Isosteviol-amino acid conjugates as highly efficient organocatalysts for the asymmetric one-pot three-component mannich reactions

Article abstract of DOI:10.1002/cjoc.201180272

Isosteviol-amino acid conjugates were synthesized and used as chiral catalysts for the asymmetric three-component Mannich reaction with hydroxyacetone as donor molecule. Good yields (up to 98%) and excellent stereoselectivities (up to 97:3 dr and 99% ee)

Full text of DOI:10.1002/cjoc.201180272

FULL PAPER
Isosteviol-amino Acid Conjugates as Highly Efficient
Organocatalysts for the Asymmetric One-pot Three-component
Mannich Reactions
An, Yajie(安雅洁)
Qin, Qian(秦倩)
Wang, Chuanchuan(王川川)
Tao, Jingchao*(陶京朝)
Department of Chemistry, New Drug Research and Development Center, Zhengzhou University,
Zhengzhou, Henan 450052, China
Abstract Isosteviol-amino acid conjugates were synthesized and used as chiral catalysts for the asymmetric
three-component Mannich reaction with hydroxyacetone as donor molecule. Good yields (up to 98%) and excellent
stereoselectivities (up to 97∶ 3 dr and 99% ee) were achieved in a short reaction time. In addition, syn- or
anti-configurations of α-hydroxy-β-amino carbonyl compounds were obtained as main products with different chiral
catalysts.
Keywords isosteviol-amino acid conjugates, asymmetric catalysis, mannich reaction, hydroxyacetone, enantiose-
lectivity
Introduction
bic and steric features of the catalysts may be used to fix
the conformation of the enamine intermediate in the
catalytic process.
The asymmetric Mannich reaction is one of the most
important carbon-carbon bond forming reactions for the
production of optically enriched β-amino carbonyl mo-
tifs. It has been considered as a crucial synthetic meth-
odology in the synthesis of pharmaceutically valuable
compounds and natural products.1-3 The first organo-
catalyst-mediated direct asymmetric Mannich reaction
was reported by List et al4,5 using L-proline as catalyst
and followed by excellent contributions from several
groups.6-10 Then, the TBS-protected hydroxy proline,11
proline-derived tetrazole12 and (2S,5S)-pyrrolidine-2,
5-dicarboxylic acid13,14 were also developed as enanti-
oselective organocatalysts for the atom-economic reac-
tion. Besides, acylic amino acids and their derivatives
were also investigated for the direct one-pot three-
component Mannich reactions.15-18 However, it should
be noted that most of the organocatalysts were prepared
with strenuous procedure, which needed tiresome puri-
fication of chromatography and created the added hur-
dles for industrial production.
Thus, we developed a series of isosteviol-amino acid
conjugates 1 — 3, which could be constructed on
large-scale from natural available Isosteviol and suitable
amino acids with a simple one-pot procedure without
protecting and deprotecting of the amino groups
(Scheme 1). Their catalytic activities and stereoselectiv-
ities on the direct three-component Mannich reaction
with hydroxyacetone as a donor were investigated.
Results and discussion
The catalytic effect of isosteviol-amino acid conju-
gates 1— 3 for asymmetric direct Mannich were inves-
tigated using the reaction of p-nitrobenzaldehyde, ani-
line and hydroxyacetone as a model with 10 mol%
catalysts loading in DMF, the configuration of Mannich
products was determined by NMR data and chiral phase
HPLC analysis comparison with that in the litera-
ture,13,18 and the results were summarized in Table 1.
First, the catalytic activity and stereoselectivity of
L-proline derivative 1b was higher than that of 1a,
which afforded the syn-isomer as main product in 91%
yield with 84∶ 16 dr (syn∶ anti) and 99% ee value
within 5 h (Entry 2). Then, all of the L-threoine deriva-
tives (2a and 2b) and L-serine derivatives (3a and 3b)
afforded the anti-isomer products as main products in
this condition, and the catalyst 3b afforded higher yield
Chiral 1,2-amino alcohols are the common structural
motifs found in a vast array of natural and biologically
active molecules,19 and can be constructed via Mannich
reaction using hydroxyketone as donor molecule. In the
transition state of Mannich reaction, hydroxyketone and
catalysts can form different enamine intermediate based
on different amino acids and affording syn- or anti-
configurational products, respectively.16 The hydropho-
*
E-mail: jctao@zzu.edu.cn
Received April 14, 2011; revised April 29, 2011; accepted May 10, 2011.
Project supported by the National Natural Science Foundation of China (No. 20772113).
Chin. J. Chem. 2011, 29, 1511— 1517 © 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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An et al.
FULL PAPER
Scheme 1 Synthetic route of catalysts 1—
3
Table 1 Catalysts screeninga
was observed in neat reaction (Entry 1), the reactions
could proceed smoothly in some organic solvent. Higher
yields, diastereoselectivities and enantioselectivities
were obtained in N-methyl pyrrolidinone (NMP) or
DMF than those in the other solvents (Entries 5, 6). The
diastereoselectivity was increased somewhat while re-
ducing the catalyst loading to 5 mol% (Entry 10). It
should be noted that the catalyst seems unfavorable in
the chlorinated media, such as methylene chloride or
1,2-dichloroethane, in which poor diastereoselectivities
and enantioselectivities were observed. Then, excellent
diastereoselectivity and enantioselectivity were obtained
when using 0.1 mL hydroxyacetone as ketone donor and
2 mL NMP as solvent (Entry 14).
Entry Catalyst Time/h Yieldb/% dr (syn∶anti)c eec/%
1
2
3
4
5
6
1a
1b
2a
2b
3a
3b
5
5
7
7
7
7
87
91
87
64
89
92
84∶16
84∶16
35∶65
39∶61
9∶91
98 (syn)
99 (syn)
52 (anti)
37 (anti)
93 (anti)
94 (anti)
Then, we extended the scope of aromatic aldehydes
and different aniline under the optimum conditions. In
most cases, the syn-Mannich products were obtained in
good to high yields and excellent stereoselectivities
within 8 h reaction time (Table 3). The rate of reaction
depends on the electronic effect of substituent aniline.
The reaction time of aniline with hydroxyacetone and
various aromatic aldehydes were much shorter than that
of p-anisidine as well as p-methylaniline. Among these,
when using o-chlorobenzaldehyde as acceptor, we
achieved the excellent diastereoselectivity and enanti-
oselectivity within 4 h (Entry 2, dr up to 98∶2 and ee
up to 98%). In the case of p-anisidine, all of the substi-
tuted aldehydes afforded the syn-products with high to
excellent diastereoselectivities and enantioselectivities
(Entries 6—10).
9∶91
a Reaction conditions: p-nitrobenzaldehyde (0.25 mmol, 1 equiv.),
aniline (0.25 mmol, 1 equiv.), cyclohexanone (0.75 mmol, 3
equiv.), and catalyst (10 mol%) in DMF (1 mL) at r.t.; b isolated
yield; c determined by chiral HPLC analysis.
and stereoselectivities (92% yield, 9∶91 dr (syn∶anti)
and 94% ee). Thus, we investigated the direct three-
component Mannich reaction using 1b and 3b as cata-
lysts, respectively.
First, we studied the effect of reaction conditions on
the three-component Mannich reaction with 1b at room
temperature (Table 2). Though poor stereoselectivity
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Chin. J. Chem. 2011, 29, 1511— 1517

Asymmetric One-pot Three-component Mannich Reactions
Table 2 Screening the reaction conditions of hydroxyacetone
with catalyst 1ba
Table 3 Direct asymmetric Mannich reactions with catalyst 1ba
dr (syn∶
Entry R1
R2 Time/h Yieldb/%
eec/%
anti)c
91∶9
98∶2
93∶7
93∶7
＞99∶1
84∶16
89∶11
94∶6
94∶6
97∶3
1
2
3
4
5
6
7
8
9
H
H
H
H
H
4
4
87
87
90
88
82
98
94
56
48
87
97
98
dr (syn∶
Entry Solvent Cat./mol% Time/h Yieldb/%
eec/%
anti)c
o-Cl
p-Cl
p-NO2
1
2
3
4
5
6
7
8
9
—
10
10
10
10
10
10
10
10
10
5
5
24
24
5
93
71
57
88
91
96
76
95
89
90
51
45
90
89
50∶50
85∶15
65∶35
77∶23
84∶16
85∶15
50∶50
76∶24
58∶42
88∶12
84∶16
88∶12
89∶11
93∶7
20
92
4
97
DMSO
3
＞99
EtOH
50
p-Me p-NO2
p-CH3O H
8
89
CH3OH
DMF
88
6
92
5
99
p-CH3O p-F
p-CH3O p-Cl
p-CH3O p-Br
18
18
18
5
91
NMP
5
99
95
ClCH2CH2Cl
THF
5
39
94
5
93
10 p-CH3O p-NO2
a
＞99
CH2Cl2
5
61
Reaction conditions: aromatic aniline (0.25 mmol, 1 equiv.),
aromatic aldehydes (0.25 mmol, 1 equiv.), hydroxyacetone (0.1
mL) and catalyst 1b (5 mol%) in NMP (2 mL) at r.t.; b isolated
yield; c determined by chiral HPLC analysis.
10 NMP
11d NMP
12e NMP
13f NMP
14g NMP
5
99
5
7
98
5
7
99
5
5
99
Table 4 Screening the reaction conditions of hydroxyacetone
with catalyst 3ba
5
6
＞99
a Reaction conditions: aniline (0.25 mmol, 1 equiv.), p-nitroal-
dehyde (0.25 mmol, 1 equiv.), hydroxyacetone (0.2 mL) and
catalyst (1b, 10 mol%) in solvent (1 mL) at r.t.; b isolated yield;
e
f
c determined by chiral HPLC analysis; d 10 ℃; 0 ℃; using 2.0
mL NMP as solvent; g using 2.0 mL NMP as solvent and 0.1 mL
hydroxyacetone as donor.
The effect of reaction conditions on the three-
component Mannich reaction were also tested with
L-threoine derivatives 3b using the model reaction (Ta-
ble 4). It should be noted that the 3b catalyzed Mannich
reactions in different solvent screened afforded the
anti-isomer as main product. High yields with low
stereoselectivities were obtained when using 1,2-di-
chloroethane or toluene as reaction solvent (Entries 1, 2).
Then, we got higher stereoselectivities with strong polar
solvent as reaction media (Entries 3—6). When using
DMF as reaction medium, we obtained the anti-isomer
product in high yield with excellent stereoselectivity
(Entry 6). Both the reaction rate and stereoselectivities
were reduced when decreasing the catalysts loading
(Entries 7, 8). In addition, the reaction rate decreased
obviously when the reaction proceeding under 10 ℃
(Entry 9).
dr (anti∶
Entry Solvent Cat./mol% Time/h Yieldb/%
eec/%
syn)c
1
2
CH2ClCH2Cl
Toluene
NMP
10
10
10
10
10
10
5
7
7
91
93
35
33
76
92
47
36
89
80∶20
73∶27
82∶18
78∶22
76∶24
91∶9
62
39
86
78
75
94
88
84
94
3
7
4
DMSO
EtOH
7
5
7
6
DMF
7
7
DMF
7
87∶13
80∶20
92∶8
8
9d
DMF
2
7
DMF
10
18
a
Reaction conditions: aniline (0.25 mmol, 1 equiv.), p-nitro-
Under the optimized reaction conditions, a variety of
benzaldehydes and aromatic aniline were also investi-
gated with catalyst 3b (Table 5). All the reactions
aldehyde (0.25 mmol, 1 equiv.), hydroxyacetone (0.2 mL) and
catalyst (3b, 10 mol%) in solvent (1 mL) at r.t.; b isolated yield;
c determined by chiral HPLC analysis; d 10 ℃.
Chin. J. Chem. 2011, 29, 1511— 1517
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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An et al.
FULL PAPER
Table 5 Direct asymmetric Mannich reactions with catalyst 3ba
collected on Bruker DPX 400 NMR spectrometer with
TMS as an internal reference. IR spectra were deter-
mined on a Thermo Nicolet IR200 unit. High resolution
mass spectra (HRMS) were obtained on a Waters Mi-
cromass Q-Tof MicroTM instrument using the ESI tech-
nique. Chromatography was performed on silica gel
(200—300 mesh). Melting points were determined us-
ing an XT5A apparatus and are uncorrected. Optical
rotations were determined on a Perkin Elmer 341
polarimeter. Enantiomeric excess was measured by
chiral HPLC at room temperature using Labtech 2006
pump equipped with Labtech UV600 ultra detector with
Chiralpak AD-H (4.6 mm×250 mm).
dr (anti∶
Entry R1
R2 Time/h Yieldb/%
eec/%
syn)c
86∶14
97∶3
76∶24
91∶9
97∶3
94∶6
64∶36
71∶29
95∶5
76∶34
92∶8
1
2
3
4
5
6
7
8
9
H
H
7
7
95
71
97
92
79
93
96
96
99
93
94
88
89
79
94
93
99
69
73
97
79
88
Preparation of chiral catalysts 1a— 3a
H
o-Cl
p-Cl
p-NO2
p-NO2
H
7
Isosteviol (6.36 g, 20 mmol) was dissolved in SOCl2
(20 mL), and the mixture was stirred at room tempera-
ture for 1 h. After evaporating the solvent under vacuum,
amino acid (20 mmol) and CF3COOH (20 mL) were
added. The resulted solution was stirred at room tem-
perature for 2 h. Under cooling with an ice/water bath,
Et2O (40 mL) was added carefully to give a fine white
precipitate that was vacuum-filtered, washed with Et2O
(5 mL×2) and dried at room temperature for 2 h to give
the hydrochloride as a fine white powder. The white
powder was dissolved in 40 mL of warmed 95% EtOH,
and propylene oxide (10 mL) was then added. Stirring
was discontinued and the solution left for crystallization
at room temperature for 7 h. The crystalline product was
vacuum-filtered and dried at room temperature in vacuo
to give product.
H
7
p-Cl
12
12
3
p-Me p-NO2
p-CH3O H
p-CH3O p-F
p-CH3O p-Cl
3
3
10 p-CH3O p-Br
3
11 p-CH3O p-NO2
3
a
Reaction conditions: aromatic aniline (0.25 mmol, 1 equiv.),
aromatic aldehydes (0.25 mmol, 1 equiv.), hydroxyacetone (0.1
mL) and catalyst 3b (10 mol%) in DMF (1 mL) at r.t.; b isolated
yield; c determined by chiral HPLC analysis.
furnished the anti-Mannich products in good-to-excel-
lent yields with up to 97∶3 dr and 99% ee within 3—
12 h. The rate of reaction depends on the electronic ef-
fect of substituent of aniline. With p-anisidine as amino
component, the reactions were completed in only 3 h
(Entries 7—11). Meanwhile, higher yield and stereose-
lectivities were obtained using p-nitrobenzaldehyde as
acceptor (Entries 4—6, 11). Among these, excellent
yield, diastero- and enantioselectivity were obtained
when p-toluidine and p-nitrobenzaldehyde were em-
ployed (Entry 6).
1a: 7.51 g, yield 83%, m.p. 176—178 ℃, [α]D20
－56.7 (c 0.13, CHCl3); 1H NMR (CDCl3, 400 MHz) δ:
5.23 (s, 1H), 4.13 (d, J＝1.68 Hz, 1H), 3.60 (s, 1H),
3.38 (s, 1H), 2.62 (d, J＝20 Hz, 1H), 2.44 (s, 1H), 2.29
(s, 1H), 2.18 (d, J＝12 Hz, 3H), 1.88—1.78 (m, 2H),
1.66—1.38 (m, 10H), 1.18 (s, 3H), 1.12—1.09 (m, 2H),
0.95 (s, 3H), 0.98—0.85 (m, 2H), 0.69 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ: 222.5, 176.5, 173.1, 72.3,
59.7, 57.0, 54.5, 54.1, 49.8, 48.6, 48.4, 43.8, 41.4, 39.6,
39.4, 38.0, 37.5, 37.2, 35.4, 28.9, 21.5, 20.3, 19.8, 19.0,
13.8; IR (KBr)－ν: 3601, 3448, 2955, 2849, 1733, 1654,
1
1149, 1130 cm ; HRMS (ESI) calcd for C25H37NNaO5
[M＋Na]＋ 454.2569, found 454.2570.
Conclusion
20
2a: 7.00 g, yield 86%, m.p. 125—126 ℃, [α]
589
The simple isosteviol-amino acid conjugates 1b and
3b were efficient for the one-pot three-component direct
asymmetric Mannich reactions of hydroxyacetone, and
afforded syn-1,2-amino alcohols with excellent stereo-
selectivities using catalyst 1b (up to 99∶1 dr and
＞99% ee) and anti-1,2-amino alcohols with excellent
stereoselectivities using catalyst 3b (up to 97∶3 dr and
99% ee), respectively.
1
－50.6 (c 0.25, CH3OH); H NMR (DMSO, 400 MHz)
δ: 7.95 (brs, 1H), 2.89 (s, 1H), 2.73 (s, 1H), 2.00 (d, J＝
13.0 Hz, 1H), 1.89—1.85 (m, 1H), 1.78—1.73 (m, 2H),
1.69—1.62 (m, 4H), 1.53—1.50 (m, 1H), 1.40—1.32
(m, 5H), 1.23—1.11 (m, 4H), 1.16 (s, 3H), 1.02—0.87
(m, 3H), 0.92 (s, 3H), 0.73 (s, 3H); 13C NMR (DMSO,
100 MHz) δ: 221.3, 179.2, 162.9, 67.8, 56.6, 54.4, 53.9,
48.4, 48.3, 43.4, 41.2, 39.9, 38.2, 37.2, 36.3, 31.3, 29.3,
22.1, 20.4, 20.3, 19.2, 13.7; IR (KBr) ν: 3418, 2949,
Experimental section
－1
2848, 1735, 1651, 1149＋, 1128 cm ; HRMS (ESI) calcd
All chemicals were used as received unless other-
wise noted. Reagent grade solvents were distilled prior
to use. All reported 1H NMR and 13C NMR spectra were
for C23H36NO5 [M＋H] 406.2593, found 406.2593.
20
3a: 7.21 g, yield 86%, m.p. 122—123 ℃, [α]
589
1
－50.3 (c 0.50, CH3OH); H NMR (DMSO, 400 MHz)
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Chin. J. Chem. 2011, 29, 1511— 1517

Asymmetric One-pot Three-component Mannich Reactions
δ: 5.19 (q, J＝2.8 Hz, 1H), 3.36 (brs, 2H), 3.33 (d, J＝
2.2 Hz, 1H), 2.11 (d, J＝12.7 Hz, 1H), 1.83—1.75 (m,
2H), 1.69—1.59 (m, 5H), 1.51—1.33 (m, 6H), 1.23 (d,
J＝6.4 Hz, 3H), 1.16—1.05 (m, 4H), 1.11 (s, 3H), 0.95
—0.81 (m, 2H), 0.86 (s, 3H), 0.61 (s, 3H); 13C NMR
(DMSO, 100 MHz) δ: 221.7, 175.9, 168.8, 70.1, 57.8,
56.8, 54.3, 53.8, 48.5, 48.4, 44.0, 41.5, 39.7, 38.0, 37.8,
37.2, 29.0, 21.6, 20.5, 20.3, 19.3, 17.2, 13.8; IR (KBr) ν:
38.1, 37.6, 34.2, 29.2, 25.5, 21.5, 21.2, 20.3, 19.3, 17.1,
14.5, 14.1; IR (KBr) ν: 3417, 2940, 2844, 1713, 1635,
－1
1453, 1406, 1228, 1147＋, 1026 cm ; HRMS (ESI) calcd
for C24H40NO5 [M＋H] 422.2906, found 422.2903.
General procedure for the asymmetric Mannich re-
actions of hydroxyacetone (Table 3)
The mixture of aldehydes (0.25 mmol, 1 equiv.),
catalyst 1b (5 mmol%) and aniline (0.25 mmol, 1 equiv.)
in NMP (N-methy1-2-pyrrolidone, 2 mL) was stirred for
1 h at room temperature followed by an addition of hy-
droxyacetone (0.1 mL). After stirring for the corre-
spondingly reaction time at room temperature, the re-
sulting mixture was purified by thin layer chromatogra-
phy on silica gel (petroleum ether/ethyl acetate) to pro-
vide the products.
－1
3412, 2948, 2847, 1734, 1638, 1165, ＋1129 cm ; HRMS
(ESI) calcd for C24H38NO5 [M＋H] 420.2750, found
420.2753.
Preparation of chiral catalysts 1b— 3b
A solution of compounds 1a— 3a (20 mmol) and so-
dium borohydride (1.71g, 30 mmol) in dry ethanol (100
mL) was stirred at 0 ℃ for 2 h. The reaction mixture
was then concentrated under vacuum, and treated with
CHCl3 and H2O. The organic layer was separated and
washed with saturated NaCl aqueous solution. Then the
solvent was dried over anhydrous MgSO4 and evapo-
rated under vacuum to afford crude product. After
re-crystallized in methanol, the catalysts 1b— 3b were
obtained as a white powder.
3-Hydroxy-4-phenyamino-4-phenylbutan-2-one
1H NMR (CDCl3, 400 MHz, syn-diastereomer) δ: 7.40
—7.23 (m, 5H), 7.14—7.07 (m, 2H), 6.71—6.65 (m,
1H), 6.56 (d, J＝7.7 Hz, 2H), 4.99 (d, J＝2.0 Hz), 4.33
(d, J＝2.0 Hz), 2.29 (s, 3H); 13C NMR (CDCl3, 100
MHz, syn-diastereomer) δ: 207.7, 146.2, 139.4, 129.2,
128.6, 127.5, 127.0, 118.0, 113.8, 80.8, 58.3, 25.3; IR
(KBr) ν: 3387, 3054, 294－2, 2857, 1713, 1602, 1503,
1b: 8.31 g, yield 96%, m.p. 167—170 ℃, [α]D20
－50.0 (c 0.12, CH3OH); 1H NMR (CDCl3, 400 MHz) δ:
5.26 (s, 1H), 4.20 (s, 1H), 3.81 (d, J＝5.6 Hz, 2H), 3.30
(d, J＝16.4 Hz, 1H), 2.39—2.30 (m, 2H), 2.14 (d, J＝
16.4 Hz, 1H), 1.74—1.70 (m, 6H), 1.53—1.38 (m, 5H),
1.29—1.23 (m, 2H), 1.17 (s, 3H), 1.07—0.73 (m, 9H),
0.89 (s, 3H), 0.73 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ: 177.0, 80.1, 72.7, 60.6, 57.0, 55.7, 55.0, 50.2, 43.8,
42.5, 42.0, 41.9, 41.6, 40.3, 39.7, 38.1, 37.7, 35.0, 33.7,
28.9, 24.9, 21.7, 20.4, 18.8, 13.8; IR (KBr) ν: 3422,
1
1357, 1099, 751, 694 cm ; HPLC (for syn): Daicel
Chiralpak AD-H, hexanes/i-PrOH, 85/15, flow rate 0.8
mL/min, UV 254 nm, tR(major)＝16.9 min; tR(minor)＝
9.8 min.
3-Hydroxy-4-phenyamino-4-phenylbutan-2-one
1H NMR (CDCl3, 400 MHz, syn-diastereomer) δ: 7.33
—7.23 (m, 2H), 7.25—7.08 (m, 4H), 6.72—6.66 (m,
1H), 6.62 (d, J＝7.7 Hz, 2H), 5.51 (d, J＝1.6 Hz, 1H),
5.39 (d, J＝3.5 Hz, 1H), 4.79 (d, J＝3.5 Hz, 1H), 3.58
(d, J＝1.6 Hz, 1H), 2.21 (s, 3H); 13C NMR (CDCl3, 100
MHz, syn-diastereomer) δ: 207.7, 134.9, 133.2, 146.0,
129.7, 129.3, 129.2, 128.9, 121.2, 118.4, 113.9, 78.4,
55.3, 27.5; IR (KBr) ν: 3448, 3055, 2918, 2836, 1713,
－1
2926, 2847, 1719, 1596, 1438, 1384, 1176, 1150 cm ;
HRMS (ESI) calcd for C25H39NNaO5 [M ＋ Na] ＋
456.2726, found 456.2726.
20
2b: 7.74 g, yield 95%, m.p. 148—149 ℃, [α]
589
－1
1
1601, 1499, 1437, 1357, 1091, 756, 697 cm ; HPLC
－43.3 (c 0.64, CH3OH); H NMR (DMSO, 400 MHz)
(for syn): Daicel Chiralpak AD-H, hexanes/i-PrOH,
85/15, flow rate 1.0 mL/min, UV 254 nm, tR(major)＝
35.7 min; tR(minor)＝10.5 min.
δ: 4.36—4.34 (m, 1H), 4.09—4.05 (m, 1H), 3.66—3.64
(m, 1H), 3.53—3.52 (m, 1H), 2.13 (d, J＝11.6 Hz, 1H),
1.72—1.48 (m, 8H), 1.43—1.39 (m, 2H), 1.32—1.22
(m, 2H), 1.19—1.16 (m, 1H), 1.12 (s, 3H), 1.09—0.91
(m, 6H), 0.81 (s, 3H), 0.65 (s, 3H); 13C NMR (DMSO,
100 MHz) δ: 176.9, 169.4, 78.8, 64.9, 57.1, 56.4, 56.0,
55.5, 53.7, 49.0, 43.7, 43.1, 42.1, 38.0, 37.7, 34.2, 29.0,
25.5, 21.6, 20.3, 19.2, 19.0, 13.6; IR (KBr) ν: 3404,
3-Hydroxy-4-(p-nitrophenyamino)-4-phenylbutan-
2-one 1H NMR (CDCl3, 400 MHz, syn-diastereomer)
δ: 7.34—7.28 (m, 4H), 7.14 (q, J＝7.8 Hz, 2H), 6.70—
6.65 (m, 1H), 6.52 (d, J＝7.9 Hz, 2H), 4.96 (s, 1H),
4.84 (d, J＝3.0 Hz, 1H), 4.63 (d, J＝3.0 Hz, 1H), 4.39
(s, 1H), 2.29 (s, 3H); 13C NMR (CDCl3, 100 MHz,
syn-diastereomer) δ: 207.4, 145.9, 138.1, 133.2, 129.2,
129.0, 128.8, 128.5, 118.3, 113.8, 80.5, 57.7, 25.2; IR
(KBr) ν: 3387, 3052, 2923, 2853, 1713, 1601, 1494,
－1
2938, 2845, 1716, 1637, 1455, 1231, 1175,＋1147 cm ;
HRMS (ESI) calcd for C23H38NO5 [M＋H] 408.2750,
found 408.2752.
20
589
3b: 7.93 g, yield 94%, m.p. 145—146 ℃, [α]
－1
－36.1 (c 0.7, CH3OH); 1H NMR (DMSO, 400 MHz) δ:
5.26 (q, J＝3.4 Hz, 1H), 3.71 (dd, J＝14.6, 4.0 Hz, 1H),
3.43—3.38 (m, 1H), 2.25 (d, J＝12.6 Hz, 1H), 1.96 (brs,
1H), 1.78—1.58 (m, 8H), 1.50—1.44 (m, 2H), 1.38—
1.22 (m, 3H), 1.31 (d, J＝6.4 Hz, 3H), 1.14 (s, 3H), 1.11
—0.96 (m, 5H), 0.87 (s, 3H), 0.93—0.83 (m, 1H), 0.71
(s, 3H); 13C NMR (DMSO, 100 MHz) δ: 175.7, 170.9,
78.8, 69.5, 60.2, 57.8, 57.0, 55.9, 49.0, 43.9, 43.0, 42.1,
1091, 1013, 806, 752, 694 cm ; HPLC (for syn): Dai-
cel Chiralpak AD-H, hexanes/i-PrOH, 85/15, flow rate
0.8 mL/min, UV 254 nm, tR(major)＝15.4 min; tR(minor)
＝11.0 min.
3-Hydroxyl-4-anilino-4-(p-nitrophenyl)butan-2-
one 1H NMR (CDCl3, 400 MHz, syn-diastereomer) δ:
8.20 (d, J＝8.5 Hz, 2H), 7.57 (d, J＝8.5 Hz, 2H), 7.13
—7.08 (m, 2H), 6.72—6.69 (m, 1H), 6.52 (d, J＝8.0 Hz,
Chin. J. Chem. 2011, 29, 1511— 1517
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1515

An et al.
FULL PAPER
－1
2H), 5.11 (s, 1H), 4.98 (d, J＝2.9 Hz, 1H), 4.73 (d, J＝
2.9 Hz, 1H), 4.47 (s, 1H), 2.37 (s, 3H); 13C NMR
(CDCl3, 100 MHz, syn-diastereomer) δ: 206.8, 147.3,
145.2, 129.4, 128.1, 123.9, 118.8, 113.8, 80.0, 57.8, 25.0;
IR (KBr) ν: 3367, 3048, 2932, 2846, 1709, 1612, 1508,
2834, 1661, 1604, 1509, 1246, 1090, 1033, 829 cm ;
HPLC (for syn): Daicel Chiralpak AD-H, hex-
anes/i-PrOH, 85/15, flow rate 1.0 mL/min, UV 254 nm,
tR(major)＝26.1 min; tR(minor)＝19.3 min.
3-Hydroxy-4-(p-methoxyphenyamino)-4-(p-bromo-
phenyl) butan-2-one 1H NMR (CDCl3, 400 MHz,
syn-diastereomer) δ: 7.45 (d, J＝8.2 Hz, 2H), 7.24 (d,
J＝8.2 Hz, 2H), 6.68 (d, J＝8.8 Hz, 2H), 6.47 (d, J＝
8.7 Hz, 2H), 4.87 (d, J＝1.5 Hz, 1H), 4.75 (d, J＝3.0 Hz,
1H), 4.64 (d, J＝3.0 Hz, 1H), 4.38 (d, J＝1.5 Hz, 1H),
3.68 (s, 3H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz,
－1
1339, 1078, 854, 807 cm ; HPLC (for syn): Daicel
Chiralpak AD-H, hexanes/i-PrOH, 85/15, flow rate 0.8
mL/min, UV 254 nm, tR(major)＝27.9 min; tR(minor)＝
24.9 min.
3-Hydroxy-4-(p-methylphenyamino)-4-(p-nitro-
phenylbutan)-2-one 1H NMR (CDCl3, 400 MHz,
syn-diastereomer) δ: 8.17 (d, J＝8.5 Hz, 2H), 7.56 (d,
J＝8.5 Hz, 2H), 6.92—6.89 (m, 2H), 6.43 (d, J＝8.5 Hz,
2H), 5.09 (s, 1H), 4.96 (d, J＝2.8 Hz, 1H), 4.72 (d, J＝
2.8 Hz, 1H), 4.46 (s, 1H), 2.37 (s, 3H), 2.17 (s, 3H); 13C
NMR (CDCl3, 100 MHz, syn-diastereomer) δ: 206.7,
147.5, 145.4, 143.0, 129.9, 128.1, 128.0, 123.8, 113.9,
80.0, 60.4, 58.1, 25.0; IR (KBr) ν: 3336, 3076, 2921,
syn-diastereomer) δ: 207.2, 152.5, 139.7, 138.6, 131.7,
128.9, 121.4, 115.2, 114.8, 80.5, 60.4, 55.6, 25.2; IR
(KBr) ν: 3310, 3062, 2931, 2834, 1662, 1605, 1510,
－1
1247, 1177, 1033, 828 cm ; HPLC (for syn): Daicel
Chiralpak AD-H, hexanes/i-PrOH, 85/15, flow rate 0.8
mL/min, UV 254 nm, tR(major)＝30.6 min; tR(minor)＝
23.1 min.
－1
2843, 1668, 1595, 1514, 1342, 1109, 857, 819 cm ;
3-Hydroxy-4-(p-methoxyphenyamino)-4-(p-nitro-
phenyl) butan-2-one 1H NMR (CDCl3, 400 MHz,
syn-diastereomer) δ: 8.12 (d, J＝8.5 Hz, 2H), 7.55 (d,
J＝8.5 Hz, 2H), 6.66 (d, J＝8.5 Hz, 2H), 6.48 (d, J＝
8.5 Hz, 2H), 5.02 (d, J＝1.5 Hz, 1H), 4.88 (d, J＝3.1 Hz,
1H), 4.68 (d, J＝3.1 Hz, 1H), 4.43 (d, J＝1.5 Hz, 1H),
3.64 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3, 100 MHz,
syn-diastereomer) δ: 206.8, 152.7, 147.5, 145.6, 139.3,
128.2, 123.7, 115.1, 114.9, 80.0, 60.4, 55.5, 25.0; IR
(KBr) ν: 3416, 3064, 2930, 2837, 1658, 1596, 1512,
HPLC (for syn): Daicel Chiralpak AD-H, hex-
anes/i-PrOH, 85/15, flow rate 1.0 mL/min, UV 254 nm,
tR(major)＝45.2 min; tR(minor)＝33.6 min.
3-Hydroxy-4-(p-methoxyphenyamino)-4-phenyl-
butan-2-one 1H NMR (CDCl3, 400 MHz, syn-di-
astereomer) δ: 7.38—7.23 (m, 5H), 6.72—6.66 (m, 2H),
6.54 (d, J＝8.8 Hz, 2H), 4.90 (d, J＝1.9 Hz, 1H), 4.79
(d, J＝3.3 Hz, 1H), 4.66 (d, J＝3.3 Hz, 1H), 4.41 (d, J
＝1.9 Hz, 1H), 3.67 (s, 3H), 2.30 (s, 3H); 13C NMR
(CDCl3, 100 MHz, syn-diastereomer) δ: 207.7, 152.4,
140.2, 139.4, 128.6, 127.5, 127.1, 115.2, 114.8, 80.8,
60.4, 55.6, 25.3; IR (KBr) ν: 3410, 3003, 2931, 2838,
－1
1343, 1247, 833 cm ; HPLC (for syn): Daicel Chiral-
pak AD-H, hexanes/i-PrOH, 85/15, flow rate 1.0
mL/min, UV 254 nm, tR(major)＝47.0 min; tR(minor)＝
45.3 min.
－1
1712, 1604, 1511, 1362, 1246, 1033, 133, 700 cm ;
HPLC (for syn): Daicel Chiralpak AD-H, hex-
anes/i-PrOH, 85/15, flow rate 1.0 mL/min, UV 254 nm,
tR(major)＝21.8 min; tR(minor)＝13.3 min.
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(m, 2H), 7.09—6.94 (m, 2H), 6.48 (d, J＝8.7 Hz, 2H),
4.89 (d, J＝1.8 Hz, 1H), 4.78 (d, J＝3.1 Hz, 1H), 4.65
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diastereomer) δ: 207.3, 163.4, 160.9, 152.5, 139.9,
135.1, 128.6, 115.7, 115.4, 114.8, 80.6, 60.4, 55.6, 25.2;
IR (KBr) ν: 3322, 3068, 2932, 2835, 1663, 1603, 1510,
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Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F.
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－1
1246, 1033, 830 cm ; HPLC (for syn): Daicel Chiral-
Córdova, A.; Notz, W.; Zhong, G. F.; Betancort, J. M.;
Barbas III, C. F. J. Am. Chem. Soc. 2002, 124, 1842.
Notz, W.; Watanabe, S.; Chowdari, N. S.; Zhong, G. F.;
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pak AD-H, hexanes/i-PrOH, 85/15, flow rate 0.8
mL/min, UV 254 nm, tR(major)＝31.1 min; tR(minor)＝
20.7 min.
3-Hydroxy-4-(p-methoxyphenyamino)-4-(p-chloro-
phenyl) butan-2-one 1H NMR (CDCl3, 400 MHz,
syn-diastereomer) δ: 7.28—7.23 (m, 4H), 6.67 (d, J＝
8.8 Hz, 2H), 6.46 (d, J＝8.8 Hz, 2H), 4.88 (d, J＝2.0 Hz,
1H), 4.76 (d, J＝3.4 Hz, 1H), 4.62 (d, J＝3.4 Hz, 1H),
4.36 (d, J＝2.0 Hz, 1H), 3.66 (s, 3H), 2.30 (s, 3H); 13C
NMR (CDCl3, 100 MHz, syn-diastereomer) δ: 207.4,
152.5, 139.8, 138.1, 133.2, 128.7, 128.5, 115.1, 114.8,
80.5, 60.4, 55.6, 25.2; IR (KBr) ν: 3320, 3067, 2931,
9
Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.
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Chin. J. Chem. 2011, 29, 1511— 1517
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1517