Asymmetric conjugate addition of unmodified propionaldehyde to β- Nitrostyrenes catalyzed by readily available proline-based dipeptidols

Article abstract of DOI:10.2174/157017809787003061

Organocatalytic asymmetric additions of unmodified aldehydes to β-nitrostyrenes are important carbon-carbon bond formation reactions and have become very attractive recently, because they are metal-free and environmentally benign. This work employed a ser

Full text of DOI:10.2174/157017809787003061

44
Letters in Organic Chemistry, 2009, 6, 44-49
Asymmetric Conjugate Addition of Unmodified Propionaldehyde to ꢀ-
Nitrostyrenes Catalyzed by Readily Available Proline-Based Dipeptidols
Ren-Yong Yang, Chao-Shan Da*, Lei Yi, Feng-Chun Wu and Hong Li
Institute of Biochemistry & Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
Received April 18, 2008: Revised July 18, 2008: Accepted July 26, 2008
Abstract: Organocatalytic asymmetric additions of unmodified aldehydes to ꢀ-nitrostyrenes are important carbon-carbon
bond formation reactions and have become very attractive recently, because they are metal-free and environmentally be-
nign. This work employed a series of L-proline-based diphenyl dipeptidols to catalyze this reaction. The results showed
that these dipeptidols were effective organocatalysts with the yield up to 99%. 3a was optimal with the highest enantiose-
lectivity up to 75% and dr (syn/anti) up to 94/6. In addition, the mechanism of this asymmetric reaction is also discussed.
Keywords: Asymmetric conjugate addition, propionaldehyde, ꢀ-nitrostyrene, proline-based dipeptidol, organocatalysis, enanti-
oselectivity.
1. INTRODUCTION
prolinol and its derivatives [12], chiral ionic liquid [13],
prolinal dithioacetals [14], amino alcohol derivatives [15]
and etc. It is suggested that an enamine transition state forms
in the reaction process, which is similar to the organocata-
lyzed asymmetric aldol reactions. Thus many organocata-
lysts successfully applied to direct aldol reactions could also
be used in asymmetric conjugation reactions, such as L-
proline and others [3a]. Recently, proline-based dipeptidol
derivatives were reported by Singh to catalyze the asymmet-
ric aldol reactions efficiently [16]. But their use in the conju-
Conjugate addition reaction is one of the most important
carbon-carbon bond-forming reactions [1]. Asymmetric con-
jugate addition of aldehydes to ꢀ-nitrostyrenes could produce
versatile chiral ꢁ-nitro aldehydes which could be easily trans-
ferred into a wide range of synthetically interesting com-
pounds such as optically active ꢁ-amino alcohols, ꢁ-amino
acids, and ꢁ-nitro acids [2]. Nowadays, organocatalytic direct
asymmetric reactions of unmodified aldehydes with ꢀ-
O
R
R
3a: R=Ph
3b: R=i-Pr
3c: R=i-Bu
3d: R=Bn
Ph
Ph
Ph
1. ClCO2i-Bu, NMM, THF
N
COOH
COOH
+
N
H2N
H
Ph
2. TFA
HO
NH
Boc
OH
2a-d
Ph
3a-d
1
O
Ph
Ph
Ph
Ph
1. ClCO2i-Bu, NMM, THF
N
H
+
N
H2N
Ph
2. TFA
HO
NH
Boc
1
OH
2e
3e
Scheme 1. Synthesis of L-proline-based diphenyl dipeptidols 3a-3e.
nitrostyrenes have become attractive because they are metal-
free and environmentally benign [3]. Since Barbas III dis-
closed the first case of organocatalytic asymmetric conjugate
addition of unmodified aldehydes to ꢀ-nitrostyrenes cata-
lyzed by proline-derived diamines [4], there have been many
effective organocatalysts reported [5]. These chiral catalysts
include diamines [6], fluorous (S)-pyrrolidine sulfonamides
[7], proline-derived tetrazoles [8], proline and substituted
prolines [9], thioureas [10], simple dipeptides [11], silylated
gate reaction has not yet been disclosed. We presumed that
this kind of catalysts could also be used in this reaction [5a].
Herein we describe these diphenyl dipeptidols as organocata-
lysts in this reaction.
2. RESULTS AND DISCUSSION
As shown in Scheme 1, these catalysts could be easily
prepared according to the typical procedure. Boc-L-proline
was condensed with a series of L-diphenyl-amino-alcohols
via the mixed anhydride method. Catalyst 3e was prepared
by using D-diphenyl-phenylglycinol instead. Then trifluoro-
*Address correspondence to this author at the Institute of Biochemistry &
Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou
730000, China; Fax: +86-931-8915208; E-mail: dachaoshan@lzu.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Asymmetric Conjugate Addition of Unmodified Propionaldehyde
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
45
Table 1. Asymmetric Catalytic Addition of Unmodified Propionaldehyde to ꢀ-Nitrostyrene [17]
O
Ph
O
Catalysts
NO2
NO2
+
Ph
H
H
Entry Catalyst
Solvent
Additive
Temperature
T (d)
Yield (%)a
dr (syn / anti)b
ee (%)c
1
3a (20 mol %)
Toluene
c-hexane
n-hexane
CHCl3
No
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
0 oC
8
98
49
97
95
58
51
88
80
54
Trace
53
88
98
99
99
85
96
90
87/13
92/8
53
56
60
29
33
26
12
42
43
-
2
3a (20 mol %)
3a (20 mol %)
3a (20 mol %)
3a (20 mol %)
3a (20 mol %)
3a (20 mol %)
3a (20 mol %)
3a (20mol %)
3a (20 mol %)
3a (20 mol %)
3a (10 mol %)
3b (10 mol %)
3c (10mol %)
3d (10 mol %)
3e (10 mol %)
3a (30 mol %)
3a (20 mol %)
No
7
3
No
3
89/11
93/7
4
No
4
5
MeOH
No
4.5
4.5
8
87/13
88/12
81/19
91/9
6
THF
No
7
NMP
No
8
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
H2O (5 eq.)
Et3N (0.2 eq.)
TFA (0.2 eq.)
4
9
3
75/25
-
10
11
12
13
14
15
16
17
18
3
m-nitrophenol (0.2 eq.)
6
89/11
89/11
90/10
92/8
51
58
34
38
29
57
56
57
No
No
No
No
No
No
No
6
3
2
1
91/9
5
90/10
90/10
90/10
2
4
aIsolated yield.
bDetermined by 1H NMR spectra.
cEe stands for enantioselectivity, determined by Chiral HPLC using Chiralcel OD-H column.
acetic acid was employed to deprotect the Boc group to
achieve catalysts 3a-3e.
The conjugate addition of propionaldehyde to various ꢀ-
nitrostyrenes were carried out with the above optimized reac-
tion conditions as shown in Table 2. Those ꢀ-nitrostyrenes
with substitutions on the phenyl ring had a worse solubility
in this solvent system, so a little toluene was added to make
them dissolve. Generally, 3a was an efficient catalyst with
yield up to 97%, dr up to 94/6 and enantioselectivity up to
75%. Some structural effects on diastereoselectivity and
enantioselectivity were observed. para-Chloro substituted
nitrostyrene gave the highest enantioselectivity up to 75%.
ortho-Chloro, meta-Chloro substituted and naphthyl nitrosty-
renes also afforded good enantioselectivity. 2,4-Dichloro
substituted nitrostyrene got the highest dr but low enantiose-
lectivity. Others achieved only moderate enantioselectivity.
The reaction of propionaldehyde with ꢀ-nitrostyrene in
the presence of 3a (20 mol %) in various solvents was inves-
tigated initially. The results showed that (Table 1, entries 1-
7) non-polar solvents were superior to polar solvents. n-
hexane, cyclo-hexane and toluene had nearly the same effect
on enantioselectivity but n-hexane gave the fastest reaction
rate. No significant improvement in the enantioselectivity
was observed with some additives (Table 1, entries 8-11). As
for chiral organocatalysts 3a-3d (Table 1, entries 12-15), all
of them were efficient catalysts and gave high yield with
good diastereoselectivity, and 3a gave the best enantioselec-
tivity. Interestingly, 3e gave almost the same diastereoselec-
tivity and enantioselectivity as 3a did (Table 1, entries 12
and 16). It seems that the configuration of the diphenyl
amino alcohol has non-impact on the diastereoselectivity and
enantioselectivity which are thoroughly determined by L-
proline segment. 3d gave the fastest rate, but achieved the
poorest enantioselectivity value. There was no significant
improvement in enantioselectivity by increasing the loading
of the catalyst (Table 1, entries 3, 12 and 17). Lowering tem-
perature did not lead to higher enantioselectivity but a much
longer reaction time (Table 1, entry 18).
It is supposed that an enamine transition state is formed
in the catalytic process [5a]. As depicted in Fig. (1), the E-
enamine would be generated between the amine group of the
pyrrolidine circle and propionaldehyde, while the hydroxyl
and amide groups might activate ꢀ-nitrostyrene by forming
two hydrogen bonds, so relatively more stable Re-rotamer E-
enamine is formed mainly. On account of the hydrogen
bonds and the bulky diphenyl groups of the catalyst, the
catalytic process would take place preferentially by the
enamine attack to the less hindered Si face of the ꢀ-

46
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Yang et al.
Table 2. Direct Michael Addition of Propionaldehyde to Various ꢀ-Nitrostyrenesa
O
O
Aryl
3a (20 mol %)
NO2
NO2
+
Aryl
H
H
n-Hexane, rt.
6a-i
5a-i
4
Yield (%)b
dr (syn / anti)c
ee (%)d
Config.e
Aryl
Entry
T (d)
1
3
7
97
81
89/11
60
58
(2R,3S)
(2R,3S)
2
Cl
92/8
3
4
Cl
7
7
74
70
92/8
61
75
(2R,3S)
(2R,3S)
89/11
Cl
5
Cl
9
50
94/6
33
(2R,3S)
Cl
6
7
9
9
9
77
50
61
85/15
86/14
89/11
42
44
56
(2R,3S)
(2R,3S)
(2R,3S)
O
8
9
CF3
9
70
90/10
46
(2R,3S)
aThe reaction was carried out in the presence of 20 mol % loading of catalyst 3a in 1ml n-hexane under room temperature. 1.0 ml toluene was introduced to make the substrate soluble
into the mixture in entries 2-6 and 9 whereas 0.4ml toluene was introduced into the reaction mixture in entries 7-8.
bIsolated yield.
cDetermined by 1H NMR spectra.
dEe stands for enantioselectivity, determined by HPLC using a Chiralcel OD-H column in entry 1 whereas using a Chiralpak AS column in other cases.
eThe major isomer's configuration of syn isomer was determined by comparison with reported retention time of the major peak on chiral HPLC [4(a), 12(c)].
nitrostyrenes and produce syn isomers mainly. The absolute
conformation of main adducts should be (2R,3S) isomers.
active in non-polar solvent with yield up to 99% and catalyst
3a was the optimal with the enantioselectivity (up to 75%).
3. CONCLUSIONS
4. EXPERIMENTAL
4.1. General
In conclusion, we have successfully employed a series of
efficient chiral diphenyl dipeptidols as organocatalysts for
the direct asymmetric Michael addition of unmodified propi-
onaldehyde to various ꢀ-nitrostyrenes. They behaved more
Solvents were dried and distilled according to established
procedures. Reactions were monitored by thin layer chro-

Asymmetric Conjugate Addition of Unmodified Propionaldehyde
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
47
O
Ph
4.2.3. Diphenyl L-prolyl-L-valinol (3b)
Ph
Ph
Prepared according to the general procedure to afford the
product 3b as a white solid; yield 79%. Mp: 207-209 C.
N
H
o
O
N
H
1
[ꢀ]2D0= -95o (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): ꢀ
O-
N+
H
0.80-0.98 (m, 6 H), 1.48-1.62 (m, 3 H), 1.95 (m, 2 H), 2.33
(s, 1 H), 2.82 (m, 1 H), 2.94 (m, 1 H), 3.61 (m, 1 H), 4.69 (d,
1H, J = 12 Hz), 7.10-7.31 (m, 3 H), 7.49-7.53 (m, 4 H), 8.20
(d, 1H, J = 9.6 Hz). ESI-MS: (C22H28N2O2 + H+) calcd. 353,
found 353, (C22H28N2O2-H2O) calcd. 335, found 335.
O
Ph
Fig. (1). The supposed transition state.
4.2.4. Diphenyl L-prolyl-L-leucinol (3c)
matography (TLC), Column chromatography purifications
were carried out using silica gel. All reagents were pur-
chased from commercial corporations. 1H NMR spectra were
measured on Bruker Am 400 MHz and DRX-200 MHz spec-
trometers (NMR in CDCl3 with TMS as an internal stan-
dard). Optical rotations were recorded on a Perkin–Elmer
341 polarimeter. The enantioselectivity value determination
was carried out using chiral HPLC with Chiralpak AS or
Chiralcel OD-H column on Waters® 600 with a 2996 UV
detector.
Prepared according to the general procedure to afford the
product 3c as a white solid; yield 83%. Mp: 198-200 C.
o
1
[ꢀ]2D0= -40o (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): ꢀ
0.81-1.17 (m, 6 H), 1.22 (m, 2 H), 1.35-1.55 (m, 3 H), 1.85
(m, 2 H), 2.60 (m, 2 H), 2.83 (m, 1 H), 3.53 (q, 1 H, J = 3.6
Hz), 4.65 (t, 1 H, 10 Hz), 7.10-7.31 (m, 6 H), 7.54-7.98 (m, 4
H), 7.99 (d, 1 H, J = 8.8 Hz). ESI-MS: (C23H30N2O2 + H+)
calcd. 367, found 367.
4.2.5. Diphenyl L-prolyl-L-phenyl alaniol (3d)
4.2. Preparation of Catalysts 3a-3e
Prepared according to the general procedure to afford the
product 3d as a white solid; yield 78%. Mp: 190-192 C;
o
4.2.1. General Procedure for the Synthesis of Catalysts
3a-e
1
[ꢀ]2D0= -91o (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): ꢀ
0.99 (m, 1 H), 1.21 (m, 1 H), 1.35 (m, 1 H), 1.79 (m, 1 H),
2.09 (s, 1 H), 2.41 (m, 1 H), 2.71 (m, 1 H), 2.83 (d, 1 H, J =
14.2 Hz), 3.21 (dd, 1 H, J = 14 Hz, 11.2 Hz), 3.49 (dd, 1 H,
9.2 Hz, 4.8 Hz), 4.60 (m, 1 H), 7.07-7.29 (m, 9 H), 7.34-7.38
(m, 2 H), 7.56-7.58 (m, 1 H), 7.68-7.70 (m, 1 H), 8.03 (d, 8.4
Hz). ESI-MS: (C26H28N2O2 + H+) calcd. 401, found 401.
N-methyl morpholine (1.21 mL, 11mmol) was added to a
solution of N-Boc-L-proline (2.153 g, 10 mmol) in dry THF
(40 mL) at -15 C. Then isobutyl chloroformate (1.439 mL,
o
11mmol) was added dropwise and the solution was stirred at
the same temperature for 6 min. Then, optically pure amino
alcohol 2a (2.834 g, 9.8 mmol) in dry THF was added and
the resulting solution was stirred at the same temperature for
2 h. And then let the reaction stir at room temperature over-
night. The whole solution was filtered. Washed the precipi-
tate with ethyl acetate, combined the organic solvents and
evaporated to dryness. The crude product was dissolved in
ethyl acetate again, washed successively with 0.1 M HCl,
water, 0.1 M NaOH and brine, dried over Na2SO4 and evapo-
rated to dryness. The residue was purified by recrystalisation
with ethyl acetate to give Boc-protected dipeptidol. TFA (9
mL) was slowly introduced into this Boc-protected dipepti-
dol in dry DCM (9 ml) at 0 oC and the resulting solution was
stirred at room temperature for 12 h. Excess TFA was care-
fully neutralized by adding 2 M Na2CO3 and the whole mix-
ture was extracted with ethyl acetate three times. The com-
bined organic layer was dried and the solvent was removed
under reduced pressure to obtain the product. Pure product
was achieved by recrystalisation with ethyl acetate/petro-
leum.
4.2.6. Diphenyl L-prolyl-D-1-phenyl-glycinol (3e)
Prepared according to the general procedure to afford the
o
product 3e as a white solid; yield 72%. Mp: 191-194 C.
1
[ꢀ]2D0= +109o (c 1.0, DMF). H NMR (400 MHz, CDCl3): ꢀ
1.60 (m, 2 H), 1.76-2.04 (m, 4 H), 2.61-2.90 (m, 2 H), 3.61
(m, 1 H), 7.08-7.33 (m, 15 H), 9.15 (s, 1 H). ESI-MS:
(C25H26N2O2 + H+) calcd. 387, found 387. (C25H26N2O2-
H2O+H+) calcd. 369, found 369.
4.3. General Procedure for the Direct Asymmetric Con-
jugate Addition of Propionaldehyde to ꢀ-Nitrostyrenes
Propionaldehyde (5 mmol) was added into the mixture of
ꢁ-nitrostyrene (0.5 mmol) and catalyst 3a (0.1 mmol) in n-
hexane (1 mL). The reaction vessel was wrapped in alumin-
ium foil, and the resulting solution was stirred under an ar-
gon atmosphere for the appropriate time and at the tempera-
ture indicated in the schemes. The reaction was then
quenched with aq. NH4Cl solution and the product was ex-
tracted three times with ethyl acetate. The organic fractions
were dried with Na2SO4 and the volatiles were removed on a
rotary evaporator. The products were purified by preparative
chromatography on silica gel (DCM/n-hexane, 1:1). The
configurations of the products were determined by compari-
son of the major isomer retention time on chiral HPLC with
the reported data. The enantiomeric excess was measured by
HPLC with Chiralpak AS or Chiralcel OD-H.
4.2.2. Diphenyl L-prolyl-L-phenyl glycinol (3a)
Prepared according to the general procedure to afford the
o
product 3a as a white solid; yield 81%; Mp: 210-212 C.
1
[ꢀ]2D0= +85o (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) ꢀ
1.61 (m, 2 H), 1.79 (m, 1 H), 1.95 (m, 1 H), 2.21 (s, 2 H),
2.66 (m, 1 H), 2.87 (m, 1 H), 3.66 (dd, 1 H, J = 9.2 Hz, 4.8
Hz), 7.07-7.34 (m, 15 H), 9.16 (s, 1 H). ESI-MS:
(C25H26N2O2-H2O+H+) calcd. 369, found 369.

48
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Yang et al.
23.8 min (syn, minor), enantioselectivity (syn) 33%. 1H NMR
(200 MHz, CDCl3): ꢁ 9.73 (d, 1 H, J = 1.4 Hz), 7.12-7.45
(m, 3 H), 4.71-4.91 (m, 2 H), 4.2-4.3 (m, 1 H), 2.93-3.07 (m,
1 H), 1.00 (d, 3 H, J = 7.4 Hz).
4.3.1. (2R,3S)-2-Methyl-4-nitro-3-phenylbutanal (6a)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined by NMR to be 85/15. The enantioselectivity was
measured by HPLC (Chiralcel OD-H, 10% 2-propanol in n-
hexane, flow 1.0 mL/min, ꢀ = 220 nm). Retention time: 24.9
min (syn, minor), 38.1 min (syn, major), enantioselectivity
(syn) 60%. Comparing to the reported retention time of the
syn isomer: major peak 29.63 min, minor peak 37.58 min
4.3.6. (2R,3S)-2-Methyl-4-nitro-3-(4-methylphenyl)butanal
(6f)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 85/15. The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow 1.0
mL/min, ꢀ = 220 nm). Retention time: 20.0 min (syn, major),
21.0 min (syn, minor), enantioselectivity (syn) 42%. 1H
NMR (200 MHz, CDCl3): ꢁ 9.71 (d, 1 H, J = 1.7 Hz), 7.02-
7.26 (m, 4 H), 4.59-4.79 (m, 2 H), 3.74-3.83 (m, 1 H), 2.70-
2.79 (m, 1 H), 2.32 (s, 3 H), 1.00 (d, 3 H, J = 7.2 Hz).
1
[4a], configuration of 6a was assigned to be (2R,3S). H
NMR (200 MHz, CDCl3): ꢁ 9.71 (d, 1H, J = 1.7 Hz), 7.26-
7.35 (m, 3 H), 7.14-7.19 (m, 2 H), 4.62-4.85 (m, 2 H), 3.75-
3.87 (m, 1 H), 2.73-2.82 (m, 1 H), 1.00 (d, 3H, J = 7.3 Hz).
4.3.2. (2R,3S)-2-Methyl-4-nitro-3-(2-Chlorophenyl)butanal
(6b)
4.3.7. (2R,3S)-2-Methyl-4-nitro-3-(4-methoxyphenyl)butan-
al (6g)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 92/8. The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow 1.0
mL/min, ꢀ =220 nm). Retention time: 21.9 min (syn, major),
27.1 min (syn, minor), enantioselectivity (syn) 58%. 1H NMR
(200 MHz, CDCl3): ꢁ 9.73 (d, 1 H, J = 1.6 Hz), 7.42 (m, 1
H), 7.21 (m, 3 H), 4.73-4.93 (m, 2 H), 4.3-4.4 (m, 1 H), 2.97-
3.05 (m, 1 H), 1.03 (d, 3 H, J = 7.4 Hz).
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 86/14. The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow1.0
mL/min, ꢀ = 220 nm). Retention time: 48.2 min (syn, minor),
73.2 min (syn, major), enantioselectivity (syn) 44%. 1H
NMR (200 MHz, CDCl3): ꢁ 9.70 (d, 1 H, J = 1.7 Hz), 7.08
(d, 2 H, J = 8.7 Hz), 6.86 (d, 2 H, J = 8.8 Hz), 4.57-4.81 (m,
2 H), 3.73-3.78 (m, 4 H), 2.69-2.77 (m, 1 H), 0.99 (d, 3 H, J
= 7.3 Hz).
4.3.3 (2R,3S)-2-Methyl-4-nitro-3-(3-Chlorophenyl)butanal
(6c)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 92/8. The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow 1.0
mL/min, ꢀ = 220 nm). Retention time: 27.6 min (syn, major),
32.2 min (syn, minor), enantioselectivity (syn) 61%. 1H
NMR (200 MHz, CDCl3): ꢁ 9.69 (d, 1 H, J = 1.5 Hz), 7.03-
7.29 (m, 4 H), 4.64 (dd, J = 9.2, 11.0 Hz), 4.79 (dd, J = 5.6,
12.9 Hz), 3.71-3.83 (m, 1 H), 2.71-2.80 (m, 1 H), 1.00 (d, 3
H, J = 7.3 Hz).
4.3.8. (2R,3S)-2-Methyl-4-nitro-3-naphthylbutanal (6h)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 89/11.The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow 1.0
mL/min, ꢀ = 220 nm). Retention time: 32.8 min (syn, major),
36.5 min (syn, minor), enantioselectivity (syn) 56%. 1H
NMR (200 MHz, CDCl3): ꢁ 9.78 (d, 1 H, J = 1.7 Hz), 8.14
(s, 1 H), 7.79-7.91 (m, 2 H), 7.34-7.60 (m, 4 H), 4.86-4.96
(m, 2 H), 4.73-4.85 (m, 1 H), 3.00-3.04(m, 1 H), 0.99 (d, 3
H, J = 7.3 Hz).
4.3.4. (2R,3S)-2-Methyl-4-nitro-3-(4-Chlorophenyl)butanal
(6d)
4.3.9. (2R,3S)-2-Methyl-4-nitro-3-(2-trifluoromethylphenyl)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 89/11. The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow 1.0
mL/min, ꢀ = 220 nm). Retention time: 30 min (syn, major),
32.7 min (syn, minor), enantioselectivity (syn) 75%. 1H
NMR (200 MHz, CDCl3): ꢁ 9.70 (d, 1 H, J = 1.5 Hz), 7.32
(d, 2 H, J = 10 Hz), 7.11 (d, 2 H, J = 8.5 Hz), 4.58-4.84 (m, 2
H), 3.73-3.85 (m, 1 H), 2.71-2.80 (m, 1 H), 1.01 (d, 3 H, J =
7.3 Hz).
butanal (6i)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 90/10. The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow 1.0
mL/min, ꢀ = 220 nm). Retention time: 14.5 min (syn, major),
16.2 min (syn, minor), enantioselectivity (syn) 46%. Com-
paring to the reported retention time of the syn isomer: major
peak 14.5 min, minor peak was not observed [12c], configu-
ration of 6i was assigned to be (2R,3S). 1H NMR (200 MHz,
CDCl3): ꢁ 9.75 (d, 1 H, J = 1.8 Hz), 7.33-7.74 (m, 4 H),
4.66-4.90 (m, 2 H), 4.09-4.15 (m, 1 H), 3.03-3.11 (m, 1 H),
0.99 (d, 3 H, J = 7.4 Hz).
4.3.5.
(2R,3S)-2-Methyl-4-nitro-3-(2,4-Dichlorophenyl)
butanal (6e)
Prepared according to the general procedure. A mixture
of diastereoisomers was obtained; syn/anti ratio was deter-
mined to be 94/6. The enantioselectivity was measured by
HPLC (Chiralpak AS, 10% 2-propanol in n-hexane, flow 1.0
mL/min, ꢀ = 220 nm). Retention time: 19.2 min (syn, major),
ACKNOWLEDGEMENT
We are greatly thankful to the part support from the Na-
tional Natural Science Foundation of China (No. 20672051).

Asymmetric Conjugate Addition of Unmodified Propionaldehyde
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
49
Int. Ed., 2006, 45, 6366; (c) Zong, Z.; Zhang, Y.; Jiao, C.; Li, B.;
Ding, J.; Zhang, Y. Chirality, 2007, 19, 307.
Xu, Y.; Zou, W.; Sundén, H.; Ibrahem, I.; Córdova, A. Adv. Synth.
Catal., 2006, 348, 418.
(a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.
Int. Ed., 2005, 44, 4212; (b) Zu, L.; Li, H.; Wang, J.; Yu, X.;
Wang, W. Tetrahedron Lett., 2006, 47, 5131; (c) Li, Y.; Liu, X.-Y.;
Zhao, G. Tetrahedron Asymmetry, 2006, 17, 2034; (d) Enders, D.;
Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature, 2006, 441, 861.
Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew.
Chem. Int. Ed., 2006, 45, 3093.
Mandal, T.; Zhao, C.-G. Tetrahedron Lett., 2007, 48, 5803.
Palomo, C.; Vera, S.; Mielgo, A.; Gómez-Bengoa, E. Angew.
Chem. Int. Ed., 2006, 45, 5984.
REFERENCES
[1]
(a) Perlmutter, A. Conjugate Additions in Organic Synthesis: Per-
gamon Press: Oxford, 1992; (b) Rossiter, B. E.; Swingle, N. M.
Chem. Rev., 1992, 92, 771.
[11]
[12]
[2]
[3]
List, B. Synlett, 2001, 1675.
(a) Pellissier, H. Tetrahedron, 2007, 63, 9267; (b) Berkessel, A.;
Gröger, H. Asymmetric Organocatalysis: From Biomimetic Con-
cepts to Applications in Asymmetric Synthesis: Wiley-VCH, Wein-
heim, 2004; (c) List, B. Chem. Commun. 2006, 819; (d) Marcelli,
T.; van Maarseveen, J.H.; Hiemstra, H. Angew. Chem. Int. Ed.,
2006, 45, 7496; (e) Palomo, C.; Mielgo, A. Angew. Chem. Int. Ed.,
2006, 45, 7876.
[13]
[14]
[15]
[4]
[5]
[6]
(a) Betancort, J. M.; Barbas III, C. F. Org. Lett. 2001, 3, 3737; (b)
Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.;
Barbas III, C. F. Synthesis, 2004, 1509.
[16]
[17]
Raj, M.; Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett.,
2006, 8, 4097.
(a) Sarah, S.-M.; Alexandre. A. Chem. Commun., 2007, 3123; (b)
Tsogoeva, S. B. Eur. J. Org. Chem., 2007, 1701; (c) Almasi, D.
Diego, A. A.; Najera, C. Tetrahedron Asymmetry, 2007, 18, 299.
(a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.
Int. Ed., 2005, 44, 4212; (b) Mase, N.; Watanabe, K.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas III, C. F. J. Am. Chem. Soc., 2006,
128, 4966; (c) Mossé, S.; Laars, M.; Kriis, K.; Kanger, T.; Alex-
akis, A. Org. Lett., 2006, 8, 2559; (d) Mase, N.; Thayumanavan,
R.; Tanaka, F.; Barbas III, C. F. Org. Lett., 2004, 6, 2527; (e) An-
drey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. Adv. Synth.
Catal., 2004, 346, 1147.
We also observed that the same configurational product as propi-
onaldehyde was afforded when butyraldehyde was employed as
substrate to reaction with ꢀ-nitrostyrene. Its enantioselectivity is
51% whereas syn/anti is 83/17. The product could be characterized
as follows:
(2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal. Prepared according to
the general procedure. A mixture of diastereoisomers was obtained;
syn/anti ratio was determined to be 83/17. The enantioselectivity
was measured by HPLC (Chiralpak AD-H, 1% 2-propanol in n-
hexane, flow 1.0 mL/min, ꢁ = 220 nm). Retention time: 23.5 min
(syn, major), 27.7 min (syn, minor), enantioselectivity (syn)
51%. 1H NMR (400 MHz, CDCl3): ꢂ 9.72 (d, 1 H, J = 2.6 Hz,),
7.28-7.36 (m, 3 H), 7.17-7.19 (m, 2 H), 4.72 (dd, 1 H, J = 12.8, 4.9
Hz), 4.63 (dd, 1 H, J =12.8, 9.7 Hz), 3.80 (ddd, 1 H, J = 9.7, 9.7,
4.9 Hz), 2.65-2.71 (m, 1 H), 1.50-1.58 (m,2 H), 0.83 (dd, 3 H, J =
7.5, 7.5 Hz).
[7]
(a) Wang, W.; Wang, J.; Li, H. Angew. Chem. Int. Ed., 2005, 44,
1369; (b) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W.
Chem. Eur. J., 2006, 12, 4321; (c) Zu, L.; Wang, J.; Li, H.; Wang,
W. Org. Lett., 2006, 8, 3077.
[8]
[9]
[10]
Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett, 2005, 611.
Gu, L.-q.; Zhao, G. Adv. Synth. Catal., 2007, 349, 1629.
(a) Cao, C.-L.;. Ye, M.-C; Sun, X.-L.; Tang, Y. Org. Lett., 2006, 8,
2901; (b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem.