Microgel supported hydantoins as new chiral auxiliaries for asymmetric Mannich reactions

Article abstract of DOI:10.1016/j.tetasy.2015.01.008

Four distinct microgel supported hydantoin chiral auxiliaries were prepared with four different cross-linkers and evaluated in asymmetric Mannich reactions, which proceeded in good chemical yields and with excellent stereoselectivities. Moreover, the micr

Full text of DOI:10.1016/j.tetasy.2015.01.008

Tetrahedron: Asymmetry 26 (2015) 180–185
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Microgel supported hydantoins as new chiral auxiliaries
for asymmetric Mannich reactions
a
a
a
b,
Feng Chen a, Cui-Fen Lu a, , Jun-Qi Nie , Gui-Chun Yang , Zu-Xing Chen , Nian-Guo Dong
⇑
⇑
a Hubei Collaborative Innovation Center for Advanced Organochemical Materials & Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic
Functional Molecules, Hubei University, Wuhan 430062, China
b Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Four distinct microgel supported hydantoin chiral auxiliaries were prepared with four different cross-
linkers and evaluated in asymmetric Mannich reactions, which proceeded in good chemical yields and
with excellent stereoselectivities. Moreover, the microgel supported hydantoin chiral auxiliaries could
be reused for at least four cycles without an appreciable reduction in the yield or stereoselectivity.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 17 November 2014
Accepted 6 January 2015
Available online 3 February 2015
1. Introduction
2. Results and discussion
Chiral auxiliary-mediated asymmetric reactions have been
studied extensively and are currently one of the most general
methods employed in modern organic synthesis.1 The optically
active hydantoin, a new chiral auxiliary, developed by Yamaguchi,
has proved to be particularly efficient in terms of stereoselectivity
and yield in asymmetric conjugate addition reactions.2
As a continuation of Yamaguchi’s work, we investigated the
asymmetric aldol and Mannich reactions induced by hydantoin
chiral auxiliaries.3 The hydantoin chiral auxiliaries could be recov-
ered by column chromatography for reuse, but this method was
not suitable for mass production. Since then, the soluble polymer
support—non-cross-linked polystyrene (NCPS), which is a valuable
2.1. Preparation of microgel supported N-propionyl chiral
hydantoin 3
As shown in Scheme 1, microgel supported N-propionyl chiral
hydantoin 3 was synthesized from the novel starting material 1,
which was prepared from L-tyrosine methyl ester hydrochloride
in three steps as previously described.4 Compound 1 was copoly-
merized with styrene and one of four different cross-linkers 2
under polymerization conditions for microgels to prepare four dis-
tinct microgel supported N-propionyl chiral hydantoin polymers
3a–d respectively in a 78–92% yield.5 Polymers 3a–d are soluble
in typical organic solvents, such as benzene, CHCl3, CH2Cl2, CH3CN,
EtOAc, THF, or DMF, and insoluble in MeOH, EtOH, or H2O; this sol-
ubility versus recovery relationship of the crystalline polymer
could lead to a better recovery with regard to the yield of the poly-
mer support when precipitated with a poor solvent. Moreover,
polymers 3a–d exhibit low viscosity even at high concentrations
and low temperatures, and because of their unique properties they
seem to be good candidates for use as chiral auxiliaries in asym-
metric synthesis and better than NCPS supported chiral hydantoin.
The 1H NMR spectrum of 3c (taking 3c as an example) (Fig. 1)
shows the aromatic protons of phenyl at 6.5–7.7 ppm (Fig. 1, peak
a) and methylene protons of polymer (–Ar–O–CH2–Ar–) and the
methyne proton (–N–CH–) at 4.90–5.25 ppm (Fig. 1, peak b). Meth-
ylene protons of the cross-linker (–O–CH2–CH2–) were observed at
4.60 ppm (Fig. 1, peak c). Methylene protons of a hydantoin moiety
(–N–CH–CH2–) and of a propanoyl group (–N–CO–CH2–CH3) were
observed at 3.35–3.80 ppm (Fig. 1, peak d) and 3.08 ppm (Fig. 1,
peak e), respectively. On the basis of the 1H NMR spectroscopic
tool to simplify chiral auxiliary recycling, has become
a
better choice.4 NCPS has good solubility characteristics, but its
solutions become extremely viscous at high concentrations and
low temperatures.
Microgel, a new type of soluble support, which is defined as
‘intramolecularly cross-linked molecules that form a stable solu-
tion in many solvents’, exhibits low viscosity even at high concen-
trations and low temperatures, so it can avoid the above problem.5
Herein we report the preparation of four microgel supported
hydantoin chiral auxiliaries with four different cross-linkers, the
application of these chiral auxiliaries in asymmetric Mannich reac-
tions, and the potential for recycling of the chiral auxiliaries.
⇑
Corresponding authors. Tel.: +86 27 50865322; fax: +86 27 88663043.
E-mail addresses: lucf@hubu.edu.cn (C.-F. Lu), dongnianguo@hotmail.com
(N.-G. Dong).
http://dx.doi.org/10.1016/j.tetasy.2015.01.008
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

F. Chen et al. / Tetrahedron: Asymmetry 26 (2015) 180–185
181
O
O
or
H2
C
O
O
2
,
n
n=2, 4, 6
O
O
AIBN, THF, reflux
N
Ph
N
Ph
N
N
O
O
O
O
3
1
O
O
Ar
OCH3
TiCl4, DIPEA, CH2Cl2
DMAP
+
NH
O
ArCH=NPMP, 0 oC
O
O
CH3OH/THF
reflux
PMP
4
N
Ph
Ar
N
6
N
Ph
HN
O
O
NH
O
PMP
7
5
3a: R=
3b: R=
y
x
CH2O(CH2)2OCH2
CH2O(CH2)4OCH2
z
R
=
3c
3d
: R=
: R=
CH2O(CH2)6OCH2
Ar = C6H5, 4-ClC6H4, 3-NO2C6H4, 2,3-(CH3O)2C6H3, 2-furyl, 2-thienyl
Scheme 1.
Figure 1. 1H NMR spectra (400 MHz, CDCl3) of polymer 3c.

182
F. Chen et al. / Tetrahedron: Asymmetry 26 (2015) 180–185
analysis, the calculated ratios (1/styrene/2 = 17.6:77.6:4.8) of the
incorporated monomers in 3c were in agreement with that of the
monomer feed (1/styrene/2 = 19:76:5). Thus, the 1H NMR spec-
trum of 3c was used to calculate the loading of chiral hydantoin
(1.01 mmol/g). The loading capacity of other polymers 3 were cal-
culated by their 1H NMR spectrum respectively as well (Table 1).
The results of the molecular weight determination of 3a–d by gel
permeation chromatography (GPC) and molecular weight distribu-
tion (Mw/Mn) show the expected discrepancy because the GPC was
calibrated with linear polystyrene standards (Table 1).
Table 1
Polymer
Yielda (%)
Loadingb (mmol/g)
Mnc
Mwc
Mw/Mnc
Theor
Obsd
3a
3b
3c
3d
82
78
92
85
1.10
1.06
1.06
1.05
0.91
1.00
1.01
0.90
6700
5560
7320
7030
16,780
15,570
15,380
17,150
2.5
2.8
2.1
2.3
Figure 3. TGA thermograms of 3a–d.
a
b
c
After purification by precipitation in EtOH.
Loading was calculated by the 1H NMR spectrum.
As determined by GPC relative to linear polystyrene standards.
2.2. Diastereocontrolled Mannich reactions
In order to demonstrate the efficiency of microgel supported
chiral hydantoin 3 as a new chiral auxiliary, the asymmetric
Mannich reaction of microgel supported chiral hydantoin 3 with
N-(4-methoxyphenyl)benzaldimine 4a was chosen as a model
reaction. As shown in Scheme 1, microgel supported chiral hydan-
toin 3a–d was deprotonated with 1.05 equiv of TiCl4 and 1.5 equiv
of DIPEA at 0 °C, to form the Z-enolate, which was reacted with
N-(4-methoxyphenyl)-benzaldimine 4a, leading to the desired
Mannich adduct 5. The four Mannich adducts 5aa–da derived from
four different microgel supported chiral hydantoin polymers 3a–d
were then alcoholized in a 3:1 mixture of THF/methanol with
DMAP as the catalyst to afford the same methyl ester 6a as well
as the quantitative recovery of the chiral auxiliary 7a–d.
The formation of polymers 3a–d were further evidenced by
TEM (Fig. 2), which provided important information about the
morphologies and size distributions of the polymer. The morphol-
ogy of a typical spherical particle was shown as polymer 3c, which
was prepared with 1,4-bis[4-(vinyl) phenoxy] butane as the cross-
linker. Spherical particles (ca. 550–800 nm in diameter) can be
observed. It can be seen that the spherical particle and size distri-
butions of the polymer 3c were more uniform than others. Further-
more, the thermal stability of polymers 3a–d was investigated by
thermogravimetric analysis in order to demonstrate that these
polymers are stable at temperatures up to 300 °C (Fig. 3). The good
thermal stability of these polymers indicates that they are appro-
priate for their use in many organic transformations at room tem-
perature or at elevated temperatures.
As shown in Table 2, product 6a was obtained in good chemical
yields (50–73%), high diastereoselectivity (dr >99:1) and excellent
enantioselectivity (ee >99%) (Table 2, entries 1–4). These data
show that the polymer’s inner structure had some effect on the
Table 2
Entry Chiral
auxiliary
Ar
Product Yielda
(%)
drb
eec
(%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3c
3c
NCPS-
hydantoin
NCPS-
hydantoin
3c
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
6a
6a
6a
6a
6a
6a
6a
50
66
73
64
62
55
40
>99:1 >99
>99:1 >99
>99:1 >99
>99:1 >99
>99:1 >99
>99:1 >99
d
e
f
92:8
90
g
8
C6H5
6a
69
>99:1 >99
9
10
11
4-ClC6H4
3-NO2C6H4
2,3-
6b
6c
6d
68
82
61
>99:1 >99
>99:1 >99
>99:1 >99
3c
3c
(CH3O)2C6H3
2-Furly
2-Thienyl
12
13
3c
3c
6e
6f
63
67
>99:1 >99
>99:1 >99
a
b
c
d
e
f
Overall isolated yield in two steps starting from 3.
Determined by HPLC.
Determined by chiral HPLC.
2.0 mmol scale in dicholoromethane (20 mL).
2.0 mmol scale in dicholoromethane (15 mL).
2.0 mmol scale in dicholoromethane (25 mL).
2.0 mmol scale in dicholoromethane (40 mL).
g
Figure 2. TEM images of 3a–d. Scale bars = 1 lm.

F. Chen et al. / Tetrahedron: Asymmetry 26 (2015) 180–185
183
reaction conversion but had little impact on stereoselectivity. In
agreement with our previous report,5a the best result was obtained
with microgel supported chiral hydantoin 3c (Table 2, entry 3),
which was prepared with 1,4-bis[4-(vinyl) phenoxy] butane as
the cross-linker.
stereoselectivity remained almost intact, the yield decreased in
each cycle. Thus the greatest advantage of microgel supported
hydantoin chiral auxiliary over non-supported hydantoin chiral
auxiliary is that it can be recovered by simple precipitation and
filtration, and can be reused for at least four cycles without an
appreciable reduction in the yield or stereoselectivity.
In order to compare the efficiency of microgel supported chiral
hydantoin with NCPS supported hydantoin chiral auxiliaries,4 we
performed the same Mannich reaction with both microgel sup-
ported hydantoin chiral auxiliaries and NCPS supported hydantoin
chiral auxiliaries under different concentration conditions (Table 2,
entries 5–8). Using microgel supported hydantoin as chiral auxil-
iary and under higher concentration conditions, product 6a was
obtained with the same stereoselectivity, but lower chemical
yields. This indicates that the above concentration with 2.0 mmol
scale in dicholoromethane (25 mL) is the best concentration. When
using the same concentration, product 6a with an NCPS supported
hydantoin chiral auxiliary was afforded in 40% chemical yield, 92:8
dr and 90% ee, which is lower than with a microgel supported
hydantoin chiral auxiliary. With a lower concentration on a 2.0
mmol scale in dicholoromethane (40 mL), using NCPS supported
hydantoin as the chiral auxiliary, product 6a was obtained with
the same stereoselectivity and in a similar chemical yield (69%).
Hence the low viscosity of the microgel is important in the asym-
metric reaction, both in terms of the chemical yield, and also
stereoselectivity.
3. Conclusions
In conclusion, we have efficiently synthesized four distinct
microgel supported hydantoin chiral auxiliaries with four different
cross-linkers and evaluated them in asymmetric Mannich
reactions. Using microgel supported chiral hydantoin 3c with
1,4-bis[4-(vinyl) phenoxy]butane as the cross-linker provided the
best results in the mode reaction, and all of the Mannich adducts
using microgel supported chiral hydantoin 3c were obtained in
high yields and with excellent stereoselectivity. Moreover, micro-
gel supported hydantoin chiral auxiliaries can be readily recovered
by simple precipitation, filtration and dried, and then be reused
more than three times without an appreciable reduction in the
yield or stereoselectivity.
4. Experimental
4.1. Materials
The Mannich reactions of microgel supported chiral hydantoin
3c with other aldimines also exhibited excellent stereoselectivity
and produced the corresponding methyl esters 6b–f in good chem-
ical yields as shown in Table 2. Compared to the same reactions
using non-supported hydantoin chiral auxiliary,3b the Mannich
reactions using the chiral auxiliary 3c exhibited higher chemical
yields and the same stereoselectivities.
All products 6a–f are known compounds and were identified by
comparison of their physical and spectroscopic data with those of
authentic samples.3b,6 The syn versus anti stereochemistry of the
Mannich adducts may be assigned on the basis of 1H NMR coupling
constants of the products 6a–f. The measured J3,4 coupling con-
stant in the 1H NMR spectrum was found to be 1.8 Hz, which
was consistent with the anti-stereochemistry reported in the
literature.3b,6 The absolute configurations of products 6a–f were
confirmed by comparing their specific rotations with those
previously reported.
The aldimines were prepared by condensation of the corre-
sponding aldehyde and p-methoxyphenylamine under standard
conditions in the literature.7 All other reagents were purchased
and dried or purified by standard procedures before use. Reactions
were monitored by TLC using precoated plates of silica gel plates
(HF254, 0.5 mm, Yantai, China). Column chromatography was per-
formed with a silica gel column (300–400 mesh, Yantai, China).
4.2. Measurements
NMR spectra were recorded on a Varian Unity Inova 600 spec-
trometer (1H at 600 MHz and 13C at 150 MHz) or a WIPM-400 spec-
trometer (1H at 400 MHz and 13C at 100 MHz) using TMS as the
internal standard. Coupling constants are recorded in Hz. Melting
points were determined on a WRS-1A digital melting point appara-
tus. Optical rotations were measured using a sodium D line on
WZZ-2B Automatic Polarimeter. IR spectra were recorded on a Per-
kin-Elmer IR-spectrum one spectrometer. HPLC analyses were car-
ried out on a Dionex chromatograph (UltiMate 3000 pump,
ChiralcelÒ OD-H column and ChiralcelÒ AD-H column, Daicel)
using hexane/2-propanol mixtures as the eluent. A UV detector
(UVD-3000) was used for peak detection. Gel permeation chro-
matographic analyses (GPC) were carried out on a PL GPC-50
preparative liquid chromatograph with a Cirrus™ integrator and
a PL-RI detector using polystyrene standards. Transmission elec-
tron microscopy (TEM) was recorded on a TecnaiG20 (Philips,
Netherlands) microscopy. TEM samples were prepared by placing
a drop of a freshly prepared solution of microgel supported hydan-
toin chiral auxiliaries onto the carbon-coated copper grids
(300 mesh), which were then dried in air overnight. Thermal gravi-
metric analysis was tested under nitrogen with a heating rate of
20 °C/min using U.S. PERKIN ELMER Company Diamond TG / DTA
thermal analysis system.
2.3. Recycling and reuse of microgel supported hydantoin chiral
auxiliary
In order to further investigate the ability of recycling microgel
supported chiral auxiliary 7, recovered chiral auxiliary 7c (taking
7c as an example) was washed and dried, and then subjected to
N-acylation with propionyl chloride, Mannich reaction with
N-(4-methoxyphenyl)benzaldimine, and alcoholysis to give the
corresponding b-amino ester 6a. After the continuous second to
fourth asymmetric Mannich reactions, the desired b-amino ester
was obtained with high diastereoselectivity (dr >99:1) and excel-
lent enantioselectivity (ee >99%) (Table 3). Although the product’s
Table 3
Cycle
Ar
Product
Yielda (%)
drb
eec (%)
1
2
3
4
C6H5
C6H5
C6H5
C6H5
6a
6a
6a
6a
73
69
68
65
>99:1
>99:1
>99:1
>99:1
>99
>99
>99
>99
4.3. General procedure for the preparation of microgel
supported N-propionyl chiral hydantoin 3
a
b
c
Overall isolated yield in two steps starting from 3.
Determined by HPLC.
Determined by chiral HPLC.
To a solution of compound 1 (0.45 g, 1.0 mmol) in THF (14 mL)
was added styrene (0.46 mL, 4.0 mmol), cross-linker
2

184
F. Chen et al. / Tetrahedron: Asymmetry 26 (2015) 180–185
(0.26 mmol), and AIBN (22 mg, 0.15 mmol, 3 mol %). The resulting
mixture was stirred at reflux for 4 d under nitrogen. After cooling
to room temperature, the reaction mixture was concentrated in
vacuo to approximately 3 mL, and then slowly added to cold vigor-
ously stirred methanol (100 mL). The precipitated polymer was fil-
tered, washed with cold methanol, and dried in vacuo to give
microgel supported N-propionyl chiral hydantoin 3 as a colorless
finely divided powder in a 78–92% yield.
125.97, 126.42, 126.71, 127.52, 127.88, 128.16, 129.24, 129.46,
130.00, 145.36, 152.71, 155.80, 158.81, 170.19, 173.57.
5da: IR (KBr)
m ;
: 3317, 1794, 1737, 1708 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.37, 22.92, 29.91, 31.04, 32.14, 34.15,
40.74, 46.52, 59.93, 63.09, 70.20, 73.04, 115.11, 125.97, 126.71,
127.52, 127.43, 127.95, 128.16, 129.47, 145.38, 152.72, 155.65,
158.82, 170.20, 173.57.
5cb: IR (KBr)
m ;
: 3361, 1774, 1737, 1721 cmÀ1 13C NMR
3a: IR (KBr)
m
: 1773, 1737, 1721 cmÀ1
;
1H NMR (400 MHz,
(100 MHz, CDCl3) d: 14.36, 22.90, 29.89, 31.01, 34.12, 40.52,
46.48, 59.90, 62.86, 70.14, 73.04, 115.07, 124.99, 125.87, 126.37,
126.68, 127.87, 128.16, 129.22, 129.44, 130.50, 130.94, 145.24,
152.68, 156.12, 158.81, 170.17, 173.54.
CDCl3): d 0.88–1.93 (30H), 2.96 (2H), 3.29–3.63 (2H), 4.82–5.09
(3H), 6.87–7.37 (43H); 13C NMR (100 MHz, CDCl3) d: 8.72, 29.92,
31.03, 34.18, 40.51, 59.94, 70.22, 115.13, 125.83, 126.73, 127.89,
128.19, 129.24, 129.47, 129.70, 130.59, 130.99, 131.14, 145.34,
152.71, 158.80, 170.19, 173.58.
5cc: IR (KBr)
m: ;
3391, 1773, 1736, 1720 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.36, 22.90, 29.90, 31.02, 34.14, 40.49,
46.50, 59.92, 62.86, 70.24, 73.07, 115.10, 125.91, 126.37, 126.70,
127.83, 128.16, 129.23, 129.45, 129.56, 130.53, 130.96, 145.38,
148.82, 152.70, 155.60, 158.79, 170.19, 173.55.
3b: IR (KBr)
m ;
: 1793, 1736, 1707 cmÀ1 1H NMR (400 MHz,
CDCl3): d 0.87–1.96 (27H), 2.95(2H), 3.29–3.63 (2H), 4.25–4.60
(1H), 4.78–5.10 (3H), 6.57–7.41 (38H); 13C NMR (100 MHz, CDCl3)
d: 8.62, 29.80, 30.91, 34.06, 40.47, 59.80, 69.82, 73.04, 115.08,
126.60, 126.76, 127.07, 127.77, 128.09, 128.61, 129.10, 129.34,
130.50, 130.87, 145.21, 152.61, 158.70, 170.07, 173.44.
5cd: IR (KBr)
m ;
: 3368, 1772, 1736, 1719 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.35, 22.89, 29.88, 31.00, 34.11, 40.43,
46.54, 55.06, 58.28, 59.91, 62.84, 70.18, 73.06, 115.06,
125.64, 125.78, 126.68, 127.79, 128.14, 128.41, 129.22, 129.44,
130.51, 130.98, 145.25, 150.13, 152.70, 156.09, 158.81, 170.17,
173.54.
3c: IR (KBr)
m ;
: 1794, 1737, 1719 cmÀ1 1H NMR (400 MHz,
CDCl3): d 0.85–1.87 (29H), 2.93 (2H), 3.30–3.57 (2H), 4.20–4.57
(1H), 4.75–5.10 (3H), 6.60–7.34 (37H); 13C NMR (100 MHz, CDCl3)
d: 8.69, 22.89, 29.89, 31.00, 34.15, 40.48, 59.92, 70.19, 73.02,
115.11, 125.65, 126.63, 126.69, 127.85, 128.17, 128.64, 129.20,
129.43, 130.57, 130.98, 145.34, 152.70, 158.76, 170.14, 173.53.
5ce: IR (KBr)
m: ;
3401, 1773, 1737, 1719 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.37, 22.91, 29.90, 31.03, 34.13, 40.48,
46.50, 55.70, 59.92, 70.17, 72.86, 115.08, 125.67, 125.81, 126.38,
126.70, 127.88, 128.17, 129.24, 129.46, 130.51, 130.97, 145.36,
152.71, 155.81, 158.77, 170.18, 173.56.
3d: IR (KBr)
m ;
: 1794, 1737, 1706 cmÀ1 1H NMR (400 MHz,
CDCl3): d 0.90–1.85 (30H), 2.93 (2H), 3.34–3.58 (2H), 4.21–4.55
(1H), 4.75–5.00 (3H), 6.46–7.41 (42H); 13C NMR (100 MHz, CDCl3)
d: 8.68, 22.89, 29.55, 29.88, 31.00, 34.11, 40.51, 59.88, 70.13, 72.87,
115.06, 125.68, 125.85, 126.67, 127.85, 128.13, 129.19, 129.42,
129.52, 130.50, 130.94, 145.34, 152.67, 158.73, 170.14, 173.51.
5cf: IR (KBr)
m: ;
3338, 1774, 1736, 1720 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.36, 22.89, 29.88, 31.01, 34.11, 40.40,
44.62, 55.68, 59.90, 70.15, 73.02, 115.07, 125.67, 125.79, 126.36,
126.68, 127.58, 128.14, 129.21, 129.44, 130.50, 130.95, 145.38,
152.68, 156.02, 158.73, 170.16, 173.53.
4.4. General procedure for the asymmetric Mannich reactions
4.5. General procedure for the alcoholysis of Mannich adduct 5
At first, TiCl4 (0.23 mL, 2.1 mmol) was added dropwise to a solu-
tion of microgel supported N-propionyl chiral hydantoin
3
To a solution of Mannich adduct 5 (1.0 mmol) in a 3:1 mixture
of THF/methanol (50 mL) was added DMAP (0.244 g, 2.0 mmol),
and the reaction mixture was refluxed for 48 h. The reaction mix-
ture was then concentrated in vacuo to approximately 3 mL, and
then slowly added to cold vigorously stirred methanol (100 mL).
The precipitated polymer was filtered, washed with cold methanol,
and dried in vacuo to recover quantitatively microgel supported
chiral auxiliary 7. The filtrate was purified by silica gel column
chromatography (n-hexane/EtOAc, 6:1, v/v) to furnish b-amino
ester 6. All of the b-amino esters herein are known compounds that
exhibited spectroscopic data identical to those reported in the
literature.3b,6
(2.0 mmol) in anhydrous CH2Cl2 (20 mL) at 0 °C under nitrogen,
after which the solution was allowed to stir at 0 °C for 15 min.
Diisopropylethylamine (DIPEA) (0.52 mL, 3.0 mmol) was then
added dropwise to the solution and the mixture was allowed to stir
at 0 °C for another 30 min, after which a solution of the corre-
sponding aldimine 4 (3.0 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 (10 mL).
The organic layer was separated and the aqueous phase was
extracted with CH2Cl2 (20 mL Â 3). The combined organic layers
were washed with saturated aqueous NaHCO3 and brine, dried
over anhydrous MgSO4, and filtered. The filtrate was then concen-
trated in vacuo to approximately 3 mL, and then slowly added to
cold vigorously stirred methanol (100 mL). The precipitated poly-
mer was filtered, washed with cold methanol, and dried in vacuo
to give Mannich adduct 5.
6a: Yield: 73% (overall yield in two steps starting from 3c);
[
a
]
20 = À48.7 (c 0.96, CH2Cl2), lit.3b
[
a
]
20 = À50.8 (c 1.02, CH2Cl2);
D
D
the enantiomeric excess of 6a was determined by chiral HPLC: col-
umn, Chiralcel AD-H; eluent, 7:93 2-propanol–hexane; tempera-
ture, 30 °C; flow rate, 1.0 mL/min; tR (RS) = 9.25 min, tR
(SR) = 8.85 min.
5aa: IR (KBr)
m ;
: 3379, 1773, 1735, 1719 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.36, 29.89, 32.12, 34.14, 40.57, 46.51,
59.87, 63.57, 70.11, 115.09, 115.77, 125.86, 125.95, 126.69,
127.51, 127.84, 128.19, 129.23, 129.45, 129.74, 145.25, 152.70,
155.69, 158.73, 170.18, 173.57.
6b: Yield: 68% (overall yield in two steps starting from 3c);
[
a
]
20 = À44.6 (c 0.85, CH2Cl2), lit.3b
[
a]
D
20 = À43.1 (c 0.57, CH2Cl2);
D
the enantiomeric excess of 6b was determined by chiral HPLC: col-
umn, Chiralcel AD-H; eluent, 7:93 2-propanol–hexane; tempera-
ture, 30 °C; flow rate, 1.0 mL/min; tR (RS) = 10.11 min, tR
(SR) = 11.57 min.
5ba: IR (KBr)
m ;
: 3385, 1793, 1736, 1707 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.36, 29.90, 31.02, 34.13, 40.54, 46.56,
59.91, 62.10, 73.25, 70.13, 115.08, 125.96, 126.69, 127.51, 127.81,
128.15, 129.23, 129.45, 129.74, 130.51, 130.97, 145.31, 152.70,
155.65, 158.80, 170.18, 173.55.
6c: Yield: 81% (overall yield in two steps starting from 3c);
[a
]
20 = À47.9 (c 1.12, CH2Cl2), lit.3b
[
a
]
20 = À48.2 (c 1.16, CH2Cl2);
D
D
the enantiomeric excess of 6c was determined by chiral HPLC: col-
umn, Chiralcel OD-H; eluent, 10:90 2-propanol–hexane; tempera-
ture, 30 °C; flow rate, 1.0 mL/min; tR (RS) = 19.25 min, tR
(SR) = 13.25 min.
5ca: IR (KBr)
m ;
: 3386, 1793, 1737, 1708 cmÀ1 13C NMR
(100 MHz, CDCl3) d: 14.37, 22.91, 29.91, 31.02, 34.14, 40.47,
46.54, 59.93, 63.31, 69.64, 73.18, 113.98, 115.10, 115.79, 125.89,

F. Chen et al. / Tetrahedron: Asymmetry 26 (2015) 180–185
185
6d: Yield: 59% (overall yield in two steps starting from 3c);
Students’ Innovation and Entrepreneurship Training Plan of the
Hubei Province (No. 201310512013) for financial support.
[
a
]
20 = À50.7 (c 1.08, CH2Cl2), lit.3b
[a
]
D
20 = À53.7 (c 2.20, CH2Cl2);
D
the enantiomeric excess of 6d was determined by chiral HPLC: col-
umn, Chiralcel OD-H; eluent, 1:99 2-propanol–hexane; tempera-
ture, 30 °C; flow rate, 0.2 mL/min; tR (RS) = 75.12 min, tR
(SR) = 72.89 min.
References
1. (a) Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry 2014, 25, 1061–1090; (b)
Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry 2013, 24, 1149–1188; (c) Lu,
C. F.; Hu, L.; Yang, G. C.; Chen, Z. X. Curr. Org. Chem. 2012, 16, 2802–2817.
2. Yamaguchi, J.; Harada, M.; Narushima, T.; Saitoh, A.; Nozaki, K.; Suyama, T.
Tetrahedron Lett. 2005, 46, 6411–6415.
3. (a) Zhang, J. S.; Lu, C. F.; Chen, Z. X.; Li, Y.; Yang, G. C. Tetrahedron: Asymmetry
2012, 23, 72–75; (b) Li, X. R.; Lu, C. F.; Chen, Z. X.; Li, Y.; Yang, G. C. Tetrahedron:
Asymmetry 2012, 23, 1380–1384.
6e: Yield: 63% (overall yield in two steps starting from 3c);
[
a]
20 = À47.8 (c 1.10, CH2Cl2), lit.3b
[
a
]
20 = À47.6 (c 1.05, CH2Cl2);
D
D
the enantiomeric excess of 6e was determined by chiral HPLC:
column, Chiralcel AD-H; eluent, 7:93 2-propanol–hexane;
temperature, 30 °C; flow rate, 1.0 mL/min; tR (RS) = 9.25 min, tR
(SR) = 10.85 min.
4. Lu, G. J.; Nie, J. Q.; Chen, Z. X.; Yang, G. C.; Lu, C. F. Tetrahedron: Asymmetry 2013,
24, 1331–1335.
6f: Yield: 67% (overall yield in two steps starting from 3c);
5. (a) Shimomura, O.; Clapham, B.; Spanka, C.; Mahajan, S.; Janda, K. D. J. Comb.
Chem. 2002, 4, 436–441; (b) Spanka, C.; Clapham, B.; Janda, K. D. J. Org. Chem.
2002, 67, 3045–3050; (c) Deng, J.; Lu, C. F.; Yang, G. C.; Chen, Z. X. React. Funct.
Polym. 2012, 72, 378–382; (d) Li, H.; Pang, Z. B.; Jiao, Z. F.; Lin, F. J. Comb. Chem.
2010, 12, 255–259.
6. Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem. Soc. 1997,
119, 2060–2061.
7. (a) Kametani, T.; Furuyama, H.; Fukuoka, Y.; Takeda, H.; Suzuki, Y.; Honda, T. J.
Heterocycl. Chem. 1986, 23, 185–187; (b) Danheiser, R. L.; Okamoto, I.; Lawlor, M.
D.; Lee, T. W. Org. Synth. 2003, 80, 160–171.
[
a]
20 = À45.1 (c 1.24, CH2Cl2), lit.3b
[
a
]
20 = À45.8 (c 1.10, CH2Cl2);
D
D
the enantiomeric excess of 6f was determined by chiral HPLC:
column, Chiralcel AD-H; eluent, 7:93 2-propanol–hexane;
temperature, 30 °C; flow rate, 1.0 mL/min; tR (RS) = 9.61 min, tR
(SR) = 10.30 min.
Acknowledgments
We gratefully acknowledge the National Natural Sciences
Foundation of China (Nos. 21342002 and 31330029) and College