Highly diastereo- and enantioselective organocatalytic addition of acetone to β-substituted α-ketoesters via dynamic kinetic resolution

Article abstract of DOI:10.1039/b822127h

l-Proline catalyzes the aldol addition reaction of acetone to β-substituted α-ketoesters with dynamic kinetic resolution, providing the desired adduct in good yield with excellent diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to 98% ee)

Full text of DOI:10.1039/b822127h

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Highly diastereo- and enantioselective organocatalytic addition of acetone to
b-substituted a-ketoesters via dynamic kinetic resolution†
Jin Yang, Ting Wang, Zhenhua Ding, Zongxuan Shen and Yawen Zhang*
Received 9th December 2008, Accepted 17th March 2009
First published as an Advance Article on the web 16th April 2009
DOI: 10.1039/b822127h
L-Proline catalyzes the aldol addition reaction of acetone to b-substituted a-ketoesters with dynamic
kinetic resolution, providing the desired adduct in good yield with excellent diastereoselectivity (up to
>99:1 dr) and enantioselectivity (up to 98% ee). The absolute configuration of the chiral adduct was
assigned by single-crystal X-ray diffraction analysis. A tentative explanation of the stereochemical
outcome is proposed.
activated carbonyl is next to a configurationally labile stereogenic
Introduction
centre (Scheme 1, structure A), DKR could be achieved during
Among the numerous synthetic methods that are capable of pro-
the asymmetric aldol reaction; indeed, our group reported the first
organocatalytic aldol reaction of an activated ketone via DKR.11
ducing chiral substances with high enantiomeric excess, catalytic
resolution of racemates is still the most important industrial
However, the diastereoselectivity of this reaction was not very
approach.1,2 Dynamic kinetic resolution (DKR)3 which overcomes
satisfactory (4:1 dr). As a logical extension of our studies on
the drawbacks of kinetic resolution,4 has become a powerful
tool to obtain products with high enantioselectivity from racemic
aldolization with functionalized ketones as acceptors, dicarbonyl
substrates of type A (Scheme 1) were investigated. Here we describe
starting materials. In DKR the kinetic resolution of a racemic
the results of the aldol process of activated ketones catalyzed by
mixture is combined with in situ racemization of the substrate, so
proline and its derivatives.
that the complete conversion of a racemate to a single diastereomer
is theoretically possible.5 However, the theoretical limit is seldom
reached, and so it is highly desirable to develop more efficient
asymmetric reaction with good diastereo- and enantioselectivity.
There are several ways to obtain compounds of high ee through
a DKR process. The use of enzymes for the DKR of racemic
substrates has always been an important strategy in synthesis.6 In
addition to biocatalysts, the use of metal complexes bearing chiral
ligands or chiral auxiliaries for DKR also gained popularity at the
end of the last century. In recent years, the rapidly developing field
of asymmetric organocatalysis has attracted an increasing number
of research groups. Although there has been an explosive growth of
research activities in organocatalysis, examples of organocatalysed
DKR processes are rare.3
Scheme 1 Racemization of activated ketone A through keto–enol trans-
formation (EWG = CO2Et or CF3).
Results and discussion
As one of the basic reactions to create C–C bond, the
organocatalytic7 intermolecular aldol reaction has received much
attention since the pioneering work of Barbas, List, and co-
workers in 2000.8 DKR processes using an intermolecular aldol
reaction between aldehydes and ketones have also been reported.9
However, in most cases, the acceptors in organocatalytic aldol
reactions are aldehydes. Recent work has shown that some
activated ketones, which have an electron-withdrawing group
adjacent to the carbonyl carbon, undergo the asymmetric aldol
reaction as acceptors under mild reaction conditions.10 If the
As there is a fast keto–enol equilibration of the activated ketone
A, it is possible that when the stereoselective aldolization creates a
new chiral center in the activated carbonyl carbon, one enantiomer
of the racemate pair might be preferred, and thus DKR would be
achieved, providing just one diastereoisomer of the four possible
products.
In our initial studies, acetone was used to react with two
different activated ketones in the presence of L-proline as shown in
Scheme 2. The ketone activated by CF3 failed to react with acetone,
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry and Chemical Engineering, Soochow University, Suzhou, 215123,
China. E-mail: zhangyw@suda.edu.cn; Fax: +86 512 65880305; Tel: +86
512 65880340
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra and HPLC data. CCDC reference number 701396. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b822127h
Scheme 2 Direct aldol reaction of acetone and activated ketones.
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Table 1 Direct asymmetric aldol reactions catalyzed by various organocatalystsa
Entry
Catalyst
Catalyst loading/mol%
Time/d
Yield/%b
drc
66:1
ee/% (major)c
1
2
3
4
5
6
7
8
9
a
a
a
a
b
c
d
e
f
5
10
20
30
20
20
20
20
20
20
3
3
3
3
6
0.5
6
6
3
48
75
81
92
46
67
74
36
67
37
97
96
96
90
96
95
70
84
84
72
32:1
43:1
11:1
25:1
29:1
85:1
40:1
22:1
>99:1
10
g
3
a All reactions ware carried out using 0.5 mmol of substrate and 3 ml of acetone at rt. b Isolated yields. c The ee and the dr of the products were determined
by HPLC analysis using a Chiralpak AD-H column.
Table 2 Results of solvents screening for the model reaction
probably because of the stability of the emamine formed between
L-proline and the substrate. However, to our delight, when an
a-ketoester (EWG = CO2Et) was used as the aldol acceptor, excel-
lent diastereoselectivity (43:1 dr) and enantioselectivity (96% ee)
were achieved.
We then undertook a detailed examination of this reaction.
We first screened some readily available proline derivatives as
the catalysts in a model reaction – the addition of acetone to
ethyl 3-methyl-2,4-dioxo-4-phenylbutanoate. As shown in Table 1,
this cross-aldol reaction proceeded smoothly at room temperature
in acetone with most of these catalysts, and excellent ee values
were obtained with L-proline (entry 3), L-prolinamide (entry 5),
or an L-proline-derived tetrazole (entry 6). L-Prolinamide and an
L-proline-derived tetrazole gave a moderate dr and yield, while
N-tosyl-L-prrolinamide showed good distereoselectivity, but poor
enantioselectivity (entry 7). The L-proline-derived amino alcohol g
displayed the best diastereoselectivity, but lower enantioselectivity
(entry 10). Moderate yield and ee were obtained with leucinol,
but the dr was poor (entry 9). Overall therefore, the results using
L-proline were the most promising.
Entry
Solvent
Time/d
Yield/%a
dr b
43:1
70:1
51:1
18:1
1.3:1
18:1
ee/% (major)b
1
2
3
4
5
6
7
8
9
Acetone
THF
3
6
6
6
6
6
6
6
6
6
81
50
57
22
40
30
48
37
20
62
96
97
97
97
29
96
96
96
96
96
CH2Cl2
Toluene
CH3OH
CHCl3
CH3CN
DMF
64:1
>99:1
90:1
DMSO
NMP
10
>99:1
a Isolated yields. b The ee value and the diastereomeric ratio (dr) of the
products were determined by HPLC analysis using a Chiralpak AD-H
column.
Using L-proline as the organocatalyst, we next studied the
influence of catalyst loading on the DKR reactions. As shown
in Table 1, even when the catalyst loading was as low as 5 mol%,
good dr and excellent ee were observed (Entry 1). However, the
reaction was quite slow, and higher catalyst loading resulted
in decreased dr (Entry 4). Therefore, 20 mol% L-proline was
employed subsequently.
We then explored the solvent effects on the DKR reaction. As
shown in Table 2, the reaction yield and diastereoselectivity were
highly solvent-dependent. High diastereomeric ratio and ee were
observed when polar aprotic solvents were used (Table 2, entries
7–10), but the yield was relatively low. The protic solvent CH3OH
seemed to have an adverse influence on enantio- and diastereose-
lectivity, as well as the reaction yield (entry 5). Tetrahydrofuran,
dichloromethane and toluene gave high ee and moderate dr values,
but low yields, as did chloroform. In contrast, in acetone, the
product was obtained in high yield with excellent ee, and the dr
was satisfactory.
Having established the optimized conditions for the model
reaction, we next probed the generality of this DKR reaction
in acetone at room temperature in the presence of 20 mol%
of L-proline. The results are summarized in Table 3. The data
showed that for most of the 3-methyl-2,4-dioxo-4-aryl-butanoates
with R = CH3, good yield, excellent dr (up to > 99:1) and
ee (up to 97%) could be achieved. Bulkier R groups such as
ethyl and isopropyl groups decreased the reaction rate and dr
of the product, although the ee was not affected. It was found
that neither para-alkyl nor para-halogen substitution of the
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Table 3 Dynamic kinetic resolution of 2,4-dioxo-3-methyl-4-aryl-butanoates a
Entry
Ar
R
Time/d
Product
Yield/%b
drc
98:2
87:13
80:20
>99:1
>99:1
>99:1
>99:1
94:6
—
>99:1
97:3
95:5
—
ee (major)c
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
CH3
C2H5
C3H7
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3
6
6
3
3
3
3
3
3
3
6
6
3
2a
2b
2c
2d
2e
2f
2g
2h
2i
81
61
51
72
76
70
72
75
<5
74
77
81
—
96
96
96
92
98
85
94
96
—
94
97
97
—
p-Cl-C6H4
p-Br-C6H4
p-MeO-C6H4
p-iPr-C6H4
2,5-Me2C6H3
2,4,6-Me3C6H2
2-Naphthyl
Furan-2-yl
Thiophen-2-yl
Pyridin-4-yl
2j
2k
2l
2m
a All reactions ware carried out using 0.5 mmol of substrate, 3 ml of acetone and 20 mol% L-proline at rt. b Isolated yield. c The ee values and the
diastereomeric ratios of the products were determined by HPLC analysis using a Chiralpak AD-H or OD-H (for 2h and 2l) column.
benzene ring significantly influenced the selectivity (entries 4, 5
and 7). However, the strongly electron-donating para-methoxyl
group lowered the stereoselectivity to some extent (entry 6). The
4-(2,5-dimethylphenyl) substrate gave a slight decrease in dr
(entry 8). Aryl groups other than phenyl groups, such as 2-naphthyl
(entry 10), furan-2-yl (entry 11) and thiophen-2-yl (entry 12),
all gave satisfactory results. However, when Ar was 2,4,6-
trimethylphenyl or pyridin-4-yl, the reactions were unsuccessful,
probably because the substrates exist almost entirely as the enol
form.12 Attempts using butanone, cyclohexanone, or propanal as
the donor for the above reaction were unsuccessful, and no desired
products were formed. For the determination of the absolute
configuration of the products, a single crystal of 2e was prepared
and X-ray-analyzed (Fig. 1).13
outcome could be explained by examination of the four plausible
transition states (Fig. 2).
In TS1 and TS2, the a-carbonyl oxygen atom is hydrogen-
bonded so that an S-stereogenic centre would be created by the
addition of an acetone molecule, where the large CH(CH3)Bz
group is close to the enamine moiety, and hence energetically less
favoured. In TS3 and TS4, the substrate molecule directs itself in
the way to create an R-stereogenic centre, where the small COOEt
group is close to the enamine. In TS3, the configurationally labile
R-configured substrate molecule is hydrogen-bonded by the pro-
line OH. As the carbonyl group is crowded, the large group on the
b-carbon, COPh, lies anti to the oxygen atom, and thus the
attacking CH2 experiences less hindrance compared to that in
TS4, where the CH3 group in the (S)-form must be consid-
ered. This arrangement results in preferential reaction via TS3,
giving (R)-ethyl 2-hydroxy-4-oxo-2-((S)-1-oxo-1-phenylpropan-2-
yl)pentanoate as the major isomer. Although the transformation
of CO to CHOH leaves the adjacent carbon geometrically fastened
and unchanged, the configuration at this carbon has changed from
(R) to (S) because the ordering of substituents has changed.
Conclusions
In summary, a DKR process employing an asymmetric aldol
addition of acetone to 2,4-dioxo-3-methyl-4-aryl-butanoates that
generates two adjacent stereogenic centers in a single transforma-
tion was developed by using configurationally labile b-substituted
a-ketoesters as aldol acceptors. This proline-catalyzed aldol reac-
tion offers an elegant way to create two adjacent stereogenic cen-
ters simultaneously in a single chemical operation with excellent
diastereoselectivity (up to >99:1 dr) and enantioselectivity (ee up
to 98% ee), providing a truly useful tool for preparing important
chiral compounds. This DKR reaction afforded essentially only
one diastereomeric product in most cases, its configuration was
determined by X-ray analysis of 2e. The stereochemical outcome
has been explained with the help of transition state models.
Fig. 1 ORTEP plot of the major diastereomer of 2e (ORTEP drawing at
10% probability level).
The L-proline-catalysed addition of acetone to the substrate
should occur through the enamine formation process.14 The faster
consumption of the substrate in the R configuration than the S and
their fast equilibration through keto–enol transformation resulted
in dynamic kinetic resolution taking place. The stereochemical
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time given in the text. The mixture was filtered, concentrated,
and purified by column chromatography over silica gel (ethyl
acetate/petroleum ether) to obtain the desired diastereomer. When
a high-boiling solvent (such as NMP, DMF, or DMSO) was used,
the reaction mixture was dissolved in 20 mL water and extracted
with ethyl acetate (3 ¥ 20 mL), the combined extracts washed
with brine (10 mL), and dried over anhydrous sodium sulfate.
After removal of the solvent, the crude products were purified by
column chromatography. The aldol products were characterized
by HRMS, IR, 1H NMR and 13C NMR spectroscopy.
(R)-Ethyl
2-hydroxy-4-oxo-2-((S)-1-oxo-1-phenylpropan-2-
yl)pentanoate (2a). White solid. 81% yield. 1H NMR (400 MHz,
CDCl3), d: 7.99 (d, J = 7.5, 2H, ArH), 7.60 (t, J = 7.4, 1H, ArH),
7.49 (t, J = 7.8, 2H, ArH), 4.68 (s, 1H, OH), 4.13 (q, J = 7.1, 2H,
OCH2CH3), 4.05 (q, J = 7.2, 1H, CH3CH), 3.17 (d, J = 16.8, 1H,
COCHH), 3.03 (d, J = 16.8, 1H, COCHH), 2.23 (s, 3H, COCH3),
1.27 (d, J = 7.2, 3H, CHCH3), 1.18 (t, J = 7.1, 3H, OCH2CH3);
13C NMR (100 MHz, CDCl3) d: 207.74, 204.64, 174.25, 137.00,
133.99, 129.09, 77.87, 62.25, 48.15, 44.90, 31.59, 14.37, 12.97; IR
(KBr) vmax: 3542.2, 3070.0, 2985.2, 1719.9, 1668.9, 1590.4, 1441.7,
1364.6, 1227.6, 966.7, 747.9, 687.4 cm-1. HRMS calculated for
C16H20O5: 292.1311; found: 292.1322. HPLC: Chiralpak AD-H
(i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, l = 254 nm):
tmajor = 14.3 min, tminor = 17.7 min; [a]21D = +31.8 (c 1.01, acetone),
ee = 96%.
(2R,3S)-Ethyl 3-benzoyl-2-hydroxy-2-(2-oxopropyl)pentanoate
1
(2b). White solid, 61% yield. H NMR (400 MHz, CDCl3), d:
8.01 (d, J = 7.5, 2H, ArH), 7.59 (t, J = 7.3, 1H, ArH), 7.48 (t, J =
7.6, 2H, ArH), 4.54 (s, 1H, OH), 4.17–4.05 (m, 2H, OCH2CH3),
3.92 (dd, J = 3.2, 11.2, 1H, CHCH2), 3.15 (s, 2H, COCH2),
2.20 (s, 3H, COCH3), 1.98–1.84 (m, 1H, CHCHHCH3), 1.70–
1.58 (m, 1H, CHCHHCH3), 1.20 (t, J = 7.1, 3H, OCH2CH3),
0.81 (t, J = 7.4, 3H, CHCH2CH3); 13C NMR (100 MHz, CDCl3)
d: 208.87, 204.27, 174.23, 139.30, 133.84, 129.10, 129.03, 78.21,
62.33, 52.32, 47.28, 31.42, 21.84, 14.41, 12.89; IR (KBr) vmax:
3503.6, 3070.5, 2976.5, 1725.7, 1658.5, 1593.9, 1447.7, 1368.3,
1221.1, 1127.4, 990.2, 849.8, 693.1 cm-1. HRMS calculated for
C17H22O5: 306.1467; found: 306.1466; HPLC: Chiralpak AD-H
(i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, l = 254 nm):
tmajor = 11.9 min, tminor = 14.3 min; [a]21D = +44.6 (c 1.04, acetone);
ee = 96%.
Fig. 2 Proposed transition states for the DKR.
Experimental
General methods and materials
General methods. 1H/13C NMR spectra were recorded on a
Varian-Inova-400 instrument at 400/100 MHz, with TMS/CDCl3
as internal standard, respectively. Infrared spectra were obtained
on a Nicolet-Avatar-360 FT-IR spectrometer. Mass spectra were
recorded on a MicroMass TOF-MS spectrometer (EI). Optical
rotations were measured at 589 nm (Na D line) on a Autopol IV
automatic polarimeter. The enantiomeric excesses of the products
were determined by HPLC analysis on a Chiralpak AD-H/or
OD-H column using 2-propanol/hexane as the eluent.
(2R,3S)-Ethyl 3-benzoyl-2-hydroxy-2-(2-oxopropyl)hexanoate
1
(2c). White solid, 51% yield. H NMR (400 MHz, CDCl3), d:
8.04–7.97 (m, 2H, ArH), 7.58 (t, J = 7.4, 1H, ArH), 7.48 (t,
J = 7.6, 2H, ArH), 4.55 (s, 1H, OH), 4.17–4.05 (m, 2H, OCH2),
3.99 (dd, J = 3.0, 11.3, 1H, CH), 3.15 (s, 2H, COCH2), 2.21 (s,
3H, COCH3), 1.97–1.84 (m, 1H), 1.56–1.46 (m, 1H), 1.28–1.06
(m, 5H, CH2CH2CH3 and OCH2CH3), 0.84 (t, J = 7.3, 3H,
CH2CH2CH3). 13C NMR (100 MHz) d: 208.98, 204.20, 174.17,
139.11, 133.81, 129.07, 129.00, 78.25, 62.29, 50.58, 47.14, 31.41,
30.82, 21.58, 14.67, 14.39; IR (KBr) vmax: 3489.5, 3062.5, 2962.4,
2871.8, 1725.6, 1677.8, 1594.3, 1448.7, 1364.8, 1217.0, 1097.9,
760.4, 693.6 cm-1. HRMS calculated for C18H24O5: 320.1624;
found: 320.1625; HPLC: Chiralpak AD-H (i-PrOH/hexane =
10/90, flow rate 1.0 mL/min, l = 254 nm): tmajor = 11.4 min,
Materials. Commercially available starting materials and sol-
vents were used without further purification. Catalysts a and b are
commercially available and c,15 d,16 e,17, f18 and g19 were prepared
according to the literature. Substrate a-ketoesters were synthesized
according to literature methods.20,21
General procedure for the aldol reactions
Catalyst (20 mol%) was added to a mixture of acetone (1 mL) in the
desired solvent (3 mL). The b-substituted a-ketoester (0.5 mmol)
was added and the mixture stirred at room temperature for the
tminor = 13.1 min; [a]21 = +44.5 (c 1.1, acetone); ee = 96%.
D
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(R)-Ethyl 2-((S)-1-(4-chlorophenyl)-1-oxopropan-2-yl)-2-hydro-
xy-4-oxopentanoate (2d). White solid, 72% yield. 1H NMR
(400 MHz, CDCl3), d: 7.92 (d, J = 8.5, 2H, ArH), 7.45 (d, J =
8.4, 2H, ArH), 4.63 (s, 1H, OH), 4.14 (q, J = 7.1, 2H, OCH2),
3.98 (q, J = 7.2, 1H, CHCH3), 3.13 (d, J = 17.0, 1H, COCHH),
3.03 (d, J = 17.0, 1H, COCHH), 2.22 (s, 3H, COCH3), 1.23–1.18
(m, 6H, CHCH3 and CH2CH3); 13C NMR (100 MHz), d: 12.88,
14.38, 31.51, 44.82, 47.72, 62.30, 77.92, 129.34, 130.55, 135.45,
140.42, 174.07, 203.27, 207.95; IR (KBr) vmax: 3507.9, 2994.9,
1745.2, 1661.4, 1585.4, 1403.4, 1221.9, 972.7, 851.1, 771.4 cm-1.
HRMS calculated for C16H17ClO4: (M+–H2O) 308.0815; found:
308.0818; HPLC: Chiralpak AD-H (i-PrOH/hexane = 5/95, flow
rate 1.0 mL/min, l = 254 nm): tmajor = 17.9 min, tminor = 26.0 min;
flow rate 1.0 mL/min, l = 254 nm): tmajor = 10.9 min, tminor
=
14.0 min; [a]21 = +22.3 (c 1.09, acetone); ee = 94%.
D
(R)-Ethyl 2-((S)-1-(2,5-dimethylphenyl)-1-oxopropan-2-yl)-2-
hydroxy-4-oxopentanoate (2h). White solid, 75% yield. 1H NMR
(400 MHz, CDCl3), d: 7.45 (s, 1H, ArH), 7.19 (d, J = 7.8, 1H,
ArH), 7.12 (d, J = 7.8, 1H, ArH), 4.54 (s, 1H, OH), 4.12 (q, J =
7.1, 2H, OCH2CH3), 3.83 (q, J = 7.2, 1H, CHCH3), 3.19 (d, J =
16.5, 1H, COCHH), 2.95 (d, J = 16.6, 1H, COCHH), 2.38 (s, 3H,
ArCH3), 2.36 (s, 3H, ArCH3), 2.22 (s, 3H, COCH3), 1.23–1.20 (m,
6H, OCH2CH3 and CHCH3); 13C NMR (100 MHz), d: 208.08,
207.32, 174.42, 138.08, 135.55, 135.47, 132.62, 132.01, 129.34,
77.50, 62.13, 48.53, 48.40, 31.54, 21.28, 20.69, 14.28, 12.32;
IR (KBr) vmax: 3510.0, 2979.4, 2933.5, 1721.9, 1569.1, 1365.7,
1177.5, 1022.7, 971.9, 873.1, 821.1 cm-1. HRMS calculated for
C18H24O5: 320.1624; found: 320.1620; HPLC: Chiralpak AD-H
(i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, l = 254 nm):
[a]21 = +37.8 (c 1.1, acetone); ee = 92%.
D
(R)-Ethyl 2-((S)-1-(4-bromophenyl)-1-oxopropan-2-yl)-2-hydro-
xy-4-oxopentanoate (2e). White solid, 76% yield. 1H NMR
(400 MHz, CDCl3), d: 7.85 (d, J = 8.6, 2H, ArH), 7.62 (d,
J = 8.6, 2H, ArH), 4.63 (s, 1H, 0H), 4.14 (qd, J = 1.1, 7.1,
2H, OCH2CH3), 3.98 (q, J = 7.2, 1H, CHCH3), 3.12 (d, J =
17.0, 1H, COCHH), 3.03 (d, J = 17.0, 1H, COCHH), 2.22 (s,
3H, COCH3), 1.23-1.18 (m, 6H, CHCH3 and OCH2CH3).; 13C
NMR (100 MHz) d: 207.99, 203.49, 174.06, 135.83, 132.34, 130.64,
129.23, 77.88, 62.32, 47.69, 44.78, 31.52 14.39, 12.89; IR (KBr) vmax:
3505.7, 3095.6, 2993.7, 1744.6, 1720.7, 1661.9, 1580.8, 1399.8,
1219.5, 1135.2, 971.8, 849.1, 767.7 cm-1, HRMS calculated for
C16H19BrO5: 372.0395; found: 372.0408; HPLC: Chiralpak AD-H
(i-PrOH/hexane = 5/95, flow rate 1.0 mL/min, l = 254 nm):
tmajor = 19.5 min, tminor = 28.3 min; [a]21D = +31.4 (c 1.01, acetone);
ee = 98%.
tmajor = 8.4 min, tminor = 11.6 min; [a]21 = +7.8 (c 1.06, acetone);
D
ee = 96%.
(R)-Ethyl 2-hydroxy-2-((S)-1-(naphthalen-2-yl)-1-oxopropan-2-
yl)-4-oxopentanoate (2j). White solid, 74% yield. 1H NMR
(400 MHz, CDCl3), d: 8.51 (s, 1H, ArH), 8.01 (t, J = 9.1, 2H, ArH),
7.96–7.84 (m, 2H, ArH), 7.62 (t, J = 7.0, 1H, ArH), 7.57 (t, J = 7.1,
1H, ArH), 4.73 (s, 1H, OH), 4.20 (q, J = 7.2, 1H, CHCH3), 4.11 (q,
J = 7.1, 2H, OCH2CH3), 3.21 (d, J = 16.8, 1H, COCHH), 3.06 (d,
J = 16.8, 1H, COCHH), 2.24 (s, 3H, COCH3), 1.32 (d, J = 7.2, 3H,
CHCH3), 1.16 (t, J = 7.1, 3H, OCH2CH3).; 13C NMR (100 MHz),
d: 207.73, 204.58, 174.35, 136.22, 134.28, 132.88, 131.08, 130.23,
129.24, 129.03, 128.20, 127.32, 124.55, 77.95, 62.30, 48.31, 45.00,
31.64, 14.41, 13.18; IR (KBr) vmax: 3539.5, 3055.9, 2983.7, 2899.4,
1722.7, 1668.7, 1629.2, 1595.8, 1465.6, 1402.3, 1367.6, 1250.6,
1221.0, 1129.4, 979.9, 833.4, 793.1, 741.4 cm-1. HRMS calculated
for C20H22O5: 342.1467; found: 342.1482; HPLC: Chiralpak AD-
H (i-PrOH/hexane = 5/95, flow rate 1.0 mL/min, l = 254 nm):
(R)-Ethyl 2-hydroxy-2-((S)-1-(4-methoxyphenyl)-1-oxopropan-
2-yl)-4-oxopentanoate (2f). White solid, 70% yield. 1H NMR
(400 MHz, CDCl3), d: 7.97 (d, J = 8.9, 2H, ArH), 6.95 (d, J = 8.9,
2H, ArH), 4.78 (s, 1H, OH), 4.11 (qd, J = 1.8, 7.1, 2H, OCH2CH3),
3.98 (q, J = 7.2, 1H, CHCH3), 3.88 (s, 3H, OCH3), 3.14 (d, J =
16.7, 1H, COCHH), 2.99 (d, J = 16.7, 1H, COCHH), 2.22 (s,
3H, COCH3), 1.25 (d, J = 7.2, 3H, CHCH3), 1.17 (t, J = 7.1,
3H, OCH2CH3).; 13C NMR (100 MHz), d: 207.30, 202.76, 174.04,
164.08, 131.18, 129.46, 113.95, 77.50, 61.79, 55.64, 48.02, 44.14,
31.27 14.04, 12.74; IR (KBr) vmax: 3525.5, 2968.2, 1746.0, 1715.6,
1657.4, 1600.1, 1368.9, 1223.5, 1178.1, 1133.9, 1024.6, 973.5,
854.7 cm-1. HRMS calculated for C17H22O6: 322.1416; found:
322.1408; HPLC: Chiralpak OD-H (i-PrOH/hexane = 5/95, flow
rate 1.0 mL/min, l = 254 nm): tmajor = 11.2 min, tminor = 12.5 min;
tmajor = 38.5 min, tminor = 45.7 min; [a]21 = -4.4 (c 1.04, acetone);
D
ee = 94%.
(R)-Ethyl 2-((S)-1-(furan-2-yl)-1-oxopropan-2-yl)-2-hydroxy-4-
oxopentanoate (2k). White solid, 77% yield. 1H NMR (400 MHz,
CDCl3), d: 7.64 (dd, J = 0.6, 1.5, 1H, ArH), 7.29 (dd, J =
0.6, 3.6, 1H, ArH), 6.57 (dd, J = 1.7, 3.6, 1H, ArH), 4.46 (s,
1H, OH), 4.16 (q, J = 7.1, 2H, OCH2CH3), 3.76 (q, J = 7.2,
1H, CHCH3), 3.15 (d, J = 17.1, 1H, COCHH), 3.04 (d, J =
17.1, 1H, COCHH), 2.21 (s, 3H, COCH3), 1.25 (d, J = 7.2, 3H,
CHCH3), 1.21 (t, J = 7.1, 3H, CH2CH3).; 13C NMR (100 MHz)
d: 207.77, 191.51, 173.90, 152.56, 147.50, 119.15, 112.81, 77.50,
62.09, 47.42, 46.02, 31.25, 14.16, 12.49; IR (KBr) vmax: 3454.8,
3128.9, 2990.1, 1723.4, 1649.7, 1564.5, 1465.1, 1397.4, 1255.6,
1214.1, 1139.4, 1028.6, 979.4, 901.5, 784.5 cm-1. HRMS calculated
for C14H18O6: 282.1103; found: 282.1098; HPLC: Chiralpak AD-
H (i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, l = 254 nm):
tmajor = 27.6 min, tminor = 35.7 min; [a]21D = +47.6 (c 1.05, acetone);
ee = 97%.
[a]21 = +13.3 (c 1.03, acetone); ee = 85%.
D
(R)-ethyl 2-hydroxy-2-((S)-1-(4-isopropylphenyl)-1-oxopropan-
2-yl)-4-oxopentanoate (2g). White solid, 72% yield. 1H NMR
(400 MHz, CDCl3), d: 7.91 (d, J = 8.3, 2H, ArH), 7.32 (d,
J = 8.3, 2H, ArH), 4.72 (s, 1H, OH), 4.12 (q, J = 7.1, 2H,
OCH2CH3), 4.01 (q, J = 7.2, 1H, CHCH3), 3.15 (d, J = 16.7, 1H,
COCHH), 3.04–2.92 (m, 2H, COCHH and CH(CH3)2), 2.22 (s,
3H, COCH3), 1.28-1.24 (m, 9H, CH(CH3)2 and CHCH3), 1.17 (t,
J = 7.1, 3H, OCH2CH3); 13C NMR (100 MHz) d: 207.30, 203.89,
173.98, 155.26, 134.40, 129.03, 126.85, 77.50, 61.81, 47.94, 44.45,
34.33, 31.23, 23.69, 13.99, 12.64; IR (KBr) vmax: 3508.0, 2966.2,
2877.8, 1721.1, 1657.3, 1600.9, 1566.4, 1404.5, 1225.0, 972.8,
858.5, 779.7 cm-1. HRMS calculated for C19H26O5: 334.1780; find:
334.1779; HPLC: Chiralpak AD-H (i-PrOH/hexane = 10/90,
(R)-Ethyl 2-hydroxy-4-oxo-2-((S)-1-oxo-1-(thiophen-2-yl)pro-
pan-2-yl)pentanoate (2l). White solid, 81% yield. 1H NMR
(400 MHz, CDCl3),d 7.83–7.77 (m, 1H, ArH), 7.69 (dd, J = 0.9,
4.9, 1H, ArH), 7.15 (dd, J = 3.9, 4.8, 1H, ArH), 4.55 (s, 1H,
OH), 4.14 (qd, J = 1.7, 7.1, 2H, OCH2CH3), 3.79 (q, J = 7.2,
1H, CHCH3), 3.13 (d, J = 17.1, 1H, COCHH), 3.04 (d, J = 17.0,
2212 | Org. Biomol. Chem., 2009, 7, 2208–2213
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1H, COCHH), 2.21 (s, 3H, COCH3), 1.29 (d, J = 7.2, 3H,
CHCH3), 1.20 (t, J = 7.1, 3H, OCH2CH3).; 13C NMR (100 MHz)
d: 207.69, 196.18, 173.99, 144.39, 135.40, 133.69, 128.70, 77.61,
62.17, 47.69, 47.12, 31.38, 14.25, 13.11; IR (KBr) vmax: 3506.9,
3091.6, 2981.0, 1727.4, 1637.6, 1518.5, 1411.1, 1223.7, 1137.0,
1021.3, 982.4, 915.0, 859.9, 829.3, 743.2 cm-1. HRMS calculated
for C14H18O5S: 298.0875; found: 298.0875; HPLC: Chiralpak
OD-H (i-PrOH/hexane = 5/95, flow rate 1.0 mL/min, l =
254 nm): tmajor = 13.8 min, tminor = 22.1 min; [a]21D = +70.2 (c 1.16,
acetone); ee = 97%.
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J. Am. Chem. Soc., 2001, 123, 5260–5267.
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Org. Lett., 2005, 7, 1181–1184; (b) V. Chan, J. G. Kim, C. Jimeno, P. J.
Carroll and P. J. Walsh, Org. Lett., 2004, 6, 2051–2053.
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Commun., 2002, 620–621; (b) O. Tokuda, T. Kano, W.-G. Gao, T.
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Samanta and C.-G. Zhao, J. Am. Chem. Soc., 2006, 128, 7442–7443;
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and Y.-W. Zhang, Chin. J. Chem., 2005, 23, 584–588; (f) Y. Wang, Z.
Shen, B. Li, Y. Zhang and Y. Zhang, Chem. Commun., 2007, 1284–1286;
(g) G. Luppi, P. G. Cozzi, M. Monari, B. Kaptein, Q. B. Broxterman
and C. Tomasini, J. Org. Chem., 2005, 70, 7418–7421; (h) A. V. Malkov,
M. A. Kabeshov, M. Bella, O. Kysilka, D. A. Malyshev, K. Pluha´cˇkova´
and P. Kocˇovsky´, Org. Lett., 2007, 9, 5473–5476; (i) Z. Tang, L.-F.
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8, 1263–1266; (j) F. Wang, Y. Xiong, X. Liu and X. Feng, Adv. Synth.
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130, 5654–5655.
Ethyl 2-hydroxy-4-mesityl-3-methyl-4-oxobut-2-enoate (1i) (ref.
1
12). White solid. H NMR (400 MHz, CDCl3), d: 1.42 (t, J =
7.1 Hz, OCH2CH3), 1.72 (s, 3H, CCH3), 2.20 (s, 6H, ArCH3 ¥2),
2.31 (s, 3H, ArH3), 4.40 (q, J = 7.1 Hz, 2H, OCH2CH3), 6.90 (s,
1H, ArH), 15.55 (s, 1H, OH).
Ethyl
2-hydroxy-3-methyl-4-oxo-4-(pyridin-4-yl)but-2-enoate
1
(1m) (ref. 12). Yellow solid. H NMR (400 MHz, CDCl3), d:
1.32 (t, J = 7.0 Hz, 3H, OCH2CH3), 1.71 (s, CCH3), 3.66-3.45
(m, 2H, OCH2CH3), 7.49 (dd, J = 1.5, 4.8 Hz, 2H, ArH), 8.71
(dd, 1.5, 4.8 Hz, 2H, ArH).
11 Y. Wang, Z. Shen, B. Li, Y. Zhang and Y.-W. Zhang, Chem. Commun.,
Acknowledgements
2007, 1284–1286.
12 See the NMR spectrum of 1i and 1m.
The authors thank The Key Laboratory of Organic Synthesis of
Jiangsu Province for financial support.
13 Crystal data for 2e: C16H19BrO5, M = 371.22, orthorhombic, space
˚
group P212121, a = 9.6480(19), b = 9.9528(19), c = 17.941(3) A, a = b =
◦
3
˚
g = 90 , V = 1722.8(6) A , T = 293(2) K, reflections collected/unique =
16895/3146, Rint = 0.0531, Goodness-of-fit on F2 1.169, final R indices
[I > 2s(I)], R1 = 0.0748, wR2 = 0.1449, R indices (all data), R1 = 0.1148,
wR2 = 0.1602, absolute structure parameter 0.03(2), largest diff. peak
and hole 0.234 and -0.287 e A-3.See CCDC 701396†.
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