Efficient asymmetric synthesis of 4H-chromene derivatives through a tandem michael addition-cyclization reaction catalyzed by a salen-cobalt(II) complex

Article abstract of DOI:10.1002/ejoc.201001151

The asymmetric synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene derivatives was achieved through a tandem Michael addition-cyclization reaction of easily available cyclohexane-1,3-dione and ethyl 2-cyano-3-phenylacrylates. Moderate to good yields (up to 81%) and high enantioselectivities (up to 89%ee) were obtained with a chiral salen-cobalt(II) complex. This process was air tolerant and easily performed, which provides an efficient method for the synthesis of chiral 4H-chromene derivatives. The asymmetric synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene derivatives was achieved through a tandem Michael addition-cyclization reaction of easily available cyclohexane-1,3-dione and ethyl 2-cyano-3-phenylacrylates catalyzed by a chiral salen-cobalt(II) complex with moderate to good yields (up to 81%) and high enantioselectivities (up to 89%ee).

Full text of DOI:10.1002/ejoc.201001151

FULL PAPER
DOI: 10.1002/ejoc.201001151
Efficient Asymmetric Synthesis of 4H-Chromene Derivatives through a Tandem
Michael Addition–Cyclization Reaction Catalyzed by a Salen–Cobalt(II)
Complex
Zhenhua Dong,[a] Xiaohua Liu,*[a] Juhua Feng,[a] Min Wang,[a] Lili Lin,[a] and
Xiaoming Feng*[a]
Keywords: Asymmetric synthesis / Cyclization / Biological activity / Michael addition / Tandem reactions
The asymmetric synthesis of 2-amino-5-oxo-5,6,7,8-tetra-
hydro-4H-chromene derivatives was achieved through a tan-
dem Michael addition–cyclization reaction of easily available
cyclohexane-1,3-dione and ethyl 2-cyano-3-phenylacrylates.
Moderate to good yields (up to 81%) and high enantio-
selectivities (up to 89%ee) were obtained with a chiral
salen–cobalt(II) complex. This process was air tolerant and
easily performed, which provides an efficient method for the
synthesis of chiral 4H-chromene derivatives.
2-naphthol with α,α-dicyanoolefins.[6c] Moderate yields and
enantioselectivities were obtained. Xie disclosed an efficient
synthesis of 2-amino-2-chromene through a different tan-
dem reaction of hydroxy substituted α,β-unsaturated
ketones and malononitrile.[6d]
Introduction
The chromene skeleton, including that of 2H-chromene
and 4H-chromene, is probably one of the most familiar
structural units in naturally occurring compounds.[1–3] Due
to various pharmacological properties such as anticoagu-
lant, anticancer, antianaphylactic, and fungicidal activities,
2-amino-4H-chromenes are rather unusual among the
chromene family members.[4] Some representative examples
are gathered in Figure 1. HA14-1 (A) can effectively induce
apoptosis of human acute myeloid leukemia cells.[4a] Pyr-
azole derivative B is an inhibitor of human Chk 1 kinase.[4b]
2-Amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene (C) has an
important antibacterial activity.[4c] Owing to the impor-
tance of the 2-amino-4H-chromene framework, its synthesis
has attracted considerable attention.[5] The conventional
method for the racemic synthesis of 2-amino-4H-chromenes
is the Brønsted base catalyzed tandem conjugate addition–
cyclization reaction; there are only a few examples of an
asymmetric synthesis of this class of compounds. Recently,
the Zhao group used cupreine and cinchona alkaloid de-
rived thioureas as organocatalysts for the asymmetric syn-
thesis of pyranopyrazole derivatives and 2-amino-8-oxo-
4H-chromene analogues by the Michael addition–cycliza-
tion reaction of α-carbonyl compounds and α,α-dicyanoole-
fins.[6a,6b] The enantioselective synthesis of naphthopyran
derivatives was performed with a bifunctional thiourea cat-
alyzed tandem asymmetric addition–cyclization reaction of
Figure 1. Selected examples of 4H-chromenes embodied with bio-
logical and pharmacological activity.
To the best of our knowledge, there is no report on a
direct catalytic asymmetric method for the synthesis of
optically
active
2-amino-5-oxo-5,6,7,8-tetrahydro-4H-
chromene derivatives using readily available reagents. Thus,
the development of an effective asymmetric method for
their preparation attracted our interest.[7] In addition, chiral
salen ligands are among the most widely useful ligands in
asymmetric synthesis. Salen–cobalt complexes have been
shown to be highly efficient in many asymmetric pro-
cedures.[8,9] Herein, we wish to present the first asymmetric
[a] Key Laboratory of Green Chemistry &Technology,
Ministry of Education, College of Chemistry,
Sichuan University,
Chengdu 610064, People’s Republic of China
Fax: +86-28-85418249
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001151.
synthesis
of
2-amino-5-oxo-5,6,7,8-tetrahydro-4H-
Eur. J. Org. Chem. 2011, 137–142
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
137

Z. H. Dong, X. H. Liu, J. H. Feng, M. Wang, L. L. Lin, X. M. Feng
FULL PAPER
chromene derivatives based on a tandem strategy of Table 1. Survey of ligand and central metal on the asymmetric tan-
dem reaction.[a]
Michael addition and cyclization between cyclohexane-1,3-
dione and ethyl 2-cyano-3-phenylacrylates catalyzed by
salen–cobalt(II) complexes.
Results and Discussion
Initially, cyclohexane-1,3-dione (3a) and ethyl 2-cyano-3-
phenylacrylate (4a) were chosen as the model compounds.
Entry
Salen
Metal
Yield [%][b] ee [%][c]
Salen 1a (Scheme 1) derived from (R,R)-1,2-diphenyle-
thane-1,2-diamine and 3,5-di-tert-butylsalicylaldehyde re-
acted in situ with various metal reagents to form complexes
to catalyze the asymmetric tandem addition–cyclization re-
action. As shown in Table 1, Co(OAc)2·4H2O was more ef-
ficient than other metals, giving the desired products in
52% yield with 53%ee (Table 1, Entry 1). Other metals in-
cluding Ni, Fe, Cu, and even Co with different counterions
either did not catalyze reaction or gave a product in a very
low yield and enantioselectivity (Table 1, Entries 2–8). The
results indicated that the central metal and negative ions
were both important for the reaction. To further improve
the reactivity and enantioselectivity of the reaction, the ste-
ric and electronic effects of the salen ligand were then exam-
ined (Table 1, Entries 9–16). As shown in Table 1, it was
found that the tert-butyl groups in the para and ortho posi-
tions to the OH group in the ligands were both crucial for
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Co(OAc)2·4H2O
Co(acac)2
Co(acac)3
CoCl2·6H2O
Ni(acac)2
52
4
53
27
–
–
–7
–
–
–
7
13
–
nr[d]
nr
17
NiCl2
Fe(OAc)2
Cu(OAc)2
nr[d]
nr[d]
nr[d]
70
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
28
nr[d]
70
8
0
5
0
45
41
94
19
1g
2a
2b
11
[a] Unless otherwise noted, all reactions were carried out with 3a
(0.1 mmol) and 4a (0.12 mmol) in THF (1.0 mL) with the catalyst
(10 mol-%, metal/ligand = 1:1) at room temperature for 24 h.
the enantioselectivity. Other substituents on the salen ligand [b] Yield of the isolated product. [c] Determined by chiral HPLC
analysis. [d] nr = no reaction.
did not provide satisfactory results. In particular, ligand 1d
bearing Br groups in the para and ortho positions to the
OH group showed no activity in this reaction (Table 1, En-
try 11). Further optimization showed that the yield and
enantioselectivity of product 5a were greatly affected by the
chiral backbone of the salen ligands. Salen 2a derived from
(R,R)-cyclohexane-1,2-diamine catalyzed the reaction in
near-quantitative yield but gave a racemic product (Table 1,
Entry 15). Although the backbone of ligands 1a and 2b
have the same absolute configuration, [H4]salen ligand 2b
To further improve the reactivity and enantioselectivity,
other parameters of the reaction conditions were optimized.
Various solvents were screened under the model reaction
conditions, and the results are summarized in Table 2 (En-
tries 1–7). Solvents such as MeOH, CH2Cl2, Et2O, PhMe,
as well as THF were all not suitable for this reaction, as
moderate yields and low enantioselectivities were obtained.
Fortunately, ethyl acetate and MeCN gave better results and
afforded the desired product in only 19% yield and 11%ee
higher enantioselectivities (Table 2, Entries 6 and 7). Ethyl
(Table 1, Entry 16). Thus, salen 1a-Co(OAc)2·4H2O was
acetate as the solvent produced a higher enantioselectivity
chosen as the catalyst for further research. Moreover, the
at room temperature. However, MeCN gave a better result
with 78% yield and 69%ee when the temperature was de-
reaction was air tolerant and easily performed with readily
available reagents.
creased to 0 °C (Table 2, Entries 8 and 9). So, we carried
out further screening at 0 °C in MeCN. The effect of addi-
tive was also investigated to further improve the enantio-
selectivity. A series of additives including acid, base,
alcohol, and phenol were tested, and we noted that the ee
could be improved to 73% with a lower yield when 10 mol-
% of 3,5-dinitrosalicylic acid was used (Table 2, Entry 10).
Adjusting the ratio of ligand, metal, and additive to 1:2:1.5
slightly increased the enantioselectivity (Table 2, Entry 11).
Increasing the catalyst loading to 15 mol-% [15 mol-%
salen, 30 mol-% Co(OAc)2·4H2O, 22.5 mol-% 3,5-dinitrosa-
licylic acid] increased the enantioselectivity to 76%ee
(Table 2, Entry 12). In the hope of enhancing the yield, the
reaction time was extended to 48 h and the ratio of reac-
tants 4a and 3a was altered to 1.1:1, which increased the
Scheme 1. Chiral ligands used in the study.
138
yield to 77% with a better enantioselectivity up to 78%ee
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Efficient Asymmetric Synthesis of 4H-Chromene Derivatives
(Table 2, Entry 13). Therefore, the optimal reaction condi- Table 3. Scope of the tandem reaction.[a]
tions were 15 mol-% salen 1a, 30 mol-% Co(OAc)2·4H2O,
and 22.5 mol-% 3,5-dinitrosalicylic acid as additive,
0.11 mmol 4a, and 0.10 mmol 3a in 1 mL MeCN at 0 °C
for 48 h.
Table 2. Optimization of reaction conditions.[a]
Entry
Solvent
T [°C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
THF
MeOH
CH2Cl2
Et2O
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
0
0
0
0
52
65
12
23
56
99
82
78
70
54
57
56
77
53
17
11
45
39
54
61
69
65
73
75
76
78
PhMe
MeCN
EtOAc
MeCN
EtOAc
MeCN
MeCN
MeCN
MeCN
10[d]
11[d,e]
12[d–f]
13[d–g]
0
[a] Unless otherwise noted, all reactions were carried out with 3a
(0.1 mmol) and 4a (0.12 mmol) in solvent (1.0 mL) with the catalyst
(10 mol-%, metal/ligand = 1:1) for 24 h. [b] Yield of the isolated
product. [c] Determined by chiral HPLC analysis. [d] 10 mol-% of
3,5-dinitrosalicylic acid was added. [e] 10 mol-% of 1a, 20 mol-%
of Co(OAc)2·4H2O, and 15 mol-% of 3,5-dinitrosalicylic acid was
used. [f] 15 mol-% catalyst loading [15 mol-% 1a, 30 mol-% Co(-
OAc)2·4H2O, and 22.5 mol-% 3,5-dinitrosalicylic acid]. [g] 48 h, 4a
(0.11 mmol) and 3 (0.10 mmol).
[a] Unless otherwise noted, all reactions were carried out with 3a
(0.10 mmol) and 4 (0.11 mmol) in MeCN (1.0 mL) with 1a (15 mol-
%), Co(OAc)2·4H2O (30 mol-%), and 3,5-dinitrosalicylic acid
(22.5 mol-%) for 48 h at 0 °C. [b] Yield of the isolated product.
[c] Determined by chiral HPLC analysis. [d] Dimedone (3b) instead
of 3a.
Under the optimized conditions, a wide range of ethyl 2-
cyano-3-phenylacrylates were explored. The corresponding
products 5a–t were obtained in moderate to good yields
with high enantioselectivities, as summarized in Table 3.
The results show that the electronic nature of the substitu-
ent in the aromatic ring has an obvious effect on the yield
and enantioselectivity. In general, except for 3-methoxy de-
rivative 5g, which gave a better yield (up to 75%; Table 3,
Entry 7), electron-withdrawing substituents gave the prod-
uct in higher yields (Table 3, 71–81%) than substrates with
electron-donating substituents (Table 3, Entries 2–6 vs. 8–
14). Additionally, most of the substrates with substituents
in the para position gave products with better enantio-
selectivities (81–83%ee; Table 3, Entries 4, 6, 9, and 13), es-
pecially for para-phenyl derivative 5o (89%ee; Table 3, En-
try 15). Moreover, the 2-naphthyl substrate also produced
the product in good yield and enantioselectivity (Table 3,
Entry 16). Heteroaromatic substrate 4q was also tested with
a moderate enantioselectivity (Table 3, Entry 17). Sub-
strates 4r and 4s with different substituents on the ester
moiety (R2) also gave good yields and ee values (Table 3,
Entries 18 and 19). In addition, dimedone (3b) was also a
good nucleophile for the reaction with 70% yield and
77%ee (Table 3, Entry 20).
Scheme 2. Proposed catalytic cycle.
Eur. J. Org. Chem. 2011, 137–142
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139

Z. H. Dong, X. H. Liu, J. H. Feng, M. Wang, L. L. Lin, X. M. Feng
FULL PAPER
Chiralcel AD, 2-propanol/n-hexane = 20:80, flow rate = 1.0 mL/
min, λ = 254 nm): tR = 6.42 (major), 8.38 (minor) min.
A possible catalytic cycle for the tandem reaction is pro-
posed, as shown in Scheme 2. The key step for the process
involves deprotonation–reprotonation. The chiral salen–co-
balt complex first abstracts a proton from the enol to form
intermediate 6. Intermediate 6 then reacts with ethyl 2-cy-
ano-3-phenylacrylate (4a) through a Michael addition pro-
cess. Cyclization then occurs quickly so that no Michael
reaction intermediate is detected. Reprotonation of 8 af-
fords imine intermediate 9, which liberated the chiral salen–
cobalt complex. Finally, product 5a is formed after tauto-
merization.
5b: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (16.7 mg, 51%, 77%ee). [α]22.3 = 15.1 (c =
0.106, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.15 (t, J =
7.2 Hz, 3 H), 1.97–2.02 (m, 2 H), 2.28–2.32 (m, 2 H), 2.53–2.59 (m,
2 H), 2.69 (s, 3 H), 3.97–4.09 (m, 2 H), 4.86 (s, 1 H), 6.18 (s, 2 H),
6.98–7.04 (m, 4 H) ppm. HPLC (Daicel Chiralcel AD, 2-propanol/
n-hexane = 10:90, flow rate = 1.0 mL/min, λ = 254 nm): tR = 11.90
(major), 14.72 (minor) min.
5c: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (16.8 mg, 52%, 71%ee). [α]22.4 = 34.6 (c =
1
0.104, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 1.14–1.17 (t, J
= 7.2 Hz, 3 H), 1.95–2.05 (m, 2 H), 2.31–2.36 (m, 5 H), 2.53–2.59
(m, 2 H), 4.00–4.05 (q, J = 7.2, 14.4 Hz, 2 H), 4.69 (s, 1 H), 6.14
(s, 2 H), 6.92 (d, J = 7.2 Hz, 1 H), 7.04–7.11 (m, 3 H) ppm. HPLC
(Daicel Chiralcel AD, 2-propanol/n-hexane = 10:90, flow rate =
1.0 mL/min, λ = 254 nm): tR = 11.39 (major), 15.20 (minor) min.
Conclusions
In summary, the chiral compound ethyl 2-amino-5-oxo-
4-aryl-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate was
synthesized through a tandem Michael addition–cyclization
process catalyzed by a salen–cobalt(II) complex. The corre-
sponding products, which have extensive biological and
pharmacological activities, can be obtained in moderate to
good yields (up to 81%) with high enantioselectivities (up
to 89%ee). This pathway is air tolerant, and the catalyst is
prepared easily with readily available reagents. A possible
catalytic cycle was proposed to explain the formation of
the products. Further efforts will be devoted to improve the
reactivity and enantioselectivity of the reaction as well as
to synthesize 4H-chromene analogues.
5d: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (15.1 mg, 46%, 83%ee). [α]22.4 = 25.9 (c =
1
0.108, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 1.15–1.18 (t, J
= 7.2 Hz, 3 H), 1.99 (m, 2 H), 2.27 (s, 3 H), 2.33 (t, J = 4.4 Hz, 2
H), 2.56 (m, 2 H), 4.00–4.05 (m, 2 H), 4.70 (s, 1 H), 6.13 (s, 2 H),
7.00–7.02 (d, J = 8.0 Hz, 2 H), 7.14–7.16 (d, J = 8.0 Hz, 2 H) ppm.
HPLC (Daicel Chiralcel AD, 2-propanol/n-hexane = 20:80, flow
rate
= 1.0 mL/min, λ = 254 nm): tR = 6.11 (major), 9.14
(minor) min.
5e: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (20.4 mg, 57%, 72%ee). [α]22.9 = 26.7 (c =
1
0.120, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 1.18–1.21 (t, J
= 7.2 Hz, 3 H), 1.95–2.07 (m, 2 H), 2.30–2.41 (m, 2 H), 2.54–2.62
(m, 2 H), 4.04–4.11 (m, 2 H), 4.67 (s, 1 H), 5.89 (d, J = 2.8 Hz, 2
H), 6.19 (s, 2 H), 6.67 (d, J = 8.8 Hz, 1 H), 6.77 (d, J = 6.0 Hz, 2
H) ppm. HPLC (Daicel Chiralcel AD, 2-propanol/n-hexane =
20:80, flow rate = 1.0 mL/min, λ = 254 nm): tR = 10.30 (major),
12.74 (minor) min.
Experimental Section
General Procedures: 1H and 13C NMR spectra were recorded in
CDCl3 with a 400 MHz spectrometer. TMS served as an internal
standard (δ = 0 ppm) for 1H NMR and CDCl3 was used as the
internal standard (δ = 77.0 ppm) for 13C NMR. Chemical shifts are
reported in ppm with the solvent reference as the internal standard
(CHCl3: δ = 7.26 ppm). Purification of reaction products was car-
ried out by flash chromatography. Enantiomeric excess (ee) values
were determined by chiral HPLC by using a Chiralcel AD column.
Optical rotations were measured with a polarimeter. HRMS were
recorded with a commercial apparatus (ESI or ES source).
5f: Purified by flash chromatography (petroleum/EtOAc, 2:1) to af-
ford a white solid (18.9 mg, 55%, 81%ee). [α]22.9 = 50.5 (c = 0.103,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.16–1.19 (t, J =
7.2 Hz, 3 H), 1.93–2.06 (m, 2 H), 2.32–2.39 (m, 2 H), 2.53–2.61 (m,
2 H), 3.76 (s, 3 H), 4.01–4.09 (m, 2 H), 4.69 (s, 1 H), 6.20 (s, 1 H),
6.75–6.77 (d, J = 8.8 Hz, 2 H), 7.19 (d, J = 8.8 Hz, 2 H) ppm.
HPLC (Daicel Chiralcel AD, 2-propanol/n-hexane = 20:80, flow
rate = 1.0 mL/min, λ = 254 nm): tR = 7.92 (major), 12.74
(minor) min.
Typical Procedure for the Enantioselective Tandem Reaction: Chiral
salen ligand 1a (9.7 mg, 0.015 mmol), Co(OAc)2·4H2O (7.5 mg,
0.03 mmol), and 3,5-dinitrosalicylic acid (5.1 mg, 0.0225 mmol)
were added into a test tube and then MeCN (0.5 mL) was added.
After stirring for 1 h at room temperature, the mixture was cooled
to 0 °C. A solution of 4a (22.1 mg, 0.11 mmol) and 3a (11.2 mg,
0.10 mmol) in MeCN (0.5 mL) was then added. The reaction mix-
ture was stirred at 0 °C for 48 h. Then, the reaction was diluted
with ethyl acetate (40 mL). After extraction with 1 n NaOH
(4ϫ30 mL), the organic layer was combined and dried with so-
dium sulfate and evaporated under reduced pressure. The crude
product was purified by column chromatography (ethyl acetate/pe-
troleum ether, 1:2) to afford product 5a. White solid (24.2 mg, 77%,
78%ee). [α]21.4 = 13.9 (c = 0.101, CH2Cl2). 1H NMR (400 MHz,
5g: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (25.7 mg, 75%, 74%ee). [α]20.4 = 4 (c = 0.10,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.15–1.18 (t, J =
7.2 Hz, 3 H), 1.94–2.02 (m, 2 H), 2.31–2.37 (m, 2 H), 2.52–2.58 (m,
2 H), 3.78 (s, 3 H), 3.95–4.10 (m, 2 H), 4.72 (s, 1 H), 6.18 (s, 2 H),
6.65–6.68 (dd, J = 2.4, 8.0 Hz, 1 H), 6.84–6.88 (t, J = 8.4 Hz, 2 H),
7.11–7.15 (t, J = 8.0 Hz, 1 H) ppm. HPLC (Daicel Chiralcel AD,
2-propanol/n-hexane = 20:80, flow rate = 1.0 mL/min, λ = 254 nm):
tR = 7.63 (major), 9.90 (minor) min.
5h: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (24.6 mg, 71%, 73%ee). [α]22.5 = 37.3 (c =
1
CDCl3): δ = 1.12 (t, J = 7.2 Hz, 3 H), 1.90–2.03 (m, 2 H), 2.28– 0.118, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 1.14–1.17 (t, J
2.36 (m, 2 H), 2.51–2.59 (m, 2 H), 3.97–4.03 (m, 2 H), 4.70 (s, 1
H), 6.14 (s, 2 H), 7.07–7.10 (t, J = 7.6 Hz, 1 H), 7.16–7.19 (t, J =
7.2 Hz, 2 H), 7.23–7.25 (d, J = 6.8 Hz, 2 H) ppm. HPLC (Daicel
= 6.8 Hz, 3 H), 2.02 (m, 2 H), 2.32–2.36 (m, 2 H), 2.59 (m, 2 H),
4.01–4.06 (q, J = 6.8, 14.0 Hz, 2 H), 4.70 (s, 1 H), 6.13 (s, 2 H),
7.10–7.22 (m, 4 H) ppm. HPLC (Daicel Chiralcel AD, 2-propanol/
140
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Efficient Asymmetric Synthesis of 4H-Chromene Derivatives
n-hexane = 10:90, flow rate = 1.0 mL/min, λ = 254 nm): tR = 12.57
(major), 15.68 (minor) min.
[M]+ 390.1661; found 390.1704. HPLC (Daicel Chiralcel AD, 2-
propanol/n-hexane = 20:80, flow rate = 1.0 mL/min, λ = 254 nm):
tR = 8.74 (major), 12.17 (minor) min.
5i: Purified by flash chromatography (petroleum/EtOAc, 2:1) to af-
ford a white solid (27.4 mg, 79%, 81%ee). [α]22.6 = 51.5 (c = 0.132,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.14–1.18 (t, J =
6.8 Hz, 3 H), 1.93–2.08 (m, 2 H), 2.30–2.40 (m, 2 H), 2.55–2.63 (m,
2 H), 4.00–4.09 (m, 2 H), 4.71 (s, 1 H), 6.22 (s, 2 H), 6.18–7.24 (m,
4 H) ppm. HPLC (Daicel Chiralcel AD, 2-propanol/n-hexane =
20:80, flow rate = 1.0 mL/min, λ = 254 nm): tR = 6.45 (major), 9.36
(minor) min.
5p: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (23.2 mg, 64%, 81%ee). [α]23.0 = 46.7 (c = 0.12,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.11–1.14 (t, J =
7.2 Hz, 3 H), 1.92–2.04 (m, 2 H), 2.30–2.32 (m, 2 H), 2.52–2.59 (m,
2 H), 3.93–4.05 (m, 2 H), 4.90 (s, 1 H), 6.25 (s, 2 H), 7.36–7.44 (m,
3 H), 7.68–7.73 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
14.21, 20.22, 26.99, 34.01, 36.86, 59.67, 80.65, 118.03, 125.15,
125.57, 126.73, 127.00, 127.37, 127.46, 127.82, 132.26, 133.33,
143.49, 158.42, 163.04, 169.11, 196.48 ppm. HRMS: calcd. for
C22H21NO4 [M]+ 364.1504; found 364.1542. HPLC (Daicel Chi-
5j: Purified by flash chromatography (petroleum/EtOAc, 2:1) to af-
ford a white solid (28.6 mg, 80%, 77%ee). [α]23.1 = 61.8 (c = 0.110,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.11–1.14 (t, J =
6.8 Hz, 3 H), 1.92–2.08 (m, 2 H), 2.33–2.36 (m, 2 H), 2.57–2.65 (m, ralcel AD, 2-propanol/n-hexane = 30:70, flow rate = 1.0 mL/min,
2 H), 3.98–4.06 (m, 2 H), 4.82 (s, 1 H), 6.28 (s, 2 H), 7.44–7.46 (d, J λ = 254 nm): tR = 5.23 (major), 9.65 (minor) min.
= 8.8 Hz, 2 H), 8.07–8.09 (d, J = 8.4 Hz, 2 H) ppm. HPLC (Daicel
5q: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (23.9 mg, 75%, 69%ee). [α]23.0 = 52.5 (c =
0.099, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 1.19–1.22 (t, J
= 7.2 Hz, 3 H), 1.98–2.04 (m, 2 H), 2.33–2.58 (m, 4 H), 4.09–4.15
(m, 2 H), 5.10 (s, 1 H), 6.23 (s, 2 H), 6.82–6.86 (m, 2 H), 7.03–7.04
(d, J = 4.8 Hz, 1 H) ppm. HPLC (Daicel Chiralcel AD, 2-propanol/
n-hexane = 20:80, flow rate = 1.0 mL/min, λ = 254 nm): tR = 7.46
(major), 10.35 (minor) min.
Chiralcel AD, 2-propanol/n-hexane = 20:80, flow rate = 1.0 mL/
min, λ = 254 nm): tR = 8.71 (major), 13.66 (minor) min.
1
5k: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (26.8 mg, 81%, 77%ee). [α]23.1 = 68.1 (c =
1
0.091, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 1.12–1.15 (t, J
= 7.2 Hz, 3 H), 1.92–2.06 (m, 2 H), 2.27–2.38 (m, 2 H), 2.53–2.62
(m, 2 H), 4.00–4.06 (q, J = 7.2 Hz, 2 H), 4.70 (s, 1 H), 6.18 (s, 2
H), 6.86–6.91 (t, J = 8.8 Hz, 2 H), 7.21–7.25 (dd, J = 5.6, 8.4 Hz,
2 H) ppm. HPLC (Daicel Chiralcel AD, 2-propanol/n-hexane =
20:80, flow rate = 1.0 mL/min, λ = 254 nm): tR = 6.24 (major), 7.99
(minor) min.
5r: Purified by flash chromatography (petroleum/EtOAc, 3:1) to
afford a white solid (21.2 mg, 71%, 73%ee). [α]29.1 = 14.1 (c =
1
0.075, CH2Cl2). H NMR (600 MHz, CDCl3): δ = 1.90–2.04 (m, 2
H), 2.16–2.43 (m, 2 H), 2.44–2.59 (m, 2 H), 3.58 (s, 3 H), 4.73 (s,
1 H), 6.18 (br. s, 2 H), 7.10–7.13 (t, J = 7.2 Hz, 1 H), 7.19–7.22 (t,
J = 7.2 Hz, 2 H), 7.26–7.27 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 20.18, 26.95, 33.54, 36.85, 50.97, 80.57,
118.27, 126.11, 127.93, 128.04, 145.87, 158.56, 163.04, 169.49,
196.48 ppm. HPLC (Daicel Chiralcel AD, 2-propanol/n-hexane =
10:90, flow rate = 1.0 mL/min, λ = 254 nm): tR = 14.60 (major),
21.08 (minor) min.
5l: Purified by flash chromatography (petroleum/EtOAc, 2:1) to af-
ford a white solid (29.7 mg, 76%, 74%ee). [α]19.7 = 13.5 (c = 0.104,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.14–1.17 (t, J =
7.2 Hz, 3 H), 1.94–2.07 (m, 2 H), 2.28–2.40 (m, 2 H), 2.50–2.65 (m,
2 H), 4.01–4.06 (q, J = 7.2 Hz, 2 H), 4.68 (s, 1 H), 6.20 (s, 2 H),
7.06–7.09 (t, J = 8.0 Hz, 1 H), 7.21–7.25 (t, J = 7.6 Hz, 2 H), 7.38
(s, 1 H) ppm. HPLC (Daicel Chiralcel AD, 2-propanol/n-hexane =
20:80, flow rate = 1.0 mL/min, λ = 254 nm): tR = 6.24 (major), 7.99
(minor) min.
5s: Purified by flash chromatography (petroleum/EtOAc, 3:1) to
afford a white solid (23.5 mg, 72%, 69%ee). [α]22.3 = 52.3 (c =
0.153, CH2Cl2). 1H NMR (600 MHz, CDCl3): δ = 0.94 (d, J =
6.2 Hz, 3 H), 1.21 (d, J = 6.2 Hz, 3 H), 1.91–2.04 (m, 2 H), 2.28–
2.36 (m, 2 H), 2.49–2.61 (m, 2 H), 4.70 (s, 1 H), 4.85–4.89 (m, 1
H), 6.16 (br. s, 1 H), 7.08–7.11 (t, J = 7.3 Hz, 1 H), 7.18–7.21 (t, J
= 7.4 Hz, 2 H), 7.26 (d, J = 7.1 Hz, 2 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 20.22, 21.58, 22.17, 26.97, 33.89, 36.88,
66.89, 81.12, 118.03, 125.98, 127.68, 128.39, 146.08, 158.13, 162.93,
168.67, 196.60 ppm. HPLC (Daicel Chiralcel AD, 2-propanol/n-
hexane = 10:90, flow rate = 1.0 mL/min, λ = 254 nm): tR = 10.11
(major), 13.81 (minor) min.
5m: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (29.7 mg, 76%, 83%ee). [α]20.5 = –8 (c = 0.10,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.12–1.16 (t, J =
7.2 Hz, 3 H), 1.92–2.06 (m, 2 H), 2.27–2.38 (m, 2 H), 2.50–2.61 (m,
2 H), 3.98–4.07 (m, 2 H), 4.68 (s, 1 H), 6.20 (s, 2 H), 7.14–7.16 (d, J
= 8.4 Hz, 2 H), 7.31–7.33 (d, J = 8.0 Hz, 2 H) ppm. HPLC (Daicel
Chiralcel AD, 2-propanol/n-hexane = 20:80, flow rate = 1.0 mL/
min, λ = 254 nm): tR = 6.51 (major), 9.77 (minor) min.
5n: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (27.4 mg, 72%, 79%ee). [α]20.7 = –16 (c = 0.10,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.11–1.15 (t, J =
7.2 Hz, 3 H), 1.92–2.07 (m, 2 H), 2.32–2.36 (m, 2 H), 2.55–2.60 (m,
2 H), 3.98–4.06 (m, 2 H), 4.78 (s, 1 H), 6.24 (s, 2 H), 7.38–7.40 (d, J
= 8.0 Hz, 2 H), 7.45–7.47 (d, J = 8.4 Hz, 2 H) ppm. HPLC (Daicel
Chiralcel AD, 2-propanol/n-hexane = 20:80, flow rate = 1.0 mL/
min, λ = 254 nm): tR = 5.22 (major), 6.63 (minor) min.
5t: Purified by flash chromatography (petroleum/EtOAc, 3:1) to af-
ford a white solid (23.9 mg, 70%, 77%ee). [α]29.1 = 16.1 (c = 0.114,
1
CH2Cl2). H NMR (600 MHz, CDCl3): δ = 0.96 (s, 3 H), 1.09 (s,
3 H), 1.14–1.17 (t, J = 7.1 Hz, 3 H), 2.14–2.24 (dd, J = 16.2 Hz, 2
H), 2.42 (s, 2 H), 3.99–4.06 (m, 2 H), 4.69 (s, 1 H), 6.17 (br. s, 2
H), 7.10 (s, 1 H), 7.18–7.21 (t, J = 7.4 Hz, 2 H), 7.25–7.26 (d, J =
7.0 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.20, 27.41,
29.09, 32.24, 33.83, 40.66, 50.72, 59.67, 80.84, 116.82, 126.03,
127.77, 128.24, 145.79, 158.32, 161.35, 169.14, 196.41 ppm. HPLC
(Daicel Chiralcel AD, 2-propanol/n-hexane = 10:90, flow rate =
1.0 mL/min, λ = 254 nm): tR = 10.11 (major), 13.81 (minor) min.
5o: Purified by flash chromatography (petroleum/EtOAc, 2:1) to
afford a white solid (28.4 mg, 73%, 89%ee). [α]20.9 = –3.8 (c =
1
0.106, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 1.15–1.18 (t, J
= 7.2 Hz, 3 H), 1.98–2.01 (m, 2 H), 2.31–2.36 (m, 2 H), 2.53–2.57
(m, 2 H), 4.02–4.12 (m, 2 H), 4.77 (s, 1 H), 6.22 (s, 2 H), 7.25–7.45
(m, 7 H), 7.53–7.55 (d, J = 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.26, 20.24, 26.99, 33.51, 36.91, 59.73, 80.62, 118.03,
126.61, 126.92, 127.00, 128.64, 128.67, 138.87, 1414.18, 145.20,
158.40, 163.17, 169.12, 196.67 ppm. HRMS: calcd. for C24H23NO4
Supporting Information (see footnote on the first page of this arti-
1
cle): HPLC traces, H and 13C NMR spectra, mass spectra.
Eur. J. Org. Chem. 2011, 137–142
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
141

Z. H. Dong, X. H. Liu, J. H. Feng, M. Wang, L. L. Lin, X. M. Feng
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We acknowledge the National Natural Science Foundation of
China (Nos. 20732003 and 20872097), the Program for Changjiang
Scholars and Innovative Research Team in University (PCSIRT,
No. IRT0846), and the National Basic Research Program of China
(973 Program: No. 2010CB833300) for financial support. We also
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Received: August 16, 2010
Published Online: November 16, 2010
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Eur. J. Org. Chem. 2011, 137–142