 3H), 7.45−7.43 (m, 2H), 7.39−7.26 (m, 3H), 4.71 (m, 2H),
4.25 (dd, J = 6.24 Hz, 9.14 Hz, 1H), 3.88 (s, 3H), 2.59 (dd, J = 9.06
Hz, 18.38 Hz, 1H), 2.34 (dd, J = 6.15 Hz, 18.38 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 173.8, 173.5, 164.6, 164.5, 135.1, 132.1, 129.8,
129.4, 128.5, 127.9, 127.0, 125.3, 70.6, 53.8, 48.2, 42.8, 30.5; HRMS
(ESI) for C21H18N2NaO4 [M + Na]+ calcd 385.1159, found 385.1147;
IR (KBr) ν = 3473, 2134, 1751, 1709, 1257, 1067 cm−1. Enantiomeric
excess: 85%, determined by HPLC (Chiralpak AD-H column, hexane/
2-propanol = 50/50, 0.6 mL/min, 220 nm), tR (minor) = 14.05 min, tR
(major) = 15.17 min.
din-3-yl)-2-phenylacetate (3e). Yield 98%; white solid: [α]20
=
D
1
−54.3 (c 0.60, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 8.33 (d, J =
8.79 Hz, 2H), 7.61−7.43 (m, 7H), 4.48 (dd, J = 6.21 Hz, 9.12 Hz,
1H), 3.89 (s, 3H), 2.85 (dd, J = 9.51 Hz, 18.74 Hz, 1H), 2.56 (dd, J =
6.0 Hz, 18.78 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 172.7, 172.0,
166.3, 164.7, 147.3, 136.6, 131.6, 130.1, 129.4, 127.1, 126.8, 125.3,
71.0, 54.6, 48.4, 30.7; HRMS (ESI) for C20H15N3NaO6 [M + Na]+
calcd 416.0859, found 416.0864; IR (KBr) ν = 3433, 2133, 1751, 1723,
1526, 1384, 1247, 1088 cm−1. Enantiomeric excess: 90%, determined
by HPLC (Chiralpak AS-H column, hexane/2-propanol = 50/50, 0.6
mL/min, 220 nm), tR (minor) = 26.23 min, tR (major) = 40.84 min.
(R)-Methyl 2-((R)-2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-isocyano-
2-phenylacetate (3f). Yield 98%; white solid: [α]20D = −47.9 (c 0.48,
(R)-Methyl 2-((R)-1-Cyclohexyl-2,5-dioxopyrrolidin-3-yl)-2-isocya-
1
no-2-phenylacetate (3l). Yield 63%; white solid: H NMR (CDCl3,
300 MHz) δ 7.59−7.56 (m, 2H), 7.46−7.35 (m, 3H), 4.18 (dd, J =
5.91 Hz, 9.31 Hz, 1H), 4.01−3.99 (m, 1H), 3.87 (s, 3H), 2.56 (dd, J =
9.42 Hz, 18.44 Hz, 1H), 2.28 (dd, J = 5.85 Hz, 18.45 Hz, 1H), 2.21−
2.10 (m, 2H), 1.84−1.80 (m, 2H), 1.66−1.63 (m, 3H), 1.32−1.21 (m,
3H); 13C NMR (CDCl3, 75 MHz) δ 174.4, 174.1, 166.7, 163.9, 132.1,
129.7, 129.3, 125.3, 70.6, 54.4, 52.3, 47.6, 30.3, 28.7, 28.6, 25.7; HRMS
(ESI) for C20H22N2NaO4 [M + Na]+ calcd 377.1472, found 377.1466.
Enantiomeric excess: 73%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 50/50, 0.5 mL/min, 220 nm), tR
(minor) = 13.92 min, tR (major) = 14.75 min.
(R)-Methyl 2-((R)-1-Allyl-2,5-dioxopyrrolidin-3-yl)-2-isocyano-2-
phenylacetate (3m). Yield 95%; colorless oil: 1H NMR (CDCl3,
300 MHz) δ 7.60−7.57 (m, 2H), 7.48−7.43 (m, 3H), 5.82−5.73 (m,
1H), 5.23 (m, 2H), 4.27 (dd, J = 6.12 Hz, 9.24 Hz, 1H), 4.14 (d, J =
5.82 Hz, 2H), 3.86 (s, 3H), 2.62 (dd, J = 9.27 Hz, 18.42 Hz, 1H), 2.34
(dd, J = 6.09 Hz, 18.47 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 173.7,
166.5, 164.3, 161.5, 132.0, 130.1, 129.9, 129.3, 125.3, 118.8, 70.7, 59.6,
53.8, 41.4, 30.4; HRMS (ESI) for C17H16N2NaO4 [M + Na]+ calcd
335.1002, found 335.0992; For major isomer, Enantiomeric excess:
61%, determined by HPLC (Chiralpak OD-H column, hexane/2-
propanol = 85/15, 1.0 mL/min, 220 nm), tR (major) = 13.15 min, tR
(minor) = 17.53 min.
1
CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.65−7.62 (m, 2H), 7.50−
7.46 (m, 3H), 7.27 (d, J = 8.54 Hz, 2H), 7.18 (d, J = 8.33 Hz, 2H),
4.41 (dd, J = 5.93 Hz, 9.36 Hz, 1H), 3.86 (s, 3H), 2.78 (dd, J = 9.43
Hz, 18.56 Hz, 1H), 2.50 (dd, J = 5.96 Hz, 18.56 Hz, 1H), 2.38 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 173.5, 173.2, 166.5, 164.4, 139.2, 131.9,
129.9, 129.4, 128.5, 126.2, 125.4, 71.1, 54.4, 48.2, 30.6, 21.2; HRMS
(ESI) for C21H19N2O4 [M + H]+ calcd 363.1339, found 363.1333; IR
(KBr) ν = 3485, 2134, 1785, 1754, 1715, 1247, 1040 cm−1
.
Enantiomeric excess: 90%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 50/50, 0.6 mL/min, 220 nm), tR
(minor) = 14.60 min, tR (major) = 25.80 min.
(R)-Methyl 2-Isocyano-2-((R)-1-(4-methoxyphenyl)-2,5-dioxopyr-
rolidin-3-yl)-2-phenylacetate (3g). Yield 97%; white solid: [α]20
=
D
1
−50.7 (c 0.66, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.65−7.64
(m, 2H), 7.48−7.46 (m, 3H), 7.21 (dd, J = 2.11 Hz, 6.85 Hz, 2H),
6.97 (dd, J = 2.16 Hz, 6.85 Hz, 2H), 4.41 (dd, J = 5.90 Hz, 9.39 Hz,
1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.78 (dd, J = 9.43 Hz, 18.56 Hz, 1H),
2.49 (dd, J = 5.89 Hz, 18.56 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
173.7, 173.3, 166.5, 164.3, 159.8, 131.9, 129.9, 129.4, 127.7, 125.4,
123.7, 114.5, 71.1, 55.5, 54.5, 48.2, 30.5; HRMS (ESI) for
C21H18N2NaO5 [M + Na]+ calcd 401.1108, found 401.1094; IR
(S)-Methyl 2-((R)-2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-isocyano-
3-phenylpropanoate (3n). Yield 71%; white solid. For major isomer,
1H NMR (CDCl3, 300 MHz) δ 7.51−7.26 (m, 10H), 3.77 (s, 3H),
2951
dx.doi.org/10.1021/jo2025288 | J. Org. Chem. 2012, 77, 2947−2953

The Journal of Organic Chemistry
Note
3.72−3.66 (m, 2H), 3.31 (d, J = 6.34 Hz, 1H), 3.11−3.05 (m, 1H),
2.97−2.31 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 173.4, 173.0,
167.1, 163.7, 132.8, 131.3, 130.2, 129.8, 129.2, 128.7, 128.4, 126.6,
69.4, 53.9, 42.6, 32.0; HRMS (ESI) for C21H18N2NaO4 [M + Na]+
calcd 385.1159, found 385.1144. Enantiomeric excess: 58%,
determined by HPLC (Chiralpak AD-H column, hexane/2-propanol
= 85/15, 1.0 mL/min, 220 nm), tR (major) = 19.75 min, tR (minor) =
35.20 min.
(S)-Methyl 2-((R)-2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-isocyano-
propanoate (3o). Yield 65%; colorless oil: For major isomer, 1H
NMR (CDCl3, 300 MHz) δ 7.50−7.42 (m, 3H), 7.29−7.28 (m, 2H),
3.90 (s, 3H), 3.63−3.60 (m, 1H), 3.12−3.06 (m, 1H), 2.92−2.86 (m,
1H), 1.81 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 173.2, 173.0, 167.9,
162.2, 131.2, 129.2, 129.0, 126.5, 63.9, 54.2, 47.3, 31.8, 25.2; HRMS
(ESI) for C15H14N2NaO4 [M + Na]+ calcd 309.0846, found 309.0841.
Enantiomeric excess: 54%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 50/50, 0.5 mL/min, 220 nm), tR
(major) = 11.88 min, tR (minor) = 15.06 min.
Synthesis of 5 from 3q. To a solution of 3q (0.2 mmol) in
absolute ethanol (2 mL), a few drops of concentrated hydrochloric
acid were added, and the reaction mixture was stirred at room
temperature for 5 h. Ethanol was evaporated under reduced pressure;
the residue was dissolved in water and brought to pH 9−10 by
addition of NH4OH solution, then extracted with ethyl acetate.
Combined ethyl acetate extract was washed with water and brine. After
evaporation under the reduced pressure, the residue was purified
through column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 5/1) to gave amino ester 5.
(R)-Ethyl 2-Amino-2-((R)-1-(4-bromophenyl)-2,5-dioxopyrrolidin-
3-yl)-2-phenylacetate (5a). Yield 86%; white solid: [α]20D = −29.5 (c
0.52, CH2Cl2); 1H NMR (CHCl3, 300 MHz) δ 7.55 (dd, J = 7.61 Hz,
10.70 Hz, 4H), 7.43−7.37 (m, 3H), 7.19 (d, J = 8.47 Hz, 2H), 4.29−
4.22 (m, 3H), 2.65 (d, J = 7.60 Hz, 2H), 2.17 (br s, NH, 2H), 1.26 (t, J
= 7.11 Hz, 3H); 13C NMR (CHCl3, 75 MHz) δ 176.3, 174.7, 173.4,
139.3, 132.2, 130.6, 128.9, 128.6, 127.9, 125.4, 122.4, 64.2, 62.3, 48.4,
31.6, 13.9; HRMS (ESI) for C20H20BrN2O4 [M + H]+ calcd 431.0601,
found 431.0588. Enantiomeric excess: 86%, determined by HPLC
(Chiralpak AD-H column, hexane/2-propanol = 50/50, 0.6 mL/min,
220 nm), tR (major) = 18.50 min, tR (minor) = 22.34 min.
(R)-Ethyl 2-((R)-2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-isocyano-2-
phenylacetate (3p). Yield 98%; white solid: [α]20 = −45.5 (c 0.58,
D
1
CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.66−7.63 (m, 2H), 7.50−
Synthesis of 6 from 5. Compound 5 (0.2 mmol) was dissolved in
2 mL of methanol, and DMAP (10%) was added, and mixture stirred
at room temperature for 24 h. The mixture was evaporated under a
vacuum, and the residue was purified through column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate = 3/1) to gave 6 as
a white solid.
7.39 (m, 6H), 7.32−7.26 (m, 2H), 4.45 (dd, J = 6.0 Hz, 9.35 Hz, 1H),
4.37−4.25 (m, 2H), 2.79 (dd, J = 9.44 Hz, 18.54 Hz, 1H), 2.51 (dd, J
= 5.92 Hz, 18.58 Hz, 1H), 1.29 (t, J = 7.16 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 173.3, 173.0, 165.9, 164.2, 132.1, 131.2, 129.8,
129.4, 129.2, 129.0, 126.5, 125.4, 71.1, 64.0, 48.1, 30.7, 13.7; HRMS
(ESI) for C21H19N2O4 [M + H]+ calcd 363.1339, found 363.1329; IR
(KBr) ν =3481, 2135, 1784, 1747, 1716, 1256, 1041 cm−1
.
(3aR,6aR)-5-(4-Bromophenyl)-6a-phenyltetrahydropyrrolo[3,4-
b]pyrrole-2,4,6(5H)-trione (6a). Yield 77%; white solid: 1H NMR
(DMSO-d6, 300 MHz) δ 9.50 (s, 1H), 7.73 (d, J = 7.61 Hz, 2H),
7.52−7.45 (m, 2H), 7.42−7.16 (m, 5H), 4.01 (d, J = 6.68 Hz, 1H),
2.90−2.81 (m, 1H), 2.74−2.73 (m, 1H); 13C NMR (DMSO-d6, 75
MHz) δ 175.4, 175.1, 174.3, 138.4, 131.9, 131.2, 129.4, 128.6, 128.4,
125.8, 121.8, 68.0, 48.0, 31.9; HRMS (ESI) for C18H13BrN2NaO3 [M
+ Na]+ calcd 407.0002, found 406.9996; IR (KBr) ν = 3480, 3423,
1783, 1713, 1693 cm−1. Enantiomeric excess: 92%, determined by
HPLC (Chiralpak AD-H column, hexane/2-propanol = 50/50, 0.6
mL/min, 220 nm), tR (minor) = 70.97 min, tR (major) = 87.33 min.
Synthesis of 7 from 6. To a stirred solution of 6 (0.2 mmol) in
THF (2 mL), LiAlH4 (0.6 mmol) was added at 0 °C. After being
stirred for 0.5 h, the mixture was heated at 70 °C for 12 h. When it
cooled to 0 °C, 10% aq NaOH solution was added, and then the
mixture was filtered. The filtrate was concentrated under reduced
pressure, and the residue was chromatographed to afford the product
as yellow oil. The oil (0.1 mmol) was dissolved in DCM with
triethylamine (0.2 mmol), then p-toluenesulfonyl chloride (0.12
mmol) was added. After being stirred for 6 h at room temperature,
the mixture was evaporated under a vacuum, and the residue was
purified through column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 15/1) to give 7 as a white solid.
(3aS,6aR)-5,6a-Diphenyl-1-tosyloctahydropyrrolo[3,4-b]pyrrole
Enantiomeric excess: 92%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 50/50, 0.6 mL/min, 220 nm), tR
(minor) = 17.64 min, tR (major) = 24.20 min.
(R)-Ethyl 2-((R)-1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (3q). Yield 92%; white solid: [α]20
=
D
1
−45.6 (c 0.63, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.64−7.55
(m, 4H), 7.55−7.46 (m, 3H), 7.25−7.19 (m, 2H), 4.45 (dd, J = 5.99
Hz, 9.42 Hz, 1H), 4.38−4.25 (m, 2H), 2.79 (dd, J = 9.45 Hz, 18.63
Hz, 1H), 2.50 (dd, J = 5.96 Hz, 18.60 Hz, 1H), 1.31 (t, J = 7.11 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ 173.1, 172.6, 165.8, 164.2, 132.4,
131.9, 130.1, 129.8, 129.4, 128.0, 125.3, 122.9, 71.1, 64.0, 48.1, 30.6,
13.7; HRMS (ESI) for C21H17BrN2NaO4 [M + Na]+ calcd 463.0264,
found 463.0260; IR (KBr) ν = 3475, 2139, 1783, 1741, 1716, 1247,
1024 cm−1. Enantiomeric excess: 86%, determined by HPLC
(Chiralpak AD-H column, hexane/2-propanol = 50/50, 0.6 mL/min,
220 nm), tR (minor) = 22.56 min, tR (major) = 24.01 min.
(R)-Ethyl 2-Isocyano-2-((R)-1-methyl-2,5-dioxopyrrolidin-3-yl)-2-
phenylacetate (3r). Yield 76%; colorless oil: [α]20 = −4.8 (c 0.70,
D
1
CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.59−7.53 (m, 2H), 7.48−
7.42 (m, 3H), 4.39−4.23 (m, 3H), 2.60 (dd, J = 9.21 Hz, 18.38 Hz,
1H), 2.31 (dd, J = 6.0 Hz, 18.36 Hz, 1H), 1.31 (t, J = 7.14 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 174.2, 174.0, 165.9, 163.8, 132.1, 129.7,
129.3, 125.3, 70.8, 64.0, 48.2, 30.5, 25.1, 13.7; HRMS (ESI) for
C16H16N2NaO4 [M + Na]+ calcd 323.1002, found 323.1018; IR (KBr)
ν = 3474, 2135, 1783, 1748, 1704, 1286, 1056 cm−1. Enantiomeric
excess: 72%, determined by HPLC (Chiralpak AS-H column, hexane/
2-propanol = 80/20, 1.0 mL/min, 220 nm), tR (minor) = 9.62 min, tR
(major) = 13.11 min.
1
(7a). Yield 55%; white solid: H NMR (CDCl3, 300 MHz) δ 7.48−
7.42 (m, 4H), 7.34−7.22 (m, 5H), 7.0 (d, J = 8.0 Hz, 2H), 6.76 (t, J =
7.22 Hz, 1H), 6.53 (d, J = 8.08 Hz, 2H), 4.36 (d, J = 11.53 Hz, 1H),
4.14 (d, J = 11.51 Hz, 1H), 3.75 (t, J = 6.90 Hz, 2H), 3.48 (t, J = 10.54
Hz, 1H), 3.0−2.93 (m, 2H), 2.29 (s, 3H), 2.07 (dd, J = 5.97 Hz, 12.98
Hz, 1H), 1.87 (dd, J = 5.12 Hz, 11.97 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 146.8, 142.8, 142.4, 137.1, 129.2, 129.1, 128.3, 127.2, 126.8,
125.9, 116.6, 112.1, 78.4, 57.7, 54.2, 50.8, 48.3, 27.5, 21.3; HRMS
(ESI) for C25H27N2O2S [M + H]+ calcd 419.1788, found 419.1797.
Enantiomeric excess: 90%, determined by HPLC (Chiralpak AD-H
column, hexane/2-propanol = 80/20, 1.0 mL/min, 220 nm), tR
(minor) = 11.12 min, tR (major) = 33.73 min.
(R)-Ethyl 2-((R)-1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-isocyano-2-
phenylacetate (3s). Yield 79%; colorless oil: [α]20 = −5.0 (c 0.79,
D
1
CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.56−7.43 (m, 5H), 7.39−
7.27 (m, 5H), 4.68 (dd, J = 8.75 Hz, 18.84 Hz, 1H), 4.37−4.25 (m,
2H), 4.37−4.23 (m, 2H), 2.57−2.55 (m, 1H), 2.33 (dd, J = 6.15 Hz,
18.41 Hz, 1H), 1.32 (t, J = 7.13 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 173.8, 173.6, 165.9, 164.1, 135.1, 134.1, 132.2, 129.7, 129.3, 128.7,
128.3, 128.0, 70.8, 64.0, 48.1, 42.8, 32.2, 13.7; HRMS (ESI) for
C22H20N2NaO4 [M + Na]+ calcd 399.1315, found 399.1322; IR (KBr)
ν = 3473, 2134, 1782, 1747, 1712, 1242, 1026 cm−1. Enantiomeric
excess: 77%, determined by HPLC (Chiralpak AD-H column, hexane/
2-propanol = 50/50, 0.6 mL/min, 220 nm), tR (major) = 14.89 min, tR
(minor) = 15.50 min.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra and HPLC analysis spectra of all
compounds and X-ray structural data (CIF) of compounds 3q
2952
dx.doi.org/10.1021/jo2025288 | J. Org. Chem. 2012, 77, 2947−2953

The Journal of Organic Chemistry
Note
Chem. Soc., Perkin Trans. 1 2000, 2862. (d) Ahmed, S. Drug Des.
Discovery 1996, 14, 77.
and 7b. This material is available free of charge via the Internet
at http://pubs.acs.org.
(7) For some recent reviews concerning bifunctional thiourea
organocatalysis: (a) Taylor, M. S.; Jacobsen, E. N. Chem. Rev. 2007,
107, 5713. (b) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 1520. For recent reviews on organocatalytic asymmetric
conjugate additions: (c) Moyano, A.; Rios, R. Chem. Rev. 2011, 111,
4703. (d) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem.
Rev. 2011, 111, 2626. (e) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 11,
1701.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wlxioc@cioc.ac.cn; xuxy@cioc.ac.cn.
Notes
■
The authors declare no competing financial interest.
(8) (a) Bai, J.-F.; Peng, L.; Wang, L.-L.; Xu, X.-Y.; Wang, L.-X.
Tetrahedron 2010, 66, 8928. (b) Bai, J.-F.; Xu, X.-Y.; Huang, Q.-C.;
Peng, L.; Wang, L.-X. Tetrahedron Lett. 2010, 51, 2803. (c) Bai, J.-F.;
Wang, L.-L.; Peng, L.; Guo, Y.-L.; Ming, J.-N.; Wang, F.-Y.; Xu, X.-Y.;
Wang, L.-X. Eur. J. Org. Chem. 2011, 4472. (d) Wang, L.-L.; Peng, L.;
Bai, J.-F.; Jia, L.-N.; Luo, X.-Y.; Huang, Q.-C.; Xu, X.-Y.; Wang, L.-X.
Chem. Commun. 2011, 47, 5593.
(9) CCDC 867331 and 851295 contain the supplementary
crystallographic 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.
ACKNOWLEDGMENTS
■
We are grateful for the partial financial support from National
Natural Science Foundation of China (No. 20802075 and
No.21042006).
REFERENCES
■
(1) For a recent book: Quaternary Stereocenters; Christoffers, J.; Baro,
A., Eds.; Wiley-VCH: Weinheim, 2005. For some recent reviews on
quaternary stereocenters: (a) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295. (b) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(c) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(10) Hamza, A.; Gab
128, 13151.
́ ́ ́
or, S.; Soos, T.; Papai, I. J. Am. Chem. Soc. 2006,
(2) For selected examples on the stereoselective construction of
adjacent quaternary and tertiary stereocenters: (a) Zhou, L.; Lin, L.-L.;
Ji, J.; Xie, M.-S.; Liu, X.-H.; Feng, X.-M. Org. Lett. 2011, 13, 3056.
(b) Trost, B. M.; Zhang, Y. Chem.Eur. J. 2010, 16, 296. (c) Xiu, Q.-
D.; Teng, H.-L.; Tong, M.-C.; Huang, H.; Tao, H.-Y.; Wang, C.-J.
Chem. Commun. 2010, 46, 6840. (d) Bui, T.; Syed, S.; Barbas, C. F. J.
Am. Chem. Soc. 2009, 131, 8758. (e) Galzerano, P.; Bencivenni, G.;
Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.;
Melchiorre, P. Chem.Eur. J. 2009, 15, 7846. (f) Wu, F.; Hong, R.;
Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301.
(g) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 6366.
(11) Sambasivarao, K.; Enugurthi, B. J. Org. Chem. 2000, 65, 1359.
(12) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776.
(13) (a) Zhao, C.; Sun, M.-H.; Bennani, Y. L.; Miller, T. R.; Witte, D.
G.; Esbenshade, T. A.; Wetter, J.; Marsh, K. C.; Hancock, A. A.; Brioni,
J. D.; Cowart, M. D. J. Med. Chem. 2009, 52, 4640. (b) Mahalingam,
P.; Raghavachary, R. Tetrahedron Lett. 2008, 64, 6461. (c) Russel, M.
G. N.; Beer, M. S.; Stanton, J. A.; Sohal, B.; Mortishire Smith, R. J.;
Casro, J. L. Bioorg. Med. Chem. Lett. 1999, 9, 2491. (d) Mahalingam,
P.; Raghavachary, R. Tetrahedron: Asymmetry 2008, 19, 2177.
(3) For some reviews on isocyanoacetate: (a) Alexander, V. L.; de
Mejiere, A. Angew. Chem., Int. Ed. 2010, 49, 9094. (b) Gulevich, A. V.;
Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010,
110, 5235.
(4) For selected examples of the asymmetric additions to
isocyanoacetates: (a) Sladojevich, F.; Trabocchi, A.; Guarna, A.;
Dixon, D. J. J. Am. Chem. Soc. 2011, 133, 1710. (b) Arron
́
iz, C.; Gil-
Gonzalez, A.; Semak, V.; Escolano, C.; Bosch, J.; Amat, M. Eur. J. Org.
́
Chem. 2011, 3755. (c) Kim, H. Y.; Oh, K. Org. Lett. 2011, 13, 1306.
(d) Monge, D.; Jensen, K. L.; Marín, I.; Jørgensen, K. A. Org. Lett.
2011, 13, 328. (e) Song, J.; Guo, C.; Chen, P.-H.; Yu, J.; Luo, S.-W.;
Gong, L.-Z. Chem.Eur. J. 2011, 17, 7786. (f) Zhang, Z.-W.; Lu, G.;
Chen, M.-M.; Lin, N.; Li, Y.-B.; Hayashi, T.; Chan, A. S. C.
Tetrahedron: Asymmetry 2010, 21, 1715. (g) Zhang, L.-J.; Xu, X.-X.;
Tan, J.; Pan, L.; Xia, W.-M.; Liu, Q. Chem. Commun. 2010, 46, 3357.
(h) Xue, M.-X.; Guo, C.; Gong, L.-Z. Synlett 2009, 2191. (i) Guo, C.;
Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47,
3414.
(5) For selected examples of the asymmetric additions to maleimides:
(a) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan,
W.-C. Adv. Synth. Catal. 2011, 353, 1720. (b) Wang, J.-J.; Dong, X.-J.;
Wei, W.-T.; Yan, M. Tetrahedron: Asymmetry 2011, 22, 690. (c) Zea,
A.; Valero, G.; Alba, A.-N. R.; Moyano, A.; Rios, R. Adv. Synth. Catal.
2010, 352, 1102. (d) Xue, F.; Liu, L.; Zhang, S.; Duan, W.; Wang, W.
Chem.Eur. J. 2010, 16, 7979. (e) Zhao, G.-L.; Xu, Y.; Eriksson, L.;
́
Sayah, M.; Cordova, A. Chem. Commun. 2007, 734. (f) Liao, Y.-H.;
Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett.
2010, 12, 2896.
(6) For selected studies on chiral substituted succinimides:
(a) Pohlmann, J.; Lampe, T.; Shimada, M.; Nell, P. G.;
Pernerstorfer, J.; Svenstrup, N.; Brunner, N. A.; Schiffer, G.;
Freiberg, C. Bioorg. Med. Chem. Lett. 2005, 15, 1189. (b) Curtin, M.
L.; Garland, R. B.; Heyman, H. R.; Frey, R. R.; Michaelidies, M. R.; Li,
J.; Pease, L. J.; Glaser, K. B.; Marcotte, P. A.; Davidsen, S. K. Bioorg.
Med. Chem. Lett. 2002, 12, 2919. (c) Mitchinson, A.; Nadin, A. J.
2953
dx.doi.org/10.1021/jo2025288 | J. Org. Chem. 2012, 77, 2947−2953