Synthesis of chiral tetronic acid derivatives via organocatalytic conjugate addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes

Article abstract of DOI:10.1016/j.tet.2012.05.082

Asymmetric conjugate addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes and subsequent intramolecular cyclization had been developed. This one-pot reaction provided tetronic acid derivatives in good yields and with excellent enantioselectivities. 6

Full text of DOI:10.1016/j.tet.2012.05.082

Tetrahedron 68 (2012) 6123e6130
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of chiral tetronic acid derivatives via organocatalytic conjugate addition
of ethyl 4-chloro-3-oxobutanoate to nitroalkenes
,
Yun-yun Yan a, Rui-jiong Lu a, Jin-jia Wang a, Yi-ning Xuan b, Ming Yan a
*
a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
b College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric conjugate addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes and subsequent
intramolecular cyclization had been developed. This one-pot reaction provided tetronic acid derivatives
in good yields and with excellent enantioselectivities. 60-Demethyl quinine was found to be the best
catalyst for the conjugate addition and AcOLi was identified as the best base for the intramolecular
Received 7 February 2012
Received in revised form 16 May 2012
Accepted 22 May 2012
Available online 28 May 2012
cyclization. Various
b
-aryl, heteroaryl, and alkyl nitroalkenes are generally applicable in the reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Asymmetric conjugate addition
Tetronic acid derivative
Ethyl 4-chloro-3-oxobutanoate
Nitroalkene
1. Introduction
Eq. 2).7 These results demonstrate variable chemical reactivities of
4-halogen-3-oxobutanoates.
During the past decade, asymmetric organocatalysis has made
great progress.1 A large number of organocatalytic reactions have
been developed successfully. Organocatalytic asymmetric conju-
gate addition is one of the most powerful organocatalytic reactions
in terms of its synthetic value and wide substrate scope.2 The
cascade reactions triggered by organocatalytic asymmetric conju-
gate addition are extremely efficient for the constitution of chiral
cyclic compounds.1a,3 Our strategy is to apply additional leaving
groups with the nucleophiles. The reactive intermediates generated
in the conjugate addition undergo subsequent intramolecular cy-
clization.4,7 Recently we have studied organocatalytic asymmetric
conjugate additions of bromonitroalkanes and bromomalonates.
The reactions provided chiral cyclopropanes in excellent yields and
with high enantioselectivities.5 As a continuation of the studies, we
envision that 4-chloro-3-oxobutanoates are valuable nucleophiles
for the synthesis of chiral products with five member rings via the
conjugate addition and cascade intramolecular cyclization. In 2006,
Jørgensen and co-workers reported the organocatalytic domino
N
H
O
1.
O
O
O
(10 mmol%)
COOEt
AcONa / CH2Cl2
K2CO3 / DMF
Cl
+
O
OEt
(1)
R
2.
R
J rgensen's work
40-57% yield, 84-97% ee
O
N
H
O
EtOOC
R
O
O
(20 mmol%)
+
Br
(2)
(3)
OEt
R
K2CO3 / CHCl3
C rdova's work
CHO
72-78% yield, 93-99% ee
O2N
catalyst
(10mmol%)
THF
O
O
O
1.
NO2
This study
X
+
R
R
OEt
2. AcOLi / THF
O
reaction of 4-chloro-3-oxobutanoates with
a,b-unsaturated
(X = Cl, Br)
EtO
aldehydes. Epoxycyclohexanone derivatives were prepared in ex-
cellent yields and enantioselectivities (Scheme 1, Eq. 1).6 Lately
Scheme 1. Organocatalytic asymmetric conjugate addition of 4-halogen-3-
oxobutanoates.
ꢀ
Cordova and co-workers found that the similar reaction of 4-
bromo-3-oxobutanoates led to chiral cyclopentanones (Scheme 1,
Tetronic acid derivatives are widespread in the nature.8 Many of
them possess potent biological activities. In addition, they are also
valuable synthetic intermediates for many natural products and
* Corresponding author. E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.082

6124
Y.-yun Yan et al. / Tetrahedron 68 (2012) 6123e6130
drugs.9 The synthesis of optically active tetronic acid derivatives is
an important research area. So far, these compounds were prepared
mostly starting from ‘chiral pool’ or other chiral reagents.10,11 In
2010, Ramachary and Kishor reported the organocatalytic asym-
metric synthesis of tetronic acid derivatives via cascade Michael
addition/aldol reaction.11 Very recently, Lu and co-workers de-
veloped an organocatalytic cascade reaction of 4-bromo-acetoa-
cetates and nitroalkenes. A series of tetronic acid derivatives were
prepared in good yields and enantioselectivities using a chiral
amino-thiourea as the catalyst.12 In this paper, we report the
organocatalytic asymmetric conjugate addition of ethyl 4-chloro-3-
oxobutanoate to nitroalkenes and subsequent intramolecular cy-
clization. The one-pot reaction provided chiral tetronic acid de-
rivatives in good yields and with excellent enantioselectivities
(Scheme 1, Eq. 3).
decrease of the reaction temperature did not improve the enan-
tioselectivity furthermore and led to a lower yield.
The effect of bases on the cyclization process was studied and the
results are listed in Table 2. Triethylamine was identified as the best
base in our previous study,13 however it provided low yield in this
reaction (Table 2, entry 1). Cs2CO3 and K2CO3 provided higher re-
action rate, but with lower enantioselectivities (Table 2, entries 2 and
3). Weak bases, such as NaHCO3, AcONa, and AcOLi worked better.
Good yieldsand excellentenantioselectivities wereachieved(Table 2,
entries 4e6). Anhydrous AcOLi and (NH4)2CO3 gave the similar yields
and enantioselectivities (Table 2, entries 7 and 8). Finally, AcOLi was
chosen concerning the reaction rate, yield, and enantioselectivity.
The reaction of ethyl 4-bromo-3-oxobutanoate with nitro-
styrene 2a was investigated (Scheme 3). Lower yield and enantio-
selectivity were obtained comparing with that of ethyl 4-chloro-3-
oxobutanoate.
For a comparison, we also examined the intramolecular cycli-
zation of ethyl 4-chloro-3-oxobutanoate in the presence of AcOLi
(Scheme 4). The tetronic acid derivative could not be obtained even
after extended reaction time. Other bases including AcONa, Et3N,
KOH, and K2CO3 also failed to promote this transformation. The
result implicates that the 2-substitution is crucial for the intra-
molecular cyclization of 4-chloro-3-oxobutanoates.
A number of nitroalkenes were examined in this one-pot con-
jugate addition/cyclization reaction, and the results are summarized
in Table 3. The substitutions at ortho-, meta-, and para-positions of
the phenyl ring are tolerated very well. Good yields and excellent
enantioselectivities were achieved generally (Table 3, entries 1e12).
The effect of electronic property of the substituent is not obvious. In
the case of 4-nitro substitution, lower yield was obtained (Table 3,
2. Results and discussion
Initially, the reaction of ethyl 4-chloro-3-oxobutanoate 1 with b-
nitrostyrene 2a was investigated in the presence of 10 mol % quinine
(Scheme 2). The adduct 3a was obtained as a mixture of two in-
separable diastereoisomers. The treatment of 3a with AcOLi or other
bases did not provide the cyclopentanone, instead tetronic acid de-
rivative 4a was obtained in excellent yield. Recently we have de-
veloped an organocatalytic asymmetric Mannich reaction of 1 with N-
Boc-imines. The Mannich products were found to undergo intra-
molecular alkylation reaction in the presence of triethylamine. Chiral
tetronic acid derivatives were obtained in good yields and with
moderate enantioselectivities.13 These results implicate that the
intramolecular cyclization of 2-substituted 4-chloro-3-oxobutanoates
is an efficient method to prepare tetronic acid derivatives.
entry 7).
b-Naphthyl nitroethylene and b-heteroaryl nitroethylenes
are suitable substrates (Table 3, entries 13e15). To our delight,
b
-
O
O
alkyl nitroethylene also worked well. The corresponding tetronic
acid derivatives 4p,q were obtained in good yields and with excel-
lent enantioselectivities (Table 3, entries 16 and 17). In the recent
study of Lu and co-workers, a chiral amino-thiourea was selected as
the catalyst and ethyl 4-bromo-acetoacetate was used as the sub-
strate. Typically 90e94% ees were achieved in the presence of
20 mol % catalyst.12 In comparison with Lu’s work, our method
possesses several distinct advantages: (1) the commercial avail-
ability of ethyl 4-chloro-acetoacetate; (2) easy access of the catalyst
60-demethyl quinine; (3) lower catalyst loading; (4) better enan-
tioselectivities. In addition, nitroalkenes with an electron-rich aryl
group was also applicable (Table 3, entry 3).
EtO
Cl
O
O
NO2
NO2
quinine
Cl
NO2
EtO
O
O
(10 mol%)
LiOAc
THF, rt
O2N
EtO
O
O
1
2a
3a
EtO
Scheme 2. Conjugate addition of 1 to 2a and subsequent intramolecular cyclization.
The reaction was found to be more efficient in one pot without
isolation of the intermediate 3a. After 1 was consumed as indicated
by TLC, AcOLi was added to promote the intramolecular cyclization.
Although 4a was obtained in good yield using quinine as the cat-
alyst, no enantioselectivity was achieved (Table 1, entry 1). Cin-
chonidine also provided racemic 4a (Table 1, entry 2). To improve
the enantioselectivity of the reaction, several organocatalysts 5aed
were examined and the results are summarized in Table 1. 60-
Demethyl quinine 5a significantly improved the enantioselectivity
(Table 1, entry 3). Free 60-hydroxyl group seems to be crucial for
achieving good enantioselectivity. Similar results were reported by
Deng and co-workers in the conjugate addition of 1,3-dicarbonyl
compounds to nitroalkenes.14 9-Benzyl-60-demethyl quinine 5b
gave inferior enantioselectivity and yield (Table 1, entry 4). Take-
moto’s amine-thiourea 5c provided moderate enantioselectivity
(Table 1, entry 5). More sterically demanding amine-thiourea 5d
gave better enantioselectivity (Table 1, entry 6).15 Quinine derived
amine-thiourea 5e was also examined, however only moderate
enantioselectivity was observed (Table 1, entry 7). Furthermore, the
most promising catalyst 5a was applied at lower reaction temper-
atures (Table 1, entries 8e10). Better yield and enantioselectivity
(76% yield, 97% ee) were achieved at ꢀ20 ꢁC. However, further
(E)-1-Nitroprop-1-ene is also an attractive substrate for the re-
action, howeverit isnot stableandenoughpure material couldnot be
obtained. Instead, the reaction of 2-acetyloxy-1-nitro-propane with
ethyl 4-chloro-acetoacetate was examined. The expected tetronic
acid derivative 4r was obtained with good enantioselectivity, but in
lower yield (Scheme 5). The in situ formation of (E)-1-nitroprop-1-
ene is supposed by the elimination of the acetyloxy group.
The absolute configuration of product 4k was assigned as R by X-
ray diffraction analysis (Fig. 1).16 Other products were suggested to
have the same absolute configuration. The enantio-facial selectivity
is in line with the reported reactions of acetoacetates with nitro-
alkenes catalyzed by 60-demethyl quinine.14
The reaction of tetronic acid 6 with nitroalkene 2c was also
examined using 5a as the catalyst (Scheme 6). The adduct 7 was
obtained in low yield. It was converted to O-methyl tetronic de-
rivatives 8 with Me3OBF4.17 Only 16% ee was observed via chiral
HPLC analysis. The fact confirms that asymmetric conjugate addi-
tion of ethyl 4-chloro-3-oxobutanoate and subsequent cyclization
is a superior method to prepare chiral tetronic acid derivatives.
Prostaglandin and their analogs possess a variety of important
biological activities. Aza-mimics of prostaglandins were reported to
have potent antiaggregatory effect.18 The treatment of product 4c

Y.-yun Yan et al. / Tetrahedron 68 (2012) 6123e6130
6125
Table 1
Screening of catalystsa
O
O
O2N
NO2
O
O
AcOLi
catalyst
Cl
NO2
O
O
EtO
(200 mol%)
(10 mol%)
Cl
+
OEt
THF, rt
THF, rt
EtO
4a
1
2a
3a
N
N
HO
N
N
HO
BnO
HO
H
H
H
H
MeO
HO
HO
N
N
N
N
quinine
cinchonidine
5a
5b
N
CF3
CF3
CF3
S
S
S
OMe
H
F3C
N
H
N
H
F3C
N
H
N
F3C
N
H
N
H
H
N
N
N
5d
5c
5e
Entry
Catalyst
Quinine
Cinchonidine
5a
5b
5c
5d
5e
5a
5a
5a
Time/h
Yieldb/%
eec/%
1
2
3
4
5
6
7
24
24
6
36
24
24
72
10
12
48
76
61
65
38
64
64
60
61
76
70
0
0
91
24
68
84
76
95
97
97
8d
9e
10f
a
Reactions were carried out with 1 (0.2 mmol), 2a (0.22 mmol), catalyst (10 mmol%) in THF (1.0 mL) at room temperature. After the complete consume of 1 as indicated by
TLC, AcOLi$2H2O (0.4 mmol) and THF (1 mL) were added. The reaction mixture was stirred at room temperature for 36 h.
b
Isolated yields of 4a.
c
ee values of 4a were determined by chiral HPLC.
d
Reaction was performed at 0 ꢁC.
e
Reaction was performed at ꢀ20 ꢁC.
f
Reaction was performed at ꢀ40 ꢁC.
with n-BuNH2 provided compound 9 in excellent yield (90%) with
retained optical purity (95% ee). This result indicted the tetronic
acid products could serve as useful intermediates for the synthesis
of aza-mimics of prostaglandins (Scheme 7).
The product 4a was hydrolyzed with aqueous hydrogen chlo-
ride, and reduced with zinc powder according to the reported
procedure.12 Chiral
g-lactam 11 was obtained in good yield, which
is a useful intermediate for the further synthesis of bioactive
compounds (Scheme 8).
Table 2
Effect of bases on the cyclizationa
3. Conclusions
O2N
O
O
Base
(200 mol%)
O
O
In conclusion, we have developed a one-pot organocatalytic
asymmetric synthesis of tetronic acid derivatives. 60-Demethyl
quinine was found to be the efficient catalyst for the conjugate
addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes. The
intramolecular cyclization of the conjugate adducts was achieved
Cl
NO2
EtO
THF, rt
EtO
4a
3a
using AcOLi as the base.
b
-Aryl, heteroaryl, and alkyl nitroalkenes
Entry
Base
Et3N
Cs2CO3
K2CO3
NaHCO3
AcONa
AcOLi
Time/h
36
0.5
0.5
72
72
36
36
36
Yield/%
ee/%
1
2
3
4
5
6
7
8
50
93
95
95
90
95
94
95
96
87
91
97
97
97
96
96
Br
O2N
NO2
O
O
1. 5a (10 mmol%)
THF, -20 oC
O
+
2.
AcOLi (200 mol%)
THF, rt
O
EtO
Anhydrous AcOLi
(NH4)2CO3
EtO
4a
2a
56% yield, 93% ee
a
Reactions were carried out with 3a (0.1 mmol) and base (0.2 mmol) in THF
(1 mL) at room temperature.
Scheme 3. Reaction of ethyl 4-bromo-3-oxobutanoate with nitrostyrene 2a.

6126
Y.-yun Yan et al. / Tetrahedron 68 (2012) 6123e6130
NO
2
O
O N
2
O N
2
O
OH
O
O
O
base (200 mol%)
THF, rt
5a (10 mmol%)
Me3OBF4
CH2Cl2, rt
42%
Cl
+
O
THF, -20 o
30%
C
O
O
OEt
MeO
HO
MeO
O
MeO
O
OMe
EtO
7
8
16% ee
2c
6
Scheme 4. Attempted intramolecular cyclization of ethyl 4-chloro-3-oxobutanoate in
Scheme 6. Reaction of tetronic acid 6 with nitroalkene 2c.
the presence of bases.
Table 3
Reactions of nitroalkenes with ethyl 4-chloro-3-oxobutanoatea
O2N
O2N
O
O
O
O
O2N
1. 5a(10mmol%)
O
NO2
MeOH
40 o
O
O
THF,-20oC
+
Cl
+
C
R
2.
AcOLi(200mol%)
THF,rt
H3CO
OEt
H3CO
EtO
HN
R
O
H2N
EtO
1
4c
2a-2q
4a
-4q
9
94% ee
90% yield, 95% ee
Entry
R
Yieldb/%
eec/%
Scheme 7. Synthesis of an aza-mimic of prostaglandin from product 4c.
1
2
3
4
5
6
7
8
Ph, 2a
4a, 76
4b, 76
4c, 65
4d, 76
4e, 74
4f, 70
4g, 54
4h, 76
4i, 79
4j, 76
4k, 75
4l, 87
4m, 81
4n, 95
4o, 94
4p, 74
4q, 70
97
98
94
98
98
97
97
97
97
96
97
98
95
97
96
97
97
4-MeeC6H4, 2b
4-MeOeC6H4, 2c
4-FeC6H4, 2d
OH
O2N
O2N
O
O
HO
4-CleC6H4, 2e
4-BreC6H4, 2f
4-NO2eC6H4, 2g
2-CleC6H4, 2h
2-BreC6H4, 2i
2-NO2eC6H4, 2j
3-CleC6H4, 2k
2,4-DiCleC6H3, 2l
1-Naphthyl, 2m
Thiophene-2-yl, 2n
Furan-2-yl, 2o
Isopropyl, 2p
Zn, AcOH
70%
6M HCl
95%
Ph
O
O
HO
HO
NH
11
O
9
4a
10
10
11
12
13
14
15
16
17
Scheme 8. Synthesis of g-lactam 11 from product 4a.
are generally applicable in this transformation. A number of
tetronic acid derivatives were prepared in good yields and with
excellent enantioselectivities. Furthermore, the products are syn-
thetically useful for the preparation of chiral aza-mimics of pros-
Cyclohexyl, 2q
a
Reactions were carried out with 1 (0.2 mmol), nitroalkene (0.22 mmol), 5a
(10 mmol%) in THF (1.0 mL) at ꢀ20 ꢁC for 12 h. AcOLi$2H2O (0.4 mmol) and THF
(1 mL) were added. The reaction mixture was stirred at room temperature for 36 h.
taglandins and g-lactams. In comparison with the study by Lu and
co-workers, this method is more practical considering the com-
mercial availability of ethyl 4-chloro-acetoacetate, easy access of
the catalyst 60-demethyl quinine, decreased catalyst loading, and
improved enantioselectivities.
b
Isolated yields.
ee values of 4aeq were determined by chiral HPLC.
c
O2N
Me
1. 5a
(20 mmol%)
O
NO2
OAc
O
4. Experimental section
4.1. General information
O
THF, rt
+
Me
Cl
2.
AcOLi (200 mol%)
OEt
O
THF, rt
EtO
4r
1H and13C NMR spectra were recorded on a Bruker Advance
400 MHz spectrometer as solutions in CDCl3 or CD3OD. Chemical
45% yield, 92% ee
shifts in 1H NMR spectra are reported in parts per million (ppm,
d)
Scheme 5. Synthesis of 4r from 2-acetyloxy-1-nitro-propane.
downfield from the internal standard Me4Si (TMS,
Chemical shifts in 13C NMR spectra are reported relative to the
central line of the chloroform signal (
d¼0 ppm).
d¼77.0 ppm). The following
abbreviations are used to designate chemical shift multiplicities:
s¼singlet, d¼doublet, m¼multiplet. High-resolution mass spectra
were obtained with Shimadazu LCMS-IT-TOF mass spectrometer.
Optical rotations were measured on a PerkineElmer 341 digital
polarimeter and are reported as ½a D20
ꢂ
(c in gram per 100 mL of
solvent). The crystallographic data were obtained with Oxford
Diffraction Xcalibur Nova diffractometer. The flash column chro-
matography was carried out over silica gel (230e400 mesh), pur-
chased from Qingdao Haiyang Chemical Co. Ltd. Melting points
were recorded on an electrothermal digital melting point apparatus
and were uncorrected. TLC analysis was performed on precoated
silica gel GF254 slides, and visualized by either UV irradiation.
Infrared (IR) spectra were recorded on a Bruker Tensor 37
spectrophotometer. Data are represented as follows: frequency of
absorption (cmꢀ1), intensity of absorption (s¼strong, m¼medium,
w¼weak). Unless otherwise stated, all reagents were obtained from
commercial sources and used as received. The solvents were used
as commercial anhydrous grade without further purification.
Fig. 1. X-ray structure of product 4k.

Y.-yun Yan et al. / Tetrahedron 68 (2012) 6123e6130
6127
Enantiomeric excesses were determined by HPLC using a Daicel
Chiralpak AS-H column (4.6 mmꢃ25 cm) and eluting with hexane/
2-PrOH solution.
IR (KBr) n
/cmꢀ1: 1691 (w),1593 (s),1551 (w),1481 (m),1384 (m),1356
(m), 1161 (s), 1077 (s); HRMS (ESI) calcd for C15H17NNaO6 (MþNa)þ:
330.0954, found: 330.0947. The enantiomeric excess was determined
by HPLC with a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
4.2. General procedure for the synthesis of racemic tetronic
acid derivatives
l¼254 nm, 0.8 mL/min); tmajor¼16.5 min, tminor¼19.1 min, 94% ee.
4.4.4. (R)-5-Ethoxy-4-(1-(4-fluorophenyl)-2-nitroethyl)furan-3(2H)-
one (4d). Prepared according to the general procedure in Section
To a solution of nitroalkene (0.22 mmol) in THF (1 mL) were
added ethyl 4-chloro-3-oxobutanoate (27
mL, 0.2 mmol) and DABCO
4.3 as a colorless oil (44.8 mg, 76% yield); ½a D20
ꢀ80.6 (c 0.64,
ꢂ
(0.04 mmol, 20 mol %). The mixture was stirred at room tempera-
ture until the complete consume of ethyl 4-chloro-3-oxobutanoate.
AcOLi$2H2O (0.40 mmol) was added and the reaction mixture was
stirred for 36 h. After the solvent was evaporated under vacuum,
the residue was purified by flash column chromatography over
silica gel (ethyl acetate/hexane¼1:5 to 1:3).
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.44e7.36 (m, 2H), 7.04e6.97
(m, 2H), 5.18 (dd, J¼12.8, 8.9 Hz, 1H), 4.89 (dd, J¼12.8, 7.3 Hz, 1H),
4.58 (d, J¼2.4 Hz, 2H), 4.54e4.39 (m, 3H), 1.46 (t, J¼7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d 194.5, 181.2, 163.4, 160.9, 135.0, 134.9,
129.4, 129.3, 115.8, 115.6, 92.3, 76.5, 74.9, 66.8, 37.2, 14.7; IR (KBr) n/
cmꢀ1: 2990 (w), 1694 (w),1612 (s), 1552 (m), 1510 (m), 1452 (s),
1389 (m), 1356 (m), 1224 (m), 1162 (s), 1041 (m); HRMS (ESI) calcd
for C14H14NNaO5F (MþNa)þ: 318.0754, found: 318.0746. The en-
antiomeric excess was determined by HPLC with a Chiralpak AS-H
4.3. General procedure for the asymmetric conjugate
addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes
and subsequent cyclization
column (hexane/2-PrOH¼60:40,
l
¼254 nm, 0.8 mL/min);
tmajor¼13.3 min, tminor¼15.7 min, 98% ee.
To a solution of nitroalkene (0.22 mmol) in THF (1 mL) were
added ethyl 4-chloro-3-oxobutanoate (27
m
L, 0.2 mmol) and 60-
4.4.5. (R)-5-Ethoxy-4-(1-(4-chlorophenyl)-2-nitroethyl)furan-3(2H)-
demethyl quinine 5a (0.02 mmol,10 mol %). The mixture was stirred
at ꢀ20 ꢁC for 12 h. AcOLi$2H2O (0.4 mmol) was added and the re-
action mixture was stirred for 36 h. After the solvent was evapo-
rated under vacuum, the residue was purified by flash column
chromatography over silica gel (ethyl acetate/hexane¼1:5 to 1:3).
one (4e). Prepared according to the general procedure in Section 4.3
as a colorless oil (46.0 mg, 74% yield); ½a D20
ꢀ107.6 (c 0.50, CH2Cl2);
ꢂ
1H NMR (400 MHz, CDCl3)
d
7.35 (d, J¼8.5 Hz, 2H), 7.31e7.25 (m, 2H),
5.16 (dd, J¼12.8, 8.8 Hz, 1H), 4.89 (dd, J¼12.8, 7.4 Hz, 1H), 4.56 (d,
J¼2.5 Hz, 2H), 4.52e4.37 (m, 3H), 1.44 (t, J¼7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 194.4, 181.2, 137.7, 133.5, 129.1, 129.0, 92.0, 76.3,
4.4. Spectral data of products 4aeq
75.0, 66.9, 37.3, 14.7; IR (KBr) n
/cmꢀ1: 2922 (w), 1695 (w), 1605 (s),
1552 (m), 1492 (m), 1452 (s), 1388 (m), 1355 (m), 1162 (s), 1072 (s);
HRMS (ESI) calcd for C14H14NNaO5Cl (MþNa)þ: 334.0458, found:
334.0457. The enantiomeric excess was determined by HPLC with
4.4.1. (R)-5-Ethoxy-4-(2-nitro-1-phenylethyl)furan-3(2H)-one
(4a). Prepared according to the general procedure in Section 4.3 as
a colorless oil (42.1 mg, 76% yield); ½a D20
ꢂ
ꢀ81.3 (c 0.76, CH2Cl2); 1H
a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
l¼254 nm,
NMR (400 MHz, CDCl3) d 7.42e7.37 (m, 2H), 7.33e7.23 (m, 3H), 5.24
0.8 mL/min); tmajor¼12.3 min, tminor¼13.3 min, 98% ee.
(dd, J¼12.7, 9.3 Hz, 1H), 4.87 (dd, J¼12.7, 6.9 Hz, 1H), 4.55 (d,
J¼2.4 Hz, 2H), 4.52e4.39 (m, 3H), 1.43 (t, J¼7.1 Hz, 3H); 13C NMR
4.4.6. (R)-5-Ethoxy-4-(1-(4-bromophenyl)-2-nitroethyl)furan-
(100 MHz, CDCl3)
74.9, 66.7, 37.9, 14.7; IR (KBr)
d
194.6, 181.2, 139.1, 128.9, 127.7, 127.6, 92.4, 76.5,
3(2H)-one (4f). Prepared according to the general procedure in
n
/cmꢀ1: 1692 (w), 1605 (s), 1552 (m),
Section 4.3 as a colorless oil (50.0 mg, 70% yield); ½a D20
ꢀ60.13 (c
ꢂ
1484 (m), 1454 (s), 1388 (m), 1354 (m), 1160 (s), 1066 (s); HRMS
(ESI) calcd for C14H15NNaO5 (MþNa)þ: 300.0848, found: 300.0843.
The enantiomeric excess was determined by HPLC with a Chiralpak
0.78, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.43 (d, J¼8.4 Hz, 2H),
7.28 (d, J¼8.4 Hz, 2H), 5.16 (dd, J¼12.8, 8.9 Hz, 1H), 4.88 (dd,
J¼12.8, 7.3 Hz, 1H), 4.56 (d, J¼2.7 Hz, 2H), 4.51e4.43 (m, 2H),
4.41e4.35 (m, 1H), 1.43 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz,
AS-H column (hexane/2-PrOH¼60:40,
l
¼254 nm, 0.8 mL/min);
tmajor¼15.0 min, tminor¼17.1 min, 97% ee.
CDCl3)
d 194.4, 181.2, 138.2, 132.0, 129.4, 121.6, 92.0, 76.2, 75.0,
66.9, 37.4, 14.7; IR (KBr)
n
/cmꢀ1: 2921 (w), 1694 (w), 1610 (s), 1552
4.4.2. (R)-5-Ethoxy-4-(2-nitro-1-(p-tolyl)ethyl)furan-3(2H)-one
(4b). Prepared according to the general procedure in Section 4.3 as
(m), 1488 (m), 1452 (s), 1388 (m), 1355 (m), 1159 (s), 1074 (s);
HRMS (ESI) calcd for C14H14NNaO5Br (MþNa)þ: 377.9953, found:
377.9949. The enantiomeric excess was determined by HPLC with
a colorless oil (44.2 mg, 76% yield); ½a D20
ꢂ
ꢀ70.0 (c 0.74, CH2Cl2); 1H
NMR (400 MHz, CDCl3)
d
7.29 (d, J¼8.1 Hz, 2H), 7.11 (d, J¼7.9 Hz,
a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
l¼254 nm,
2H), 5.21 (dd, J¼12.6, 9.3 Hz, 1H), 4.85 (dd, J¼12.7, 7.0 Hz, 1H), 4.54
0.8 mL/min); tmajor¼13.1min, tminor¼14.6 min, 97% ee.
(d, J¼2.8 Hz, 2H), 4.49e4.36 (m, 3H), 2.31 (s, 3H), 1.43 (t, J¼7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d
194.6, 181.2, 137.3, 136.2, 129.6,
4.4.7. (R)-5-Ethoxy-4-(1-(4-nitrophenyl)-2-nitroethyl)furan-3(2H)-
127.5, 92.5, 76.6, 74.9, 66.7, 37.6, 21.0, 14.7; IR (KBr)
n
/cmꢀ1: 1695
one (4g). Prepared according to the general procedure in Section
(w), 1612 (s), 1552 (w), 1514 (w), 1443 (m), 1387 (m), 1354 (m), 1164
(s), 1074 (s); HRMS (ESI) calcd for C15H17NNaO5 (MþNa)þ: 314.1004,
found: 314.0998. The enantiomeric excess was determined by HPLC
4.3 as a yellow oil (34.8 mg, 54% yield); ½a D20
ꢀ67.1 (c 0.48, CH2Cl2);
ꢂ
1H NMR (400 MHz, CDCl3)
d 8.19e8.14 (m, 2H), 7.62e7.56 (m, 2H),
5.16 (dd, J¼13.1, 8.3 Hz, 1H), 5.00 (dd, J¼13.1, 7.8 Hz, 1H), 4.59 (d,
with a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
l¼254 nm,
J¼3.8 Hz, 2H), 4.55e4.45 (m, 3H), 1.45 (t, J¼7.1 Hz, 3H); 13C NMR
0.8 mL/min); tmajor¼13.0 min, tminor¼15.1 min, 98% ee.
(100 MHz, CDCl3) d 194.2, 181.2, 147.4, 146.4, 128.7, 124.2, 91.3, 75.7,
75.1, 67.2, 37.6, 14.7; IR (KBr) n
/cmꢀ1: 2921 (w), 1695 (w), 1599 (s),
4.4.3. (R)-5-Ethoxy-4-(1-(4-methoxyphenyl)-2-nitroethyl)furan-
1553 (m), 1452 (m), 1387 (m), 1350 (m), 1162 (s), 1074 (s); HRMS
(ESI) calcd for C14H14N2NaO7 (MþNa)þ: 345.0699, found: 345.0691.
The enantiomeric excess was determined by HPLC with a Chiralpak
3(2H)-one (4c). Prepared according to the general procedure in
Section 4.3 as a colorless oil (39.9 mg, 65% yield); ½a D20
ꢀ75.0 (c 0.72,
ꢂ
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.32 (d, J¼8.7 Hz, 2H), 6.83 (d,
AS-H column (hexane/2-PrOH¼85:15,
l
¼254 nm, 0.8 mL/min);
J¼8.7 Hz, 2H), 5.17 (dd, J¼12.6, 9.2 Hz, 1H), 4.84 (dd, J¼12.6, 7.1 Hz,
1H), 4.54 (d, J¼2.0 Hz, 2H), 4.50e4.41 (m, 2H), 4.37 (dd, J¼9.1, 7.1 Hz,
1H), 3.77 (s, 3H), 1.43 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
tmajor¼96.5 min, tminor¼105.0 min, 97% ee.
4.4.8. (S)-5-Ethoxy-4-(1-(2-chlorophenyl)-2-nitroethyl)furan-3(2H)-
one (4h). Prepared according to the general procedure in Section
d
194.6,181.2,159.0,131.3,128.8,114.2, 92.7, 74.9, 66.7, 55.2, 37.2,14.7;

6128
Y.-yun Yan et al. / Tetrahedron 68 (2012) 6123e6130
4.3 as a colorless oil (47.3 mg, 76% yield); ½a D20
ꢂ
ꢀ131.8 (c 0.44,
4.59 (d, J¼3.5 Hz, 2H), 4.51e4.43 (m, 2H), 1.43 (t, J¼7.1 Hz, 3H); 13
C
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.60 (dd, J¼7.5, 2.0 Hz, 1H),
NMR (100 MHz, CDCl3)
d
194.6, 181.5, 134.7, 134.0, 133.9, 130.4,
7.37 (dd, J¼7.6, 1.7 Hz, 1H), 7.25e7.18 (m, 2H), 5.27 (dd, J¼12.9,
9.9 Hz, 1H), 4.99 (dd, J¼9.9, 5.8 Hz, 1H), 4.77 (dd, J¼12.9, 5.8 Hz, 1H),
4.58 (d, J¼2.4 Hz, 2H), 4.50e4.41 (m, 2H), 1.42 (t, J¼7.1 Hz, 3H); 13C
129.6, 127.7, 90.6, 75.0, 74.7, 67.0, 33.8, 14.6. IR (KBr) n
/cmꢀ1: 2921
(w), 1603 (s), 1552 (m), 1452 (m), 1387 (m), 1355 (m), 1162 (s), 1076
(s); HRMS (ESI) calcd for C14H13NNaO5Cl2 (MþNa)þ: 368.0068,
found: 368.0065. The enantiomeric excess was determined by
HPLC with a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
NMR (100 MHz, CDCl3)
d 194.7, 181.6, 136.0, 133.2, 129.8, 129.5,
128.8, 127.4, 90.7, 75.0, 74.8, 66.8, 34.3, 14.6; IR (KBr) n
/cmꢀ1: 2360
(w), 1599 (m), 1453 (w), 1383 (w), 1351 (w), 1162 (s), 1075 (s); HRMS
(ESI) calcd for C14H14NNaO5Cl (MþNa)þ: 334.0458, found:
334.0456. The enantiomeric excess was determined by HPLC with
l¼254 nm, 0.8 mL/min); tmajor¼9.8 min, tminor¼10.8 min, 98% ee.
4.4.13. (R)-5-Ethoxy-4-(1-(naphthalen-1-yl)-2-nitroethyl)furan-
3(2H)-one (4m). Prepared according to the general procedure in
Section 4.3 as a yellow solid (53.0 mg, 81% yield); mp 90e91 ꢁC;
a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
l¼254 nm,
0.8 mL/min); tmajor¼11.3 min, tminor¼13.5 min, 97% ee.
½
a 2D0
ꢂ
ꢀ116.0 (c 0.88, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 8.29 (d,
4.4.9. (S)-5-Ethoxy-4-(1-(2-bromophenyl)-2-nitroethyl)furan-
J¼8.5 Hz,1H), 7.86 (d, J¼7.8 Hz,1H), 7.76 (d, J¼8.2 Hz,1H), 7.64e7.59
(m, 1H), 7.60e7.55 (m, 1H), 7.53e7.47 (m, 1H), 7.44e7.39 (m, 1H),
5.41 (dd, J¼12.0, 9.9 Hz, 1H), 5.34 (dd, J¼9.9, 5.1 Hz, 1H), 4.90 (dd,
J¼12.1, 5.1 Hz, 1H), 4.56 (d, J¼1.2 Hz, 2H), 4.46e4.37 (m, 2H), 1.38 (t,
3(2H)-one (4i). Prepared according to the general procedure in
Section 4.3 as a colorless oil (56.1 mg, 79% yield); ½a D20
ꢀ156.3 (c
ꢂ
0.88, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.62 (dd, J¼7.8, 1.6 Hz,
1H), 7.56 (dd, J¼8.0, 1.2 Hz, 1H), 7.31e7.26 (m, 1H), 7.12 (ddd, J¼7.9,
7.5, 1.7 Hz, 1H), 5.28 (dd, J¼12.9, 10.0 Hz, 1H), 4.98 (dd, J¼10.0,
5.7 Hz, 1H), 4.75 (dd, J¼12.9, 5.7 Hz, 1H), 4.59 (d, J¼1.9 Hz, 2H),
4.52e4.40 (m, 2H), 1.43 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 194.7, 181.4, 134.1, 134.0,
130.8, 129.1, 128.2, 126.7, 125.8, 125.4, 125.0, 122.8, 91.9, 75.7, 75.0,
66.8, 32.8, 14.6; IR (KBr) n
/cmꢀ1: 2929 (w), 1686 (w), 1586 (s), 1544
(m), 1453 (m), 1379 (m),1357 (m), 1167 (s), 1123 (m), 1079 (s); HRMS
(ESI) calcd for C18H17NNaO5 (MþNa)þ: 350.1004, found: 350.1001.
The enantiomeric excess was determined by HPLC with a Chiralpak
d
194.7, 181.7, 137.8, 133.2, 129.7, 129.1, 128.0, 123.7, 91.1, 75.0, 74.9,
66.8, 37.1, 14.6; IR (KBr) n
/cmꢀ1: 3000 (w), 2920 (w), 1689 (w), 1597
(s), 1550 (m), 1451 (m), 1420 (s), 1379 (m), 1349 (m), 1164 (s), 1071
(s); HRMS (ESI) calcd for C14H14NNaO5Br (MþNa)þ: 377.9953,
found: 377.9950. The enantiomeric excess was determined by HPLC
AS-H column (hexane/2-PrOH¼60:40,
l
¼254 nm, 0.8 mL/min);
tmajor¼14.0 min, tminor¼15.5 min, 95% ee.
with a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
l
¼254 nm,
4.4.14. (R)-5-Ethoxy-4-(2-nitro-1-(thiophen-2-yl)ethyl)furan-3(2H)-
one (4n). Prepared according to the general procedure in Section 4.3
0.8 mL/min); tmajor¼11.4 min, tminor¼14.0 min, 97% ee.
as a colorless oil (53.8 mg, 95% yield); ½a D20
ꢂ
ꢀ81.7 (c 0.74, CH2Cl2); 1H
4.4.10. (R)-5-Ethoxy-4-(2-nitro-1-(2-nitrophenyl)ethyl)furan-3(2H)-
one (4j). Prepared according to the general procedure in Section 4.3
NMR (400 MHz, CDCl3)
d
7.32 (d, J¼1.2 Hz,1H), 6.29 (dd, J¼3.2,1.8 Hz,
1H), 6.17 (d, J¼3.2 Hz, 1H), 5.04 (dd, J¼12.8, 9.1 Hz, 1H), 4.90 (dd,
as a yellow oil (48.9 mg, 76% yield); ½a D20
ꢂ
ꢀ215.3 (c 0.36, CH2Cl2); 1H
J¼12.8, 6.6 Hz, 1H), 4.63 (dd, J¼9.0, 6.7 Hz, 1H), 4.59 (s, 2H), 4.48 (q,
NMR (400 MHz, CDCl3)
d
7.88 (dd, J¼7.9, 1.2 Hz, 1H), 7.82 (dd, J¼8.1,
J¼7.1 Hz, 2H),1.43 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 194.0,
1.2 Hz, 1H), 7.58 (td, J¼7.8, 1.3 Hz, 1H), 7.45e7.40 (m, 1H), 5.36 (dd,
J¼13.1, 9.3 Hz, 1H), 5.03 (dd, J¼9.2, 5.9 Hz, 1H), 4.94 (dd, J¼13.1,
5.9 Hz, 1H), 4.61 (d, J¼5.1 Hz, 2H), 4.50e4.42 (m, 2H), 1.42 (t,
181.0, 141.1, 127.1, 125.5, 124.7, 92.2, 75.0, 66.9, 32.6, 14.7; IR (KBr)
n
/cmꢀ1: 1610 (s), 1552 (m), 1485 (m), 1452 (m), 1388 (m), 1355 (m),
1165 (s), 1076 (s); HRMS (ESI) calcd for C12H13NNaO5S (MþNa)þ:
306.0412, found: 306.0408. The enantiomeric excess was de-
termined by HPLC with a Chiralpak AS-H column (hexane/2-
J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 194.8, 181.8, 149.9,133.4,
133.2, 130.6, 128.6, 124.5, 91.3, 75.1, 74.9, 67.3, 32.6, 14.5. IR (KBr) n/
cmꢀ1: 2922 (w), 1605 (s), 1554 (m), 1453 (m), 1389 (m), 1357 (m),
1163 (s), 1077 (s); HRMS (ESI) calcd for C14H14N2NaO7 (MþNa)þ:
345.0699, found: 345.0695. The enantiomeric excess was de-
termined by HPLC with a Chiralpak AS-H column (hexane/2-
PrOH¼60:40,
l
¼254 nm, 0.8 mL/min); tmajor¼21.0 min,
tminor¼23.3 min, 97% ee.
4.4.15. (R)-5-Ethoxy-4-(1-(furan-2-yl)-2-nitroethyl)furan-3(2H)-one
PrOH¼60:40,
l
¼254 nm, 0.8 mL/min); tmajor¼17.1 min,
(4o). Prepared according to the general procedure in Section 4.3 as
tminor¼19.3 min, 96% ee.
a colorless oil (50.2 mg, 94% yield); ½a D20
ꢂ
ꢀ4.6 (c 0.54, CH2Cl2); 1H
NMR (400 MHz, CDCl3)
d
7.17 (d, J¼5.1 Hz,1H), 7.02 (d, J¼3.1 Hz,1H),
4.4.11. (R)-5-Ethoxy-4-(1-(3-chlorophenyl)-2-nitroethyl)furan-
3(2H)-one (4k). Prepared according to the general procedure in
Section 4.3 as a milky-white solid (46.7 mg, 75% yield); mp
6.92 (dd, J¼5.0, 3.6 Hz, 1H), 5.15 (dd, J¼12.6, 9.2 Hz, 1H), 4.87 (dd,
J¼12.6, 6.8 Hz,1H), 4.77 (dd, J¼8.8, 7.1 Hz, 1H), 4.57 (s, 2H), 4.49 (qd,
J¼7.1, 2.2 Hz, 2H), 1.45 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
91e92 ꢁC; ½a 2D0
ꢂ
ꢀ76.5 (c 0.54, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 194.4, 181.6, 150.6, 142.1, 110.5, 107.0, 90.0, 75.1, 74.6, 67.1, 31.2,
d
7.38 (s, 1H), 7.33e7.29 (m, 1H), 7.26e7.21 (m, 2H), 5.17 (dd, J¼12.9,
14.6; IR (KBr) n
/cmꢀ1: 1695 (w), 1612 (s), 1546 (s), 1459 (m), 1424
8.9 Hz, 1H), 4.89 (dd, J¼12.9, 7.3 Hz, 1H), 4.58 (d, J¼0.4 Hz, 2H),
4.54e4.44 (m, 2H), 4.40 (dd, J¼8.8, 7.3 Hz,1H),1.45 (t, J¼7.1 Hz, 3H);
(m), 1390 (m), 1357 (m), 1168 (s), 1123 (m), 1080 (s); HRMS (ESI)
calcd for C12H13NNaO6 (MþNa)þ: 290.0641, found: 290.0639. The
enantiomeric excess was determined by HPLC with a Chiralpak AD-
13C NMR (100 MHz, CDCl3)
d 194.4, 181.2, 141.1, 134.6, 130.2, 127.8,
127.8, 125.9, 91.8, 76.1, 76.0, 66.9, 37.5, 14.7; IR (KBr)
n
/cmꢀ1: 1691
H
column (hexane/2-PrOH¼60:40,
l
¼254 nm, 0.8 mL/min);
(w), 1593 (s), 1551 (w), 1481 (m), 1384 (m), 1356 (m), 1161 (s), 1077
(s); HRMS (ESI) calcd for C14H14NNaO5Cl (MþNa)þ: 334.0458,
found: 334.0452. The enantiomeric excess was determined by HPLC
tmajor¼7.90 min, tminor¼7.42 min, 96% ee.
4.4.16. (R)-5-Ethoxy-4-(3-methyl-1-nitrobutan-2-yl)furan-3(2H)-
with a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
l
¼254 nm,
one (4p). Prepared according to the general procedure in Section
0.8 mL/min); tmajor¼14.1 min, tminor¼19.7 min, 97% ee.
4.3 as a colorless oil (36.0 mg, 74% yield); ½a D20
þ36.1 (c 0.70,
ꢂ
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
4.91 (dd, J¼11.9, 10.4 Hz, 1H),
4.4.12. (S)-5-Ethoxy-4-(1-(2,4-dichlorophenyl)-2-nitroethyl)furan-
4.59 (dd, J¼12.0, 5.2 Hz, 1H), 4.56 (s, 2H), 4.45 (qd, J¼7.1, 1.5 Hz, 2H),
2.99 (ddd, J¼10.3, 7.5, 5.2 Hz, 1H), 2.06e1.96 (m, 1H), 1.43 (t,
J¼7.1 Hz, 3H), 0.96 (d, J¼6.7 Hz, 3H), 0.89 (d, J¼6.7 Hz, 3H); 13C NMR
3(2H)-one (4l). Prepared according to the general procedure in
Section 4.3 as a colorless oil (60.0 mg, 87% yield); ½a D20
ꢀ105.5 (c
ꢂ
0.38, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.57 (d, J¼8.5 Hz, 1H),
(100 MHz, CDCl3)
20.7, 20.1, 14.7; IR (KBr)
(m), 1443 (m), 1387 (m), 1354 (m), 1166 (s), 1077 (s); HRMS (ESI)
d 195.2, 182.0, 90.8, 75.7, 74.7, 66.4, 38.9, 29.6,
7.39 (d, J¼2.2 Hz, 1H), 7.22 (dd, J¼8.4, 2.2 Hz, 1H), 5.22 (dd, J¼12.9,
9.6 Hz, 1H), 4.94 (dd, J¼9.6, 6.1 Hz, 1H), 4.78 (dd, J¼12.9, 6.1 Hz, 1H),
n
/cmꢀ1: 2964 (w), 1694 (w), 1611 (s), 1550

Y.-yun Yan et al. / Tetrahedron 68 (2012) 6123e6130
6129
calcd for C11H17NNaO5 (MþNa)þ: 266.1004, found: 266.0997. The
J¼8.7 Hz, 2H), 5.22 (dd, J¼12.6, 9.3 Hz, 1H), 4.83 (dd, J¼12.6, 6.9 Hz,
1H), 4.58 (d, J¼2.6 Hz, 2H), 4.37 (dd, J¼9.3, 6.9 Hz, 1H), 4.08 (s, 3H),
enantiomeric excess was determined by HPLC with a Chiralpak AS-
H
column (hexane/2-PrOH¼60:40,
l
¼254 nm, 0.8 mL/min);
3.79 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
193.5, 181.5, 158.0, 130.1,
/cmꢀ1: 2964
tmajor¼12.6 min, tminor¼9.8 min, 97% ee.
127.8, 113.3, 91.6, 74.0, 55.7, 54.3, 36.3, 13.3; IR (KBr)
n
(w), 2922 (w), 1604 (m), 1387 (w), 1354 (w), 1261 (w), 1163 (s), 1076
(s); HRMS (ESI) calcd for C14H15NNaO6 (MþNa)þ: 316.0797, found:
316.0796. The enantiomeric excess was determined by HPLC with
4.4.17. (R)-5-Ethoxy-4-(1-cyclohexyl-2-nitroethyl)furan-3(2H)-one
(4q). Prepared according to the general procedure in Section 4.3 as
a colorless oil (39.6 mg, 70% yield); ½a D20
ꢂ
þ29.8 (c 0.44, CH2Cl2); 1H
a Chiralpak AS-H column (hexane/2-PrOH¼60:40,
l¼254 nm,
NMR (400 MHz, CDCl3)
d
4.89 (dd, J¼11.8, 10.5 Hz, 1H), 4.60 (dd,
0.8 mL/min); tmajor¼18.6 min, tminor¼21.4 min, 16% ee.
J¼11.9, 5.1 Hz, 1H), 4.54 (s, 2H), 4.44 (qd, J¼7.1, 0.8 Hz, 2H), 3.01
4.7. Synthesis of (R)-5-(butylamino)-4-(1-(4-methoxyphenyl)-
2-nitroethyl)furan-3(2H)-one (9)
(ddd, J¼10.4, 7.5, 5.1 Hz, 1H), 1.78e1.60 (m, 6H), 1.42 (t, J¼7.1 Hz,
3H), 1.26e0.87 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 195.2, 182.0,
90.7, 75.5, 74.7, 66.4, 38.8, 38.1, 31.1, 30.5, 26.1, 26.0, 25.9, 14.7; IR
A solution of 4c (31 mg, 0.1 mmol) and butylamine (0.4 mmol) in
methanol (3 mL) was stirred at 40 ꢁC for 12 h. After the solvent was
evaporated under vacuum, the residue was purified by flash col-
umn chromatography over silica gel (ethyl acetate/hexane¼1:5 to
(KBr)
n
/cmꢀ1: 2925 (w), 2853 (w), 1695 (m), 1614 (s), 1549 (m),1485
(w), 1451 (m), 1387 (m), 1355 (m), 1162 (s), 1061 (s); HRMS (ESI)
calcd for C14H21NNaO5 (MþNa)þ: 306.1317, found: 306.1311. The
enantiomeric excess was determined by HPLC with a Chiralpak AS-
1:3) to give 9 as a yellow oil (30 mg, 90% yield). ½a D20
ꢀ7.5 (c 1.08,
ꢂ
H
column (hexane/2-PrOH¼60:40,
l
¼254 nm, 0.8 mL/min);
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.34e7.29 (m, 2H), 6.86 (d,
tmajor¼16.6 min, tminor¼15.4 min, 97% ee.
J¼8.7 Hz, 2H), 5.44 (dd, J¼13.2, 7.2 Hz, 1H), 5.22 (t, J¼5.4 Hz, 1H),
4.88 (dd, J¼13.2, 8.3 Hz, 1H), 4.47 (s, 2H), 4.29 (t, J¼7.7 Hz, 1H), 3.78
(s, 3H), 3.27e3.19 (m, 2H),1.45e1.37 (m, 2H), 1.21 (td, J¼14.9, 7.5 Hz,
4.4.18. (R)-5-Ethoxy-4-(1-nitropropan-2-yl)furan-3(2H)-one
(4r). To a solution of 2-acetyloxy-1-nitro-propane (0.22 mmol) in
3H), 0.87 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 192.1, 177.2,
THF (1 mL) were added ethyl 4-chloro-3-oxobutanoate (27
mL,
159.2, 130.4, 128.9, 114.5, 89.5, 76.7, 73.9, 55.3, 41.2, 38.1, 31.8, 19.6,
0.2 mmol) and 60-demethyl quinine 5a (0.04 mmol). The mixture was
stirred at room temperature for 96 h. After the solvent was evapo-
rated under vacuum, the residue was purified by flash column
chromatography over silica gel (ethyl acetate/hexane¼1:3). The
13.5; IR (KBr) n
/cmꢀ1: 1673 (w), 1614 (w), 1545 (w), 1514 (w), 1439
(m), 1383 (m), 1254 (w), 1162 (s), 1066 (s); HRMS (ESI) calcd for
C17H22N2NaO5 (MþNa)þ: 357.1421, found: 357.1426. The enantio-
meric excess was determined by HPLC with a Chiralpak AS-H col-
product 4r was obtained as a colorless oil (19.4 mg, 45% yield). ½a D20
ꢂ
umn (hexane/2-PrOH¼60:40,
l
¼254 nm, 0.8 mL/min);
þ20.6(c 0.56, CH2Cl2); 1HNMR (400 MHz, CDCl3)
d 4.80e4.61 (m,1H),
tmajor¼15.4 min, tminor¼7.5 min, 97% ee.
4.54 (s, 2H), 4.52e4.42 (m, 3H), 3.34 (dd, J¼14.3, 7.2 Hz, 1H), 1.44 (t,
J¼7.0 Hz, 3H), 1.25 (d, J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.8. Synthesis of (E)-3-(1,2-dihydroxyethylidene)-4-
195.0, 181.2, 93.0, 78.1, 74.8, 66.5, 26.7, 16.1, 14.7; IR (KBr) n :
/cmꢀ1
phenylpyrrolidin-2-one (11)12
d
2923 (w), 2852 (w), 1600 (s), 1550 (m), 1443 (m), 1386 (m), 1335 (w),
1094 (w), 1022 (w); HRMS (ESI) calcd for C9H13NNaO5 (MþNa)þ:
238.0686, found:238.0693. Theenantiomeric excesswasdetermined
by HPLC with a Chiralpak AS-H column (hexane/2-PrOH¼85:15,
To a solution of 4a (0.2 mmol) in THF (2 mL) was added 6 M HCl
(2 mL). The mixture was stirred at room temperature for 2 h and
then concentrated under vacuum. The residue was extracted with
ethyl acetate (5 mLꢃ3). The combined organic layers were dried
over anhydrous MgSO4. After the solvent was evaporated under
vacuum, the residue was purified by flash column chromatography
over silica gel (ethyl acetate/hexane¼1:1 to 10:1) afforded tetronic
acid 10 as a pale yellow solid (47.5 mg, 95% yield).
l
¼220 nm, 0.8 mL/min); tmajor¼29.9 min, tminor¼31.3 min, 92% ee.
4.5. Synthesis of (R)-5-hydroxy-4-(1-(4-methoxyphenyl)-2-
nitroethyl)furan-3(2H)-one (7)
To
a solution of b-(4-methoxy-phenyl)-nitroethylene 2c
Compound 10 (0.18 mmol) was dissolved in a mixture of THF
(1 mL) and AcOH (0.8 mL). Zn powder (1.8 mmol) was added and
the resulting mixture was stirred at room temperature for 24 h. The
mixture was filtered through a layer of Celite, and the filtrate was
concentrated under vacuum. The residue was purified by flash
chromatography (CH2Cl2/MeOH¼5:1 to CH2Cl2/MeOH/TEA¼5:1:1)
(0.22 mmol) in THF (1 mL) were added tetronic acid (20.0 mg,
0.20 mmol) and 60-demethyl quinine 5a (0.02 mmol, 10 mol %). The
mixture was stirred at ꢀ20 ꢁC for 48 h. After the solvent was
evaporated under vacuum, the residue was purified by flash col-
umn chromatography over silica gel (CH2Cl2/MeOH¼20:1) to give 7
as a white solid (16.7 mg, 30% yield). Mp 160 ꢁC (decomposed); 1H
to afford
NMR (400 MHz, CD3OH)
g
-lactam 11 as a pale yellow solid (27.6 mg, 70% yield). 1H
NMR (400 MHz, CD3OD)
d
7.27 (d, J¼8.8 Hz, 2H), 6.82 (d, J¼8.7 Hz,
d
7.45e7.28 (m, 4H), 7.24 (dd, J¼10.0,
2H), 5.18 (dd, J¼13.1, 9.5 Hz, 1H), 4.81 (dd, J¼13.1, 6.8 Hz, 1H), 4.61
4.1 Hz, 1H), 4.58e4.32 (m, 2H), 3.99 (dd, J¼7.2, 3.9 Hz, 1H), 3.56 (dd,
(s, 2H), 4.54 (dd, J¼9.4, 6.9 Hz, 1H), 3.74 (s, 3H); 13C NMR (100 MHz,
J¼12.4, 7.4 Hz, 1H), 3.31e3.29 (m, 1H); 13C NMR (100 MHz, CD3OH)
CD3OD)
d 176.8, 176.5, 160.6, 131.9, 129.9, 115.2, 100.5, 77.7, 68.2,
d
191.0,182.3,141.9,129.8, 129.0,128.1, 92.5, 71.2, 45.3, 40.2; IR (KBr)
/cmꢀ1: 2962 (w), 2923 (w), 1634 (s), 1559 (m), 1423 (m), 1384 (m),
55.7, 39.1, 34.0; IR (KBr) n
/cmꢀ1: 1599 (m), 1513 (m), 1385 (m), 1355
n
(m), 1162 (s), 1078 (s); HRMS (ESI) calcd for C13H13BrNO6 (MꢀH)ꢀ:
1261 (m), 1097 (s), 1032 (s); HRMS (ESI) calcd for C12H14NO3
(MþH)þ: 220.0967, found: 220.0968.
278.0665, found: 278.0670.
Acknowledgements
4.6. Synthesis of (R)-5-methoxy-4-(1-(4-methoxyphenyl)-2-
nitroethyl)furan-3(2H)-one (8)
Financial supports from National Natural Science Foundation of
China (Nos. 20972195, 21172270) and Guangdong Engineering Re-
search Center of Chiral Drugs are gratefully acknowledged.
To a solution of 7 (27.8 mg, 0.10 mmol) in dry methylene
dichloride (2 mL) was added trimethyloxonium fluoroborate
(44.4 mg, 0.30 mmol). The resulting suspension was refluxed for
24 h. After the solvent was evaporated under vacuum, the residue
was purified by flash column chromatography over silica gel (ethyl
acetate/hexane¼1:5 to 1:3) to give 8 as a yellow oil (12.3 mg, 42%
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.082.
yield). 1H NMR (400 MHz, CDCl3)
d
7.34 (d, J¼8.7 Hz, 2H), 6.85 (d,

6130
Y.-yun Yan et al. / Tetrahedron 68 (2012) 6123e6130
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