Asymmetric and diastereoselective Mannich reactions using hydantoin as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2012.09.006

The Mannich reaction of titanium enolates of a chiral hydantoin with various aldimines smoothly occurred in good yields and with high anti-diastereoselectivity. The Mannich adducts can be readily cleaved by alcoholysis to afford several β-amino ester derivatives in good yields and in almost enantiomerically pure form.

Full text of DOI:10.1016/j.tetasy.2012.09.006

Tetrahedron: Asymmetry 23 (2012) 1380–1384
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Tetrahedron: Asymmetry
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Asymmetric and diastereoselective Mannich reactions using hydantoin as a
chiral auxiliary
⇑
Xuan-Ran Li, Cui-Fen Lu, Zu-Xing Chen, Yan Li, Gui-Chun Yang
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules & School of Chemistry and Chemical Engineering, Hubei University,
Wuhan 430062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 August 2012
Accepted 13 September 2012
The Mannich reaction of titanium enolates of a chiral hydantoin with various aldimines smoothly
occurred in good yields and with high anti-diastereoselectivity. The Mannich adducts can be readily
cleaved by alcoholysis to afford several b-amino ester derivatives in good yields and in almost enantio-
merically pure form.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
that utilize hydantoin as a chiral auxiliary, with a series of
aldimines using a TiCl4/DIPEA reagent system.
b-Amino ester derivatives are key synthons in the synthesis of
b-lactam antibiotics, which are important components of many
natural products and therapeutic agents.1 Therefore, the asymmet-
ric synthesis of b-amino ester derivatives has become a field of
increasing interest in organic synthetic chemistry over the past
few years.2 In fact, the asymmetric Mannich reaction is one of
the most general methods widely used in these syntheses.3
Previously4 we reported asymmetric aldol reactions which uti-
lized hydantion as a chiral auxiliary to give aldols in reasonable
yields and with high diastereoselectivity. When the aldol adducts
were subjected to hydrolysis, the chiral auxiliary could be recov-
ered quantitatively, and b-hydroxy acid derivatives were obtained
as almost pure enantiomers. It has been proven that hydantoin is
an excellent chiral auxiliary in asymmetric synthesis. With these
results in mind, we herein report asymmetric Mannich reactions
2. Results and discussion
Previously,4 N-propionylhydantoin 3 was derived from
L-valine
methyl ester hydrochloride 1 (Scheme 1). The Mannich reaction of
N-propionylhydantoin 3 with N-(4-methoxyphenyl)benzaldimine
was examined first (Scheme 2). At first, TiCl4 and the base [1 equiv
of TiCl4 and 2.5 equiv of the base] were added.5 The use of diisopro-
pylethylamine afforded higher chemical yields than the use of (ꢀ)-
sparteine, since many by-products were obtained when we used
(ꢀ)-sparteine. We attempted to use n-Bu2BOTf or Sn(OTf)2 as the
Lewis acid, but neither of them gave the Mannich adduct 4a. When
the reaction temperature was changed from ꢀ78 °C to 0 °C, the dia-
stereomeric ratio exhibited only small variations, but we obtained
lower chemical yields when the reaction temperature was kept at
O
O
O
CH3CH2COCl
DMAP, Et3N
O
O
NH2·HCl
1) PhNCO
N
NH
N
N
pyridine, r.t.
2) 2M HCl, reflux
CH2Cl2, 0°C
O
O
3
1
2
Scheme 1.
⇑
Corresponding author. Tel.: +86 27 50865322; fax: +86 27 88663043.
E-mail address: yangguichun@hubu.edu.cn (G.-C. Yang).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.09.006

X.-R. Li et al. / Tetrahedron: Asymmetry 23 (2012) 1380–1384
1381
PMP
Ar
O
O
HN
O
O
1) TiCl4, DIPEA
0 oC, CH2Cl2
N
N
N
N
2) ArCH=NPMP, 0°C
O
O
4a-f
3
Scheme 2.
O
PMP
ꢀ78 °C. The Mannich reactions with other aldimines were next
examined; these reactions resulted in similar diastereomeric ratios
(91:9–96:4) (Table 1).
HN
O
N
NaHMDS
H3CO
PMP
THF, -20°C
Table 1
Mannich reactions of N-propionylhydantion 3 with several aldimines
6a
5a
Entry
Product
Ar
Diastereomeric ratioa
Yieldb (%)
Scheme 4.
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
C6H5
91:9
96:4
92:8
93:7
94:6
94:6
71
82
74
78
61
58
4-ClC6H4
3-O2NC6H4
2,3-(CH3O)2C6H3
2-Furyl
Comparison of the observed J3,4 coupling constants
(J3,4 = 1.8 Hz) in the 1H NMR spectrum with those reported in the
literature7 (J3,4 = 5.8 Hz for the syn-isomer and J3,4 = 2.2 Hz for the
anti-isomer) revealed that the newly prepared b-lactam 6a was
an anti-isomer. Furthermore, comparing the specific rotation of
2-Thienyl
a
Determined by HPLC (C18 reversed-phase column, 254 nm, methanol/H2O
80:20, 1.00 mL/min).
the newly prepared b-lactam 6a {½a D20
¼ ꢀ46:1 (c 0.89, CHCl3) ver-
ꢁ
b
sus literature7
½
a 2D5
ꢁ
¼ þ45:2 (c 1.01, CHCl3) (3S, 4R)} allowed us to
Yield of product after silica gel chromatography.
establish the absolute configuration of 6a to be (3R,4S), which
could be extended to the b-amino esters 5a–f and the Mannich ad-
ducts 4a–f.
The Mannich adducts 4a–f were subjected to alcoholysis,6
which resulted in the quantitative recovery of chiral auxiliary 2
(Scheme 3), and afforded the corresponding methyl esters 5a–f
in good yields and in almost enantiomerically pure forms (Table 2).
Based on the previous literature2a,5 reports of asymmetric Man-
nich reactions directed by chiral auxiliaries, we proposed that N-
propionylhydantoin 3 and the aldimines were subjected to TiCl4
to form the Z-enolate, while the anti-products could be rationalized
by a chelated transition state involving attack of the preformed Z-
enolate on the less hindered Si face of the aldimines with the C@N
azomethine bond in an E-configuration, which can place the imine
Ar substituent in an axial position in the cyclic transition state and
therefore afford the diastereoisomer with the relative anti-config-
uration (Scheme 5).
Table 2
Alcoholysis of Mannich adducts 4a–f
Entry
Product
Ar
Eea (%)
Yieldb (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
C6H5
>99
>99
>99
>99
>99
>99
78
85
75
77
70
80
4-ClC6H4
3-O2NC6H4
2,3-(CH3O)2C6H3
2-Furyl
2-Thienyl
O
PMP
Determined by HPLC (ChiralcelÒ OD-H column, 254 nm, n-hexane/2-propanol
90:10, 1.00 mL/min).
N
a
HN
O
O
b
O
N
Yield of product after silica gel chromatography.
N
Ar
N
N
Ar
TiLn
O
H
In order to determine the absolute configuration of the Mannich
adducts, b-amino ester 5a was treated with NaHMDS at ꢀ20 °C in
anhydrous THF to afford the known b-lactam 6a (Scheme 4).
O
H
Me
PMP
Scheme 5.
PMP
O
HN
O
PMP
Ar
O
HN
O
DMAP
N
NH
N
Ar
N
CH3OH, reflux
H3CO
O
O
5a-f
4a-f
2
Scheme 3.

1382
X.-R. Li et al. / Tetrahedron: Asymmetry 23 (2012) 1380–1384
CDCl3): d 0.70 (d, J = 7.2 Hz, 3H), 1.14 (d, J = 6.0 Hz, 3H), 1.16 (d,
3. Conclusion
J = 7.2 Hz, 3H), 2.52 (m, 1H), 3.65 (s, 3H), 4.46 (m, 1H), 4.49 (d,
J = 9.6 Hz, 1H), 4.62 (d, J = 3.6 Hz, 1H), 6.51 (d, J = 9.0 Hz, 2H),
6.65 (d, J = 9.0 Hz, 2H), 7.18–7.52 (m, 10H); 13C NMR (150 MHz,
CDCl3): d 15.09, 15.35, 17.91, 29.61, 45.00, 55.53, 63.53, 63.59,
114.55, 115.53, 126.54, 127.03, 127.50, 128.60, 129.13, 129.38,
130.43, 140.72, 141.05, 152.23, 153.79, 169.08, 175.29; HRMS cal-
culated for C29H31N3O4 [M+Na]+: 508.2213, found 508.2206.
In conclusion, a very easy and efficient synthetic protocol for
asymmetric Mannich reactions has been developed using hydan-
toin as a chiral auxiliary. Moreover, the Mannich adducts, after
the alcoholysis reaction allowed recovery of the chiral auxiliary
hydantoin, and afforded a series of b-amino ester derivatives in al-
most enantiomerically pure forms.
4. Experimental
4.1. General
4.3.2. (5S,20R,30S)-5-Isopropyl-3-phenyl-1-[20-methyl-30-(p-meth-
oxyphenylamino)-30-(p-chloro-phenyl)-propionyl]hydantoin 4b
Yield: 82%; white solid; Mp 73.8–74.7 °C; ½a D20
¼ ꢀ24:2 (c 1.11,
ꢁ
CH2Cl2); IR: 3383, 1788, 1732, 1703 cmꢀ1 1H NMR (600 MHz,
;
The aldimines were prepared by condensation of the corre-
sponding aldehyde and p-methoxyphenylamine under standard
conditions in the literature.8 All other reagents were used as pur-
chased. All solvents were dried or purified by standard procedures
before use. Separations by flash chromatography were performed
on 300–400 mesh silica gel. Melting points were measured on a
WRS-1A digital melting point apparatus. Optical rotations were
measured using a sodium D line on WZZ-2B Automatic Polarime-
ter. HPLC analyses were carried out on a Dionex chromatograph
equipped with a diode-array UV detector. IR spectra were obtained
on KBr pellets or CH2Cl2 solvent. NMR spectra were recorded on a
Varian Unity Inova 600 spectrometer in CDCl3 (1H at 600 MHz and
13C at 150 MHz) using TMS as the internal standard. High-resolu-
tion mass spectra (HRMS) were recorded on a Varian 7.0T FTMS
mass spectrometer using ESI (electrospray ionization).
CDCl3): d 0.72 (d, J = 6.6 Hz, 3H), 1.15 (d, J = 6.0 Hz, 3H), 1.17 (d,
J = 7.2 Hz, 3H), 2.51 (m, 1H), 3.67 (s, 3H), 4.44 (m, 1H), 4.47 (d,
J = 9.6 Hz, 1H), 4.61 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 7.2 Hz, 2H),
6.66 (d, J = 9.0 Hz, 2H), 7.24–7.53 (m, 9H); 13C NMR
(150 MHz, CDCl3): d 14.96, 15.21, 17.83, 29.57, 44.74, 55.49,
63.41, 63.47, 114.51, 114.57, 126.45, 128.39, 128.71, 129.11,
129.32, 130.29, 133.14, 139.51, 140.14, 152.40, 153.73, 168.88,
174.85; HRMS calculated for C29H30ClN3O4 [M+Na]+: 542.1823,
found 542.1820.
4.3.3. (5S,20R,30S)-5-Isopropyl-3-phenyl-1-[20-methyl-30-(p-meth-
oxyphenylamino)-30-(m-nitro-phenyl)-propionyl]hydantoin 4c
Yield: 74%; yellow solid; Mp 80.3–81.5 °C; ½a D20
¼ ꢀ23:5 (c 0.92,
ꢁ
CH2Cl2); IR: 3377, 1789, 1732, 1704 cmꢀ1 1H NMR (600 MHz,
;
CDCl3): d 0.73 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.0 Hz, 6H), 2.55 (m,
1H), 3.67 (s, 3H), 4.51 (m, 1H), 4.63 (d, J = 3.6 Hz, 1H), 4.65 (d,
J = 9.6 Hz, 1H), 6.53 (d, J = 7.2 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H),
7.35–8.19 (m, 9H); 13C NMR (150 MHz, CDCl3): d 15.03, 15.28,
17.83, 29.62, 44.60, 55.48, 63.54, 63.56, 114.70, 115.84, 121.97,
122.77, 126.44, 129.20, 129.38, 129.68, 130.24, 133.36, 139.62,
143.36, 148.42, 153.01, 153.74, 168.80, 174.30; HRMS calculated
for C29H30N4O6 [M+Na]+: 553.2063, found 553.2052.
4.2. Preparation of (S)-5-isopropyl-3-phenyl-1-propionylhydan-
toin 3
The general procedure for N-propionylhydantoin 3 was de-
scribed in our previous Letter,4 and compound 3 obtained in 64%
from
L
-valine methyl ester hydrochloride 1. ½a D20
¼ þ10:4 (c 6.33,
ꢁ
CH2Cl2); IR: 1792, 1732, 1713 cmꢀ1 1H NMR (600 MHz, CDCl3): d
;
0.95 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.6 Hz,
3H), 2.64 (m, 1H), 3.02 (q, J = 7.2 Hz, 2H), 4.63 (d, J = 2.4 Hz, 1H),
7.32–7.49 (m, 5H); 13C NMR (150 MHz, CDCl3): d 8.37, 15.49,
18.01, 29.47, 30.84, 62.97, 126.41, 128.87, 129.23, 130.56, 153.02,
169.28, 173.03.
4.3.4. (5S,20R,30S)-5-Isopropyl-3-phenyl-1-[20-methyl-30-(p-meth-
oxyphenylamino)-30-(200,300-dimethoxyphenyl)-propionyl]hydan-
toin 4d
Yield: 78%; white solid; Mp 71.9–72.6 °C; ½a D20
¼ ꢀ30:6 (c 1.85,
ꢁ
CH2Cl2); IR: 3373, 1788, 1732, 1704 cmꢀ1 1H NMR (600 MHz,
;
4.3. General procedure for Mannich reactions
CDCl3): d 0.78 (d, J = 6.0 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.18 (d,
J = 7.2 Hz, 3H), 2.58 (m, 1H), 3.66 (s, 3H), 3.81 (s, 3H), 3.85 (s,
3H), 4.54 (m, 1H), 4.66 (d, J = 3.0 Hz, 1H), 4.89 (d, J = 9.6 Hz, 1H),
6.60–7.53 (m, 12H); 13C NMR (150 MHz, CDCl3): d 15.08, 15.13,
17.88, 29.51, 44.37, 55.47, 55.50, 55.53, 60.90, 63.48, 111.41,
114.38, 115.91, 119.66, 123.97, 126.53, 128.98, 129.28, 130.50,
140.91, 140.99, 147.25, 152.36, 152.39, 153.51, 169.22, 175.62;
The N-propionylhydantoin 3 (0.548 g, 2.0 mmol) was dissolved
in anhydrous CH2Cl2 (10 mL) and placed in a dry flask under N2.
The solution was cooled to 0 °C, and TiCl4 (0.22 mL, 2.0 mmol)
was added dropwise. The solution was stirred at 0 °C for
15 min, then diisopropyl-ethylamine (0.87 mL, 5.0 mmoL) was
added slowly. The solution was stirred at 0 °C for another
HRMS calculated for
568.2417.
C
31H35N3O6 [M+Na]+: 568.2424, found
30 min, and then
a solution of the corresponding aldimine
(2.6 mmol) in anhydrous CH2Cl2 (5 mL) was added dropwise.
The reaction mixture was stirred at 0 °C for 4–8 h, and then
quenched with saturated aqueous NH4Cl. The organic layer was
separated and the aqueous phase was extracted with CH2Cl2
(3 ꢂ 20 mL). The combined organic layer was washed with satu-
rated aqueous NaHCO3 and brine, dried over anhydrous MgSO4,
filtered, and concentrated. Purification of the crude product by
silica gel column chromatography (n-hexane/EtOAc, 8:1, v/v) gave
the Mannich adducts 4a–f.
4.3.5. (5S,20R,30S)-5-Isopropyl-3-phenyl-1-[20-methyl-30-(p-meth-
oxyphenylamino)-30-(200-furyl)-propionyl]hydantoin 4e
Yield: 61%; white solid; Mp 64.5–66.0 °C; ½a D20
¼ ꢀ28:4 (c 0.83,
ꢁ
CH2Cl2); IR: 3364, 1787, 1734, 1706 cmꢀ1 1H NMR (600 MHz,
;
CDCl3): d 0.81 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H), 1.16 (d,
J = 6.6 Hz, 3H), 2.54 (m, 1H), 3.68 (s, 3H), 4.56 (m, 1H), 4.59 (d,
J = 9.6 Hz, 1H), 4.64 (d, J = 3.0 Hz, 1H), 6.15–7.50 (m, 12H); 13C
NMR (150 MHz, CDCl3): d 14.58, 15.19, 17.86, 29.40, 43.42, 55.48,
57.74, 63.36, 107.81, 110.01, 114.44, 116.14, 126.48, 129.00,
129.27, 130.43, 140.59, 141.95, 152.75, 153.29, 153.41, 169.10,
174.87; HRMS calculated for C27H29N3O5 [M+Na]+: 498.2005,
found 498.2000.
4.3.1. (5S,20R,30S)-5-Isopropyl-3-phenyl-1-[20-methyl-30-(p-meth-
oxyphenylamino)-30-phenyl-propionyl]hydantoin 4a
Yield: 71%; white solid; Mp 66.2–66.9 °C; ½a D20
¼ ꢀ21:3 (c 1.04,
ꢁ
CH2Cl2); IR: 3372, 1787, 1734, 1706 cmꢀ1 1H NMR (600 MHz,
;

X.-R. Li et al. / Tetrahedron: Asymmetry 23 (2012) 1380–1384
1383
4.3.6. (5S,20R,30S)-5-Isopropyl-3-phenyl-1-[20-methyl-30-(p-meth-
114.84, 119.91, 123.80, 124.10, 147.19, 152.37, 152.68, 152.81,
176.28.
oxyphenylamino)-30-(200-thienyl)-propionyl]hydantoin 4f
Yield: 58%; white solid; Mp 62.5–63.1 °C; ½a D20
¼ ꢀ25:9 (c 1.45,
ꢁ
CH2Cl2); IR: 3367, 1789, 1732, 1698 cmꢀ1 1H NMR (600 MHz,
;
4.4.5. (2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-
(20-furyl)-propanoate 5e
CDCl3): d 0.74 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.23 (d,
J = 7.2 Hz, 3H), 2.51 (m, 1H), 3.68 (s, 3H), 4.53 (m, 1H), 4.63 (d,
J = 3.0 Hz, 1H), 4.79 (d, J = 8.4 Hz, 1H), 6.58–7.52 (m, 12H); 13C
NMR (150 MHz, CDCl3): d 15.08, 15.21, 17.83, 29.47, 45.72, 55.41,
59.52, 63.36, 114.47, 115.78, 124.31, 126.45, 126.72, 129.02,
129.27, 130.33, 132.50, 140.39, 140.43, 152.61, 153.43, 168.96,
174.82; HRMS calculated for C27H29N3O4 [M+Na]+: 514.1777,
found 514.1772.
Yield: 70%; ½a 2D0
ꢁ
¼ ꢀ47:6 (c 1.05, CH2Cl2); IR: 3372, 1732 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d 1.12 (d, J = 7.2 Hz, 3H), 3.03 (m, 1H),
3.67 (s, 3H), 3.69 (s, 3H), 4.61 (d, J = 7.8 Hz, 1H), 6.15 (d,
J = 3.0 Hz, 1H), 6.24 (dd, J = 1.8, 3.0 Hz, 1H), 6.61 (d, J = 9.0 Hz,
2H), 6.72 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 1.2 Hz, 1H); 13C NMR
(150 MHz, CDCl3): d 14.38, 44.33, 51.98, 55.66, 56.10, 107.54,
110.15, 114.68, 115.84, 140.69, 141.96, 152.74, 153.59, 175.27.
4.4. General procedure for the alcoholysis of Mannich adducts
4a–f
4.4.6. (2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-
(20-thienyl)-propanoate 5f
Yield: 80%; ½a 2D0
ꢁ
¼ ꢀ45:8 (c 1.10, CH2Cl2); IR: 3384, 1732 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d 1.19 (d, J = 7.2 Hz, 3H), 2.93 (m, 1H),
3.67 (s, 3H), 3.69 (s, 3H), 4.76 (d, J = 7.2 Hz, 1H), 6.60 (d,
J = 7.8 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 6.89–6.92 (m, 2H), 7.15 (d,
J = 4.2 Hz, 1H); 13C NMR (150 MHz, CDCl3): d 14.95, 46.98, 52.15,
55.75, 57.89, 114.76, 115.53, 124.46, 125.06, 126.88, 140.63,
145.91, 152.64, 175.26.
To a solution of Mannich adducts 4a–f (1.0 mmol) in methanol
(50 mL) was added DMAP (0.244 g, 2.0 mmol), after which the
reaction mixture was refluxed for 8 h. Next, the mixture was con-
centrated under reduced pressure. Purification of the crude prod-
uct by silica gel column chromatography (n-hexane/EtOAc, 6:1,
v/v) recovered the chiral hydantoin 2 and gave b-amino esters
5a–f.
4.5. Preparation of (3R,4S)-1-(4-methoxyphenyl)-3-methyl-4-
phenylazetidin-2-one 6a
4.4.1. (2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-
phenylpropanoate 5a
Yield: 78%; ½a 2D0
ꢁ
¼ ꢀ50:8 (c 1.02, CH2Cl2); IR: 3377, 1731 cmꢀ1
;
The b-amino ester 5a (0.224 g, 0.75 mmol) was dissolved in
anhydrous THF (15 mL) and placed in a dry flask under N2. The
solution was cooled to ꢀ20 °C, then a solution of NaHMDS
(0.75 mmol) in THF (0.38 mL, 2 M) was added dropwise. The reac-
tion mixture was then stirred at ꢀ20 °C for 30 min, and then
quenched with saturated aqueous NH4Cl. The mixture was ex-
tracted with CH2Cl2 (3 ꢂ 10 mL). The combined organic layers were
washed with saturated aqueous NaHCO3 and brine, dried over
anhydrous MgSO4, filtered, and concentrated. Purification of the
crude product by silica gel column chromatography (n-hexane/
EtOAc, 8:1, v/v) gave a white needle solid 6a (0.178 g, 89%). Mp
1H NMR (600 MHz, CDCl3): d 1.13 (d, J = 7.2 Hz, 3H), 2.84 (m, 1H),
3.63 (s, 3H), 3.66 (s, 3H), 4.43 (d, J = 7.8 Hz, 1H), 6.50 (d,
J = 7.8 Hz, 2H), 6.65 (d, J = 9.0 Hz, 2H), 7.20–7.30 (m, 5H); 13C
NMR (150 MHz, CDCl3):
d 15.20, 46.63, 51.80, 55.55, 61.68,
114.54, 114.99, 126.82, 127.36, 128.48, 140.68, 141.02, 152.02,
175.47.
4.4.2. (2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-
(p-chloro-phenyl) propanoate 5b
Yield: 85%; ½a 2D0
ꢁ
¼ ꢀ43:1 (c 0.57, CH2Cl2); IR: 3393, 1731 cmꢀ1
;
122–124 °C; ½a 2D0
ꢁ
¼ ꢀ46:1 (c 0.89, CHCl3); IR: 1745 cmꢀ1
;
1H
1H NMR (600 MHz, CDCl3): d 1.15 (d, J = 7.2 Hz, 3H), 2.81 (m, 1H),
3.64 (s, 3H), 3.67 (s, 3H), 4.41 (d, J = 6.6 Hz, 1H), 6.47 (d,
J = 7.8 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H),
7.27 (d, J = 8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3): d 15.21,
46.46, 51.87, 55.59, 61.01, 114.62, 114.93, 128.21, 128.70, 133.00,
139.76, 140.44, 152.17, 175.20.
NMR (600 MHz, CDCl3): d 1.47 (d, J = 7.2 Hz, 3H), 3.11 (dq, J = 2.4,
7.2 Hz, 1H), 3.73 (s, 3H), 4.54 (d, J = 1.8 Hz, 1H), 6.77 (d,
J = 9.0 Hz, 2H), 7.22 (d, J = 9.6 Hz, 2H), 7.31–7.38 (m, 5H); 13C
NMR (150 MHz, CDCl3): d 13.23, 55.50, 55.57, 63.03, 114.50,
118.41, 126.02, 128.53, 129.23, 131.69, 138.27, 156.13, 167.85.
Acknowledgments
4.4.3. (2R,3S)-Methyl 2-methyl-3-(p-methoxyphenylamino)-3-
(m-nitro-phenyl) propanoate 5c
We gratefully acknowledge the National Natural Sciences Foun-
dation of China (No. 20772026 and 21042005) and the Natural Sci-
ences Foundation of Hubei province in China (No. 2010CDA019) for
financial support.
Yield: 75%; ½a 2D0
ꢁ
¼ ꢀ48:2 (c 1.16, CH2Cl2); IR: 3398, 1733 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d 1.21 (d, J = 7.2 Hz, 3H), 2.92 (m, 1H),
3.65 (s, 3H), 3.68 (s, 3H), 4.58 (d, J = 7.8 Hz, 1H), 6.49 (d,
J = 7.8 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 7.48–8.21 (m, 4H); 13C
NMR (150 MHz, CDCl3):
d 15.21, 46.13, 52.10, 55.62, 61.10,
114.69, 115.00, 121.88, 122.65, 129.51, 133.14, 139.75, 143.29,
148.42, 152.53, 174.67.
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ꢁ
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;
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