Simple and inexpensive threonine-based organocatalysts for the highly diastereo- and enantioselective direct large-scale syn-aldol and anti-Mannich reactions of α-hydroxyacetone

Article abstract of DOI:10.1016/j.tetasy.2011.06.022

Simple and inexpensive threonine-based organocatalysts that promote syn-aldol reactions and three-component asymmetric anti-Mannich reactions of α-hydroxyacetone achieving a respectable level of enantioselectivities are reported. The syn-aldol products co

Full text of DOI:10.1016/j.tetasy.2011.06.022

Tetrahedron: Asymmetry 22 (2011) 1063–1073
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Tetrahedron: Asymmetry
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Simple and inexpensive threonine-based organocatalysts for the highly
diastereo- and enantioselective direct large-scale syn-aldol and
anti-Mannich reactions of a-hydroxyacetone
⇑
Chuanlong Wu, Xiangkai Fu , Shi Li
College of Chemistry and Chemical Engineering Southwest University, Research Institute of Applied Chemistry Southwest University,
The Key Laboratory of Applied Chemistry of Chongqing Municipality, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and inexpensive threonine-based organocatalysts that promote syn-aldol reactions and three-
Received 23 April 2011
Accepted 13 June 2011
Available online 27 July 2011
component asymmetric anti-Mannich reactions of
a-hydroxyacetone achieving a respectable level of
enantioselectivities are reported. The syn-aldol products could be obtained with up to a 99:1 syn/anti
ratio and >99% ee while the anti-Mannich products could be obtained with up to a 96:4 anti/syn ratio
and >99% ee. Catalyst 1c can be used efficiently on a large-scale with the enantioselectivities of the
syn-aldol and anti-Mannich reactions being maintained at the same level, which offers a great possibility
for application in industry.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
synthetically attractive.5 The first example of a direct organocata-
lytic three-component Mannich reaction was reported by List
Chiral 1,2-diols and 1,2-amino alcohols are common structural
motifs found in a vast array of natural and biologically active mol-
ecules.1 Recently, significant efforts has been applied toward the
development of direct catalytic asymmetric approaches to the
construction of these units based on the addition of unmodified
et al.,6 and was followed by the excellent work of several other
groups.7–14 In addition to (S)-proline,5–10 proline-derived tetra-
zoles,11 acylic amino acids and their derivatives,12,15a and chiral
phosphoric acids13 have been developed as enantioselective
organocatalysts for the direct one-pot three-component Mannich
reactions. Although 1,2-amino alcohol and 1,2-diols can be con-
structed via Mannich reactions and aldol reactions of hydroxyke-
tone to imines or aldehydes, hydroxyacetone is seldom used as a
donor in the asymmetric-catalyzed direct Mannich reactions and
aldol reactions.5,11,12,14 Threonine derivatives were developed as
organocatalysts for the direct one-pot three-component asymmet-
ric anti-Mannich reactions and syn-aldol reactions of hydroxyke-
tone to imines or aldehydes and were reported by Barbas, Lu,
and our group.12b,c,15a The main limitation associated with anti-
Mannich reactions and syn-aldol reactions is the requirement of
a high catalyst loading.6,12b,15a This will raise a cost concern when
large amounts of chiral materials are used for the large-scale
synthesis. Therefore, the development of a new type of highly
active organocatalysts with a natural crude chiral pool, simple
preparation procedure, and inexpensive reagents is urgently
needed. In our earlier studies,15 we successfully developed simple
and inexpensive threonine-based organocatalysts for a variety of
reactions (including anti-aldol15b,c and three-component anti-
Mannich15a) that work efficiently in both organic and aqueous
media.
a-hydroxyketone to imines or aldehydes in aldol and Mannich-
type reactions, respectively.2,3 Although the studies of Shibasaki
and Trost have provided routes to both syn-1,2-diols and anti-
1,2-amino alcohols using metal-based catalysis,2 highly enantiose-
lective organocatalytic approaches have remained limited to anti-
1,2-diols and syn-1,2-amino alcohols.3 On the other hand, the aldol
and Mannich reactions are some of the most powerful methods for
the formation of C–C bonds in organic synthesis.3 The classical
aldol and Mannich reactions are highly atom-economic but suffer
from problems with selectivity, notably, with respect to chemo-
and regioselectivity. One of the most difficult challenges is the de-
sign of sustainable organocatalysis processes, which are not only
more economical but also more benign toward the environment
and more practicable both in industry and in practice.4 Stimulated
by this challenge, a great deal of effort is currently being made in
the search for elegant and practical solutions for preparing highly
stereoselective syn-1,2-diols and anti-1,2-amino alcohols. Due
to the atom-economy, the direct one-pot three-component
asymmetric Mannich reactions are some of the most elegant and
Given the success of threonine-based organocatalysts for
anti-Mannich reactions and syn-aldol reactions pioneered by
Barbas and Lu et al.,12b,c we herein report simple, inexpensive,
⇑
Corresponding author. Tel.: +86 23 6825; fax: +86 23 6825 4000.
E-mail addresses: chuanlong666@yahoo.cn (C. Wu), fxk@swu.edu.cn (X. Fu).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.022

1064
C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
gave the best yield, diastereoselectivity and enantioselectivity for
n
O
the syn-aldol reaction (Table 1, entries 3). Meanwhile, lower dia-
stereoselectivities and enantioselectivities (Table 1, entries 6–8)
were obtained using the more sterically hindered O-acylation of
1a
1b
1c
1d
1e
n=2
n=4
n=6
n=8
n=10
O
O
O
CO2H
NH2
CO2H
NH2
L
-threonine 1f–h compared to the less sterically hindered O-acyla-
tion of -threonine 1c. The results suggested that the steric hin-
drance of the O-acylation of -threonine did not have an effect on
L
L
1f
the stereoselectivity. Therefore, we chose threonine-based organo-
catalyst 1c as a catalyst for the syn-aldol reaction.
O
O
Next, NMP (2 equiv H2O) was used as the media for the
syn-aldol reaction of p-nitrobenzaldehyde and hydroxyacetone.
We investigated the above reactions employing different amounts
of threonine-based derivative 1c (Table 2). When using a larger
amount (20 mol %) of organocatalyst 1c, the syn-aldol reaction
was faster but diastereoselectivity was lower (Table 2, entry 1).
The amount was changed to 3 mol %, after 48 h the yield was not
good although the dr and ee values were high (Table 2, entry 5).
Noticeably, when using 5 mol % of catalyst 1c after 36 h, we
obtained a good yield and excellent stereoselectivity (Table 2,
entry 4).
A solvent screen was then performed at 0 °C to identify the best
reaction conditions (Table 3, entries 1–5). Amongst the organic
solvents tested, NMP–water was slightly better in terms of both
diastereoselectivities and enantioselectivity for the syn-aldol reac-
tion of p-nitrobenzaldehyde and hydroxyacetone, 99% ee was
obtained for syn-aldol product 2a (Table 3, entry 3). When the
reaction was performed in DMSO, DMF, CH3CN, or ClCH2CH2Cl,
the enantioselectivity was slightly inferior to the results obtained
in NMP–water. Thus, NMP (2 equiv H2O) was selected as the
solvent for the syn-aldol reaction.
O
O
CO2H
NH2
CO2H
NH2
1g
1h
Figure 1. Threonine-based organocatalysts 1a–h.
and efficient routes to not only highly enantiomerically enriched
anti-1,2-amino alcohols but also to syn-1,2-diols through direct
asymmetric anti-Mannich15a and syn-aldol reactions of unpro-
tected hydroxyacetone catalyzed by threonine-based organocata-
lysts (Fig. 1). We first report that the catalyst 1c can be used in
large-scale anti-Mannich reactions and syn-aldol reactions with
the enantioselectivities being maintained at the same level, which
offers a great possibility for application in industry.
2. Results and discussion
Some aldol reactions have been performed under aqueous
conditions, with the presence of water reported to increase the
reactivity and stereoselectivity.12b Using catalyst 1c (5 mol %) we
investigated the effect of different amounts of water (Table 4).
When in the presence of only 1 equiv of water (Table 4, entry 2),
the syn-aldol product was obtained in good yield with good
diastereo- and excellent enantioselectivity. However, using 2 or
more equivalents of water (Table 4, entries 2–5) a high yield was
observed. In each case, the stereoselectivity was high, but when a
large amount of water (8 equiv) was employed, while we obtained
excellent diastereo- and enantioselectivity, the yield decreased.
Conditions were optimized for the 1c-catalyzed syn-aldol reac-
tions. In order to test the substrate generality of this organocata-
lyzed direct syn-aldol reaction, the reactions of various aromatic
On the basis of our design considerations, we first evaluated a
variety of threonine-based derivatives 1a–h for the syn-aldol reac-
tions of hydroxyacetone in wet NMP to afford syn-aldol product 2a
(Fig. 1 and Table 1). In accordance with our hypothesis, threonine-
based derivatives 1a–h predominantly provided syn-aldol product
2a, but the syn/anti ratios and ee’s did vary. With all catalysts
tested, the carbon-carbon formation with hydroxyacetone selec-
tively occurred at the carbon bearing the hydroxyl group. Amongst
the five synthesized threonine-based derivatives 1a–e by the O-
acylation of L-threonine with acyl chlorides, it was found that the
chain length (n) dramatically affected the yields and the enantiose-
lectivities for the syn-aldol reaction. Neither very long (n = 8, 10)
nor very short carbon chains (n = 2, 4) were effective; the threo-
nine-based derivative 1c containing the n-octanoic group (n = 6)
Table 1
Evaluation of catalysts for the syn-aldol reactionsa
O
OH
O
O
Cat. 1 (20 mol%)
+
H
NMP (2 equiv H2O)
0 °C
OH
syn-2a
OH
NO2
NO2
Entry
Cat.
Time (h)
Yieldb (%)
dr (syn:anti)c
eed (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
36
24
24
36
36
36
24
24
89
91
95
90
85
83
91
92
8:1
7:3
6:1
7:1
3:1
4:1
5:1
5:1
80
84
98
84
70
80
89
93
1g
1h
a
b
c
The reaction was performed with p-nitrobenzaldehyde (1 mmol), hydroxyacetone (3 mmol), and catalyst (0.2 mmol) in NMP–water (1 mL) at 0 °C.
Isolated yield after chromatography on silica gel.
The anti to syn ratio was determined by 1H NMR analysis of the crude product.
Determined by chiral HPLC analysis (AD-H).
d

C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
1065
Table 2
Effects of catalyst loading on the syn-aldol reactiona
O
OH
O
O
Cat. 1c (X mol%)
+
H
NMP (2 equiv H2O)
0 °C
OH
syn-2a
OH
NO2
NO2
Time (h)
Entry
Catalyst (mol %)
Yieldb (%)
dr (syn:anti)c
eed (%)
1
2
3
4
5
20
15
10
5
24
24
36
36
48
95
92
94
94
83
6:1
20:1
49:1
49:1
19:1
98
98
99
99
93
3
a
b
c
The reaction was performed with p-nitrobenzaldehyde (1 mmol), hydroxyacetone (3 mmol) and catalyst (see Table 2) in NMP–water (1 mL) at 0 °C.
Isolated yield after chromatography on silica gel.
The anti to syn ratio was determined by 1H NMR analysis of the crude product.
Determined by chiral HPLC analysis (AD-H).
d
Table 3
Effects of solvent on the syn-aldol reactiona
O
O
O
OH
Cat. 1c (5 mol%)
+
H
solvent, 0 °C, 36h
OH
OH
syn-2a
NO2
NO2
Entry
Solvent
Yieldb (%)
dr (syn:anti)c
eed (%)
1
2
3
4
5
DMSO
DMF
NMP (2 equiv H2O)
CH3CN
91
89
94
80
85
4:1
8:1
49:1
4:1
78
80
99
80
90
ClCH2CH2Cl
4:1
a
b
c
The reaction was performed with p-nitrobenzaldehyde (1 mmol), hydroxyacetone (3 mmol) and catalyst (0.05 mmol) in solvent (1 mL, see Table 3) 0 °C.
Isolated yield after chromatography on silica gel.
The anti to syn ratio was determined by 1H NMR analysis of the crude product.
Determined by chiral HPLC analysis (AD-H).
d
Table 4
Effects of the amount of water on the syn-aldol reactionsa
O
O
OH
O
Cat. 1c (5 mol%)
+
H
NMP-H2O, 0 °C, 36h
OH
OH
syn-2a
dr (syn:anti)c
NO2
NO2
Entry
Water (equiv)
Yieldb (%)
eed (%)
1
2
3
4
5
0
1
2
4
8
89
90
94
92
85
30:1
38:1
49:1
44:1
40:1
90
92
99
97
97
a
b
c
The reaction was performed with p-nitrobenzaldehyde (1 mmol), hydroxyacetone (3 mmol) and catalyst (0.05 mmol) in NMP–water (see Table 4) 0 °C.
Isolated yield after chromatography on silica gel.
The anti to syn ratio was determined by 1H NMR analysis of the crude product.
Determined by chiral HPLC analysis (AD-H).
d
aldehydes with hydroxyacetone were studied. The results are sum-
marized in Table 5. It can be seen that a wide range of aromatic
aldehydes can effectively participate in the syn-aldol reactions. In
general, the syn-aldol reaction between hydroxyacetone and
aromatic aldehydes bearing electron-withdrawing substituents
furnished b-hydroxy carbonyl aldol products in good yields
p-nitrobenzaldehyde and m-nitrobenzaldehyde (Table 5, entries 1
and 2, up to 99% ee). In contrast, longer reaction times (96 h) were
required for aromatic aldehydes containing an electron-donating
group to give comparatively lower yields (62–72%) (Table 5, entries
11, 12). This can be explained by the fact that the electron-with-
drawing groups enhance the electrophilicity of the carbonyl car-
bons in aldehydes which facilitates the reaction, while electron-
donating groups lessen the electrophilicity. Moreover, the direct
(80–96%)
and
excellent
enantioselectivities
(92–>99%)
within 36–72 h (Table 5, entries 1–10), especially the

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C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
Table 5
Scope of the organocatalyzed direct syn-aldol reactions under optimal conditionsa
O
O
O
OH
Cat. 1c (5 mol-%)
+
H
R2
R2
NMP(2 equiv H2O)
0 °C
R1
OH
R1
OH
2a-p
b
Entry
Product (R)
Time (h)
Yield (%)
dr (syn:anti)c
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a (R1 = H, R2 = 4-NO2)
2b (R1 = H, R2 = 3-NO2)
2c (R1 = H, R2 = 2-NO2)
2d (R1 = H, R2 = 4-CN)
2e (R1 = H, R2 = 4-Cl)
2f (R1 = H, R2 = 2-Cl)
2g (R1 = H, R2 = 4-Br)
2h (R1 = H, R2 = 3-Br)
2i (R1 = H, R2 = 2-Br)
2j (R1 = H, R2 = 4-F)
36
36
36
72
72
72
72
72
72
72
96
96
96
96
96
30
94
95
94
96
84
80
85
82
81
83
72
62
75
73
56
96
49:1
32:1
24:1
49:1
6:1
32:1
6:1
4:1
16:1
6:1
4:1
4:1
9:1
99
99
98
>99
95
96
97
93
96
92
96
95
97
94
90
99
2k (R1 = H, R2 = 4-MeO)
2l (R1 = H, R2 = 4-CH3)
2m (R1 = H, R2 = 1-naphthyl)
2n (R1 = H, R2 = 2-naphthyl)
2o (R1 = H, R2 = H)
6:1
4:1
32:1
2p (R1 = OH, R2 = 4-NO2)
a
b
c
The reaction was carried out using aldehyde (1.0 mmol), hydroxyacetone (3 mmol) and catalyst 1c (0.05 mmol) in NMP–water (1 mL) at 0 °C.
Isolated yield after chromatography on silica gel.
The anti to syn ratio was determined by 1H NMR analysis of the crude product.
Determined by chiral HPLC analysis (AD-H, OD-H or OJ-H).
d
syn-aldol reaction of neutral aromatic aldehydes catalyzed by cat-
alyst 1c also afforded the products in high enantioselectivities and
diastereoselectivities (Table 5, entries 13–15). Next, the direct syn-
aldol reaction of dihydroxyacetone with 4-nitrobenzaldehyde
afforded the corresponding product 2p with excellent enantiose-
lectivity (99% ee for syn-isomer) and diastereoselectivity (32:1
syn/anti) (Table 5, entry 16). All reactions of hydroxyacetone or
dihydroxyacetone with aromatic aldehydes provided the corre-
sponding products with excellent enantioselectivities (90–99% ee
for syn-isomers) and good diastereoselectivities (syn/anti 4:1 to
49:1) (Table 5, entries 1–16).
We further investigated threonine-based organocatalyst 1c as a
catalyst in the three-component anti-Mannich reactions between
aromatic aldehydes, aniline, and hydroxyacetone. The catalytic
results are summarized in Table 6. When using a larger amount
(20 mol %) of organocatalyst 1c, the anti-Mannich reaction was
Table 6
The three-component direct asymmetric anti-Mannich reactions of different aldehydesa
R2
NH2
O
CHO
O
HN
Cat. 1c (20 mol-%)
+
R2
+
R1
R1
NMP, 0 °C, 4-24h
OH
OH
3a-o
Entry
Product (R1)
Time (h)
Yieldb (%)
dr (anti:syn)c
eed (%)
1
2e
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3a (R1 = 4-NO2; R2 = 4-OMe)
3a (R1 = 4-NO2; R2 = 4-OMe)
3b (R1 = 3-NO2; R2 = 4-OMe)
3c (R1 = 2-NO2; R2 = 4-OMe)
3d (R1 = 4-CN; R2 = 4-OMe)
3e (R1 = 4-F; R2 = 4-OMe)
3f (R1 = 4-Cl; R2 = 4-OMe)
3g (R1 = 2-Cl; R2 = 4-OMe)
3h (R1 = 4-Br; R2 = 4-OMe)
3i (R1 = H; R2 = 4-OMe)
4
4
4
4
4
8
8
8
8
12
12
4
5
5
92
80
93
90
91
92
90
87
90
75
78
91
93
95
95
89
11.5:1
3:1
4:1
6:1
4:1
1.3:1
4:1
8:1
9:1
1:1
98
86
90
91
>99
94
96
97
98
70
76
99
96
96
95
98
3j (R1 = 4-OMe; R2 = 4-OMe)
3k (R1 = 4-NO2; R2 = 3-MeO)
3l (R1 = 4-NO2; R2 = 4-Me)
3m (R1 = 4-NO2; R2 = 2,4-Me2)
3n (R1 = 4-NO2; R2 = 4-Cl)
3o (R1 = 4-NO2; R2 = H)
2:1
>10:1
>13:1
24:1
24:1
9:1
4
10
a
b
c
The reaction was performed with aldehydes (1.1 mmol), hydroxyacetone (3 mmol), aniline (1 mmol), and catalyst1c (0.2 mmol) in NMP (3 mL) at 0 °C.
Isolated yield.
The anti to syn ratio was determined by 1H NMR analysis of the crude product.
Determined by chiral HPLC analysis (AD-H).
The catalyst loading was 10 mol %.
d
e

C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
1067
O
H
NH2
O
PMP
O
HN
Cat. 1c (4.9 g, 20 mol-%)
+
+
OH
NMP (300 mL), 0 °C, 4h
OH
3a
NO2
OMe
NO2
22.224 g
(3 equiv)
16.623 g
(1.1 equiv)
12.315 g
(1 equiv)
29.731 grams prepared
90% yield, 97% ee, 11:1 dr
Figure 2. Large-scale example of enantioselective anti-Mannich reaction.
faster, the diastereoselectivity and enantioselectivity were higher
than the other case (10 mol %) (Table 6, entries 1 and 2). Using
the optimized conditions, the direct anti-Mannich reaction in N-
methylpyrrolidone (NMP) catalyzed by catalyst 1c was extended
to a series of aromatic aldehydes to explore the generality of this
catalytic system. It can be seen that a wide range of aromatic alde-
hydes can effectively participate in the reaction. In general, the
reaction between hydroxyacetone, 4-methoxyaniline, and aro-
matic aldehydes bearing electron-withdrawing substituents fur-
nished chiral 1,2-amino alcohols in excellent yields (87–92%), up
to 99% ee (anti-isomer) and dr (anti/syn) values ranging from 1.2/
1 to12/1 within 4–8 h (Table 6, entries 1–8), Moreover, the Man-
nich reactions of neutral and electron rich aromatic aldehydes cat-
alyzed by the catalyst 1c afforded the products in moderate
enantioselectivities (70–76% ee) and diastereoselectivities (anti/
syn = 1.3/1 to 2/1) (Table 6, entries 9, 10). The stereochemical out-
come depended significantly on the electronic properties of the
substituent groups on benzaldehydes. The electron-withdrawing
groups had a positive effect on the enantioselectivities (Table 6,
entries 1–10). In addition, different aniline components were also
investigated (Table 6, entries 11–16); all of the selected aromatic
amines furnished Mannich products in good yields (89–95%) with
excellent diastereoselectivities (anti/syn = 9/1 to 24/1) and enanti-
oselectivities (95–98% ee).
threonine-based organocatalyst 1c was required to furnish the
syn-aldol products in excellent diastereoselectivity (up to 99:1
syn/anti) and enantioselectivity (>99% for syn-isomers). Notably,
these organocatalyzed direct asymmetric anti-Mannich and syn-
aldol reactions can be performed on a large-scale with the enanti-
oselectivity being maintained at the same level, which offers a
great possibility for application in industry.
4. Experimental
4.1. General
All reagents were commercial products. The reactions were
monitored by TLC (thin layer chromatography). The column and
preparative TLC purification were carried out using silica gel. Flash
column chromatography was performed on silica gel (200–300
mesh). NMR spectra were recorded on a Bruker Avance 300 spec-
trometer at ambient temperature with tetramethylsilane (TMS)
as an internal standard. IR spectra were recorded on a Bruker Ten-
ser 27 FTIR Spectrometer. Melting points were determined by dif-
ferential scanning calorimetry (TAQ100) at a heating rate of 10 °C/
min under an Ar atmosphere. Mass spectra (MS) were measured
with a Bruker HCT Mass Spectrometer. Analytical high perfor-
mance liquid chromatography (HPLC) was carried out on Agilent
1200 instrument using Chiralpak AD (4.6 mm ꢀ 250 mm), Chiralcel
OD-H (4.6 mm ꢀ 250 mm), or Chiralcel OJ-H (4.6 mm ꢀ 250 mm)
columns. Optical rotations were measured on a JASCO P-1010
Polarimeter at k = 589 nm.
We first performed
a large-scale asymmetric direct anti-
Mannich reaction with 110 mmol of p-benzaldehydes, 4-methoxy-
aniline (100 mmol), and 3 equiv of hydroxyacetone (Fig. 2) using a
500 mL round-bottomed flask. Although the diastereoselectivity
and enantioselectivity (88% yield, 97% ee, 98:1 dr) were main-
tained at the same level for the large-scale reaction, the main
limitation associated with anti-Mannich reaction is the require-
ment of a high catalyst loading of 1c (4.9 g, 20 mol %). This will
raise a cost concern when large amounts of chiral materials are
used for a large-scale synthesis in practical applications.
We further performed large-scale asymmetric direct syn-aldol
reactions with 100 mmol of aromatic aldehydes and 3 equiv of
hydroxyacetone using a 500 mL round-bottomed flask. The only
catalyst loading of 5 mol % 1c as in the experimental scale was
used. The large-scale experiments can be easily carried out using
the same procedure as for the experimental scale reactions. As
can be seen from the results summarized in Table 7, delightfully,
the enantioselectivity maintained at the same level for the large-
scale reactions.
4.2. Typical experimental procedure for the preparation of the
O-acylation threonine organocatalysts 1a–h15,16
A 500 mL round-bottomed flask was charged with CF3CO2H
(120 mL) and placed in an ice/water bath. Powdered threonine
(250 mmol) was added in small portions with vigorous stirring to
give a viscous solution (leaving some small pieces of undissolved
material). The reaction mixture was stirred for 15 min, and then re-
moved from the ice/water bath. After 5 min of stirring, acyl chlo-
ride (375 mmol) was added in one portion. The reaction flask
was fitted with a loose glass stopper, and the reaction mixture
was stirred at room temperature without any external tempera-
ture adjustment for 12 h, giving a clear and colorless solution.
The reaction flask was then cooled in an ice/water bath, and Et2O
(360 mL) was added under vigorous stirring over a period of
20 min, slowly at first. The resulting white suspension was stirred
at 0 °C for 15 min, and then filtered by vacuum. The crystals were
washed with two portions of Et2O and dried at room temperature
for 23 h in a ventilated hood to give the O-acylation threonine
hydrochloride. This essentially pure material could be used for
the next step. The O-acylation threonine hydrochloride was
dissolved in water, and to it was added an equivalent amount of
triethylethanamine (Et3N). The resulting white suspension was
stirred at room temperature for 10 min, and then filtered by
3. Conclusion
In conclusion, we have developed threonine-based organocata-
lysts, which efficiently catalyze the one-pot three-component
anti-Mannich reactions of unprotected hydroxyacetone with high
diastereo- and enantioselectivities in NMP. These catalysts also
efficiently and selectively catalyze syn-aldol reactions of
unprotected hydroxyacetone with excellent diastereo- and enanti-
oselectivities in NMP–water. Furthermore, only 5 mol
% of

1068
C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
Table 7
Large-scale asymmetric syn-aldol reactionsa
O
O
O
OH
catalyst 1c (5 mol%)
+
H
X
X
OH
NMP (2 equiv H2O), 0 °C
OH
Entry
1
Product
Time (h)
Yieldb (%)
dr (syn:anti)c
eed (%)
O
OH
36
72
93
95
99:1
99:1
98
OH
NO2
CN
2a
OH
O
O
2
3
>99
OH
OH
2d
OH
72
84
5:1
94
Cl
2e
O
O
OH
4
5
72
96
85
72
6:1
4:1
96
96
OH
OH
Br
2g
OH
OMe
2k
OH
O
O
6
7
96
96
75
57
9:1
6:1
97
90
OH
OH
2m
OH
2o
a
b
c
The reaction was carried out using aldehyde (100 mmol), hydroxyacetone (300 mmol) and catalyst (5 mmol) in NMP–water (100 mL) at 0 °C.
Isolated yield after chromatography on silica gel.
The anti to syn ratio was determined by 1H NMR analysis of the crude product.
Determined by chiral HPLC analysis (AD-H and OD-H).
d
vacuum. The white crystals were washed with two portions of H2O
and dried to give O-acylation threonine-based organocatalysts 1a–
h. This essentially pure material was used for the next step without
further purification
4.2.2. (2S,3R)-O-(n-Hexanoyl)-L-threonine 1b
White solid; 61.38 g, yield: 97%; mp: 126–127 °C; ½a D20
ꢁ
¼ þ15:0
(c 1, MeOH). 1H NMR (300 MHz, DMSO-d6) d = 0.84–0.88 (m, 3H),
1.05–1.26(m, 4H), 1.32–1.34 (d, J = 6.5 Hz, 3H), 1.45–1.60 (m,
2H), 2.27–2.32 (m, 2H), 4.13 (d, J = 2.7 Hz, 1H), 5.25–5.28 (dp,
J = 3.6 Hz and 6.0 Hz, 1H)ppm; 13C NMR (75 MHz, DMSO-d6)
d = 13.9, 16.7, 21.8, 24.0, 30.6, 33.4, 55.4, 67.7, 168.5, 171.9 ppm.
MS (ESI) m/z calcd for (C10H19NO4) 217.13. Found: 217.51. IR
4.2.1. (2S,3R)-O-(n-Butyl)-L-threonine 1a
White solid; 51.17 g, yield: 96%; mp: 120–121 °C; ½a D20
¼ þ16:1
ꢁ
(c 1, MeOH); 1H NMR (300 MHz, DMSO-d6) d = 0.84–0.92 (m, 3H),
1.32–1.34 (d, J = 6.5 Hz, 3H), 1.45–1.60 (m, 2H), 2.26–2.31 (m,
2H), 4.13 (d, J = 2.7 Hz, 1H), 5.26–5.29 (dp, J = 3.5 Hz and 6.2 Hz,
1H) ppm. 13C NMR (75 MHz, DMSO-d6) d = 13.4, 16.7, 17.9, 35.4,
55.4, 67.7, 168.4, 171.7 ppm. MS (ESI) m/z calcd for (C8H15NO4)
(KBr):
m
2959, 1759, 1737, 1413, 1340, 1166, 1125, 1057, 783,
.
715 cmꢂ1
4.2.3. (2S,3R)-O-(n-Octanoyl)-L-threonine 1c
189.10. Found: 189.51. IR (KBr):
m
2968, 1754, 1737, 1588, 1493,
White solid; 66.77 g, yield: 95%; mp: 127–128 °C; ½a D20
¼ þ13:2
ꢁ
1415, 1167, 1124, 1056, 747, 709 cmꢂ1
.
(c 1, MeOH); 1H NMR (300 MHz, DMSO-d6) d = 0.86–0.90 (m, 3H),

C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
1069
1.27 (br s, 8H), 1.34–1.36 (d, J = 6.6 Hz, 3H), 1.51–1.55 (m, 2H),
4.3. General procedure for catalytic asymmetric syn-aldol
2.29–2.34 (m, 2H), 4.15 (d, J = 2.7 Hz, 1H), 5.27–5.30 (dp,
J = 3.6 Hz and 6.0 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6)
d = 14.0, 16.7, 22.1, 24.3, 28.4, 31.2, 33.5, 55.4, 67.6, 168.5,
171.8 ppm. MS (ESI) m/z calcd for (C12H23NO4) 245.16. Found:
reactions using 1c as a catalyst
To a solution of the aldehyde (1 mmol, 1 equiv) and catalyst 1c
(0.05 mmol) in NMP (2 equiv water) was added hydroxyacetone or
dihydroxyacetone (3 mmol, 3 equiv). The resulting reaction mix-
ture was stirred at room temperature until the aldehyde was con-
sumed as monitored by TLC (30–96 h). The reaction mixture was
diluted with ethyl acetate (5 mL) and poured into a half saturated
NH4Cl solution. The mixture was extracted with ethyl acetate and
the organic layers were combined and washed with brine, dried
(Na2SO4), concentrated, and purified by flash column chromatogra-
phy (mixtures of hexanes/ethyl acetate) to afford the desired aldol
products 2a–p.
245.56. IR (KBr):
m 2957, 1758, 1737, 1413, 1383, 1208, 1164,
1122, 1055, 789, 635 cmꢂ1
.
4.2.4. (2S,3R)-O-(n-Decanoyl)-L-threonine 1d
White solid; 74.20 g, yield: 96%; mp: 128–129 °C; ½a D20
¼ þ13:0
ꢁ
(c 1, MeOH). 1H NMR (300 MHz, DMSO-d6) d = 0.84–0.86 (m, 3H),
1.24 (br s, 12H), 1.32–1.34 (d, J = 6.3 Hz, 3H), 1.40–1.42 (m, 2H),
2.27–2.31 (m, 2H), 4.15 (d, J = 2.7 Hz, 1H), 5.26–5.27 (dp,
J = 3.6 Hz and 6.0 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6)
d = 14.0, 16.7, 22.2, 24.3, 28.5, 28.8, 28.8, 28.9, 31.4, 33.5, 55.4,
67.7, 168.5, 171.8 ppm. MS (ESI) m/z calcd for (C14H27NO4)
4.3.1. (3R,4S)-3,4-Dihydroxy-4-(4-nitrophenyl) butan-2-one
2a12b
273.19. Found: 273.55. IR (KBr):
m
= 2923, 2854, 1753, 1412,
.
Yield 211.7 mg (0.94 mmol, 94%), syn:anti = 49:1, enantiomeric
excess: 99% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 80:20), 20 °C, 254 1 nm, 0.8 mL/min; major enantiomer
tR = 21.7 min, minor enantiomer tR = 16.2 min. 1H NMR (300 MHz,
CDCl3) d = 2.36 (s, 3H, CH3), 2.68 (d, J = 8.1 Hz, 1H), 3.71 (d,
J = 4.6 Hz, 1H), 4.40–4.42 (m, 1H), 5.20–5.22 (m, 1H), 7.60–7.63
(m, 2H), 8.24–8.27 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d = 27.0, 74.4, 82.0, 124.0, 128.6, 148.5, 150.8, 211.6 ppm.
1353, 1159, 1141, 1076, 744, 705 cmꢂ1
4.2.5. (2S,3R)-O-(n-Dodecanoyl)-L-threonine 1e
White solid; 79.24 g, yield: 94%; mp: 127–128 °C; ½a D20
¼
ꢁ
þ11:6 (c 1, MeOH). 1H NMR (300 MHz, DMSO-d6) d = 0.84–0.86
(m, 3H), 1.24 (br s, 16H), 1.31–1.33 (d, J = 6.6 Hz, 3H), 1.39–
1.41 (m, 2H), 2.26–2.31 (m, 2H), 4.13 (d, J = 2.6 Hz, 1H),
5.25–5.28 (dq, J = 3.6 Hz and 6.3 Hz, 1H) ppm; 13C NMR
(75 MHz, DMSO-d6) d = 14.1, 16.8, 22.3, 24.4, 28.5, 28.8, 28.9,
29.0, 29.2, 31.5, 33.5, 55.5, 67.7, 168.6, 171.9 ppm. MS (ESI) m/
4.3.2. (3R,4S)-3,4-Dihydroxy-4-(3-nitrophenyl) butan-2-one 2b3j
Yield 213.9 mg (0.95 mmol, 95%), syn:anti = 32:1, enantiomeric
excess: 99% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 85:15), 20 °C, 254 nm, 1.0 mL/min; major enantiomer tR =
20.99 min, minor enantiomer tR = 16.00 min. 1H NMR (300 MHz,
CDCl3) d = 2.36 (s, 3H), 2.70 (d, J = 8.2 Hz, 1H), 3.74–3.75 (m, 1H),
4.42–4.47 (m, 1H), 5.21–5.24 (m, 1H), 7.56–7.60 (m, 1H), 7.77–
7.79 (m, 1H), 8.18–8.21 (m, 1H), 8.31–8.33 (m, 1H) ppm. 13C
NMR (75 Hz, CDCl3) d = 26.0, 72.8, 80.0, 121.4, 123.1, 129.6,
132.4, 142.5, 148.5, 206.9 ppm.
z
m
calcd for (C16H31NO4) 301.23. Found: 301.59. IR (KBr):
= 2922, 2852, 1753, 1717, 1412, 1353, 1159, 1141, 1076, 744,
705 cmꢂ1
.
4.2.6. (2S,3R)-O-(Benzoyloxy)-L-threonine 1f
White microcrystals, yield 50.78 g (227.5 mmol, 91 %); mp 144–
145 °C; ½a 2D0
ꢁ
¼ ꢂ12:8 (c 1.02, MeOH). 1H NMR (300 MHz, DMSO-
d6): d = 1.46–1.48 (d, 3J = 6.6 Hz, 3H, CH3), 4.35 (br s, 1H, NCH),
5.55–5.58 ((dq, 3J = 3.0 Hz and 6.5 Hz, 1H, 3-H, OCH), 7.52–
7.57(m, 2H, Ph–H), 7.67–7.71(m, 1H, Ph–H), 8.10–8.13(m, 2H,
Ph–H) ppm. 13C NMR (75 MHz, DMSO): d = 16.7, 55.6, 68.9, 128.7,
129.0, 129.9, 133.9, 164.6, 168.5 ppm. MS (ESI) m/z calcd for
4.3.3. (3R,4S)-3, 4-Dihydroxy-4-(2-nitrophenyl) butan-2-one 2c3j
Yield 211.7 mg (0.94 mmol, 94%), syn:anti = 24:1, enantiomeric
excess: 98% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak OJ-H column (hexane/2-propa-
nol = 80:20), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 30.3 min, minor enantiomer tR = 35.8 min. 1H NMR (300 MHz,
CDCl3) d = 2.51 (s, 3H), 4.55–4.56 (m, 1H), 5.89 (m, 1H), 7.48–
7.53 (m, 1H), 7.70–7.74 (m, 1H), 7.79–7.81 (m, 1H), 8.09–8.11
(m, 1H) ppm. 13C NMR (75 MHz, CDCl3) d = 25.2, 68.7, 78.9,
124.9, 128.8, 129.3, 33.9, 137.1, 147.0, 207.2 ppm.
(C11H13NO4) 223.23. Found: 223.47. IR (KBr):
m = 2985, 1759,
1716, 1650, 1602, 1586, 1493, 1415, 1157 cmꢂ1
.
4.2.7. (2S,3R)-O-(Cyclohexylcarbonyl)-L-threonine 1g
White microcrystals, yield 51.64 g (225 mmol, 90%); mp
97–100 °C;
½
a 2D0
ꢁ
¼ þ15:7 (c 1.1, MeOH). 1H NMR (300 MHz,
DMSO-d6): d = 1.27–1.38 (m, 8H, cyclo–CH2), 1.42–1.44 (d,
3J = 6.6 Hz, 3H, CH3), 1.84–1.88 (m, 2H, cyclo–CH2), 2.30–2.38 (m,
1H, cyclo–CH2), 4.22 (br s, 1H, NCH), 5.30–5.33 ((dq, 3J = 3.2 Hz
and 6.5 Hz, 1H, 3-H, OCH) ppm. 13C NMR (75 MHz, DMSO-d6):
d = 16.9, 25.1, 25.2, 25.7, 28.6, 28.7, 42.4, 55.8, 67.9,
168.8, 174.2 ppm. MS (ESI) m/z calcd for (C11H19NO4) 229.27.
4.3.4. 4-(3R,4S)-(1,2-Dihydroxy-3-oxobutyl) benzonitrile 2d3j,12b
Yield 197.0 mg (0.96 mmol, 96%), syn:anti = 49:1, enantiomeric
excess: >99% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 80:20), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 23.4 min, minor enantiomer tR = 26.3 min. 1H NMR (300 MHz,
CDCl3) d = 2.34 (s, 3H), 2.72 (d, J = 8.0 Hz, 1H), 3.71 (d, J = 4.6 Hz,
1H), 4.38–4.39 (m, 1H), 5.13–5.16 (m, 1H), 7.54–7.56 (m, 2H),
7.67–7.70 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3) d = 27.0, 74.6,
81.9, 111.8, 119.9, 128.6, 132.9, 149.0, 211.6 ppm.
Found: 229.50. IR (KBr):
m = 3026, 2947, 2929, 2857, 1735,
1629 cmꢂ1
.
4.2.8. (2S,3R)-O-(1-Adamantylcarbonyl)-L-threonine 1h
White microcrystals, yield 63.34 g (225 mmol, 90%); mp 97–
100 °C; ½a 2D0
ꢁ
¼ þ5:4 (c 1.2, MeOH). 1H NMR (300 MHz, DMSO-d6):
d = 1.28–1.30 (d, 3J = 6.6 Hz, 3H, CH3), 1.66 (m, 6H, cyclo–CH2),
1.81 (m, 6H, cyclo–CH2), 1.95 (m, 3H, cyclo–CH), 4.19 (br s, 1H,
NCH), 5.24–5.27 ((dq, 3J = 2.9 Hz and 6.6 Hz, 1H, 3-H, OCH) ppm.
13C NMR (75 MHz, D DMSO-d6): d = 15.6, 16.6, 27.7, 36.3, 38.2,
40.5, 55.8, 65.3, 67.8, 168.8, 175.6 ppm. MS (ESI) m/z calcd for
4.3.5. (3R,4S)-4-(4-Chlorophenyl)-3,4-dihydroxybutan-2-one
2e3j
Yield 171.7 mg (0.80 mmol, 80%), syn:anti = 6:1, enantiomeric
excess: 95% of syn diastereomer; Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/
(C15H23NO4) 281.35. Found: 281.52. IR (KBr):
m = 3026, 2968,
1758, 1726, 1601, 1575, 1493, 1415, 1157 cmꢂ1
.

1070
C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
2-propanol = 90:10), 20 °C, 220 nm, 1.0 mL/min; major syn enantio-
mer tR = 45.1 min, minor syn enantiomer tR = 35.2 min. 1H NMR
(300 MHz, CD3OD) d = 2.26 (s, 3H), 4.20 (d, J = 2.74 Hz, 1H). 5.06 (d,
J = 2.74 Hz, 1H), 7.31–7.43 (m, 4H) ppm. 13C NMR (75 MHz, CD3OD)
d = 27.1, 74.6, 82.1, 129.1, 129.2, 134.0, 141.7, 211.9 ppm.
(m, 1H), 7.37–7.40 (m, 1H), 7.53–7.55 (m, 1H), 7.60–7.78 (m, 1H)
ppm. 13C NMR (75 MHz, CDCl3) d = 27.5, 67.8, 79.6, 115.3, 124.4,
127.8, 128.2, 129.8, 159.4, 207.2 ppm.
4.3.11. (3R,4S)-4-(4-Methoxy-phenyl)-3,4-dihydroxybutan-2-
one 2k3j
4.3.6. (3R,4S)-4-(2-Chlorophenyl)-3,4-dihydroxybutan-2-one
2f3j
Yield 151.4 mg (0.72 mmol, 72%), syn:anti = 4:1, enantiomeric
excess: 96% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 230 nm, 0.8 mL/min; major syn enantiomer
tR = 34.3 min, minor syn enantiomer tR = 27.6 min. 1H NMR
(300 MHz, CD3OD) d = 2.23 (s, 3H), 3.77 (s, 3H), 4.18 (d,
J = 3.29 Hz, 1H), 4.95 (d, J = 3.57 Hz, 1H), 6.86–6.91 (m, 2H), 7.30–
7.36 (m, 2H) ppm. 13C NMR (75 Hz, CD3OD) d = 27.2, 75.1, 82.6,
114.5, 128.8, 129.4, 134.7, 160.6, 212.1 ppm.
Yield 180.3 mg (0.84 mmol, 84%), syn:anti = 32:1, enantiomeric
excess: 96% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak OD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 220 nm, 1.0 mL/min; major syn enantiomer
tR = 16.2 min, minor syn enantiomer tR = 18.4 min. 1H NMR
(300 MHz, CDCl3) d = 2.41 (s, 3H), 2.79 (br s, 1H), 3.71(d,
J = 4.3 Hz, 1H), 4.47–4.48 (m, 1H), 5.53–5.55 (m, 1H), 7.26–7.3
(m, 1H), 7.35–7.39 (m, 2H), 7.52–7.54 (m, 1H) ppm. 13C NMR
(75 Hz, CDCl3) d = 25.4, 70.0, 78.5, 127.1, 128.0, 129.1, 129.7,
131.2, 137.8, 207.5 ppm.
4.3.12. (3R,4S)-4-(4-Tolyl)-3,4-dihydroxybutan-2-one 2l
Yield 120.4 mg (0.62 mmol, 62%), syn:anti = 4:1, enantiomeric
excess: 95% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 96:4), 20 °C, 220 nm, 0.8 mL/min; major syn enantiomer
tR = 52.0 min, minor syn enantiomer tR = 37.9 min. 1H NMR
(300 MHz, CDCl3) d = 2.31 (s, 3H), 2.35 (s, 3H), 4.59 (d, J = 2.6 Hz,
1H), 5.15–5.16(d, J = 2.2 Hz, 1H), 7.17–7.28 (m, 4H) ppm. 13C
NMR (75 Hz, CDCl3) d = 27.2, 75.1, 80.2, 114.5, 128.8, 129.4,
134.7, 161.5, 212.3 ppm.
4.3.7. (3R,4S)-4-(4-Bromophenyl)-3,4-dihydroxybutan-2-one
2g3j,12b
Yield 220.2 mg (0.85 mmol, 85%), syn:anti = 6:1, enantiomeric
excess: 97% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 220 nm, 1.0 mL/min; major syn enantiomer
tR = 36.2 min, minor syn enantiomer tR = 38.5 min. 1H NMR
(300 MHz, CD3OD) d = 2.26 (s, 3H), 4.20 (d, J = 2.8 Hz, 1H), 5.05
(d, J = 2.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H)
ppm. 13C NMR (75 MHz, CD3OD) d = 27.1, 74.6, 82.1, 122.0, 129.6,
132.1, 142.2, 211.8 ppm.
4.3.13. (3R,4S)-4-(1-Naphthyl)-3,4-dihydroxybutan-2-one 2m12b
Yield 172.7 mg (0.75 mmol, 75%), syn:anti = 9:1, enantiomeric
excess: 97% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 254 nm, 1 mL/min; major syn enantiomer
tR = 36.6 min, minor syn enantiomer tR = 28.9 min. 1H NMR
(300 MHz, CD3OD) d = 2.32 (s, 3H), 4.35 (d, J = 2.0 Hz, 1H), 5.07
(d, J = 2.0 Hz, 1H), 7.48–7.93 (m, 6H), 8.27 (d, J = 8.4 Hz, 1H) ppm.
13C NMR (75 MHz, CD3OD) d = 27.4, 72.0, 81.1, 123.5, 125.8,
126.3, 126.4, 127.2, 128.0, 130.0, 131.3, 135.1, 138.0, 213.4 ppm.
4.3.8. (3R,4S)-4-(3-Bromophenyl)-3,4-dihydroxybutan-2-one
2h3j
Yield 212.4 mg (0.82 mmol, 82%), syn:anti = 4:1, enantiomeric
excess: 93% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 220 nm, 1.0 mL/min; major syn enantiomer
tR = 28.4 min, minor syn enantiomer tR = 20.7 min. 1H NMR
(300 MHz, CDCl3): d = 2.29 (s, 3H), 2.64 (d, J = 7.1 Hz, 1H), 3.67 (d,
J = 4.4 Hz, 1H), 4.36–4.38 (m, 1H), 4.99–5.01 (m, 1H), 7.24–7.28
(m, 1H), 7.34–7.36 (m, 1H), 7.45–7.47 (m, 1H), 7.59–7.60 (m, 1H)
ppm. 13C NMR (75 Hz, CDCl3) d = 26.2, 73.2, 80.4, 122.8, 124.9,
129.5, 130.2, 131.3, 142.5, 207.5 ppm.
4.3.14. (3R,4S)-4-(2-Naphthyl)-3,4-dihydroxybutan-2-one
2n3j,12b
Yield 168.1 mg (0.73 mmol, 73%), syn:anti = 6:1, enantiomeric
excess: 94% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 254 nm, 1 mL/min; major syn enantiomer
tR = 46.5 min, minor syn enantiomer tR = 31.5 min. 1H NMR
(300 MHz, CDCl3) d = 2.28 (s, 3H), 4.45 (d, J = 2.1 Hz, 1H), 5.05 (d,
J = 2.2 Hz, 1H), 7.40–7.88 (m, 6H), 8.11 (d, J = 8.4 Hz, 1H) ppm.
13C NMR (75 MHz, CDCl3) d = 27.4, 72.0, 81.1, 123.5, 125.8, 126.3,
126.4, 127.2, 128.0, 130.0, 131.3, 133.1, 134.0, 211.4 ppm.
4.3.9. (3R,4S)-4-(2-Bromophenyl)-3,4-dihydroxybutan-2-one
2i3j
Yield 209.9 mg (0.81 mmol, 81%), syn:anti = 16:1, enantiomeric
excess: 96% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 220 nm, 1.0 mL/min; major syn enantiomer
tR = 16.9 min, minor syn enantiomer tR = 20.2 min. 1H NMR
(300 MHz, CDCl3) d = 2.43 (s, 3H), 2.83 (d, J = 8.5 Hz, 1H), 3.71(d,
J = 4.3 Hz, 1H), 4.48–4.50 (m, 1H), 5.49–5.51 (m, 1H), 7.18–7.22
(m, 1H), 7.37–7.40 (m, 1H), 7.50–7.53 (m, 1H), 7.56–7.58 (m, 1H)
ppm. 13C NMR (75 MHz, CDCl3) d = 25.5,72.1, 78.5, 121.4, 127.7,
128.4, 129.5, 132.7, 139.3, 207.4 ppm.
4.3.15. (3R,4S)-4-(Phenyl)-3,4-dihydroxybutan-2-one 2o3j,12b
Yield 100.9 mg (0.56 mmol, 56%), syn:anti = 4:1, enantiomeric
excess: 90% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 220 nm, 1.0 mL/min; major syn enantiomer
tR = 27.4 min, minor syn enantiomer tR = 20.4 min. 1H NMR
(300 MHz, CD3OD) d = 2.23 (s, 3H), 4.23 (d, J = 3.29 Hz, 1H), 5.04
(d, J = 3.02 Hz, 1H), 7.23–7.27 (m, 1H), 7.33 (t, J = 7.41 Hz, 2H),
7.42 (t, J = 8.23 Hz, 2H) ppm. 13C NMR (75 Hz, CD3OD) d = 27.2,
75.4, 82.5, 127.6, 128.5, 129.1, 142.8, 212.1 ppm.
4.3.10. (3R,4S)-4-(4-Fluorophenyl)-3,4-dihydroxybutan-2-one
2j3j
Yield 164.5 mg (0.83 mmol, 83%), syn:anti = 6:1, enantiomeric
excess: 92% of syn diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 220 nm, 1.0 mL/min; major syn enantiomer
tR = 20.7 min, minor syn enantiomer tR = 18.2 min. 1H NMR
(300 MHz, CDCl3) d = 2.33 (s, 3H), 2.83 (d, J = 8.5 Hz, 1H), 3.71(d,
J = 4.3 Hz, 1H), 4.48–4.50 (m, 1H), 5.49–5.51 (m, 1H), 7.18–7.22
4.3.16. (3R,4S)-1,3,4-Trihydroxy-4-(4-nitrophenyl) butan-2-one
2p3j
Yield 231.6 mg (0.96 mmol, 96%), syn:anti = 32:1, enantiomeric
excess: 99% of syn diastereomer; Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/

C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
1071
2-propanol = 80:20), 20 °C, 254 1 nm, 1.0 mL/min; major enantio-
mer tR = 65.7 min, minor enantiomer tR = 73.2 min. 1H NMR
(300 MHz, CD3OD) d = 4.42 (d, J = 2.47 Hz, 1H), 4.59 (d,
J = 1.65 Hz, 2H), 5.26 (d, J = 2.20 Hz, 1H), 7.71 (d, J = 8.78 Hz, 2H),
8.23 (dt, J = 8.78 Hz, 1.92 Hz, 2H) ppm. 13C NMR (75 MHz, CD3OD)
d 68.1, 74.6, 80.6, 124.1, 128.7, 148.6, 150.8, 212.6 ppm.
2-propanol = 80:20), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 31.4 min, minor enantiomer tR = 38.4 min. 1H NMR (300 MHz,
CDCl3) d = 2.20 (s, 3H), 3.55 (br s, 1H), 3.69 (s, 3H), 3.54 (br s,
1H), 4.68 (d, J = 3.5 Hz, 1H), 4.82 (d, J = 3.5 Hz, 1H), 6.52(d,
J = 9.0 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 9.0 Hz, 2H),
7.57 (d, J = 9.0 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): d = 26.6,
55.6, 60.2, 79.5, 111.9, 114.9, 115.6, 118.4, 128.3, 132.3, 139.4,
143.1, 152.9, 206.6 ppm.
4.4. General procedure for three-component anti-Mannich
reaction using 1c as a catalyst
4.4.5. (3R,4R)-3-Hydroxyl-4-(4-methoxyanilino)-4-(4-
A mixture of 1-methyl-2-pyrrolidinone (NMP, 3 mL), p-anisi-
dine (1 mmol), aldehyde (1.1 mmol), hydroxyacetone (3 mmol),
and catalyst 1c (0.2 mmol) was vigorously stirred at 0 °C (moni-
tored by TLC). Next, the mixture was diluted with AcOEt and a half
saturated ammonium chloride solution was added. The mixture
was extracted with AcOEt (three or four times). The combined or-
ganic layers were washed with brine, dried over MgSO4, concen-
trated in vacuo, and purified by flash column chromatography
(hexanes/ethyl acetate) to afford the desired Mannich addition
products 3a–n.
fluorophenyl) butan-2-one 3e11e
Yield 279.1 mg (0.92 mmol, 92%), anti:syn = 1.3:1, enantiomeric
excess: 94% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 85:15), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 20.4 min, minor enantiomer tR = 15.3 min. 1H NMR (300 MHz,
CDCl3) d = 2.09 (s, 3H), 3.62 (s, 3H), 4.31 (d, J = 2.5 Hz, 1H), 4.80
(d, J = 2.5 Hz, 1H), 6.39–6.41 (m, 1H), 6.48–6.50 (m, 1H), 6.60–
6.65 (m, 2H), 6.84–6.97 (m, 2H), 7.18–7.19 (m, 1H), 7.21–7.27
(m, 1H) ppm. 13C NMR (75 Hz, CDCl3) d = 25.2, 55.6, 58.6, 80.7,
114.9, 115.3, 115.4, 115.6, 128.7, 128.8, 140.0, 152.6, 207.4 ppm.
4.4.1. (3R,4R)-3-Hydroxy-4-(p-methoxyphenyamino)-4-(p-
nitrophenyl) butan-2-one 3a12b
4.4.6. (3R,4R)-3-Hydroxyl-4-(4-methoxyanilino)-4-(4-
Yield 303.9 mg (0.92 mmol, 92%), anti:syn = 11.5:1, enantio-
meric excess: 98% of anti diastereomer; Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-
propanol = 80:20), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 28.0 min, minor enantiomer tR = 22.8 min. 1H NMR (300 MHz,
CDCl3) d = 2.23 (s, 3H), 3.55 (br s, 1H), 3.69 (s, 3H), 4.56 (br s,
1H), 4.71 (d, J = 3.5 Hz, 1H), 4.88 (d, J = 3.5 Hz, 1H), 6.53 (d,
J = 9.0 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 9.0 Hz, 2H),
8.13 (d, J = 9.0 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): d = 26.6,
55.6, 60.1, 79.5, 114.9, 115.6, 123.7, 128.5, 139.4, 145.1, 147.6,
153.0, 206.4 ppm.
chlorophenyl) butan-2-one 3f12b
Yield 287.8 mg (0.90 mmol, 90%), anti:syn = 4:1, enantiomeric
excess: 96% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 30.3 min, minor enantiomer tR = 46.8 min. 1H NMR (300 MHz,
CDCl3) d = 2.15 (s, 3H), 3.54 (br s, 1H), 3.69 (s, 3H), 3.54 (br s,
1H), 4.64 (d, J = 3.5 Hz, 1H), 4.75 (d, J = 3.5 Hz, 1H), 6.54 (d,
J = 9.0 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 7.21–7.26 (m, 4H) ppm.
13C NMR (75 MHz, CDCl3): d = 26.6, 55.6, 59.9, 79.6, 114.8, 115.6,
128.7, 128.8, 133.8, 135.9, 139.9, 152.7, 207.0 ppm.
4.4.2. (3R,4R)-3-Hydroxyl-4-(4-methoxyanilino)-4-(3-
nitrophenyl) butan-2-one 3b11e
4.4.7. (3R,4R)-3-Hydroxyl-4-(4-methoxyanilino)-4-(2-
chlorophenyl) butan-2-one 3g11e
Yield 307.2 mg (0.93 mmol, 93%), anti:syn = 4:1, enantiomeric
excess: 90% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 23.9 min, minor enantiomer tR = 19.6 min. 1H NMR (300 Hz,
CD3OD) d = 2.30 (s, 3H), 3.60 (s, 3H), 4.36 (d, J = 2.2 Hz, 1H), 4.95
(d, J = 2.2 Hz, 1H), 6.41 (d, J = 9.0 Hz, 2H), 6.61 (d, J = 9.0 Hz, 1H),
7.44–7.41 (m, 1H), 7.63 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H),
8.20 (s, 2H) ppm. 13C NMR (75 Hz, CD3OD): d = 27.2, 75.1, 82.6,
114.5, 128.8, 129.4, 134.7, 160.6, 212.1 ppm.
Yield 278.2 mg (0.87 mmol, 87%), anti:syn = 8:1, enantiomeric
excess: 97% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 23.7 min, minor enantiomer tR = 21.8 min. 1H NMR (300 MHz,
CDCl3) d = 2.28 (s, 3H), 3.67 (s, 3H), 4.40 (d, J = 2.4 Hz, 1H), 4.86
(d, J = 2.4 Hz, 1H), 6.49–6.51 (m, 1H), 6.57–6.58 (m, 1H), 6.66–
6.73 (m, 2H), 7.07–7.09 (m, 1H), 7.13–7.17 (m, 2H), 7.21–7.27
(m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 24.7, 54.9, 55.6, 78.1,
114.8, 114.9, 127.2, 128.7, 128.8, 129.6, 132.8, 136.3, 139.5,
152.5, 207.1 ppm.
4.4.3. (3R,4R)-3-Hydroxyl-4-(4-methoxyanilino)-4-(2-
nitrophenyl) butan-2-one 3c11e
4.4.8. (3R,4R)-3-Hydroxyl-4-(4-methoxyanilino)-4-(4-
bromophenyl) butan-2-one 3h12b
Yield 397.3 mg (0.90 mmol, 90%), anti:syn = 6:1, enantiomeric
excess: 91% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 80:20), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 25.3 min, minor enantiomer tR = 14.5 min. 1H NMR (300 MHz,
CDCl3) d = 2.44 (s, 3H), 3.67 (s, 3H), 4.64 (d, J = 1.1 Hz, 1H), 5.80 (d,
J = 1.1 Hz, 1H), 6.41 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.9 Hz, 2H), 7.41–
7.45 (m, 1H), 7.54–7.59 (m, 2H), 8.09 (d, J = 8.3 Hz, 1H) ppm. 13C
NMR (75 Hz, CDCl3) d = 24.6, 53.7, 55.6, 78.6, 114.8, 115.0, 125.3,
128.5, 129.8, 133.7, 135.8, 139.0, 148.9, 152.7, 207.1 ppm.
Yield 327.8 mg (0.90 mmol, 90%), anti:syn = 9:1, enantiomeric
excess: 98% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 90:10), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 30.5 min, minor enantiomer tR = 27.3 min. 1H NMR (300 MHz,
CDCl3) d = 2.26 (s, 3H), 3.61(s, 3H), 4.32 (d, J = 2.3 Hz, 1H), 4.79
(d, J = 2.3 Hz, 1H), 6.40 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H),
7.17 (d, J = 8.4 Hz,2H), 7.39 (d, J = 8.4 Hz, 2H) ppm. 13C NMR
(75 MHz, CDCl3): d = 26.7, 55.6, 60.0, 79.6, 114.8, 115.6, 122.0,
129.1, 131.7, 136.4, 139.8, 152.7, 206.9 ppm.
4.4.4. (3R,4R)-3-Hydroxyl-4-(4-methoxyanilino)-4-(4-
cyanophenyl) butan-2-one 3d12b
Yield 282.4 mg (0.91 mmol, 91%), anti:syn = 4:1, enantiomeric
excess: >99% of anti diastereomer; Enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/
4.4.9. (3R,4R)-3-Hydroxy-4-(p-methoxyphenyamino)-4-
phenylbutan-2-one 3i11e
Yield 214.0 mg (0.75 mmol, 75%), anti:syn = 1:1, enantiomeric
excess: 70% of anti diastereomer; Enantiomeric excess was

1072
C. Wu et al. / Tetrahedron: Asymmetry 22 (2011) 1063–1073
determined by HPLC with a Chiralpak AD-H column (hexane/2-
propanol = 95:5), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 58.5 min, minor enantiomer tR = 51.7 min. 1H NMR (300 MHz,
CDCl3) d = 2.24 (s, 3H), 3.60 (s, 3H), 4.34 (d, J = 2.6 Hz, 1H), 4.81
(d, J = 2.6 Hz,1H), 6.60 (d, J = 8.9 Hz, 2H), 6.42 (d, J = 8.9 Hz, 2H),
7.20–7.16 (m, 1H), 7.29–7.24 (m, 4H) ppm. 13C NMR (75 MHz,
CDCl3): d = 26.7, 55.6, 60.5, 79.8, 114.7, 115.6, 127.4, 128.0, 128.5,
137.3, 140.2, 152.6, 207.4 ppm.
4.4.14. (3R,4R)-3-Hydroxyl-4-(4-chloroanilino)-4-(4-
nitrophenyl) butan-2-one 3n11e
Yield 318.0 mg (0.95 mmol, 95%), anti:syn = 24:1, enantiomeric
excess: 95% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 80:20), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 19.4 min, minor enantiomer tR = 17.7 min. 1H NMR (300 MHz,
CDCl3) d = 2.37 (s, 3H), 4.45 (d, J = 2.5 Hz, 1H), 5.04 (s, 1H), 6.44
(d, J = 11.0 Hz, 2H), 7.04 (d, J = 11.0 Hz, 2H), 7.54 (d, J = 10.5 Hz,
2H), 8.18 (d, J = 10.5 Hz, 2H) ppm. 13C NMR (75 Hz, CDCl3)
d = 25.6, 58.6, 80.5, 115.6, 124.1, 124.6, 128.7, 129.2, 144.5, 147.3,
148.1, 207.0 ppm.
4.4.10. (3R,4R)-3-Hydroxy-4-(p-methoxyphenyamino)-4-(p-
methoxyphenyl)butan-2-one 3j11e
Yield 246.0 mg (0.78 mmol, 78%), anti:syn = 2:1, enantiomeric
excess: 76% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 95:5), 20 °C, 254 nm, 0.8 mL/min; major enantiomer
tR = 60.5 min, minor enantiomer tR = 53.3 min. 1H NMR (300 MHz,
CDCl3) d = 2.12 (s, 3H), 3.68 (s, 3H), 3.74 (s, 3H), 4.62 (d, 1H,
J = 3.6 Hz), 4.73 (d, 1H, J = 3.6 Hz), 6.57 (d, 2H, J = 8.8 Hz), 6.70 (d,
2H, J = 8.8 Hz), 6.79 (d, 2H, J = 8.8 Hz), 7.19 (d, 2H, J = 8.8 Hz)
ppm. 13C NMR (75 MHz, CDCl3): mixture of diastereomers
d = 25.27, 26.66, 55.08, 55.15, 55.56, 58.62, 59.83, 79.77, 80.81,
113.90, 11404, 114.71, 115.16, 115.63, 128.03, 128.44, 129.15,
131.17, 140.15, 14028, 152.32, 152.51, 158.90, 159.17, 207.52,
207.55 ppm.
4.4.15. (3R,4R)-3-Hydroxyl-4-anilino-4-(4-nitrophenyl) butan-
2-one 3o
Yield 267.3 mg (0.89 mmol, 89%), anti:syn = 9:1, enantiomeric
excess: 98% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 85:15), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 23.6 min, minor enantiomer tR = 35.8 min. 1H NMR (300 MHz,
CDCl3) d = 2.31 (s, 3H), 4.40 (d, J = 2.0 Hz, 1H), 5.02 (d, J = 2.0 Hz,
1H), 6.43 (d, J = 7.8 Hz, 2H), 6.65–6.62 (m, 1H), 7.05–7.01 (m,
2H), 7.49 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H) ppm. 13C NMR
(75 Hz, CDCl3) d = 25.5, 58.4, 80.5, 114.3, 119.3, 124.4, 128.7,
130.0, 145.9, 147.9, 207.3 ppm.
4.4.11. (3R,4R)-3-Hydroxyl-4-(3-methoxyanilino)-4-(4-
nitrophenyl) butan-2-one 3k11e
4.5. General procedure for large-scale anti-Mannich and syn-
Yield 330.6 mg (0.91 mmol, 91%), anti:syn >10:1, enantiomeric
excess: 99% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 85:15), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 38.1 min, minor enantiomer tR = 47.6 min. 1H NMR (300 MHz,
CDCl3) d = 2.38 (s, 3H), 3.71 (s, 3H), 4.46 (d, J = 2.0 Hz, 1H), 5.08
(d, J = 2.0 Hz, 1H), 6.05–6.07 (m, 1H), 6.12–6.15 b(m, 1H), 6.26–
6.29 (m, 1H), 7.00–7.02 (m, 1H), 7.58–7.57 (m, 2H), 8.12–8.19
(m, 2H) ppm. 13C NMR (75 Hz, CDCl3) d = 25.5, 55.6, 58.4, 80.5,
100.8, 104.1, 107.3, 124.4, 128.6, 130.8, 147.3, 147.9, 148.0,
161.3, 207.2 ppm.
aldol reactions
4.5.1. anti-Mannich reaction
A mixture of 1-methyl-2-pyrrolidinone (NMP, 300 mL), p-
methoxyaniline (100 mmol), p-nitrobenzaldehyde (110 mmol),
hydroxyacetone (300 mmol) and catalyst 1c (4.9 g, 20 mol %) using
a 1 L round-bottomed flask. The resulting mixture was vigorously
stirred at 0 °C (monitored by TLC). Then, the mixture was diluted
with AcOEt (200 mL) and a half saturated ammonium chloride
solution was added. The mixture was extracted with AcOEt
(3 ꢀ 300 mL). The combined organic layers were washed with
brine, dried over MgSO4, concentrated in vacuo, and purified by
flash column chromatography (hexanes/ethyl acetate) to afford
the desired anti-Mannich addition products 3a (29.731 g).
4.4.12. (3R,4R)-3-Hydroxyl-4-(4-methyanilino)-4-(4-
nitrophenyl) butan-2-one 3l11e
Yield 292.3 mg (0.93 mmol, 93%), anti:syn >13:1, enantiomeric
excess: 96% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 85:15), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 29.7 min, minor enantiomer tR = 34.7 min. 1H NMR (300 MHz,
CDCl3) d = 2.17 (s, 3H), 2.36 (s, 3H), 4.45 (d, J = 2.3 Hz, 1H), 5.07
(d, J = 2.3 Hz, 1H), 6.42 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H),
7.54 (d, J = 8.7 Hz, 2H), 8.17 (d, J = 8.7 Hz, 2H) ppm. 13C NMR
(75 Hz, CDCl3) d = 20.9, 25.5, 58.7, 80.6, 114.5, 124.5, 128.7,
130.6, 143.5, 148.0, 207.1 ppm.
4.5.2. syn-Aldol reactions
To a mixture of catalyst 1c (5 mmol) and ketone (300 mmol)
were added aromatic aldehyde (100 mmol) and NMP (2 equiv
water) (100 mL) using a 250 mL round-bottomed flask. The result-
ing mixture was stirred at 0 °C. The reaction was monitored by TLC.
It was then quenched with 80 mL saturated NH4Cl solution, ex-
tracted with EtOAc(3 ꢀ 200 mL), and dried over Na2SO4. Purifica-
tion by flash chromatography afforded the corresponding pure
products 2a (20.943 g), 2d (19.494 g), 2e (18.301 g), 2g
(22.023 g), 2k (15.136 g), 2m (17.269 g), 2o (10.271 g).
4.4.13. (3R,4R)-3-Hydroxyl-4-(2,4-dimethyanilino)-4-(4-
nitrophenyl) butan-2-one 3m11e
Acknowledgment
Yield 311.9 mg (0.95 mmol, 95%), anti:syn = 24:1, enantiomeric
excess: 96% of anti diastereomer; Enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 85:15), 20 °C, 254 nm, 1.0 mL/min; major enantiomer
tR = 48.8 min, minor enantiomer tR = 34.5 min. 1H NMR (300 MHz,
CDCl3) d = 2.18 (s, 6H), 2.37 (s, 3H), 4.49 (d, J = 2.4 Hz, 1H), 5.11
(d, J = 2.4 Hz, 1H), 6.19 (d, J = 10.0 Hz, 1H), 6.75 (d, J = 10.0 Hz,
1H), 6.90 (s, 1H), 7.54 (d, J = 11.0 Hz, 2H), 8.20 (d, J = 11.0 Hz, 2H)
ppm. 13C NMR (75 Hz, CDCl3) d = 17.9, 20.9, 25.6, 58.7, 80.8,
111.9, 123.6, 124.6, 128.0, 128.3, 128.6, 132.1, 141.4, 148.0,
148.1, 207.1 ppm.
Authors are grateful to Southwest University of China for finan-
cial support.
References
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