Direct asymmetric allylic alkenylation of N-itaconimides with Morita-Baylis-Hillman carbonates

Article abstract of DOI:10.1021/jo3012539

The asymmetric allylic alkenylation of Morita-Baylis-Hillman (MBH) carbonates with N-itaconimides as nucleophiles has been developed using a commercially available Cinchona alkaloid catalyst. A variety of multifunctional chiral α-methylene-β-maleimide esters were attained in moderate to excellent yields (up to 99%) and good to excellent enantioselectivities (up to 91% ee). The origin of the regio- and stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed regio- and enantioselectivity.

Full text of DOI:10.1021/jo3012539

Article
pubs.acs.org/joc
Direct Asymmetric Allylic Alkenylation of N‑Itaconimides with
Morita−Baylis−Hillman Carbonates
Wenguo Yang,† Davin Tan,§ Lixin Li,† Zhiqiang Han,† Lin Yan,† Kuo-Wei Huang,*,§
Choon-Hong Tan,*,‡,¶ and Zhiyong Jiang*,†,‡
†Institute of Chemical Biology, Henan University, Kaifeng, Henan, P. R. China, 475004
‡Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan, P. R. China,
475004
§KAUST Catalysis Center and Division of Chemical and Life Sciences and Engineering, King Abdullah University of Science and
Technology, Thuwal, Kingdom of Saudi Arabia, 23955-6900
¶Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371
S
* Supporting Information
ABSTRACT: The asymmetric allylic alkenylation of Morita−
Baylis−Hillman (MBH) carbonates with N-itaconimides as
nucleophiles has been developed using a commercially available
Cinchona alkaloid catalyst. A variety of multifunctional chiral α-
methylene-β-maleimide esters were attained in moderate to
excellent yields (up to 99%) and good to excellent
enantioselectivities (up to 91% ee). The origin of the regio- and
stereoselectivity was verified by DFT methods. Calculated
geometries and relative energies of various transition states strongly support the observed regio- and enantioselectivity.
Inspired by this progress and furthering our research interest,
we herein report the first example of enantioselective allylic
alkenylation6p of N-itaconimides with O-Boc-protected MBH
carbonates to produce α-methylene-β-maleimide esters in high
yields and good to excellent ee values. As shown in Scheme 1,
we propose that the reaction between N-itaconimides 1 and
MBH carbonates 2 should give an intermediate A, which could
smoothly tautomerize to compound 3.
INTRODUCTION
■
Succinimides are present in a variety of biologically interesting
molecules and are studied as potential pharmacophores in drug
discovery research.1 In this context, many synthetic strategies
have been developed in recent years for the asymmetric
synthesis of succinimide derivatives. The application of N-
maleimides as electrophiles has been largely recognized as a
straightforward approach for their preparation.2 Recently, N-
itaconimides,3 derived from N-maleimides, have been intro-
duced by our group for the assembly of succinimide motifs
owing to their dense functionalization. This functionalization
exploits the activated exocyclic double bond and enolizable
amide moiety.4 For instance, we disclosed the first example of a
highly enantioselective protonation of the N-itaconimides with
secondary phosphine oxides4a or thiols4b to synthesize chiral
succinimides. Later, we applied N-itaconimides as nucleophiles
in a bicyclic-guanidine-catalyzed highly enantioselective allylic
addition reaction to imines to produce various maleimides,
which could be readily converted to succinimides.4c Despite
this, the reaction scope of N-itaconimides used as nucleophiles
is still limited due to their low reactivity.4c
RESULTS AND DISCUSSION
■
Our initial investigation was carried out with a series of
Cinchona alkaloids as Lewis base organocatalysts12 in the model
reaction between N-phenyl itaconimide 1a and MBH carbonate
2a in 1,2-dichloroethane (DCE) at room temperature (Table 1,
entries 1−11). The best enantioselectivity with 61% ee was
achieved for hydroquinidine (HQD) resulting in the desired
allylic alkenylation adduct 3aa (entry 6). Furthermore, we
screened the solvent effect with hydroquinidine as catalyst, and
the results revealed that toluene was the best reaction solvent
regarding the enantioselectivity (Table 1, entry 14). However,
when the temperature was lowered to 0 °C, the enantiose-
lectivity did not improve (Table 1, entry 17). When acetonitrile
was used as solvent, the ee value of 3aa was increased to 85%
with 72% yield (Table 1, entry 19). Lowering the temperature
to −20 °C showed a mild positive effect to the
enantioselectivity (Table 1, entry 21). When 4 Å molecular
Recently, Lewis base-catalyzed asymmetric allylic substitu-
tions of MBH5 adducts have become an alternative and viable
option for accessing various chiral C-,6 N-,7 O-,8 P-,9 and S-,10
allylic and spirocyclic11 compounds. We have also demon-
strated that modified Cinchona alkaloids are effective catalysts
for the asymmetric allylic alkylation6m of bis(phenylsulfonyl)-
methane (BSM), fluoro-bis(phenylsulfonyl)methane (FBSM)
and allylic hydroxylation8f using water with MBH carbonates.
Received: June 16, 2012
© XXXX American Chemical Society
A
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Scheme 1. Postulated Mechanism for the Allylic Alkenylation of N-Itaconimides and MBH Carbonates Catalyzed by Lewis Base
sieves were utilized as additive [1:1, m/m (2a: 4 Å molecular
sieve)] in order to remove the trace amounts of water,13 the
allylic alkenylation reaction of N-phenyl itaconimide 1a with
MBH carbonate 2a could be conducted at −10 °C, affording
the adduct 3a with 97% yield and 89% ee (Table 1, entry 22).
When the reaction scale was increased from 0.1 to 0.5 mmol,
no loss of ee was observed. It is worth noting that 4 Å molecular
sieves did not increase the enantioselectivity when the reaction
was conducted at −20 °C (Table 1, entry 23).
Table 1. Allylic Alkenylation of N-Phenyl Itaconimide 1a
with MBH Carbonate 2a
a
T
(°C)
t
yield
b
ee
(%)
c
entry
catalyst
solvent
(h)
(%)
Under the established conditions, allylic alkenylations of
different N-itaconimides (Table 2, 1b−h) and MBH carbonate
1
QD
QN
CN
DCE
rt
rt
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
24
24
24
30
48
68
80
61
59
67
65
63
88
trace
52
47
62
55
90
94
89
66
88
91
68
72
88
67
97
84
52
−10
33
41
17
61
27
17
10
10
47
66
65
80
62
70
79
72
85
86
87
2
DCE
Table 2. Allylic Alkenylation of N-Itaconimides 1 and MBH
3
DCE
rt
a
Carbonate 2a Catalyzed by Hydroquinidine
4
CND
DCE
rt
5
HQN
DCE
rt
6
HQD
DCE
rt
7
(DHQ)2PHAL
(DHQD)2AQN
(DHQD)2PYR
(DHQ)2AQN
(DHQD)2PHAL
HQD
DCE
rt
8
DCE
rt
9
DCE
rt
10
11
12
13
14
15
16
17
18
19
20
21
DCE
rt
DCE
rt
CH2Cl2
CH3CN
Toluene
THF
rt
b
c
entry
1, R
3
t (h)
yield (%)
ee (%)
HQD
rt
1
2
3
4
5
6
7
1b, 4-BrC6H4
1c, 3-BrC6H4
1d, 3,5-F2C6H3
1e, 4-tBuC6H4
1f, 2-naphthyl
1g, 4-MeOC6H4
1h, nBu
3ba
3ca
3da
3ea
3fa
58
54
48
62
96
96
96
83
99
96
86
72
97
62
90
90
87
91
88
90
83
HQD
rt
HQD
rt
HQD
Et2O
rt
HQD
Toluene
Et2O
0
HQD
0
3ga
3ha
HQD
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0
HQD
−10
−20
−10
−20
a
Unless otherwise noted, the reaction was carried out with 0.2 mmol
HQD
d
ef
,
of a, 0.1 mmol of 2a, and 0.01 mol of hydroquinidine in 1.0 mL of
22
HQD
89
b
d
e
solvent. Isolated yield after silica gel column chromatography.
23
HQD
87
c
Determined by HPLC analysis.
a
Unless otherwise noted, the reaction was carried out with 0.04 mmol
of 1a, 0.02 mmol of 2a, and 0.002 mol of catalyst in 0.2 mL of solvent.
b
c
Isolated yield after silica gel column chromatography. Determined
d
e
by HPLC analysis. 4 Å molecular sieve (1:1, m/m) was added. 0.1
mmol scale in 1.0 mL of CH3CN. 0.5 mmol scale in 5.0 mL of
2a afforded the products 3ba−ha with good to excellent ee
values (Table 2). N-Itaconimides (Table 2, 1b−d) with
electron-withdrawing groups on the aromatic rings were more
active than those with electron-neutral and donating groups
(Table 2, 1e−g). However, the enantioselectivity slightly
deviated from this trend, as the best ee value was achieved
when 1e with para-substituted tert-butyl group on the aromatic
ring was utilized (91% ee, 86% yield, 62 h, Table 2, 1e). Good
enantioselectivity but moderate yield was achieved for N-
itaconimide with n-butyl as aliphatic substituted group (83% ee,
62% yield, 96 h, Table 2, 1h).
f
CH3CN, yield = 90%, ee = 90%. DCE = 1,2-dichloroethane, QD =
quinidine, QN = quinine, CN = cinchonine, CND = cinchonidine,
HQN = hydroquinine, HQD = hydroquinidine, (DHQ)2PHAL =
hydroquinine 1,4-phthalazinediyl diether, (DHQD)2AQN = hydro-
quinidine (anthraquinone-1,4-diyl) diether, (DHQD)2PYR = hydro-
quinidine-2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQ)2AQN =
hydroquinine anthraquinone-1,4-diyl diether, (DHQD)2PHAL =
hydroquinidine 1,4-phthalazinediyl diether.
B
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With N-itaconimide 1e as the nucleophile, we investigated
the scope of MBH carbonates in the presence of 10 mol %
hydroquinidine in acetonitrile at −10 °C using 4 Å molecular
sieve as additive (Table 3). All reactions proceeded smoothly
calculations also revealed that the activation barrier for the R-
enantiomer was higher by +1.3 kcal/mol (refer to the
Supporting Information). Upon closer inspection of the 3-D
model of the transition state, we discovered that there is also a
regioselectivity issue in this reaction: the alkenylation C−C
bond can also occur at the γ-position of the nucleophile
(Scheme 2), forming a totally different product. However, this
Table 3. Allylic Alkenylation of N-Itaconimide 1e with MBH
a
Carbonates 2 Catalyzed by Hydroquinidine
Scheme 2. Regioselectivity for the Formation of Different
Alkenylation Products
b
c
entry
2, Ar
3
t (h)
yield (%)
ee (%)
1
2b, 4-NO2C6H4
2c, 4-CF3C6H4
2d, 4-FC6H4
3eb
3ec
3ed
3ee
3ef
48
64
96
32
83
74
96
60
70
96
96
68
60
85
75
67
85
81
86
62
64
72
57
40
63
67
79
90
85
91
91
85
89
91
91
89
90
90
90
2
3
4
2e, 4-ClC6H4
2f, 4-BrC6H4
2g, 3-CF3C6H4
2h, 3-ClC6H4
2i, 2-FC6H4
5
6
3eg
3eh
3ei
7
8
9
2j, 2-ClC6H4
2k, 4-MeC6H4
2l, 4-iPrC6H4
2m, 4-MeOC6H4
2n, 3-MeOC6H4
3ej
10
11
12
13
3ek
3el
3em
3en
a
Unless otherwise noted, the reaction was carried out with 0.2 mmol
of 1e, 0.1 mmol of 2, and 0.01 mol of hydroquinidine in 1.0 mL of
b
solvent. Isolated yield after silica gel column chromatography.
c
Determined by HPLC analysis.
product was not observed experimentally, and DFT calculations
revealed that the activation barrier for the S-enantiomer of this
product was much higher, by +3.4 kcal/mol. With these
information in mind, we were able to formulate a possible
catalytic cycle for this reaction (Scheme 3).
In addition, we demonstrated that the chiral allylic
alkenylation adducts can be easily converted to important
biologically active intermediates,17 which are shown in Scheme
4. A highly diastereoselective 1,3-dipolar cycloaddition between
3aa and nitrile N-oxide, generated in situ from 4a, occurred to
deliver the desired product 5a with vicinal quaternary−tertiary
chiral centers without compromising the ee value. The protocol
was readily extended to afford other 1,3-dipolar cycloaddition
adducts with good results, such as 5b. The absolute
configurations of the allylic alkenylation products were assigned
on the basis of X-ray crystallographic analysis of a single crystal
of 5b.18
with moderate to good yields (up to 86%) and good to
excellent ee values (up to 91%). The trend of the electronic and
steric effects of the substitutents on the aromatic ring of the
MBH carbonates 2 did not have an observable effect on the
outcome of the reaction. Unfortunately, this asymmetric allylic
alkenylation reaction is not applicable to the aliphatic MBH
carbonates due to many side reactions.14
In order to fully comprehend the reaction mechanism and
confirm our proposed transition state, we employed density
functional theory (DFT) calculations using the Gaussian 09
program15 and modeling experiments at the B3LYP/6-31G**
level of theory16 for the allylic alkenylation of MBH carbonate
with N-itaconimide. Mechanistically, it is comprehensible that
the Cinchona alkaloid moiety of the HQD catalyst is a strong
tertiary amine nucleophile, which can attack to the β position of
the α,β unsaturated MBH carbonate 2a, which then
subsequently undergoes a decarboxylation of the Boc moiety
to extrude a molecule of CO2 and tBuO−. Subsequently, tBuO−
can abstract a proton from 1a to generate an aromatic enolate
intermediate that can be further stabilized by intermolecular H-
bonding to the free hydroxyl group of the HQD-2a adduct,
forming a pretransition state intermediate with a relative free
energy of +6.5 kcal/mol with respect to the starting materials.
The bifunctionality of the catalyst then allows it to bring the
two substrates closer for the desired C−C bond formation,
forming the S-enantiomer with an activation energy of +22.0
kcal/mol. Subsequent intramolecular proton rearrangement
and decomplexation from the catalyst affords the product with
an extremely stable relative free energy of −25.1 kcal/mol. DFT
CONCLUSION
■
In conclusion, we have developed an efficient allylic
alkenylation of MBH carbonates with N-itaconimides. The
reactions employed a commercially available Cinchona alkaloid
as Lewis base catalyst and an experimentally simple protocol
with mild reaction conditions. From this methodology, various
synthetically valuable chiral α-methylene-β-maleimide esters
were achieved in moderate to excellent yields (up to 99%) and
good to excellent enantioselectivities (up to 91%). Several
enantio-enriched compounds could be prepared from the allylic
products. The origin of regio- and stereoselectivity were
elucidated by DFT calculations. We believe this work should
C
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staining KMnO4, Ceric Ammonium Molybdate, or para-anisaldehyde
solution. For those using the aqueous stains, the TLC plates were
heated on a hot plate.
Columns for flash chromatography (FC) contained silica gel 200−
300 mesh. Columns were packed as slurry of silica gel in petroleum
ether (60−90 °C) and equilibrated using the appropriate solvent
system. The elution was assisted by applying pressure of about 2 atm
with an air pump.
Scheme 3. Proposed Catalytic Cycle for the Asymmetric
Allylic Alkenylation of N-Itaconimides with MBH
Carbonates Catalyzed by HQD
Instrumentations. Proton nuclear magnetic resonance (1H NMR)
and carbon NMR (13C NMR) spectra were recorded in CDCl3 unless
otherwise stated. 1H (400 MHz) and 13C (100 MHz) were performed
on a 400 MHz spectrometer. Chemical shifts are reported in parts per
million (ppm), using the residual solvent signal as an internal standard:
CDCl3 (1H NMR: δ 7.26, singlet; 13C NMR: δ 77.0, triplet). Low
resolution mass spectra were obtained in EI or ESI mode. MS and
HRMS (Analyzer: TOF) were reported in units of mass of charge ratio
(m/z). Mass samples were dissolved in CH3CN (HPLC grade) unless
otherwise stated. Optical rotations were recorded with a sodium lamp
of wavelength 589 nm and reported as follows; [α]Tλ °C (c = g/100 mL,
solvent).
Enantiomeric excesses were determined by chiral high performance
liquid chromatography (HPLC) analysis with manual injection valve.
HPLC samples were dissolved in HPLC grade isopropanol (IPA)
unless otherwise stated.
Materials. All commercial reagents were purchased with the
highest purity grade. They were used without further purification
unless specified. All solvents used, mainly petroleum ether and ethyl
acetate, were distilled. THF and toluene were freshly distilled from
sodium/benzophenone before use. DCE and MeCN were distilled
from CaH2 and stored under N2 atomosphere. All compounds
synthesized were stored in a −20 °C freezer, and light-sensitive
compounds were protected with aluminum foil.
General Procedure for the Asymmetric Allylic Alkenylation
of N-Itaconimides 1 with Morita−Baylis−Hillman Carbonates 2
in the Presence of Hydroquinidine As Lewis Base. MBH
carbonate 2 (0.1 mmol, 1.0 equiv), hydroquinidine (3.3 mg, 0.01
mmol, 0.1 equiv) and 4 Å molecular sieve [m/m (molecular sieve: 2)
= 1:1] were dissolved in acetonitrile (1.0 mL) in 4 mL sample vials
and stirred at −10 °C for 30 min. Then N-itaconimides 1 (0.2 mmol,
2.0 equiv) was added. The reaction mixtures were stirred and
maintained at −10 °C, and the reaction progress was monitored by
TLC. Upon complete consumption of 2, the reaction mixtures were
loaded onto a short silica gel column, followed by separation with flash
chromatography using gradient elution with petroleum ether/ethyl
acetate (10:1 to 5:1). After removal of solvent under vacuum, the
corresponding adducts 3 were obtained.
Scheme 4. Synthetic Transformations of Multifunctional
Adducts
3aa, (S)-(+)-Methyl 2-((4-methyl-2,5-dioxo-1-phenyl-2,5-di-
hydro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate). Yellow oil: 163.2
mg (0.5 mmol), 90% yield; 90% ee; [α]2D6 +27.4 (c 0.19, CHCl3); H
1
potentially expand the synthetic utility of α-methylene-β-alkene
esters in organic and medicinal chemistry.
NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 7.4 Hz, 2H), 7.39−7.35 (m,
4H), 7.33−7.30 (m, 2H), 7.26−7.24 (m, 2H), 6.52 (s, 1H), 5.47 (d, J
= 1.5 Hz, 1H), 5.35 (s, 1H), 3.77 (s, 3H), 1.94 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ = 170.7, 169.9, 166.6, 139.8, 139.6, 138.4, 137.6,
131.8, 129.0, 128.9, 128.8, 128.4, 127.6, 127.4, 125.6, 52.3, 43.3, 9.1;
LRMS (ESI) m/z 383.9 (M + Na+); HRMS (ESI) m/z 384.1218 (M +
Na+), calc. for C22H19NNaO4 384.1206. The ee was determined by
HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time = 10.5 min (major) and 11.5 min (minor).
EXPERIMENTAL SECTION
■
General Procedures and Methods. Experiments involving
moisture and/or air sensitive components were performed under a
positive pressure of nitrogen in oven-dried glassware equipped with a
rubber septum inlet. Dried solvents and liquid reagents were
transferred by oven-dried syringes or hypodermic syringe cooled to
ambient temperature in a desiccator. Reactions mixtures were stirred
in 4 mL sample vial with Teflon-coated magnetic stirring bars unless
otherwise stated. Moisture in nonvolatile reagents/compounds was
removed in high vacuo by means of an oil pump and subsequent
purging with nitrogen. Solvents were removed in vacuo under ∼30
mmHg and heated with a water bath at 30−35 °C using rotary
evaporator with aspirator. The condenser was cooled with running
water at 0 °C.
3ba, (S)-(+)-Methyl 2-((1-(4-bromophenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate.
Colorless oil: 36.7 mg (0.1 mmol), 83% yield; 90% ee; [α]2D6 +16.4 (c
1
0.25, CHCl3); H NMR (400 MHz, CDCl3, ppm) δ 7.55 (d, J = 8.8
Hz, 2H), 7.36 (dd, J = 16.4, 8.8 Hz, 3H), 7.32−7.26 (m, 2H), 7.24 (d,
J = 7.2 Hz, 2H), 6.51 (s, 1H), 5.46 (s, 1H), 5.32 (s, 1H), 3.77 (s, 3H),
1.94 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.4, 169.6,
166.6, 139.9, 139.7, 138.6, 137.5, 132.0, 130.9, 129.0, 128.8, 128.5,
127.7, 126.9, 120.9, 52.4, 43.3, 9.1; LRMS (EI) m/z 438.9 (M+);
All experiments were monitored by analytical thin layer
chromatography (TLC). TLC was performed on precoated plates,
60 F254. After elution, plate was visualized under UV illumination at
254 nm for UV active material. Further visualization was achieved by
+
HRMS (EI) m/z 439.0396 (M ), calc. for C22H18NO4Br 439.0414.
The ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm
D
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i.d. × 250 mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min;
25 °C; 254 nm; retention time = 14.6 min (minor) and 18.7 min
(major).
250 mm); hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C;
210 nm; retention time = 16.1 min (major) and 20.6 min (minor).
3ha, (S)-(+)-Methyl 2-((1-butyl-4-methyl-2,5-dioxo-2,5-dihy-
dro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate. Yellow oil: 21.3 mg
(0.1 mmol), 62% yield; 83% ee; [α]2D6 +16.4 (c 0.3, CHCl3); 1H NMR
(400 MHz, CDCl3, ppm) δ 77.33 (t, J = 6.9 Hz, 2H), 7.29−7.25 (m,
1H), 7.18 (d, J = 7.2 Hz, 2H), 6.47 (s, 1H), 5.38 (s, 1H), 5.25 (s, 1H),
3.73 (s, 3H), 3.47 (t, J = 7.2 Hz, 2H), 1.81 (s, 3H), 1.58−1.50 (m,
2H), 1.32−1.23 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3, ppm) δ 172.1, 171.3, 166.6, 140.0, 139.3, 138.2, 137.8,
128.9, 128.7, 128.0, 127.4, 52.2, 43.0, 37.9, 30.6, 19.9, 13.5, 8.8; LRMS
(ESI) m/z 364.1 (M + Na+); HRMS (ESI) m/z 364.1529 (M + Na+),
calc. for C20H23NNaO4 364.1519. The ee was determined by HPLC
analysis. CHIRALCEL OD-H (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time = 6.6 min (minor), 7.3 min (major).
3eb, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(4-nitrophenyl)methyl)-
acrylate. Yellow oil: 39.4 mg (0.1 mmol), 85% yield; 79% ee; [α]D26
+10.0 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 8.23 (d, J
= 8.6 Hz, 2H), 7.45 (dd, J = 8.6, 3.8 Hz, 4H), 7.24 (d, J = 8.6 Hz, 2H),
6.60 (s, 1H), 5.54 (d, J = 0.9 Hz, 1H), 5.47 (s, 1H), 3.78 (s, 3H), 1.98
(s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.3,
169.7, 166.1, 150.8, 147.3, 145.4, 139.6, 138.4, 138.0, 129.7, 129.1,
128.7, 126.0, 125.2, 124.1, 52.6, 42.9, 34.6, 31.2, 9.3; LRMS (ESI) m/z
461.1 (M−H+); HRMS (ESI) m/z 461.1710 (M−H+), calc. for
C26H26N2O6 461.1718. The ee was determined by HPLC analysis.
CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-propanol = 80/
20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time = 18.8 min
(major) and 37.5 (minor).
3ec, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(4-(trifluoromethyl)phenyl)-
methyl)acrylate. Yellow oil: 36.3 mg (0.1 mmol), 75% yield; 90% ee;
[α]2D6 +65.9 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.63
(d, J = 8.2 Hz, 2H), 7.46−7.43 (m, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.26
(s, 1H), 7.24 (t, J = 2.1 Hz, 1H), 6.56 (s, 1H), 5.50 (d, J = 1.5 Hz,
1H), 5.42 (s, 1H), 3.78 (s, 3H), 1.96 (s, 3H), 1.32 (s, 9H); 13C NMR
(100 MHz, CDCl3, ppm) δ 170.5, 169.8, 166.3, 150.6, 141.9 (two
peaks), 139.1, 139.0, 138.6, 129.2, 128.8, 126.1, 126.0, 125.9 (two
peaks), 125.5, 125.2, 52.4, 43.0, 34.6, 31.2, 9.2; LRMS (ESI) m/z 485.2
(M+); HRMS (ESI) m/z 485.1803 (M+), calc. for C27H26F3NO4
485.1814. The ee was determined by HPLC analysis. CHIRALPAK IA
(4.6 mm i.d. × 250 mm); hexane/2-propanol = 80/20; flow rate 1.0
mL/min; 25 °C; 254 nm; retention time = 8.6 min (major) and 14.0
(minor).
3ed, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(4-fluorophenyl)methyl)-
acrylate. Yellow oil: 29.4 mg (0.1 mmol), 67% yield; 85% ee; [α]D26
+7.8 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 77.46−7.42
(m, 2H), 7.27 (s, 1H), 7.25−7.20 (m, 3H), 7.06 (t, J = 8.6 Hz, 2H),
6.52 (s, 1H), 5.47 (d, J = 1.5 Hz, 1H), 5.32 (s, 1H), 3.77 (s, 3H), 1.94
(s, 3H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.8,
167.0, 166.5, 163.3, 160.9, 150.5, 139.7, 139.4, 138.5, 133.4, 130.5,
130.4, 128.9, 128.4, 126.0, 125.2, 116.0, 115.8, 52.4, 42.6, 34.6, 31.2,
9.1; LRMS (ESI) m/z 434.2 (M−H+); HRMS (ESI) m/z 434.1756
(M−H+), calc. for C26H25FNO4 434.1773. The ee was determined by
HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 230 nm; retention
time = 11.0 min (major) and 14.8 min (minor).
3ca, (S)-(+)-Methyl 2-((1-(3-bromophenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate. Yel-
low oil: 43.8 mg (0.1 mmol), 99% yield; 90% ee; [α]2D6 +40.5 (c 0.2,
CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.59 (s, 1H), 7.45 (d, J
= 7.9 Hz, 1H), 7.37 (t, J = 7.6 Hz, 3H), 7.31 (t, J = 6.7 Hz, 2H), 7.27−
7.23 (m, 2H), 6.52 (s, 1H), 5.46 (s, 1H), 5.32 (s, 1H), 3.77 (s, 3H),
1.95 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 169.5, 166.6,
140.0, 139.8, 138.6, 137.5, 133.1, 130.4, 130.1, 129.0, 128.9, 128.5,
128.4, 127.7, 123.9, 122.2, 52.3, 43.4, 9.1; LRMS (ESI) m/z 437.9
(M−H+); HRMS (ESI) m/z 438.0344 (M−H+), calc. for
C22H17BrNO4 438.0346. The ee was determined by HPLC analysis.
CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-propanol = 80/
20; flow rate 1.0 mL/min; 25 °C; 230 nm; retention time = 7.3 min
(major) and 10.1 min (major).
3da, (S)-(+)-Methyl 2-((1-(3,5-difluorophenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate. Yel-
low oil: 38.2 mg (0.1 mmol), 96% yield; 87% ee; [α]2D6 +39.1 (c 0.2,
1
CHCl3); H NMR (400 MHz, CDCl3, ppm) δ 7.37 (t, J = 7.3 Hz,
2H), 7.31 (dd, J = 8.6, 5.9 Hz, 1H), 7.23 (d, J = 7.1 Hz, 2H), 7.13−
7.07 (m, 2H), 6.78−6.73 (m, 1H), 6.52 (s, 1H), 5.45 (s, 1H), 5.31 (s,
1H), 3.77 (s, 3H), 1.95 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ
169.9, 169.1, 166.6, 164.0, 163.9, 161.6, 161.4, 140.2, 139.7, 138.7,
137.3, 129.1, 128.8, 128.6, 127.8, 108.3, 108.0, 102.8, 102.6, 102.3,
52.4, 43.4, 9.1; LRMS (ESI) m/z 420.1 (M + Na+); HRMS (ESI) m/z
420.1019 (M + Na+), calc. for C22H17F2NNaO4 420.1018. The ee was
determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time = 5.4 min (major) and 6.1 min (minor).
3ea, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate. Yel-
low oil: 35.8 mg (0.1 mmol), 86% yield; 91% ee; [α]2D6 +22.0 (c 0.4,
1
CHCl3); H NMR (400 MHz, CDCl3, ppm) δ 7.44−7.24 (m, 9H),
6.51 (s, 1H), 5.47 (s, 1H), 5.34 (s, 1H), 3.76 (s, 3H), 1.93 (s, 3H),
1.32 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.9, 170.1,
166.6, 150.5, 139.9, 139.7, 138.5, 137.8, 129.1, 129.0, 128.9, 128.4,
127.6, 125.9, 125.2, 52.3, 43.3, 34.6, 31.3, 9.1; LRMS (ESI) m/z 440.1
(M + Na+); HRMS (ESI) m/z 440.1841 (M + Na+), calc. for
C26H27NNaO4 440.1832. The ee was determined by HPLC analysis.
CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-propanol = 90/
10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time = 10.0 min
(major) and 12.6 min (minor).
3fa, (S)-(+)-Methyl 2-((4-methyl-1-(naphthalen-2-yl)-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate. Yel-
low oil: 29.7 mg (0.1 mmol), 72% yield; 88% ee; [α]2D6 +117.1 (c 0.2,
1
CHCl3); H NMR (400 MHz, CDCl3, ppm) δ 7.90 (dd, J = 8.8, 3.3
Hz, 1H), 7.86−7.82 (m, 3H), 7.52−7.47 (m, 3H), 7.43−7.37 (m, 3H),
7.34−7.31 (m, 1H), 7.29 (d, J = 1.5 Hz, 1H), 6.54 (d, J = 1.6 Hz, 1H),
5.49 (d, J = 1.6 Hz, 1H), 5.38 (s, 1H), 3.79 (s, 3H), 1.98 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 170.9, 170.1, 166.6, 139.8 (two
peaks), 138.6, 137.6, 133.2, 132.2, 129.2, 129.0, 128.9, 128.7, 128.5,
128.0, 127.6 (two peaks), 126.4 (two peaks), 124.2, 123.5, 52.4, 43.3,
9.2; LRMS (ESI) m/z 434.1 (M + Na+); HRMS (ESI) m/z 434.1361
(M + Na+), calc. for C26H21NNaO4 434.1363. The ee was determined
by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/
2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 210 nm; retention
time = 20.7 min (minor), 25.9 min (major).
3ee, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(4-chlorophenyl)methyl)-
acrylate. Yellow oil: 38.3 mg (0.1 mmol), 85% yield; 91% ee; [α]D26
+59.7 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 1 H NMR
(400 MHz, CDCl3) δ 7.44 (d, J = 8.6, 2H), 7.34 (d, J = 8.4, 2H),
7.27−7.24 (m, 2H), 7.20 (d, J = 8.5, 2H), 6.52 (s, 1H), 5.49 (d, J = 1.5,
1H), 5.32 (s, 1H), 3.76 (s, 3H), 1.94 (s, 3H), 1.32 (s, 9H); 13C NMR
(100 MHz, CDCl3, ppm) δ 170.6, 169.9, 166.4, 150.5, 139.4, 139.0,
138.7, 136.3, 133.5, 130.2, 129.1, 128.9, 128.4, 125.9, 125.2, 52.3, 42.7,
34.6, 31.2, 9.1; LRMS (ESI) m/z 474.0 (M + Na+); HRMS (ESI) m/z
474.1461 (M + Na+), calc. for C26H26ClNO4Na 474.1443. The ee was
determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250
3ga, (S)-(+)-Methyl 2-((1-(4-methoxyphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(phenyl)methyl)acrylate. Yel-
low oil: 38.1 mg (0.1 mmol), 97% yield; 90% ee; [α]2D6 +236 (c 0.1,
1
CHCl3); H NMR (400 MHz, CDCl3, ppm) δ 7.41−7.28 (m, 4H),
7.25−7.23 (m, 3H), 6.95−6.93 (m, 2H), 6.51 (s, 1H), 5.46 (d, J = 1.4
Hz, 1H), 5.33 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 1.92 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 171.0, 170.2, 166.6, 158.7, 139.8,
139.5, 138.4, 137.6, 128.9, 128.8, 128.4, 127.6, 127.1, 124.4, 114.2,
55.4, 52.3, 43.2, 9.1; LRMS (ESI) m/z 414.0 (M + Na+); HRMS (ESI)
m/z 414.1302 (M + Na+), calc. for C23H21NNaO5 414.1312. The ee
was determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. ×
E
dx.doi.org/10.1021/jo3012539 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time = 10.0 min (major) and 12.6 min (minor).
3ef, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(4-bromophenyl)methyl)-
acrylate. Yellow oil: 40.1 mg (0.1 mmol), 81% yield; 91% ee; [α]D26
+48.1 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.46 (dd, J
= 19.6, 8.6 Hz, 5H), 7.24 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.53 (d, J =
1,5 Hz, 1H), 5.49 (d, J = 1.5, 1H), 5.29 (s, 1H), 3.76 (s, 3H), 1.94 (s,
3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.6, 169.9,
166.4, 150.5, 139.2, 139.0, 138.7, 136.8, 132.1, 130.5, 128.9, 128.5,
125.9, 125.1, 121.6, 52.4, 42.7, 34.6, 31.2, 9.2; LRMS (EI) m/z 495.1
(M +); HRMS (ESI) m/z 496.1124 (M + H +), calc. for C26H27O4NBr
496.1123. The ee was determined by HPLC analysis. CHIRALPAK IA
(4.6 mm i.d. × 250 mm); hexane/2-propanol = 80/20; flow rate 1.0
mL/min; 25 °C; 254 nm; retention time = 9.6 min (major) and 14.4
min (minor).
3eg, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(3-(trifluoromethyl)phenyl)-
methyl)acrylate. Yellow oil: 41.9 mg (0.1 mmol), 86% yield; 85% ee;
[α]2D6 +31.6 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.46
(t, J = 9.0 Hz, 6H), 7.28 (s, 1H), 7.24 (s, 1H), 6.47 (d, J = 1.6 Hz,
1H), 5.49 (s, 1H), 5.43 (s, 1H), 3.77 (s, 3H), 1.95 (s, 3H), 1.33 (s,
9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.7, 170.5, 166.2, 150.7,
150.6, 145.7, 139.1, 139.0, 138.8, 138.6, 129.4, 128.8 (two peaks),
127.4, 126.1, 126.0, 125.4, 125.1, 52.4, 42.9, 34.6, 31.2, 9.2; LRMS
(ESI) m/z 484.1 (M−H+); HRMS (ESI) m/z 484.1749 (M−H+), calc.
for C27H25F3NO4 484.1741. The ee was determined by HPLC analysis.
CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-propanol = 90/
10; flow rate 1.0 mL/min; 25 °C; 210 nm; retention time = 11.0 min
(major) and 14.8 min (minor).
mL/min; 25 °C; 210 nm; retention time = 14.2 min (major) and 17.5
min (minor).
3ek, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(p-tolyl)methyl)acrylate. Yel-
low oil: 24.6 mg (0.1 mmol), 57% yield; 89% ee; [α]2D6 +43.7 (c 0.4,
CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.45 (dd, J = 15.4 Hz,
8.7, 2H), 7.26 (d, J = 8.7 Hz, 2H), 7.15 (q, J = 8.3 Hz, 4H), 6.50 (s,
1H), 5.48 (d, J = 1.2 Hz, 1H), 5.29 (s, 1H), 3.76 (s, 3H), 2.35 (s, 3H),
1.94 (s, 3H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ
171.0, 170.1, 166.7, 150.4, 139.9, 139.8, 138.2, 137.3, 134.6, 129.6,
129.0, 128.7, 128.2, 125.9, 125.2, 52.3, 42.9, 34.6, 31.2, 21.0, 9.1;
LRMS (ESI) m/z 454.2 (M + Na+); HRMS (ESI) m/z 454.1993 (M +
Na+), calc. for C27H29NO4Na 454.1989. The ee was determined by
HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 230 nm; retention
time = 9.2 min (major) and 15.6 min (minor).
3el, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(4-isopropylphenyl)methyl)-
acrylate. Yellow oil: 18.4 mg (0.1 mmol), 40% yield; 90% ee; [α]D26
−7.0 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.46−7.41
(m, 2H), 7.27−7.24 (m, 2H), 7.22−7.15 (m, 4H), 6.50 (s, 1H), 5.48
(d, J = 1.2 Hz, 1H), 5.30 (s, 1H), 3.76 (s, 3H), 2.93−2.86 (m, 1H),
1.95 (s, 3H), 1.31 (s, 9H), 1.24 (d, J = 6.9 Hz, 6H); 13C NMR (100
MHz, CDCl3, ppm) δ 171.0, 170.1, 166.7, 150.4, 148.2, 140.0, 139.8,
138.2, 134.8, 129.1, 128.8, 128.3, 127.0, 125.9, 125.2, 52.3, 42.9, 34.6,
33.7, 31.3, 23.9, 23.9, 9.1; LRMS (ESI) m/z 459.2 (M+); HRMS (ESI)
m/z 459.2401 (M+), calc. for C29H33NO4 459.2410. The ee was
determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250
mm); hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time = 5.4 min (major) and 8.0 min (minor).
3em, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(4-methoxyphenyl)methyl)-
acrylate. Yellow oil: 28.1 mg (0.1 mmol), 63% yield; 90% ee; [α]D26
+24.0 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.43 (d, J
= 8.6 Hz, 2H), 7.27 (s, 1H), 7.24 (s, 1H), 7.17 (d, J = 8.6 Hz, 2H),
6.89 (d, J = 8.6 Hz, 2H), 6.49 (s, 1H), 5.47 (s, 1H), 5.27 (s, 1H), 3.81
(s, 3H), 3.76 (s, 3H), 1.94 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz,
CDCl3, ppm) δ 171.0, 170.1, 166.7, 158.9, 150.4, 140.1, 139.9, 138.0,
130.0, 129.5, 129.0, 128.2, 125.9, 125.2, 114.3, 55.3, 52.3, 42.6, 34.6,
31.3, 9.1; LRMS (ESI) m/z 447.2 (M+); HRMS (ESI) m/z 447.2034
(M+), calc. for C27H29NO5 447.2046. The ee was determined by HPLC
analysis. CHIRALCEL AD-H (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 210 nm; retention
time = 13.5 min (major) and 20.6 min (minor).
3eh, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(3-chlorophenyl)methyl)-
acrylate. Yellow oil: 28.2 mg (0.1 mmol), 62% yield; 89% ee; [α]D26
+7.0 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.45 (d, J =
8.6 Hz, 2H), 7.30−7.24 (m, 5H), 7.15 (d, J = 6.2 Hz, 1H), 6.55 (s,
1H), 5.50 (s, 1H), 5.33 (s, 1H), 3.77 (s, 3H), 1.95 (s, 3H), 1.32 (s,
9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.6, 169.9, 166.3, 150.5,
139.8, 139.1, 138.9, 138.8, 134.8, 130.2, 128.9, 128.7, 127.8, 127.0,
125.9, 125.2, 52.4, 42.8, 34.6, 31.2, 9.2; LRMS (ESI) m/z 451.2 (M+);
HRMS (ESI) m/z 451.1541 (M+), calc. for C26H26ClNO4 451.1550.
The ee was determined by HPLC analysis. CHIRALPAK IA (4.6 mm
i.d. × 250 mm); hexane/2-propanol = 80/20; flow rate 1.0 mL/min;
25 °C; 254 nm; retention time = 5.8 min (minor major) and 9.1 min
(minor).
3en, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(3-methoxyphenyl)methyl)-
acrylate. Yellow oil: 30.0 mg (0.1 mmol), 67% yield; 90% ee; [α]D26
−16.3 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.46−7.42
(m, 2H), 7.30−7.26 (m, 2H), 7.25 (d, J = 2.9 Hz, 1H), 6.86−6.78 (m,
3H), 6.51 (s, 1H), 5.50 (d, J = 1.3 Hz, 1H), 5.31 (s, 1H), 3.80 (s, 3H),
3.76 (s, 3H), 1.94 (s, 3H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3,
ppm) δ 174.2, 174.1, 164.2, 156.6, 152.1, 149.6, 133.1, 130.6, 129.70,
129.2, 129.0, 128.6, 128.4, 123.2, 120.2, 85.0, 54.6, 34.0, 30.0, 24.9,
23.6, 23.6; LRMS (ESI) m/z 447.2 (M+); HRMS (ESI) m/z 447.2040
(M+), calc. for C27H29NO5 447.2046. The ee was determined by HPLC
analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time = 7.2 min (major) and 11.9 min (minor).
3ei, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(2-fluorophenyl)methyl)-
acrylate. Yellow oil: 27.7 mg (0.1 mmol), 64% yield; 91% ee; [α]D26
+18.1 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.47−7.45
(m, 2H), 7.35−7.25 (m, 4H), 7.18−7.09 (m, 2H), 6.55 (d, J = 1.5 Hz,
1H), 5.61 (s, 1H), 5.53 (d, J = 1.5 Hz, 1H), 3.78 (s, 3H), 1.95 (s, 3H),
1.33 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.6, 169.8,
166.3, 161.7, 159.2, 150.4, 139.1, 138.3, 138.0, 129.9, 129.9, 129.5,
129.4, 128.9, 128.1, 125.9, 125.1, 124.4 (two peaks), 115.9, 115.7, 52.4,
36.6, 36.6, 34.6, 31.2, 8.9; LRMS (ESI) m/z 435.2 (M+); HRMS (ESI)
m/z 435.1835 (M+), calc. for C26H26FNO4 435.1846. The ee was
determined by HPLC analysis. CHIRALPAK IA (4.6 mm i.d. × 250
mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254
nm; retention time = 8.5 min (major) and 10.5 min (minor).
3ej, (S)-(+)-Methyl 2-((1-(4-tert-butylphenyl)-4-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-3-yl)(2-chlorophenyl)methyl)-
acrylate. Yellow oil: 32.8 mg (0.1 mmol), 72% yield; 91% ee; [α]D26
−17.2 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3, ppm) δ 7.47−7.41
(m, 4H), 7.29−7.27 (m, 3H), 7.26−7.23 (m, 1H), 6.55 (d, J = 1.5 Hz,
1H), 5.72 (s, 1H), 5.47 (d, J = 1.5 Hz, 1H), 3.76 (s, 3H), 1.86 (s, 3H),
1.32 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.6, 169.8,
166.2, 150.4, 139.6, 138.4, 138.1, 135.7, 134.2, 130.1, 129.7, 129.0,
128.2, 127.0, 125.9, 125.1, 52.4, 40.4, 34.6, 31.2, 9.0; LRMS (ESI) m/z
451.2 (M+); HRMS (ESI) m/z 451.1558 (M+), calc. for C26H26ClNO4
451.1550. The ee was determined by HPLC analysis. CHIRALPAK IA
(4.6 mm i.d. × 250 mm); hexane/2-propanol = 98/2; flow rate 1.0
5a, (R)-(−)-Methyl 3-(4-chlorophenyl)-5-((R)-(4-methyl-2,5-
dioxo-1-phenyl-2,5-dihydro-1H-pyrrol-3-yl)(phenyl)methyl)-
4,5-dihydroisoxazole-5-carboxylate. White solid: mp 73.2−74.9
°C; 36.7 mg (0.1 mmol), 71% yield; 90% ee; 9:1 dr; [α]2D6 −15.2 (c 0.2,
1
CHCl3), H NMR (400 MHz, CDCl3, ppm) δ = 7.45 (t, J = 8.1 Hz,
6H), 7.39−7.27 (m, 6H), 7.24 (d, J = 7.4 Hz, 2H), 5.00 (s, 1H), 3.93
(d, J = 18.0 Hz, 1H), 3.72 (s, 3H), 3.68 (d, J = 18.0 Hz, 1H), 1.99 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm) δ = 171.0, 170.7, 170.0,
156.1, 142.4, 137.4, 136.5, 135.6, 131.4, 129.5, 129.0 (two peaks),
128.7, 127.9, 127.8, 126.7, 125.8, 91.1, 53.2, 46.7, 42.6, 9.6; LRMS
(ESI) m/z 537.1 (M + Na+); HRMS (ESI) m/z 537.1183 (M + Na+),
calc. for C29H23ClN2NaO5 537.1188. The ee was determined by HPLC
analysis. CHIRALPAK IA (4.6 mm i.d. × 250 mm); hexane/2-
F
dx.doi.org/10.1021/jo3012539 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time = 11.7 min (major) and 16.2 min (minor).
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5b, (R)-(−)-Methyl 3-(4-bromophenyl)-5-((R)-(1-(4-bromo-
phenyl)-4-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-
(phenyl)methyl)-4,5-dihydroisoxazole-5-carboxylate. White
solid: mp 92.5−94.3 °C; 48.4 mg (0.1 mmol), 76% yield; 89% ee;
7:1 dr; [α]2D6 −17.8 (c 0.1, CHCl3) 1H NMR (400 MHz, CDCl3, ppm)
δ = 7.56 (d, J = 8.7 Hz, 2H), 7.46 (t, J = 9.5 Hz, 4H), 7.38 (d, J = 8.5
Hz, 2H), 7.33−7.24 (m, 3H), 7.16 (d, J = 8.7 Hz, 2H), 4.98 (s, 1H),
3.92 (d, J = 17.9 Hz, 1H), 3.71 (s, 3H), 3.65 (d, J = 17.9 Hz, 1H), 1.98
(s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ = 13C NMR (101
MHz, CDCl3) δ = 170.7, 170.6, 169.6, 156.1, 142.5, 137.7, 135.4,
132.2, 132.0, 130.4, 129.5, 128.7, 128.1, 128.0, 127.1, 124.9, 121.4,
91.1, 77.3, 77.0, 76.7, 53.2, 46.7, 42.6, 9.6.; LRMS (ESI) m/z 659.0 (M
+ Na+); HRMS (ESI) m/z 658.9786 (M + Na+), calc. for
C29H22O5N2Br2Na 658.9788. The ee was determined by HPLC
analysis. CHIRALPAK IC (4.6 mm i.d. × 250 mm); hexane/2-
propanol = 80/20; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time = 9.7 min (minor) and 17.1 min (major).
ASSOCIATED CONTENT
* Supporting Information
■
S
General information, HPLC spectra of chiral products,
crystallographic data of 5b, details of DFT calculations, and
NMR spectra of the compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chmjzy@henu.edu.cn; hkw@kaust.edu.sa;
choonhong@ntu.edu.sg.
■
Notes
́
Ed. 2011, 50, 9684. (o) Companyo, X.; Valero, G.; Ceban, V.; Calvet,
The authors declare no competing financial interest.
T.; Font-Bardía, M.; Moyano, A.; Rios, R. Org. Biomol. Chem. 2011, 9,
7986. (p) Cui, H.-L.; Sun, X.-H.; Jiang, L.; Dong, L.; Chen, Y.-C. Eur.
J. Org. Chem. 2011, 2011, 7366.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21072044), Excellent Youth Foundation
of Henan Scientific Committee (114100510003), and the
Program for New Century Excellent Talents in University of
Ministry of Education (NCET-11-0938) is greatly appreciated.
We also thank Professor Hongwei Zhou (Zhejiang University)
and Professor Fuwei Li (Lanzhou Institute of Chemical
Physics) for their generous help in high resolution mass
spectrum analysis.
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dx.doi.org/10.1021/jo3012539 | J. Org. Chem. XXXX, XXX, XXX−XXX