Addition of acetone towards β-cyano-α-oxoesters catalyzed by L-proline: Dynamic kinetic resolution

Article abstract of DOI:10.1002/cjoc.201090219

β-Cyano-α-oxoesters were found to undergo asymmetric aldol addition reaction with acetone in the presence of 10mol% of L-proline. With the racemic starting material, dynamic kinetic resolution (DKR) was achieved in quantitative yields with good diastreros

Full text of DOI:10.1002/cjoc.201090219

FULL PAPER
Addition of Acetone towards β-Cyano-α-oxoesters Catalyzed
by L-Proline: Dynamic Kinetic Resolution
Wang, Yajun*,a(王亚军)
Zhang, Yawen*,b(张雅文)
a School of Life Sciences, Huzhou Teachers College, Huzhou, Zhejiang 313000, China
b Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou, Jiangsu 215123, China
β-Cyano-α-oxoesters were found to undergo asymmetric aldol addition reaction with acetone in the presence of
10 mol% of L-proline. With the racemic starting material, dynamic kinetic resolution (DKR) was achieved in quan-
titative yields with good diastreroselectivity of up to 85∶ 15 dr and excellent ee up to 99% for the major di-
astereomer.
Keywords addition, acetone, L-proline, β-cyano-α-oxoester, dynamic kinetic resolution
Introduction
asymmetric aldol reactions are aldehydes, which have
higher activity than ketones. Recently, L-proline-cata-
lyzed direct aldol reactions of activated ketones as aldol
acceptors were reported.8-10 We recently described a
novel aldol addition system in which an α-ketoester
functions as an acceptor and the donor is an aliphatic
methyl ketone, such as acetone. Direct asymmetric aldol
addition of methyl ketones to α-ketoesters was achieved
using L-proline as the chiral catalyst. Various optically
active α-hydroxyesters were obtained in good-to-excel-
lent yield with enantioselectivity up to 81% ee.11 On the
basis of these results, we hypothesized that a new type
of substrates related with α-ketoesters, which possesses
a labile chiral centre adjacent to the keto carbonyl car-
bon, may reach dynamic kinetic resolution (DKR) in
direct asymmetric aldol addition. We have demonstrated
the first highly enantio- and diastereoselective organo-
catalytic dynamic kinetic resolution (DKR) of 2-oxo-
3-arylsuccinates.12
Further studies focused on modifying structure of
α-ketoesters. Introducing an electron-withdrawing cya-
no group to the β-position of the ester group, created a
labile chiral centre. This feature of α-cyanoketone al-
lows the molecule to racemize in solution under very
mild conditions via keto-enol tautomerization.13 When
the asymmetric aldol reaction is undergone, the sub-
strate and catalyst double asymmetric induction may
greatly improve the selectivity of the aldol reaction,
providing a product with two adjacent chiral centres.
Thus, a dynamic kinetic resolution could be achieved.
Indeed, DKR of the racemic starting material was ob-
served.
The search for new and efficient methods for the
synthesis of optically pure compounds has been an ac-
tive area of research in organic synthesis. While tre-
mendous advances have been made in asymmetric syn-
thesis, either substrate driven or catalytically induced
resolution of racemates is still the most important in-
dustrial approach to the synthesis of enantiomerically
pure compounds. Despite the success of enzyme-cata-
lysed or non-enzyme-catalysed kinetic resolutions for
the generation of a wide range of chiral building blocks,
there is an increasing desire to develop transformations
that are not limited by a maximum yield of only 50% of
the desired product. Increasing attention has been given
in recent years to the discovery of dynamic kinetic
resolution (DKR) reactions, which can result in quanti-
tative yields with enantiomeric excesses approaching
100%.1
DKR is a powerful tool to obtain products with high
enantioselectivity from racemic starting materials,
which combines the resolution step of kinetic resolution,
with an in situ equilibration or racemization of the
chirally labile substrate.2 If the asymmetric reaction cre-
ates a second stereogenic center, the diastereoselectivity
of the product can also be controlled.3
Significant advances have been made in recent years
in the research of asymmetric intermolecular aldol reac-
tion, catalyzed by organomolecules. However, examples
of DKR that achieved through this reaction are rare.4 To
broaden the applicability of the present method is still a
challenging task.5-7 Traditionally, the substrates as ac-
ceptors or electrophiles in nearly all intermolecular
*
E-mail: wyj@hutc.zj.cn; zhangyw@suda.edu.cn; Tel.: 0086-0572-2321166; 0086-0512-65880339; Fax: 0086-0572-2321166; 0086-0512-65880305
Received November 2, 2009; revised February 3, 2010; accepted March 8, 2010.
Project supported by the Civic Natural Science Foundation of Huzhou (No. 2009YZ04) and Outstanding Young Teachers Foundation of Zhejiang
Province (No. 2008[201]).
Chin. J. Chem. 2010, 28, 1267— 1271
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1267

Wang & Zhang
Table 2 Solvent effects for DKR of 1aa
FULL PAPER
Results and discussion
eed/%
Yieldb/
%
d.r.c
We first inveastigated the addition of acetone to-
wards ethyl 3-cyano-2-oxo-3-phenylpropanoate 1a,14 in
the presence of L-proline. As expected, when compound
1a was stired in pure acetone at room temperature for 24
h in the presence of 10 mol% of L-proline, DKR was
achieved. Quantitative yield was obtained with d.r. of
77∶23. 90% and 65% ee were observed for the major
and the minor product, respectively, as determined by
chiral HPLC analysis (Table 1, Entry 1). We next inves-
tigated the effects of the catalyst loading. With reduced
catalyst amount of 5 mol%, prolonged reaction time was
necessary (Entry 2). Elevated reaction rate was observed
as the catalyst loading was increased. However, more
than 80 mol% catalyst resulted in slightly droped selec-
tivity (Entries 5 and 6). In all cases, the yield was quan-
titative.
Entry Product
Solvent
t/h
Major Minor
1
2
2a Acetone
24 ＞99 77∶23 94
65
54
52
51
45
42
42
52
36
4
2a CH3CO2C2H5 36 ＞99 79∶21 96
3
2a CH2Cl2
2a Toluene
2a CH3CN
2a CHCl3
48 ＞99 73∶27 93
48 ＞99 79∶21 96
60 ＞99 79∶21 94
60 ＞99 77∶23 92
4
5
6
7
2a 1,4-Dioxane 72 ＞99 82∶18 91
8
2a THF
108 ＞99 81∶19 94
192 ＞99 83∶17 85
288 ＞99 83∶17 36
9
2a C2H5OC2H5
2a C2H5OH
2a DMF
10
11
12
108 Trace
⎯
⎯
⎯
⎯
⎯
⎯
2a DMSO
124
⎯
b
c
a Isolated yield. By HPLC analysis. The ee value of product
was determined by HPLC analysis using a Chiralpak AS-H col-
umn, the absolute configuration of the product was unknown.
Table 1 DKR of 1a in acetone
Table 3 Temperature effects in the DKR of 1a
eec/%
Temp./
Yielda/
%
Entry Product
t/h
d.r. b
℃
Major Minor
eec/%
Catalyst/
mol%
Yielda/
%
Entry Product
t/h
d.r.b
1
2
3
4
2a
2a
2a
2a
reflux 5
＞99 58∶42
80
94
96
⎯
43
65
69
⎯
Major Minor
20 24
＞99 77∶23
1
2
3
4
5
6
2a
2a
2a
2a
2a
2a
10
5
24 ＞99 77∶23 94
45 ＞99 75∶25 94
12 ＞99 77∶23 94
10 ＞99 75∶25 92
65
65
65
65
64
60
0
148 ＞99 78∶22
－30 360 Trace
⎯
20
40
80
100
a Isolated yield. By HPLC analysis. The ee value of product
was determined by HPLC analysis using a Chiralpak AS-H col-
umn, the absolute configuration of the product was unknown.
b
c
8
8
＞99 73∶27 93
＞99 70∶30 93
a Isolated yield. By HPLC analysis. The ee value of the prod-
uct was determined by HPLC analysis using a Chiralpak AS-H
column, the absolute configuration of the product was unknown.
b
c
20 ℃, improved d.r. of 77∶23 was observed, and the
ee was 94% and 65% for the major and the minor prod-
uct, respectively. Reaction at even lower temperature (0
℃) improved the selectivities slightly further, while
much longer time was necessary (Entry 3). At －30 ℃,
no reaction was observed (Entry 4).
In an effort to improve the diastereoselsctivity of
DKR reaction of 1a, various solvents have been exam-
ined, as shown in Table 2. DMSO and DMF were found
unsuitable for this reaction (Entries 11—12). In all other
solvents explored, including acetone, ethyl acetate, ethyl
ether, THF, 1,4-dioxane, toluene, ethanol, acetonitrile,
methylene chloride and chloroform, quantitative yield
was obtained. Various solvents of distinguishing nature
had little effects on the stereoselectivity of the reaction,
but in ethanol, significantly diminished ee was observed,
probably due to its hydrogen bonding donor property.
The reaction went most quickly in acetone (Table 2,
Entry 1). Influence of the temperature on the reaction of
compound 1 with acetone was then examined. The re-
sults are summarized in Table 3. At the refluxing tem-
perature, the reaction was completed in 8 h, affording
quantitative yield of adduct of 58∶42 d.r. The enanti-
omeric excess of the major and the minor product was
80% and 43%, respectively (Table 3, Entry 1). At
Based on the above results, DKR reactions of a se-
ries of substrates were then conducted at 20 ℃ in ace-
tone, using 10 mol% of L-proline as the catalyst. The
results are shown in Table 4. In every case, the com-
bined yields of diastereomers was quantitative, and high
ee for the major adduct could be achieved. Substituent
on 3-phenyl did not affect the reaction a lot. It looks
likely that, small alkyl in the ester group tended to pro-
vide higher stereoselectivity than the larger ones (En-
tries 8 and 9).
In summary, we have developed an efficient method
for the dynamic kinetic resolutionthe of β-cyano-α-
oxoesters via L-proline catalyzed asymmetric aldol re-
action, which proceeded well for a number of substrates
in various solvents providing quantitative yield with
high ee of the major diastereomeric isomer up to 99%.
1268
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Chin. J. Chem. 2010, 28, 1267— 1271

Addition of Acetone towards β-Cyano-α-oxoesters
Table 4 Results of dynamic kinetic resolutions (DKR) of 1b— 1j a in acetone
eec/%
Entry
R
R1
Product
t/h
Yielda/%
d.r.b
Major
No separation
95
Minor
1
2
3
4
5
6
7
8
9
o-F-Ph
p-F-Ph
p-Cl-Ph
p-Br-Ph
o-CF3-Ph
p-OCH3-Ph
PhCH2
Ph
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
2b
2c
2d
2e
2f
12
30
39
60
78
24
24
30
24
＞99
＞99
＞99
＞99
＞99
＞99
＞99
＞99
＞99
75∶ 25 e
78∶ 22
74∶ 26
85∶ 15
81∶ 19
71∶ 29
68∶ 32
76∶ 24
72∶ 28
66
59
63
85
42
43
63
61
87
97
87
88
86
99
91
2g
2h
2i
Ph
CH2Ph
2j
a Isolated yield. by HPLC analysis. c The ee value of product was determined by HPLC analysis using a Chiralpak AS-H column or a
Chiralpak AD-H colum, the absolute configuration of the product was unknown. e By analysis of the 1H NMR spectrum.
b
Experimental
CDCl3, two diastereomers) δ: 1.16, 1.29 (t, J＝7.2 Hz,
7.2 Hz, 3H, OCH2CH3), 2.13, 2.21 (s, 3H, COCH3),
3.21 (d, J＝17.2 Hz, 1H, COCHH), 3.34 (d, J＝17.2 Hz,
1H, COCHH), 3.90 (br, 1H, OH), 4.07—4.28 (m, 3H,
PhCH, OCH2CH3), 7.27—7.38 (m, 5H, Ar-H); IR (film)
1H NMR and 13C NMR spectra were recorded on a
Varian Inova-400 spectrometer with TMS as internal
standard at 400 and 100 MHz, respectively. Infrared
spectra were obtained on a Nicolet Avatar 360 FT-IR
spectrometer. Elemental analyses were carried out using
Carlo-Erba 1110 Analyzer. Optical rotations were
measured at 589 nm (Na D line) on a WZZ-1 polarime-
ter. The ee values of the products were determined by
HPLC analyses, using Chiralpak AS-H, or Chiralpak
AD-H column. For preparative column chromatography,
silica gel (H60) was used with the solvent system given
in the text. Organic solvents were dried and distilled
prior to use.
ν
max: 3488.4, 3063.9, 2986.8, 2940.5, 2245.9, 1736.5,
1628.4, 1497.2, 1450.9, 1373.8, 1234.8, 1180.8, 1119.1,
－
1
1018.7, 748.6, 702.3 cm . Anal. calcd for C15H17NO4:
C 65.44, H 6.22, N 5.09; found C 65.26, H 6.36, N 5.05.
Enantiomeric excess was determined by HPLC on a
Daicel Chiralpak AS-H column using i-PrOH/hexane＝
20/80 (V/V) as the eluent at a constant flow rate of 1.0
mL/min, monitored at 210 nm, major diastereomer, tR＝
16.15, 17.80, and minor diastereomer, tR＝20.57, 24.37
min.
Ethyl 2-(cyano(2-fluorophenyl)methyl)-2-hydro-
xy-4-oxopentanoate (2b) White sticky solid, yield＞
General procedure
To a suspension of L-proline (10 mol%) in anhy-
drous donor ketone (4 mL) was added the corresponding
α-ketoester (1 mmol). The resulting mixture was stirred
for a certain time in a closed vessel. The reaction pro-
gress was monitored by TLC. After the acceptor
α-ketoester was consumed, the reaction mixture was
treated with saturated ammonium chloride solution, the
organic layer was separated, and the aqueous layer was
extracted with ethyl acetate three times. The combined
organic layers were dried over anhydrous sodium sul-
fate. After removal of the solvent, the residue was puri-
fied through column chromatography on silica gel to
give the pure adduct.
1
99%; d.r.＝75∶25; H NMR (400 MHz, CDCl3, two
diastereomers) δ: 1.20 (t, J＝7.2 Hz, 3H, OCH2CH3),
2.22 (s, 3H, COCH3), 3.25 (d, J ＝17.2 Hz, 1H,
COCHH), 3.41 (d, J＝17.2 Hz, 1H,COCHH), 4.07—
4.20 (m, 2H, OCH2CH3), 4.49 (s, 1H, PhCH),
7.02—7.65 (m, 4H, Ar-H); δ: 1.34 (t, J＝7.2 Hz, 3H,
OCH2CH3), 2.10 (s, 3H, COCH3), 2.70 (d, J＝17.2 Hz,
1H, COCHH), 3.13 (d, J＝17.2 Hz, 1H, COCHH),
4.34—4.36 (m, 2H, OCH2CH3), 4.48 (s, 1H, PhCH),
7.02—7.65 (m, 4H, Ar-H); IR (KBr) νmax: 3542.4,
2994.5, 2955.9, 2245.9, 1736.5, 1620.7, 1589.9, 1497.2,
1458.7, 1373.8, 1242.6, 1173.1, 1126.8, 1018.7, 764.1
－
1
cm . Anal. calcd for C15H16FNO4: C 61.43, H 5.50, N
4.78; found C 61.17, H5.38, N 4.68. Enantiomeric ex-
cess was not determined.
Ethyl 2-(cyano(phenyl)methyl)-2-hydroxy-4-oxo-
pentanoate (2a) White sticky solid, yield＞99%;
1
d.r.＝77∶23, ee＝94%, 65%; H NMR (400 MHz,
Chin. J. Chem. 2010, 28, 1267— 1271
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1269

Wang & Zhang
FULL PAPER
Ethyl 2-(cyano(4-fluorophenyl)methyl)-2-hydro-
2940.5, 2253.6, 1744.2, 1713.3, 1589.9, 1489.5, 1420.1,
1381.5, 1258.0, 1211.7, 1165.4, 1088.2, 1011.0, 825.8
xy-4-oxopentanoate (2c) White sticky solid, yield＞
－
1
1
99%; d.r.＝78∶22, ee＝95%, 66%; H NMR (400
cm . Anal. calcd for C15H16BrNO4: C 50.86, H 4.55, N
3.95; found C 50.57, H 4.55, N 3.86. Enantiomeric ex-
cess was determined by HPLC on a Daicel Chiralpak
AD-H column using i-PrOH/hexane＝10/90 (V/V) as
the eluent at a constant flow rate of 1.0 mL/min, moni-
tored at 210 nm, major diastereomer, tR＝16.86, 22.46,
and minor diastereomer, tR＝18.47, 27.66 min.
MHz, CDCl3, two diastereomers) δ: 1.18, 1.31 (t, J＝7.2
Hz, 3H, OCH2CH3), 2.22 (s, 3H, COCH3), 3.20 (d, J＝
17.2 Hz, 1H, COCHH), 3.33 (d, J＝17.2 Hz, 1H,
COCHH), 3.86 (s, 1H, OH), 4.04 (s, 1H, PhCH), 4.11
(q, J＝7.2 Hz, 2H, OCH2CH3), 7.03—7.11 (m, 2H,
Ar-H), 7.29—7.38 (m, 2H, Ar-H); δ: 1.31 (t, J＝7.2 Hz,
3H, OCH2CH3), 2.15 (s, 3H, COCH3), 2.84 (d, J＝17.2
Hz, 1H, COCHH), 3.17 (d, J＝17.2 Hz, 1H, COCHH),
3.86 (s, 1H, OH), 4.04 (s, 1H, PhCH), 4.09—4.14,
4.23—4.30 (m, 2H, OCH2CH3), 7.03—7.38 (m, 4H,
Ar-H); IR (KBr) νmax: 3364.9, 3056.2, 2994.5, 2940.5,
2215.0, 1705.6, 1651.6, 1474.1, 1404.6, 1381.5, 1350.6,
1242.6, 1157.7, 995.6, 864.4 cm－ 1. Anal. calcd for
C15H16FNO4: C 61.43, H 5.50, N 4.78; found C 61.36,
H 5.02, N 4.71. Enantiomeric excess was determined by
HPLC on a Daicel Chiralpak AD-H column using
i-PrOH/hexane＝15/85 (V/V) as the eluent at a constant
flow rate of 1.0 mL/min, monitored at 210 nm, major
diastereomer, tR＝10.26, 11.45, and minor diastereomer,
tR＝10.86, 14.25 min.
Ethyl
2-(cyano(2-(trifluoromethyl)phenyl)-me-
thyl)-2-hydroxy-4-oxopentanoate (2f) White sticky
1
solid, yield＞99%; d.r.＝19∶81, ee＝85%, 87%; H
NMR (400 MHz, CDCl3, two diastereomers) δ: 1.03,
1.37 (t, J＝7.2 Hz, 7.2 Hz, 3H, OCH2CH3), 2.04, 2.23 (s,
3H, COCH3), 3.28 (d, J＝17.2 Hz, 1H, COCHH), 3.44
(d, J＝17.2 Hz, 1H, COCHH), 3.89—3.95, 4.02—4.08
(m, 2H, OCH2CH3), 4.24 (s, 1H, OH), 4.40—4.42 (m,
1H, PhCH), 7.47—7.49 (m, 1H, Ar-H), 7.51—7.74 (m,
2H, Ar-H), 8.16—8.18 (m, 1H, Ar-H); IR (KBr) ν
:
max
3488.4, 2986.8, 2940.5, 2245.9, 1736.5, 1628.4, 1497.2,
1450.9, 1373.8, 1296.6, 1219.4, 1126.8, 1018.7, 740.9
－
1
cm . Anal. calcd for C16H16F3NO4: C 55.98, H 4.70, N
4.08; found C 55.84, H 4.66, N 4.01. Enantiomeric ex-
cess was determined by HPLC on a Daicel Chiralpak
AD-H column using i-PrOH/hexane＝5/95 (V/V) as the
eluent at a constant flow rate of 1.0 mL/min, monitored
at 210 nm, minor diastereomer, tR＝17.84, 21.59 min,
and major diastereomer tR＝19.40, 23.22 min.
Ethyl 2-((4-chlorophenyl)(cyano)methyl)-2-hydr-
oxy-4-oxopentanoate (2d) White sticky solid, yield＞
1
99%; d.r.＝74∶26, ee＝87%, 59%; Major isomer: H
NMR (400 MHz, CDCl3, two diastereomers) δ: 1.19 (t,
J＝7.2 Hz, 3H, OCH2CH3), 2.14 (s, 3H, COCH3), 3.18
(d, J＝17.2 Hz, 1H, COCHH), 3.32 (d, J＝17.2 Hz, 1H,
COCHH), 3.60—4.00 (br, 1H, OH), 4.04 (s, 1H, PhCH),
4.10 (q, J＝7.2 Hz, 2H, OCH2CH3), 7.25—7.36 (m, 4H,
Ar-H); Minor isomer: 1.31 (t, J ＝ 7.2 Hz, 3H,
OCH2CH3), 2.22 (s, 3H, COCH3), 2.83 (d, J＝17.2 Hz,
1H), 3.16 (d, J＝17.2 Hz, 1H), 3.60—4.00 (br, 1H, OH),
4.27 (s, 1H), 4.10 (q, J＝7.2 Hz, 2H, OCH2CH3),
7.25—7.36 (m, 4H, Ar-H); IR (KBr) νmax: 3403.5,
2986.8, 2940.5, 2253.6, 1744.2, 1721.1, 1597.6, 1489.5,
1420.1, 1381.5, 1288.9, 1211.7, 1173.1, 1088.2, 1018.7,
Ethyl 2-(cyano(4-methoxyphenyl)methyl)-2-hy-
droxy-4-oxopentanoate (2g) White sticky solid, yield
1
＞99%; d.r.＝72 : 28, ee＝83%, 63%; H NMR (400
MHz, CDCl3, two diastereomers) δ: 1.19 (t, J＝7.2 Hz,
3H, OCH2CH3), 2.21 (s, 3H, COCH3), 3.18 (d, J＝17.2
Hz, 1H, COCHH), 3.32 (d, J＝17.2 Hz, 1H, COCHH),
3.80 (s, 1H, OCH3), 3.83 (s, 1H, OH), 4.02 (s, 1H,
PhCH), 4.09—4.15 (m, 2H, OCH2CH3), 6.86—6.91 (m,
2H, Ar-H), 7.22—7.29 (m, 2H, Ar-H); δ: 1.31 (t, J＝7.2
Hz, 3H, OCH2CH3), 2.13 (s, 3H, COCH3), 2.83 (d, J＝
17.2 Hz, 1H, COCHH), 3.15 (d, J＝17.2 Hz, 1H,
COCHH), 3.82 (s, 1H, OCH3), 3.83 (s, 1H, OH), 4.05 (s,
1H, PhCH), 4.25—4.31 (m, 2H, OCH2CH3), 6.86—
6.91 (m, 2H, Ar-H), 7.22—7.29 (m, 2H, Ar-H); IR (KBr)
－
1
825.8 cm . Anal. calcd for C15H16ClNO4: C 58.16, H
5.21, N 4.52; found C 57.92, H 5.21, N 4.66. Enantio-
meric excess was determined by HPLC on a Daicel
Chiralpak AD-H column using i-PrOH/hexane＝20/80
(V/V) as the eluent at a constant flow rate of 1.0 mL/min,
monitored at 210 nm, major diastereomer, tR＝8.75,
10.57, and minor diastereomer, tR＝9.25, 12.67 min.
ν
max: 3488.4, 2979.0, 2940.5, 2840.1, 2245.9, 1744.2,
1613.0, 1512.7, 1458.7, 1373.8, 1304.3, 1250.3, 1180.8,
－
1
1119.1, 1095.9, 1034.2, 841.2 cm . Anal. calcd for
C16H19NO4: C 62.94, H 6.27, N 4.59; found C 62.81, H
6.07, N 4.47. Enantiomeric excess was determined by
HPLC on a Daicel Chiralpak AD-H column using
i-PrOH/hexane＝10/90 (V/V) as the eluent at a constant
flow rate of 1.0 mL/min, monitored at 210 nm, major
diastereomer, tR＝44.48, 58.05, and minor diastereomer,
tR＝50.39, 63.39 min.
Ethyl
2-((4-bromophenyl)(cyano)methyl)-2-hy-
droxy-4-oxopentanoate (2e)
White sticky solid,
1
yield＞99%; d.r.＝85∶15, ee＝97%, 63%; H NMR
(400 MHz, CDCl3, two diastereomers) δ: 1.19 (t, J＝7.2
Hz, 3H, OCH2CH3), 2.22 (s, 3H, COCH3), 3.19 (d, J＝
17.2 Hz, 1H, COCHH), 3.31 (d, J＝17.2 Hz, 1H,
COCHH), 3.87 (brs, 1H, OH), 4.02 (s, 1H, PhCH),
4.10—4.15 (m, 2H, OCH2CH3), 7.19—7.52 (m, 4H,
Ar-H); δ: 1.31 (t, J＝7.2 Hz, 3H, OCH2CH3), 2.14 (s,
3H, COCH3), 2.83 (d, J＝17.2 Hz, 1H, COCHH), 3.16
(d, J＝17.2 Hz, 1H, COCHH), 3.87 (brs, 1H, OH), 4.07
(s, 1H, PhCH), 4.26—4.29 (m, 2H, OCH2CH3), 7.19—
7.52 (m, 4H, ArH); IR (KBr) νmax: 3403.5, 2986.8,
Ethyl 2-(1-cyano-2-phenylethyl)-2-hydroxy-4-oxo-
pentanoate (2h) White sticky solid, yield＞99%;
1
d.r.＝68∶32, ee＝86%, 43%; H NMR (400 MHz,
CDCl3, two diastereomers) δ: 1.30—1.37, 1.38—1.40
(m, 3H, OCH2CH3), 2.17, 2.20 (s, 3H, COCH3),
2.75—2.97 (m, 1H, PhCH2CHCN), 3.00—3.03 (m, 1H,
1270
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1267— 1271

Addition of Acetone towards β-Cyano-α-oxoesters
PhCH2CHCN), 3.04—3.07 (m, 1H, PhCH2CHCN),
3.12 (d, J＝17.2 Hz, 1H, COCHH), 3.28 (d, J＝17.2 Hz,
1H, COCHH), 4.12 (s, 1H, OH), 4.25—4.34 (m, 2H,
H 5.68, N 4.15; found C 71.30, H 5.54, N 4.07. Enan-
tiomeric excess was determined by HPLC on a Daicel
Chiralpak AS-H column using i-PrOH/hexane＝15/85
(V/V) as the eluent at a constant flow rate of 1.0 mL/min,
monitored at 210 nm, major diastereomer, tR＝26.09,
29.34, and minor diastereomer, tR＝35.66, 42.69 min.
OCH2CH3), 7.21—7.35 (m, 5H, Ar-H); IR (KBr) ν
:
max
3488.4, 2986.8, 2932.7, 2855.6, 2253.6, 1744.2, 1721.1,
－
1
1605.3, 1512.7, 1381.5, 1258.0, 1219.4, 1088.2 cm .
Anal. calcd for C16H19NO4: C 66.42, H 6.62, N 4.84;
found C 66.40, H 6.48, N 4.37. Enantiomeric excess
was determined by HPLC on a Daicel Chiralpak AD-H
column using i-PrOH/hexane＝20/80 (V/V) as the eluent
at a constant flow rate of 1.0 mL/min, monitored at 210
nm, major diastereomer, tR＝7.89, 10.21, and minor
diastereomer, tR＝8.64, 10.97 min.
References
1
(a) Huerta, F. F.; Bäckvall, J. E. Org. Lett. 2001, 3, 1209.
(b) Eustache, F.; Dalko, P. I.; Cossy, J. J. Org. Chem. 2003,
68, 9994.
2
3
For review, see: Pellissier, H. Tetrahedron 2003, 59, 8291.
(a) Mordant, C.; Dünkelmann, P.; Ratovelomanana-Vidal,
V.; Genet, J. P. Eur. J. Org. Chem. 2004, 3017.
(b) Studer, M.; Blaser, H. U.; Burkhardt, S. Adv. Synth.
Catal. 2002, 344, 511.
Methyl 2-(cyano(phenyl)methyl)-2-hydroxy-4-oxo-
pentanoate (2i) White sticky solid, yield＞99%; d.r.
＝76∶24, ee＝99%, 63%; 1H NMR (400 MHz, CDCl3,
two diastereomers) major δ: 2.22 (s, 3H, COCH3), 3.21
(d, J＝17.2 Hz, 1H, COCHH), 3.35 (d, J＝17.2 Hz,
1H,COCHH), 3.66 (s, 1H, OCH3), 3.70—3.95 (brs, 1H,
OH), 4.06 (s, 1H, PhCH), 7.29—7.38 (m, 5H, Ar-H);
minor δ: 2.14 (s, 3H, COCH3), 2.87 (d, J＝17.2 Hz, 1H,
COCHH), 3.19 (d, J ＝ 17.2 Hz, 1H, COCHH),
3.70—3.95 (brs, 1H, OH), 3.80 (s, 1H, OCH3), 4.11 (s,
4
(a) Chan, V.; Kim, J. G.; Jimeno, C.; Carroll, P. J.; Walsh, P.
J. Org. Lett. 2004, 6, 2051.
(b) Ward, D. E.; Jheengut, V.; Akinnusi, T. Org. Lett. 2005,
7, 1181.
5
6
(a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(b) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3,
573.
(a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. III. J. Am.
Chem. Soc. 2001, 123, 5260.
1H, PhCH), 7.29—7.38 (m, 5H, Ar-H); IR (KBr) ν
:
max
3488.4, 3033.1, 3009.9, 2940.5, 2245.9, 1751.9, 1713.3,
1628.4, 1489.5, 1435.5, 1381.5, 1250.3, 1219.4, 1173.1,
1142.2, 1088.2, 740.9, 702.3 cm－ 1. Anal. calcd for
C14H15NO4: C 64.36, H 5.79, N 5.36; found C 64.14, H
6.04, N 5.37. Enantiomeric excess was determined by
HPLC on a Daicel Chiralpak AS-H column using
i-PrOH/hexane＝15/85 (V/V) as the eluent at a constant
flow rate of 1.0 mL/min, monitored at 210 nm, major
diastereomer, tR＝23.82, 24.74, and minor diastereomer,
tR＝36.20, 43.36 min.
(b) Córdova, A.; Notz, W.; Barbas, C. F. III. J. Org. Chem.
2002, 67, 301.
7
For the first example for proline-catalyzed direct asymmet-
ric aldol addition between ketone and aldehyde, see: List, B.;
Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000,
122, 2395.
8
9
Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem.
Commun. 2002, 620.
Tokuda, O.; Kano, T.; Gao, W. G.; Ikemoto, T.; Maruoka,
K. Org. Lett. 2005, 7, 5103.
Benzyl 2-(cyano(phenyl)methyl)-2-hydroxy-4-oxo-
pentanoate (2j) White sticky solid, yield＞99%; d.r.
＝72∶28, ee＝91%, 61%; 1H NMR (400 MHz, CDCl3,
two diastereomers) δ: 2.19 (s, 3H, COCH3), 3.21 (d, J＝
17.2 Hz, 1H, COCHH), 3.36 (d, J＝17.2 Hz, 1H,
COCHH), 3.83 (s, 1H, OH), 4.04 (s, 1H, PhCH),
5.00—5.09 (m, 2H, OCH2Ph), 7.19—7.40 (m, 10H,
Ar-H); δ: 2.09 (s, 3H, COCH3), 2.86 (d, J＝17.2 Hz, 1H,
COCHH), 3.19 (d, J＝17.2 Hz, 1H, COCHH), 4.10 (s,
1H, PhCH), 4.17 (s, 1H, OH), 5.19 (s, 2H, OCH2Ph),
7.19—7.40 (m, 10H, Ar-H); IR (KBr) νmax: 3488.4,
3063.9, 3033.1, 2940.5, 2253.6, 1751.9, 1713.3, 1605.3,
1497.2, 1458.7, 1381.5, 1250.3, 1211.7, 1173.1, 1088.2,
10 Samanta, S.; Zhao, C. G. J. Am. Chem. Soc. 2006, 128,
7442.
11 Wang, Y. J.; Shen, Z. X.; Zhang, Y. W. Chin. J. Chem.
2006, 24, 1196.
12 Wang, Y. J.; Shen, Z. X.; Li, B.; Zhang, Y.; Zhang, Y. W.
Chem. Commun. 2007, 1284.
13 Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett.
2001, 3, 2543.
14 Substrates were prepared according to the literature method:
(a) Moffitt, M.; Schultz, H. P. J. Org. Chem. 1977, 42, 2504.
(b) Skinner, G. S. J. Am. Chem. Soc. 1933, 55, 2036.
－
1
740.9, 702.3 cm . Anal. calcd for C20H19NO4: C 71.20,
(E0911022 Zhao, X.; Dong, H.)
Chin. J. Chem. 2010, 28, 1267— 1271
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1271