Catalytic enantioselective conjugate addition of aromatic amines to fumarate derivatives: asymmetric synthesis of aspartic acid derivatives

Article abstract of DOI:10.1016/j.tet.2009.05.037

The catalytic enantioselective conjugate addition of aromatic amines to fumarate derivatives promoted by chiral palladium complexes is described. Treatment of aniline derivatives with fumaryl pyrrolidinone as Michael acceptor under mild reaction condition

Full text of DOI:10.1016/j.tet.2009.05.037

Tetrahedron 65 (2009) 5676–5679
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Tetrahedron
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Catalytic enantioselective conjugate addition of aromatic amines to fumarate
derivatives: asymmetric synthesis of aspartic acid derivatives
*
Seung Hee Kang, Young Ku Kang, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2009
Received in revised form 15 May 2009
Accepted 16 May 2009
Available online 23 May 2009
The catalytic enantioselective conjugate addition of aromatic amines to fumarate derivatives promoted
by chiral palladium complexes is described. Treatment of aniline derivatives with fumaryl pyrrolidinone
as Michael acceptor under mild reaction conditions afforded the corresponding chiral aspartic acid de-
rivatives with excellent enantiomeric excesses (83–96% ee).
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Chiral palladium catalysts
Conjugate addition
Fumarates
Aspartic acids
1. Introduction
amines to furmaryl oxazolidinone catalyzed by chiral samarium
iodobinaphtholate.5
Aspartic acid derivatives are widely used as pharmaceuticals and
fundamental synthetic building blocks for preparation of biologically
valuable molecules.1 The development of stereoselective synthetic
2. Results and discussion
methods for the preparation of natural and non-natural a-amino
As part of a research program related to the development of
synthetic methods for the enantioselective construction of stereo-
genic carbon centers,11 we reported the catalytic enantioselective
acid derivatives has attracted considerable attention over the past
decades.2 The most popular methods for the catalytic asymmetric
synthesis of aspartic acid derivatives are C–C bond formation using
chiral templates3 and include the Mannich reaction4 of chiral sulfi-
nimines and Michael addition of aromatic amines with chiral Lewis
acid.5
Michael reaction to a,b a-hydrazination
-unsaturated ketones12 and
of active methines13 promoted by chiral catalysts. We decided to
study the asymmetric aza-Michael reaction of aromatic amines
to fumarate derivatives affording chiral aspartic acid derivatives. To
the best of our knowledge, there are no examples of asymmetric
aza-Michael reaction of amines to fumarate derivatives in the
presence of chiral palladium complexes.
In this article, we wish to report the catalytic enantioselective
conjugate addition of aromatic amines to fumarate derivatives in the
presence of air- and moisture-stable chiral palladium complexes.14
A survey of some reaction parameters was performed, and some
representative results are presented in Table 1. Our investigation
began with the catalytic enantioselective conjugate addition of an-
iline (2a) to fumaryl oxazolidinone 1a in toluene at room tempera-
ture in the presence of 5 mol % of dicationic palladium complexes 4
(Fig. 1). We surveyed the effect of structure of palladium complexes
4. High yields with moderate to high enantioselectivities (29–83%
ee) were observed for structurally variable palladium catalysts
(entries 1–12). Under the standard reaction conditions, catalyst 4a
exhibited better enantioselectivity (81% ee, entry 1). Changing the
substituent of the fumaryl functionality effects the rate of the
The catalytic enantioselective aza-Michael reaction6 of aromatic
amines to
a,b-unsaturated carbonyl compounds was first in-
vestigated by Jørgensen et al.7 The reaction of aniline with N-alke-
noyl oxazolidinones proceeds well in the presence of Ni(II)–
bisoxazoline complexes as the Lewis acid catalyst. In 2003, Togni
reported the addition of aromatic amines to a,b-unsaturated com-
pounds catalyzed by Ni-complexes coordinated by chiral tridendate
phosphines.8 Subsequently, Hii and Sodeoka groups reported the
enantioselective addition of aromatic amines to
a,b-unsaturated
carbonyl compounds such as N-alkenoyl oxazolidinones or N-alke-
noyl carbamates using cationic BINAP–palladium complexes.9,10
Recently, Collin reported the aza-Michael addition of aromatic
* Corresponding author. Tel.: þ82 41 530 1244; fax: þ82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.037

S.H. Kang et al. / Tetrahedron 65 (2009) 5676–5679
5677
Table 1
Table 2
Optimization of the reaction conditions
Catalytic enantioselective conjugate addition of aromatic amines to fumarates
Ph
Ar
O
O
O
O
O
4
NH
O
4a
NH
O
cat.
cat.
O
(5 mol %)
solvent, rt
(5 mol %)
PhNH2
ArNH2
+
+
EtO2C
N
X
EtO2C
N
EtO2C
N
X
EtO2C
N
p-xylene, rt
2a
2
1b
3
1a : X = O
3aa
3ba
1b
: X =CH2
Entry
2, Ar
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
2a, Ph
15
24
20
15
12
12
12
3ba, 91
3bb, 90
3bc, 95
3bd, 92
3be, 95
3bf, 80
3bg, 81
93 (R)c
95
96
91
89
83
83
Entry
1
Cat. 4
Solvent
Time (h)
Yielda (%)
eeb (%)
2b, p-EtO2C–Ph
2c, p-n-BuO2C–Ph
2d, p-Cl–Ph
2e, p-Et–Ph
2f, m-CF3–Ph
2g, p-OMe–Ph
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
4a
4b
4c
4d
4e
4f
4g
4h
4i
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
p-Xylene
Benzene
Hexane
THF
74
3aa, 90
3aa, 94
3aa, 91
3aa, 90
3aa, 95
3aa, 92
3aa, 96
3aa, 90
3aa, 91
3aa, 97
3aa, 94
3aa, 90
3ba, 91
3ba, 90
3ba, 91
3ba, 91
3ba, 94
3ba, 90
3ba, 71
3ba, 50
3ba, 0
81
80
75
61
80
78
69
51
53
34
29
33
87
85
85
93
87
77
93
93
d
80
82
82
3 d
3 d
3 d
3 d
6 d
8 d
6 d
5 d
24
24
20
15
a
Yield of isolated product.
Enantiopurity of 3 was determined by HPLC analysis using Chiralpak AD-H (for
b
9
3ba, 3bc, 3bd, 3be, 3bf, and 3bg) and Chiralcel OD-H (for 3bb) columns.
c
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
Absolute configuration was determined by comparison of the optical rotation
and the chiral HPLC data of the corresponding hydrolyzed mono-ethyl ester 5a.5.
4a
4e
4i
4a
4a
4a
4a
4a
4a
the conjugate addition of secondary aromatic amines 2h to fumaryl
pyrrolidinone 1b using chiral palladium catalyst 4a at room tem-
perature. In the presence of 5 mol % of catalyst 4a, the aza-Michael
7
14
50
47
80
reaction proceeded to afford the a-amino acid 3bh after 24 h with
87% ee (Scheme 1). In contrast, the conjugate addition of secondary
amines such as piperidine and pyrrolidine proceeded with excellent
yields (>95%) but at much lower enantioselectivties of between 13
and 10% ee after 6 h at room temperature.
DCM
MeOH
a
Yield of isolated product.
b
Enantiopurity of 3 was determined by HPLC analysis using Whelk-O1 (for 3aa)
and Chiralpak AD-H (for 3ba) columns.
N
O
O
cat. 4a
O
O
(5 mol %)
+
2+
Pd
P
P
N
OH2
EtO2C
EtO2C
N
N
H
p-xylene
2X
*
P
P
PAr2
PAr2
rt, 24 h
=
NCMe
*
2h
1b
3bh
60% yield
87% ee
4a
: Ar = Ph: (R)-BINAP, X = BF4
Scheme 1.
4b: Ar = Ph: (R)-BINAP, X = OTf
4c
: Ar = Ph: (R)-BINAP, X = PF6
: Ar = Ph: (R)-BINAP, X = SbF6
4d
Finally, the pyrrolidinone-derived products of these reactions
were readily converted to the corresponding N-phenyl aspartic acid
mono-ethyl esters. Product 3 was hydrolyzed by employing LiOH at
0 ꢀC, affording N-phenyl aspartic acid mono-ethyl esters 5a without
loss of enantioselectivity (Scheme 2).
4e: Ar = 4-Me-C6H4: (R)-Tol-BINAP, X = BF4
4f
: Ar = 4-Me-C6H4: (R)-Tol-BINAP, X = OTf
4g: Ar = 4-Me-C6H4: (R)-Tol-BINAP, X = PF6
4h
: Ar = 4-Me-C6H4: (R)-Tol-BINAP, X = SbF6
4i
: Ar = 3,5-Me2-C6H3: (R)-Xylyl-BINAP, X = BF4
4j: Ar = 3,5-Me2-C6H3: (R)-Xylyl-BINAP, X = OTf
4k
: Ar = 3,5-Me2-C6H3: (R)-Xylyl-BINAP, X = PF6
4l: Ar = 3,5-Me2-C6H3: (R)-Xylyl-BINAP, X = SbF6
Ph
Ph
NH
O
O
NH
O
LiOH
Figure 1. Structures of chiral palladium catalysts.
0 °C, 0.5 h
EtO2C
OH
N
EtO2C
X
5a
THF:H2O (3:1)
75% yield,
3aa
3ba
80% ee, from
reaction and enantioselectivities (entries 1 and 13). Fumaryl pyrro-
lidinone 1b15 was found tobe a superior Michael acceptor in termsof
reaction time and enantioselectivity. Next, we examined the re-
action in various solvents. Reactions performed in non-polar sol-
vents such as p-xylene, THFand dichloromethane generallyafforded
better results in terms of enantioselectivities (entries 13 and 16–21).
No reaction occurred in MeOH. From these observations, we choose
the p-xylene as solvent of choice in further studies. The absolute
configuration of 3aa was established by comparison of the optical
rotation and chiral HPLC analysis with previously reported values.5
To examine the generality of the addition of aromatic amines 2 to
fumaryl pyrrolidinone 1b in the presence ofchiralpalladium catalyst
4a, we studied the aza-Michael reaction of other aniline derivatives
2b–2f. As it can be seen by the results summarized in Table 2, the
corresponding aspartic acid derivatives 3 were obtained in high to
excellent yields with enantioselectivities (83–96% ee). We examined
3aa, X = O, 81% ee
3ba,
81% yield,
X = CH2, 93% ee
93% ee, from
Scheme 2.
3. Conclusion
In conclusion, we have developed an efficient catalytic aza-Mi-
chael reaction of aromatic amines using air- and moisture-stable
chiral palladium complexes. The desired aspartic acid derivatives
were obtained in excellent yields (80–95%) with enantioselectivities
(83–96% ee). We believe that this synthetic method provides an
efficient route for the preparation of chiral aspartic acid derivatives,
and the availability of these compounds should facilitate medicinal
chemical studies in various fields. Further details and application of
this aza-Michael reaction will be presented in due course.

5678
S.H. Kang et al. / Tetrahedron 65 (2009) 5676–5679
4. Experimental section
4.2.3. Butyl 4-(4-ethoxy-1,4-dioxo-1-(2-oxopyrrolidin-1-yl)butan-
2-ylamino)benzoate (3bc)
26
4.1. General
[
a
]
D
ꢁ7.1 (c 1.0, CHCl3) for 96% ee; 1H NMR (200 MHz, CDCl3):
d
¼7.89–7.85 (m, 2H), 6.65–6.61 (m, 2H), 5.0 (d, J¼8.5 Hz, 1H), 4.59–
All reactions were performed under an atmosphere of nitrogen
in oven-dried glassware with magnetic stirring and monitored by
analytical thin layer chromatography (TLC) using Merck pre-
coated silica gel plates with F254 indicator. Visualization on TLC
was achieved by use of UV light (254 nm) and treatment with
phosphomolybdic acid stain followed by heating. Dry tetrahy-
drofuran (THF) was freshly distilled from Ph2CO–Na. Other sol-
vents were purified by usual methods. Visualization was
accomplished by UV light (254 nm), I2, p-anisaldehyde, ninhydrin,
and phosphomolybdic acid, solution as an indicator. Purification
of reaction products was carried out by flash chromatography
using E. Merck silica gel 60 (230–400 mesh). 1H NMR and 13C
NMR spectra were recorded on a Bruker AC 200 (200 MHz for 1H,
4.49 (m, 1H), 4.29–4.09 (m, 4H), 3.79 (t, J¼7.2 Hz, 2H), 3.65–3.37 (m,
2H), 2.59–2.47 (t, J¼8.1 Hz, 2H), 2.11–1.96 (m, 2H), 1.78–1.65 (m,
2H), 1.55–1.36 (m, 2H), 1.26 (t, J¼8 Hz, 3H), 0.96 (t, J¼7.2 Hz, 3H);
13C NMR (50 MHz, CDCl3):
d
¼175.4, 171.5, 170.6, 166.3, 150.1, 131.1,
119.2, 111.8, 63.8, 61.3, 51.7, 44.9, 39.0, 33.0, 30.5, 18.9, 16.8, 13.7,
13.4; ESI-HRMS: m/z calcd for C21H29N2O6 [MþH]þ: 405.2026;
found: 405.2025; HPLC (AD-H, n-hexane/2-propanol: 80/20)
1.0 mL/min, 254 nm, tR¼52.2 min (major), tR¼79.5 min (minor).
4.2.4. Ethyl 2-(4-chlorophenylamino)-4-oxo-4-(2-oxopyrrolidin-
1-yl)butanoate (3bd)
24
[
a
]
D
ꢁ13.0 (c 1.0, CHCl3) for 91% ee; 1H NMR (200 MHz, CDCl3):
d
¼7.14–7.10 (m, 2H), 6.63–6.58 (m, 2H), 4.51–4.44 (m, 2H), 4.19 (q,
50 MHz for 13C). Chemical shift values (
million relative to Me4Si ( 0.0 ppm). The proton spectra are
reported as follows (multiplicity, coupling constant J, number of
d) are reported in parts per
J¼7.0 Hz, 2H), 3.79 (t, J¼7.2 Hz, 2H), 3.62–3.37 (m, 2H), 2.60 (t,
d
J¼7.9 Hz, 2H), 2.11–1.96 (m, 2H) 1.24 (t, J¼7.0 Hz, 3H); 13C NMR
d
(50 MHz, CDCl3):
d
¼175.2, 171.9, 170.6, 144.8, 128.7, 122.6, 114.4,
protons). Multiplicities are indicated by s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), and br (broad). Mass spectra
were measured on Sciex API-2000 and Jeol HX110/110A using
electrospray ionization technique. Optical rotations were mea-
sured on a JASCO-DIP-1000 digital polarimeter with a sodium
lamp. Melting points were determined using an electrothermal
apparatus. The enantiomeric excesses (ee’s) were determined by
HPLC. HPLC analysis was performed on Younglin M930 Series and
Younglin M720 Series, measured at 254 nm using the indicated
chiral column. Fumaryl derivatives 115,16 and chiral palladium
complexes 49,14 were prepared by previous reports.
61.1, 52.7, 44.9, 39.0, 33.0, 16.67, 13.7; ESI-HRMS: m/z calcd for
C16H20ClN2O4 [MþH]þ: 339.1112; found: 339.1109; HPLC (AD-H, n-
hexane/2-propanol: 80/20) 1.0 mL/min, 254 nm, tR¼32.9 min
(major), tR¼53.8 min (minor).
4.2.5. Ethyl 2-(4-ethylphenylamino)-4-oxo-4-(2-oxopyrrolidin-
1-yl)butanoate (3be)
26
[
a
]
ꢁ3.8 (c 1.0, CHCl3) for 89% ee; 1H NMR (200 MHz, CDCl3):
D
d
¼7.03–6.98 (m, 2H), 6.64–6.60 (m, 2H), 4.46–4.43 (m, 2H), 4.19 (q,
J¼7.1 Hz, 2H), 3.78 (t, J¼7.2 Hz, 2H), 3.61–3.38 (m, 2H), 2.62–2.47
(m, 4H), 2.09–1.98 (m, 2H), 1.27–1.13 (m, 6H); 13C NMR (50 MHz,
CDCl3):
d
¼175.4, 172.6, 171.1, 144.3, 134.2, 128.4, 114.5, 61.2, 53.3,
4.2. General procedure for the aza-Michael reaction
of aromatic amines 2 to fumaryl pyrrolidinone 1b
45.1, 39.5, 33.2, 28.1, 17.0, 15.7, 13.1; ESI-HRMS: m/z calcd for
C18H25N2O4 [MþH]þ: 333.1814; found: 333.1816; HPLC (AD-H, n-
hexane/2-propanol: 80/20) 1.0 mL/min, 254 nm, tR¼23.9 min
(major), tR¼30.8 min (minor).
To a stirred solution of fumaryl pyrrolidinone 1b (317 mg,
1.5 mmol) and catalyst 4a (48 mg, 0.05 mmol) in p-xylene (5 mL)
was added the aromatic amine 2 (1.0 mmol) dropwise at room
temperature. Reaction mixture was stirred for 12–24 h, concen-
trated, and purified by flash chromatography (silica gel, ethyl ace-
4.2.6. Ethyl 2-(3-trifluoromethylphenylamino)-4-oxo-4-(2-
oxopyrrolidin-1-yl)butanoate (3bf)
24
Mp: 96–97.5 ꢀC; [
a]
D
ꢁ7.0 (c 1.0, CHCl3) for 83% ee; 1H NMR
tate/hexane¼1/2) to afford the
b-amino N-acylpyrrolidinones 3.
(200 MHz, CDCl3):
d
¼7.30–7.22 (m, 1H), 6.98–6.79 (m, 3H), 4.74 (d,
J¼8.7 Hz, 1H), 4.54–4.45 (m, 1H), 4.20 (q, J¼7.2 Hz, 2H), 3.79 (t,
J¼7.2 Hz, 2H), 3.65–3.38 (m, 2H) 2.60 (t, J¼8.1 Hz, 2H), 2.11–1.96 (m,
4.2.1. (R)-Ethyl 4-oxo-4-(2-oxopyrrolidin-1-yl)-2-
phenylaminobutanoate (3ba)
2H), 1.24 (t, J¼7 Hz, 3H); 13C NMR (50 MHz, CDCl3):
¼175.6, 171.9,
d
24
[a
]
ꢁ1.9 (c 1.0, CHCl3) for 93% ee; 1H NMR (200 MHz, CDCl3):
170.7, 146.8, 131.2 (q, J¼31.5 Hz), 129.5, 124.1 (q, J¼270 Hz), 115.9,
114.4,119.1, 61.4, 52.4, 45.1, 39.3, 33.1,16.9,13.8; ESI-HRMS: m/z calcd
for C17H20F3N2O4 [MþH]þ: 373.1375; found: 373.1372; HPLC (AD-H,
n-hexane/2-propanol: 80/20) 1.0 mL/min, 254 nm, tR¼14.7 min
(major), tR¼20.5 min (minor).
D
d
¼7.19–7.06 (m, 2H), 6.72–6,64 (m, 3H), 4.70–4.41 (m, 2H), 4.18 (q,
J¼7.4 Hz, 2H), 3.75 (t, J¼7.8 Hz, 2H), 3.66–3.38 (m, 2H), 2.54 (t,
J¼7.8 Hz, 2H), 2.05–1.9 (m, 2H), 1.22 (t, J¼7.3 Hz, 3H); 13C NMR
(50 MHz, CDCl3):
d
¼175.5, 172.4, 170.9, 146.4, 129.1, 117.6, 113.5,
61.3, 52.8, 45.1, 39.4, 33.2, 16.9, 13.9; ESI-HRMS: m/z calcd for
C16H21N2O4 [MþH]þ: 305.1501; found: 305.1498; HPLC (AD-H, n-
hexane/2-propanol: 80/20) 1.0 mL/min, 254 nm, tR¼25.4 min
(major), tR¼32.0 min (minor).
4.2.7. Ethyl 2-(4-methoxyphenylamino)-4-oxo-4-(2-oxopyrrolidin-
1-yl)butanoate (3bg)
24
[
a
]
D
ꢁ13.4 (c 1.1, CHCl3) for 83% ee; 1H NMR (200 MHz, CDCl3):
d
¼6.71–6.67 (m, 2H), 6.61–6.57 (m, 2H), 4.33–4.31 (m, 1H), 4.17–
4.2.2. Ethyl 4-(4-ethoxy-1,4-dioxo-1-(2-oxopyrrolidin-1-yl)butan-
4.12 (m, 1H), 4.10 (q, J¼6.8 Hz, 2H), 3.71 (t, J¼7.1 Hz, 2H), 3.65 (s,
3H), 3.52–3.24 (m, 2H), 2.50 (t, J¼8.2 Hz, 2H), 1.98–1.90 (m, 2H), 1.15
2-ylamino)benzoate (3bb)
25
Mp: 119.5–121 ꢀC; [
a]
ꢁ3.9 (c 1.0, CHCl3) for 95% ee; 1H NMR
(t, J¼6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3):
¼175.5, 172.8, 171.2,
d
D
(200 MHz, CDCl3):
d
¼7.89–7.85 (m, 2H), 6.65–6.60 (m, 2H), 4.99 (d,
152.8, 140.7, 115.6, 114.7, 61.3, 55.6, 54.4, 45.2, 39.2, 33.4, 17.1, 14.0;
ESI-HRMS: m/z calcd for C17H23N2O5 [MþH]þ: 335.1607; found:
335.1605; HPLC (AD-H, n-hexane/iso-propanol: 80/20) 1.0 mL/min,
254 nm, tR¼30.5 min (major), tR¼42.4 min (minor).
J¼8.7 Hz, 1H), 4.59–4.49 (m, 1H), 4.31 (q, J¼7.0 Hz, 2H), 4.21 (q,
J¼7.0 Hz, 2H), 3.79 (t, J¼7.0 Hz, 2H), 3.65–3.41 (m, 2H), 2.59 (t,
J¼7.9 Hz, 2H), 2.11–1.96 (m, 2H), 1.35 (t, J¼6.9 Hz, 3H), 1.25 (t, 3H,
J¼7.0 Hz); 13C NMR (50 MHz, CDCl3):
¼175.6, 171.7, 170.8, 166.5,
d
150.2, 131.3, 119.5, 112.0, 61.5, 60.1, 51.9, 45.1, 39.2, 33.2, 17.0, 14.3,
13.9; ESI-HRMS: m/z calcd for C19H25N2O6 [MþH]þ: 377.1713;
found: 377.1716; HPLC (OD-H, n-hexane/2-propanol: 80/20) 1.0 mL/
min, 254 nm, tR¼23.7 min (major), tR¼32.6 min (minor).
4.2.8. Ethyl 3-(indolin-1-yl)-4-oxo-4-(2-oxopyrrolidin-1-
yl)butanoate (3bh)
24
[
a
]
D
þ64.7 (c 1.0, CHCl3) for 89% ee; 1H NMR (200 MHz, CDCl3):
d
¼7.06–6.99 (m, 2H), 6.68–6.52 (m, 2H), 4.87–4.80 (m, 1H), 4.14 (q,

S.H. Kang et al. / Tetrahedron 65 (2009) 5676–5679
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3. (a) Ender, D.; Schankat, J.; Klatt, M. Synlett 1994, 795; (b) Takatori, K.; Nichihara,
M.; Kajiwara, M. J. Labelled Compd. Radiopharm. 1999, 42, 701; (c) Alvarez-
Ibarra, C.; Casky, A.; Maroto, R.; Quiroga, M. L. J. Org. Chem. 1995, 60, 7934; (d)
Burtin, G.; Corringer, P.-J.; Young, D. W. J. Chem. Soc., Perkin Trans. 1 2000, 3451;
(e) Rees, D. O.; Bushby, N.; Harding, J. R.; Song, C.; Willis, C. J. Labelled Compd.
Radiopharm. 2007, 50, 399.
4. Jacobsen, M. F.; Skrydstrup, T. J. Org. Chem. 2003, 68, 7112.
5. (a) Reboule, I.; Gil, R.; Collin, J. Tetrahedron: Asymmetry 2005, 16, 3881; (b)
Reboule, I.; Gil, R.; Collin, J. Eur. J. Org. Chem. 2008, 532.
6. (a) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633; (b) Davies, S. G.; Smith, A.
D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833; (c) Hong, S.; Marks, T. J.
Acc. Chem. Res. 2004, 37, 673; (d) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033.
7. Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem. Commun. 2001, 1240.
8. Fadini, L.; Togni, A. Chem. Commun. 2003, 30.
9. (a) Li, K.; Hii, K. K. Chem. Commun. 2003, 1132; (b) Li, K.; Cheng, X.; Hii, K. K. Eur.
J. Org. Chem. 2004, 959; (c) Phua, P. H.; de Vries, J. G.; Hii, K. K. Adv. Synth. Catal.
2005, 347, 1775; (d) Phua, P. H.; White, A. J. P.; de Vries, J. G.; Hii, K. K. Adv. Synth.
Catal. 2006, 348, 587; (e) Phua, P. H.; Mathew, S. P.; White, A. J. P.; de Vries, J. G.;
Blackmond, D. G.; Hii, K. K. Chem.dEur. J. 2007, 13, 4602.
J¼7.0 Hz, 2H), 3.83–3.17 (m, 6H), 2.96 (t, J¼8.3 Hz, 2H), 2.59 (t,
J¼8.0 Hz, 2H), 2.10–1.95 (m, 2H), 1.17 (t, J¼7.1 Hz, 3H); 13C NMR
(50 MHz, CDCl3):
d¼175.2, 171.1, 170.4, 148.4, 129.3, 126.8, 124.2,
117.7, 106.9, 60.1, 54.4, 48.9, 45.1, 35.0, 33.2, 28.0, 16.8, 13.9; ESI-
HRMS: m/z calcd for C18H23N2O4 [MþH]þ: 331.1658; found:
331.1655; HPLC (AD-H, n-hexane/2-propanol: 80/20) 1.0 mL/min,
254 nm, tR¼9.4 min (major), tR¼11.5 min (minor).
4.2.9. (R)-4-Ethoxy-4-oxo-3-(phenylamino)butanoic acid (5a)
26
[
a]
þ8.6 (c 1.0, CHCl3) for 85% ee; 1H NMR (200 MHz, CDCl3):
D
d
¼7.44 (br, 2H), 7.22–7.14 (m, 2H), 6.81–6.65 (m, 3H), 4.46–4.40 (m,
1H), 4.19 (q, J¼7.0 Hz, 2H), 2.91–2.83 (m, 2H), 1.95 (t, J¼7.0 Hz, 3H);
13C NMR (50 MHz, CDCl3):
d
¼176.2, 172.2, 146.0, 130.9, 119.0, 114.0,
61.7, 53.4, 37.1, 14.0; HPLC (AD-H, n-hexane/2-propanol: 80/20)
1.0 mL/min, 254 nm, tR¼11.7 min (minor), tR¼12.4 min (major).
10. Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004,
6, 1861.
Acknowledgements
11. (a) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545; (b) Park, E. J.; Kim, M. H.; Kim, D.
Y. J. Org. Chem. 2004, 69, 6897; (c) Kim, H. R.; Kim, D. Y. Tetrahedron Lett. 2005,
46, 3115; (d) Kang, Y. K.; Cho, M. J.; Kim, S. M.; Kim, D. Y. Synlett 2007, 1135; (e)
Kang, Y. K.; Kim, D. Y. Bull. Korean Chem. Soc. 2008, 29, 2093; (f) Lee, N. R.; Kim,
S. M.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 829.
12. (a) Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42, 6299; (b) Kim, D.
Y.; Huh, S. C. Tetrahedron 2001, 57, 8933; (c) Kim, D. Y.; Choi, Y. J.; Park, H. Y.;
Joung, C. U.; Koh, K. O.; Mang, J. Y.; Jung, K. Y. Synth. Commun. 2003, 33, 435.
13. (a) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565; (b) Lee, J. H.; Bang, H.
T.; Kim, D. Y. Synlett 2008, 1821; (c) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008,
2659; (d) Jung, S. H.; Kim, D. Y. Tetrahedron Lett. 2008, 49, 5527; (e) Kim, D. Y.
Bull. Korean Chem. Soc. 2008, 29, 2036; (f) Mang, J. Y.; Kim, D. Y. Bull. Korean
Chem. Soc. 2008, 29, 2091; (g) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. J. Fluorine
Chem. 2009, 130, 259; (h) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. Bull. Korean Chem.
Soc. 2009, 30, 249.
This research was financially supported by the Ministry of Ed-
ucation, Science, Technology (MEST) and Korea Industrial Tech-
nology Foundation (KOTEF) through the Human Resource Training
Project for Regional Innovation.
References and notes
1. (a) Iijima, K.; Katada, J.; Hayashi, Y. Bioorg. Med. Chem. Lett.1999, 9, 413; (b) Petrov,
V. I.; Sergeev, V. S.; Onishchenko, N. V.; Piotrovskii, L. B. Bull. Exp. Biol. Med. 2001,
342; (c) Bai, R. L.; Verdier-Pinard, P.; Gangwar, S.; Stessman, C. C.; McClure, K. J.;
Sausville, E. A.; Pettit, G. R.; Bates, R. B.; Hamel, E. Mol. Pharmacol. 2001, 59, 462; (d)
Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710; (e) Xiong,
X.-B.; Mahmud, A.; Uludag, H.; Lavasanifar, A. Biomacromolecules 2007, 8, 874.
14. (a) Li, K.; Horton, P. N.; Hursthouse, M. B.; Hii, K. K. J. Organomet. Chem. 2003,
665, 250; (b) Kim, S. M.; Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309; For an
aquapalladium complex, see: (c) Shimada, T.; Bajracharya, G. B.; Yamamoto, Y.
Eur. J. Org. Chem. 2005, 59 and references cited therein; (d) Vicente, J.; Arcas, A.
Coord. Chem. Rev. 2005, 249, 1135.
2. Reviews on synthesis of
a-amino acids, see: (a) Duthaler, R. O. Tetrahedron
1994, 50, 1539; (b) Arend, M. Angew. Chem., Int. Ed. 1999, 38, 2873; (c) Kotha, S.
Acc. Chem. Res. 2003, 36, 342; (d) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107,
15. Pyrrolidinone-derived enoates as Michael acceptor, see: (a) Sibi, M. P.; Liu, M.
Org. Lett. 2000, 2, 3393; (b) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124,
2134.
16. (a) Evans, D. A.; Miller, S. J.; Leckta, T.; Vonmatt, P. J. Am. Chem. Soc. 1999, 121,
7559; (b) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
4584; Reviews on synthesis of
b-amino acids, see: (e) Juaristi, E. Enantioselective
Synthesis of -Amino Acids; Wiley-VCH: New York, NY, 1997; (f) Cardillo, G.;
b
Tomasini, C. Chem. Soc. Rev. 1996, 25, 117; (g) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991; (h) Seebach, D.; Beck, A. K.; Capone, S.; Deniau, G.; Groselj, U.;
Zass, E. Synthesis 2009, 1.