Enantioselective michael addition of malonates to aromatic α,β-unsaturated aldehydes organocatalyzed by (s)-2-[bis(3,4,5- trifluorophenyl) trimethylsilanyloxymethyl]pyrrolidine

Article abstract of DOI:10.2174/157017811796504927

The Michael addition of malonates to aromatic α,β-unsaturated aldehydes was efficiently organocatalyzed by (S)-2-[bis(3,4,5-trifluorophenyl) trimethylsilanyoxymethyl]pyrrolidine, derived from L-proline to afford the corresponding adducts in good yields wi

Full text of DOI:10.2174/157017811796504927

520
Letters in Organic Chemistry, 2011, 8, 520-525
Enantioselective Michael Addition of Malonates to Aromatic ꢀ,ꢁ-Unsatur-
ated Aldehydes Organocatalyzed by (S)-2-[bis(3,4,5-Trifluorophenyl)
trimethylsilanyloxymethyl]pyrrolidine
Haiwei Ye, Yemin Zheng, Chuanming Yu and Weihui Zhong*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P.R. China
Received July 09, 2010: Revised May 03, 2011: Accepted May 30, 2011
Abstract: The Michael addition of malonates to aromatic ꢀ,ꢁ-unsaturated aldehydes was efficiently organocatalyzed by
(S)-2-[bis(3,4,5-trifluorophenyl)trimethylsilanyoxymethyl]pyrrolidine, derived from L-proline to afford the corresponding
adducts in good yields with good to excellent enantioselectivities.
Keywords: (S)-2-[bis(3,4,5-trifluorophenyl)trimethylsilanyloxymethyl]pyrrolidine, enantioselectivity, Michael addition,
organocatalysis.
INTRODUCTION
the subject of intensive research. Among them, chiral secon-
dary amines especially pyrrolidine analogues such as O-
TMS protected diphenylprolinols 1a were proven to be ef-
fective catalysts by activating them through an iminium-ion
As a new field in asymmetric synthesis, organocatalysis
has been growing rapidly in the past few years. It is usually
associated with mild and simple reaction conditions [1], and
1,2-addition reation
O
CO2R2
CO2R2
Lewis acid
R1
CO2R2
CO2R2
R1
Michael addition reation
O
O
CO2R2
chiral catalyst
CO2R2
CO2R2
R1
CO2R2
R1
Fig. (1).
has been proven to be a useful tool in the development of
new methodologies for stereoselective synthesis of optically
active drugs and bioactive natural products.
mechanism [3]. Many other groups had reported ꢀ,ꢀ-
disubstituted 2-pyrrolidinemethanol derivatives also exhib-
ited excellent diastereo- and enantioselectivity [4-6].
It is well known that ꢀ,ꢀ-disubstituted 2-pyrrolidin-
emethanol derivatives are efficient organocatalysts for many
kinds of asymmetric reactions with the iminium mechanism.
The Michael addition is widely recognized as one of the
most versatile carbon-carbon bond forming reactions in or-
ganic synthesis (Fig. 1) [2]. Therefore, to develop the enanti-
oselective and catalytic protocols for this reaction have been
Recently, our group had developed a novel fluoro-
substituted pyrrolidinemethanol derivative 1b to promote
successfully the asymmetric Michael addition-cyclization
between 1,3-dicarbonyl compounds with ꢀ,ꢁ-unsaturated
aldehydes at room temperature (Scheme 1), the ee of the 3,4-
dihydropyran derivatives could be up to 91% [7].
Encouraged by these results, we would extend the scope
of fluoro-substituted pyrrolidinemethanol derivatives for
catalyzing Michael addition of malonates to aromatic ꢀ,ꢁ-
unsaturated aldehydes to afford optically active adducts
which could be transformed into the lactones (Fig. 1).
*Address correspondence to this author at the Key Laboratory of Pharma-
ceutical Engineering of Ministry of Education, College of Pharmaceutical
Sciences, Zhejiang University of Technology, Hangzhou 310014,
P.R. China; Tel/Fax: (0086)57188320752; E-mail: pharmlab@zjut.edu.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers

Enantioselective Michael Addition of Malonates
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
521
R2
O
O
AcO
O
1) 1b (10 mol%), CH2Cl2, PhCO2H
R2
CHO
R1
2) Ac2O, CH2Cl2, Et3N, DMAP
R2
R2
R1
O
R1= alkyl or aryl; R2 = H or Me
up to 91% ee
Scheme 1.
O
O
CO2Et
CO2Et
3a
CO2Et
CO2Et
Cat. 1 (10 mol%)
EtOH, PhCO2H
r.t.
MeO
MeO
2a
4a
R
1a R=Ph, Z=TMS
CO2H
1b R=3,4,5-F3C6H2, Z=TMS
1c R=3,4,5-F3C6H2, Z=H
1d R=3-FC6H4, Z=TMS
R
N
H
N
H
OZ
1e
Scheme 2.
RESULT AND DISCUSSION
are revealed in Table 3. Apparently, acid additives with ap-
propriate pKa values enhanced both the reactivity and enanti-
oselectivity. The primary investigation showed that bases
could not efficiently improve the Michael addition reaction
(Table 3, entry 9). It was found that the additive PhCO2H
could give 87% yield with 91% ee at room temperature
within only 24 hours (Table 3, entry 2). Further research
demonstrated that the ee value could be slightly increased
when the reaction was first carried out at 0oC for 32 hours
(Table 3, entry 4). Other acids additive, such as acetic acid,
3-nitrobenzoic acids, 4-methoxybenzoic acids were suitable
to accelerate this addition and gave better conversion and
enantioselectivity (Table 3, entries 1, 5 and 6). However, few
products were detected in the case of CF3CO2H due to the
decomposition of the catalyst (Table 3, entry 9).
Initially, we chose the addition of diethyl malonate 3a to
4-methoxycinnamaldehyde 2a as a model reaction promoted
by various catalysts. The results in Table 1 indicated that the
reaction conversion and enantioselectivity were influenced
by both the ꢀ-substituted group (Ar) and the O-substituted
group (Z) of the amine catalyst 1 (Scheme 2). A protection
group in the O-position was essential for the reaction. Cata-
lyst 1c was less active to bring out the poor yield and lower
enantioselectivity (Table 1, entry 3). When using compound
1b as catalyst, this reaction was achieved within 24 hours to
give 87% yield and 91% ee of the adduct 4a (Table 1, entry
2), while catalyst 1a afforded only 80% yield and 56% ee of
the adduct (Table 1, entry 1).
Secondly, the effect of various solvents on this reaction
was investigated and the results were illustrated in Table 2. It
was found that EtOH was the optimal solvent to produce
87% yield of the addition product with 91% ee (Table 2,
entry 4). MeOH gave slightly lower yield (76%) and lower
ee (73%) value (Table 2, entry 3). Other solvents such as
acetonitrile, toluene, 2-methyltetrahydrofuran and chloro-
form were less efficient to afford poor yields and ee value
(Table 2, entries 8~11). ꢀ
With the optimal conditions in hand, we examined vari-
ous ꢀ,ꢁ-unsaturated aldehydes and two malonates (Scheme
3), and the results are summarized in Table 4. Generally,
these reactions were completed within 48 h to afford the
good yields and enantioselectivities. The electronic effect of
the substituents at the aromatic ring seems have little influ-
ence on this reaction (Table 4, entries 1-13). The reaction
proceeds especially well for malonate derivatives with di-
ethyl and methyl esters 2. Furthermore, aliphatic ꢀ,ꢁ-
unsaturated aldehydes as substrates failed to produce the
At last, the effects of various additives including acids,
bases and salts were examined and the representative results
Table 1. Catalysts Screening for the Addition of 3a to 2aa
Entry
Catalysts
Time(h)
Yield (%)b
ee (%)c
1
2
3
4
5
1a
1b
1c
1d
1e
24
24
72
24
72
80
87
56
91
69
73
--
40
85
<10
aFor a representative experimental procedure, see experimental. bIsolated total yield based on 2a.cDetermined by chiral HPLC analysis of the corresponding lactone [8].

522 Letters in Organic Chemistry, 2011, Vol. 8, No. 7
Ye et al.
Table 2. Solvents Screening for the Addition of 3a to 2a Catalyzed by 1ba
Entry
Solvents
Time(h)
Yield (%)b
ee (%)c
1
2
EtOAc
H2O
72
72
24
24
72
72
72
72
72
72
72
10
37
76
87
42
23
26
<5
<5
<5
<10
67
72
73
91
66
76
54
--
3
MeOH
EtOH
4
5
i-PrOH
DMSO
DMF
6
7
8
CH3CN
toluene
2-MeTHF
CHCl3
9
--
10
--
11
--
aFor a representative experimental procedure, see experimental. bIsolated total yield based on 2a. cDetermined by chiral HPLC analysis of the corresponding lactone [8].
Table 3. Additive Screening for the Addition of 3a to 2a Catalyzed by 1ba
Entry
Additive s
Time(h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
AcOH
PhCO2H
24
24
24
32
24
24
72
48
72
72
87
79
85
71
79
<5
77
32
75
91
87
97
85
85
--
AcONa
PhCO2Hd
3-NO2C6H4CO2H
4-MeOC6H4CO2H
CF3CO2H
--
76
74
Et3N
c
aFor a representative experimental procedure, see experimental. bIsolated total yield based on 2a. Determined by chiral HPLC analysis of the corresponding lactone [8]. d Reaction
temperature was ꢀoC.
O
O
CO2R2
Cat. 1b, 0oC
CO2R2
CO2R2
R1
CO2R2
EtOH, PhCO2H
R1
2
3
4
Scheme 3.
desired adduct due to predominant side reactions with the
solvent ethanol (Table 4, entry 14).
ꢀ,ꢁ-unsaturated aldehydes, which furnished the products in
good yield with good to excellent enantioselectivities.
Moreover, we developed short procedures for the formation
of chiral lactones, which is the important intermediate of
some chiral drug. More efficient L-proline derived bifunc-
tional organocatalysts and their applications on asymmetric
transformations are now in progress in our lab.
The proposed mechanism for the silyl-protected diaryl-
prolinols catalyzed the similar reaction course was summa-
rized by Jøgensen et al. [9]. The fluorinated catalyst 1b pos-
sibly is attributed to the enhanced catalytic activity and
stronger binding of the substrate via hydrogen bonding in the
transition state (Scheme 4).
EXPERIMENTAL
CONCLUSION
General
In conclusion, we have developed a new organocatalytic
methodology for the Michael addition of malonate esters to
Melting points were determined with a Büchi B-540 cap-
illary melting point apparatus and are uncorrected. H and
1

Enantioselective Michael Addition of Malonates
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
523
Table 4. Reaction of Malonates with ꢀ,ꢁ-Unsaturated Aldehydes Catalyzed by 1ba
Entry
R1
R2
Time (h)
Product/ Yield (%)b
ee (%)c
1
2
4-MeOC6H4
4-MeOC6H4
4-FC6H4
Et
Me
Me
Et
32
24
24
24
36
48
36
48
36
48
36
48
24
48
4a/85
4b/81
4c/85
4d/87
4e/79
4f/75
4g/72
4h/76
4i/68
4j/65
4k/81
4l/80
4m/83
--
97
92
91
98
90
90
88
99
93
98
92
89
99
--
3
4
4-FC6H4
5
4-ClC6H4
4-ClC6H4
3-ClC6H4
3-ClC6H4
4-MeC6H4
3-MeC6H4
2-MeOC6H4
2-MeOC6H4
Ph
Me
Et
6
7
Me
Et
8
9
Me
Et
10
11
12
13
14
Me
Et
Me
Et
Me
aFor a representative experimental procedure, see experimental. bIsolated total yield based on 2a. cDetermined by chiral HPLC analysis of the corresponding lactone [8].
13C NMR spectra were recorded on Varian (400 MHz) in-
struments using TMS as an internal standard. Mass spectra
were measured with a Finnigan Trace DSQ instrument. Op-
tical rotations were measured on a Perkin Elmer Model 341
digital polarimeter. Enantiomeric excesses of products were
determined by HPLC using a Daicel Chiralcel AS-H or OD-
H column and eluting with n-hexane/i-PrOH. All spectro-
scopic data of the products were identical to data from
authentic samples. Starting materials and solvents were pur-
chased from common commercial sources and were used
without additional purification. For chromatography silica-
gel was purchased from Qingdao Haiyang Chemical Co.,
Ltd. (200-300 mesh). All spectral data of the products were
identical to authentic samples.
The mixture was stirred at 0ºC until the starting materials 2
were consumed (monitored by TLC). Then the reaction was
quenched with saturated NaHCO3 solution and extracted
with ethyl acetate (5 mLꢀ3). The combined organic layers
were dried over Na2SO4 and concentrated under vacuum.
The residue was purified by flash column chromatography
(silica gel, petroleum ether:AcOEt) to afford the Michael
adducts 4.
Preparation of Lactons from Michael Adducts
The representative procedure for the synthesis of lactone:
A solution of Michael adduct 4 (1.6 mmol) in methanol (10
mL) was cooled to 0 oC and NaBH4 (1.8 mmol) was added in
portion. The mixture was stirred at room temperature for 30
minutes, then quenched with water and extracted with ethyl
acetate (10 mLꢀ3). The combined organic phases were
washed with brine, dried over anhydrous Na2SO4 and evapo-
rated under vacuum. The residue was dissolved in CH2Cl2
(10 mL) at 0 °C, followed by the addition of trifluoroacetic
acid (0.1 mmol) and stirred for 6 h at room temperature to
complete the lactonization. The reaction was quenched with
aqueous sodium bicarbonate. The organic layer was washed
with water, dried over Na2SO4, and concentrated under vac-
uum. The residue was purified by flash column chromatog-
raphy (silica gel, petroleum ether:AcOEt) to afford the corre-
sponding lactones. The enantiomeric excess (ee) was deter-
mined by HPLC on a chiral phase.
F
F
F
OTMS
F
N
H
F
F
O
R1
O
OR2
OR2
(R)-Diethyl 2-(2-formyl-1-(4-methoxyphenyl)ethy-l)-malo-
nate (4a) [6]
Scheme 4.
20
1
Viscous oil; [ꢀ]D = -32.9º(c = 0.18, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.59 (t, J=1.2 Hz, 1H), 7.16 (d, J=6.8
Hz, 2H), 6.82 (d, J=6.8 Hz, 2H), 4.21 (q, J=7.2 Hz, 2H),
3.99-3.94 (m, 3H), 3.77 (s, 3H), 3.66 (d, J=10.4 Hz, 1H),
2.89-2.84 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.04 (t, J=7.2 Hz,
3H).
General Procedure for the Synthesis of Michael Adducts
(4)
To a suspension of catalyst 1b (0.2 mmol), malonates 3
(2.5 mmol) and benzoic acid (0.2 mmol) in ethanol (2 mL)
was added ꢀ,ꢁ-unsaturated aldehydes 2 (2.0 mmol) at 0ºC.

524 Letters in Organic Chemistry, 2011, Vol. 8, No. 7
Ye et al.
The corresponding lactone is (S)-ethyl 6-hydroxy-4-(4-
methoxyphenyl)-3,4-dihydro-2H-pyran-5-carboxylate. HPLC
(CHIRALPAK AS, Hexane:i-PrOH = 85:15, flow rate 1.0
mL/min, ꢀ = 246nm), tR = 5.45 (major), 6.46 (minor) min.
97% ee.
(R)-Diethyl 2-(1-(4-chlorophenyl)-2-formylethyl)-malonate
(4f) [6]
20
1
Viscous oil; [ꢁ]D = -26.5º(c = 0.19, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.74 (s, 1H), 7.41 (d, J=8.8 Hz, 2H),
7.34 (d, J=8.0 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 4.17-4.09
(m, 3H), 3.81 (d, J=10.0 Hz, 1H), 3.12-2.98 (m, 2H), 1.40 (t,
J=7.2 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H).
(R)-Dmiethyl 2-(2-formyl-1-(4-methoxyphenyl)-ethyl)-
malonate (4b) [4]
20
1
Viscous oil; [ꢁ]D = -28.1º(c = 0.39, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.58 (d, J=1.6 Hz, 1H), 7.16 (d, J=6.8
Hz, 2H), 6.82 (d, J=6.8 Hz, 2H), 3.99-3.97 (m, 1H), 3.77-
3.74 (m, 6H), 3.71 (d, J=10.0 Hz, 1H), 3.52 (s, 3H), 2.90-
2.86 (m, 2H).
The corresponding lactone is (S)-ethyl 4-(4-chlo-
rophenyl)-6-hydroxy-3,4-dihydro-2H-pyran-5-carboxylate.
HPLC (CHIRALPAK AS, Hexane:i-PrOH = 85:15, flow
rate 1.0 mL/min, ꢀ = 246nm), tR = 6.06 (minor), 6.66 (major)
min. 90% ee.
The corresponding lactone is (S)-methyl 6-hydroxy-4-(4-
methoxyphenyl)-3,4-dihydro-2H-pyran-5-carboxylate. HPLC
(CHIRALPAK AS, Hexane:i-PrOH = 85:15, flow rate 0.8
mL/min, ꢀ = 246nm), tR = 9.00 (major), 10.22 (minor) min.
92% ee.
(R)-Dimethyl 2-(1-(3-chlorophenyl)-2-formylethyl)-malo-
nate (4g) [6]
20
1
Viscous oil; [ꢁ]D = -11.4º(c = 0.09, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.61 (s, 1H), 7.26-7.14 (m, 4H), 4.04-
4.00 (m, 1H), 3.75 (s, 3H), 3.75 (d, J=8.0 Hz, 1H), 3.55 (s,
3H), 2.96-2.91 (m, 2H).
(R)-Dimethyl 2-(1-(4-fluorophenyl)-2-formylethyl)- malo-
nate (4c) [4]
The corresponding lactone is (S)-methyl 4-(3-chlo-
rophenyl)-6-hydroxy-3,4-dihydro-2H-pyran-5-carboxylate.
HPLC (CHIRALPAK AS, Hexane:i-PrOH = 83:17, flow
rate 1.0 mL/min, ꢀ = 246nm), tR = 5.78(minor), 6.11 (major)
min. 88% ee.
20
1
Viscous oil; [ꢁ]D = -25.1º(c = 0.27, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.69 (s, 1H), 7.38-7.34 (m 2H), 7.09 (t,
J=8.8 Hz, 2H), 4.18-4.12 (m, 1H), 3.86 (d, J=10.0 Hz, 1H),
3.84 (s, 3H), 3.61 (s, 3H), 3.09-3.02 (m, 2H).
The corresponding lactone is (S)-methyl 4-(4-fluo-
rophenyl)-6-hydroxy-3,4-dihydro-2H-pyran-5-carboxylate.
HPLC (CHIRALPAK AS, Hexane:i-PrOH = 82:18, flow
rate 1.0 mL/min, ꢀ = 246nm), tR = 6.09 (minor), 6.39 (major)
min. 91% ee.
(R)-Diethyl 2-(1-(3-chlorophenyl)-2-formylethyl)-malonate
(4h) [6]
20
1
Viscous oil; [ꢁ]D = -25.4º(c = 0.13, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.75 (s, 1H), 7.41-7.28 (m, 4H), 4.34
(q, J=7.2 Hz, 2H), 4.17-4.10 (m, 3H), 3.82 (d, J=10.0 Hz,
1H), 3.13-2.99 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.18 (t,
J=7.2 Hz, 3H).
(R)-Diethyl 2-(1-(4-fluorophenyl)-2-formylethyl)-malonate
(4d) [6]
o
20
White solid; mp 52.8-53.4 C; [ꢁ]D = -32.7º(c = 0.13,
The corresponding lactone is (S)-ethyl 4-(3-chlo-
rophenyl)-6-hydroxy-3,4-dihydro-2H-pyran-5-carboxylate.
HPLC (CHIRALPAK AS, Hexane:i-PrOH = 80:20, flow
rate 1.0 mL/min, ꢀ = 246nm), tR = 4.98 (major), 5.61 (minor)
min. 99% ee.
1
CHCl3); H NMR (400 MHz, CDCl3): ꢂ 9.60 (s, 1H), 7.27-
7.21 (m, 2H), 6.98 (t, J=4.4 Hz, 2H), 4.21 (q, J=7.2 Hz, 2H),
4.05-3.94 (m, 3H), 3.67 (d, J=9.6 Hz, 1H), 2.98-2.83 (m,
2H), 1.26 (t, J=7.2 Hz, 3H), 1.04 (t, J=6.8 Hz, 3H).
The corresponding lactone is (S)-ethyl 4-(4-fluoro-
phenyl)-6-hydroxy-3,4-dihydro-2H-pyran-5-carboxylate. Vis-
cous oil; HPLC (CHIRALPAK AS, Hexane:i-PrOH = 80:20,
flow rate 1.0 mL/min, ꢀ = 246nm), tR = 4.96 (major), 5.59
(minor) min. 98% ee; 1H NMR (400 MHz, CDCl3): ꢂ 7.84 (s,
1H), 7.18-7.15 (m, 2H), 7.01-6.96 (m, 2H), 4.15-4.05 (m,
3H), 3.90 (d, J=4.8 Hz, 1H), 3.81-3.77 (m, 1H), 2.21-2.13
(m, 1H), 1.83-1.79 (m, 1H), 1.15 (t, J=7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): ꢂ 167.1, 162.7, 160.3, 156.4,
140.3, 129.1, 129.0, 115.2, 115.0, 62.5, 59.8, 34.2, 29.8,
14.2.
(R)-Dimethyl 2-(2-formyl-1-(4-methylphenyl)-ethyl)-malo-
nate (4i) [6]
20
1
Viscous oil; [ꢁ]D = -24.8º(c = 0.23, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.58 (t, J=2.0 Hz, 1H), 7.13-7.08 (m,
4H), 4.03-3.95 (m, 1H), 3.74 (s, 3H), 3.71 (d, J=8.0 Hz, 1H),
3.51 (s, 3H), 2.91-2.87 (m, 2H), 2.29 (s, 3H).
The corresponding lactone is (S)-methyl 6-hydroxy-4-p-
tolyl-3,4-dihydro-2H-pyran-5-carboxylate. HPLC (CHIRA
LPAK AS, Hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, ꢀ
= 246nm), tR = 5.04 (minor), 5.36 (major) min. 93% ee.
(R)-Dimethyl 2-(1-(4-chlorophenyl)-2-formylethyl)- malo-
nate (4e) [6]
(R)-Diethyl 2-(2-formyl-1-(3-methylphenyl)ethyl)-malonate
(4j) [6]
20
1
20
Viscous oil; [ꢁ]D = -37.3º(c = 0.13, CHCl3); 1H NMR
Viscous oil; [ꢁ]D = -19.2º(c = 0.16, CHCl3); H NMR
(400 MHz, CDCl3): ꢂ 9.60 (s, 1H), 7.28-7.18 (m, 4H), 4.02-
3.98 (m, 1H), 3.74 (s, 3H), 3.72 (d, J=9.6 Hz, 1H), 3.53 (s,
3H), 2.95-2.90 (m, 2H).
(400 MHz, CDCl3): ꢂ 9.60 (s, 1H), 7.17 (t, J=7.6 Hz, 1H),
7.03 (d, J=9.6 Hz, 3H), 4.21 (q, J=7.2 Hz, 2H), 4.01-3.93
(m, 3H), 3.69 (d, J=10.0 Hz, 1H), 2.90-2.86 (m, 2H), 2.31 (s,
3H), 1.26 (t, J=7.2 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H).
The corresponding lactone is (S)-methyl 4-(4-chlo-
rophenyl)-6-hydroxy-3,4-dihydro-2H-pyran-5-carboxylate.
HPLC (CHIRALPAK AS, Hexane:i-PrOH = 85:15, flow
rate 1.0 mL/min, ꢀ = 246nm), tR = 5.78(minor), 6.36 (major)
min. 90% ee.
The corresponding lactone is (S)-ethyl 6-hydroxy-4-m-
tolyl-3,4-dihydro-2H-pyran-5-carboxylate. HPLC (CHIRA
LPAK AS, Hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, ꢀ
= 246nm), tR = 5.06 (major), 5.86 (minor) min. 98% ee.

Enantioselective Michael Addition of Malonates
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
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cence. Angew. Chem., Int. Ed. 2008, 47, 4638.
(a) Vicario, J. L.; Badía, D.; Carrillo, L. Organocatalytic Enantiose-
lective Michael and Hetero-Michael Reactions. Synthesis 2007,
2065; (b) Guillena, G.; Ramón, D. J.; Yus, M. Organocatalytic
enantioselective multicomponent reactions. Tetrahedron: Asymme-
try 2007, 18, 693; (c) Enders, D.; Lüttgen, K.; Narine, A. A.
Asymmetric Sulfa-Michael Additions. Synthesis 2007, 959; (d)
Pellissier, H. Asymmetric organocatalysis. Tetrahedron 2007, 63,
9267.
(R)-Dimethyl 2-(2-formyl-1-(2-methoxyphenyl)-ethyl)-
malonate (4k) [6]
20
1
Viscous oil; [ꢀ]D = -34.5º(c = 0.22, CHCl3); H NMR
(400 MHz, CDCl3): ꢁ 9.60 (t, J=0.8 Hz, 1H), 7.27-7.15 (m,
2H), 6.89-6.84 (m, 2H), 4.22-4.19 (m, 1H), 4.10 (d, J=10.8
Hz, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.49 (s, 3H), 2.99 (dd,
J=9.2, 6.8 Hz, 1H), 2.89 (dd, J=4.0, 1.2 Hz, 1H).
[2]
[3]
The corresponding lactone is (S)-methyl 6-hydroxy-
4-(2-methoxyphenyl)-3,4-dihydro-2H-pyran-5-carboxylate.
HPLC (CHIRALPAK AS, Hexane:i-PrOH = 85:15, flow
rate 1.0 mL/min, ꢂ = 246nm), tR = 5.93 (major), 7.08 (minor)
min. 92% ee.
(a) Gaunt, M. J.; Johnsson, C. C. C.; McNally, A.; Vo, N. T. Enan-
tioselective organocatalysis. Drug Discovery Today 2007, 12, 8; (b)
Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.; Hayashi, Y. Enantiose-
(R)-Diethyl 2-(2-formyl-1-(2-methoxyphenyl)ethyl)-malo-
nate (4l) [6]
lective ene reaction of cyclopentadiene and ꢀ,ꢁ -enals catalyzed by
a diphenylprolinol silyl ether. Angew. Chem., Int. Ed. 2006, 45,
6853; (c) Bertelsen, S.; Diner, P.; Johansen, R. L.; Jørgensen, K. A.
Asymmetric organocatalytic ꢃ-hydroxylation of ꢀ,ꢃ-unsaturated al-
dehydes. J. Am. Chem. Soc. 2007, 129, 1536. (d) Bertelsen, S.; Ma-
rigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A. Dienamine ca-
talysis: organocatalytic asymmetric ꢄ-Aamination of ꢀ,ꢃ-unsatura-
ted aldehydes. J. Am. Chem. Soc. 2007, 129, 12973.
Brandau, S.; Landa, A.; Franzén, J.; Marigo, M. and Jørgensen, K.
A.. Organocatalytic conjugate addition of malonates to ꢀ,ꢁ-
unsaturated aldehydes: asymmetric formal synthesis of (-)-
Paroxetine, chiral lactams, and lactones. Angew. Chem., Int. Ed.
2006, 45, 4305.
Ma, A.; Zhu, S.; Ma, D. Enantioselective organocatalytic Michael
addition of malonates to ꢀ,ꢁ -unsaturated aldehydes in water.
Tetrahedron Lett. 2008, 49, 3075.
Wang, Y.; Li, P.; Liang, X.; Ye, J. Base–base bifunctional cataly-
sis: a practical strategy for asymmetric Michael addition of
malonates to ꢀ,ꢁ-unsaturated aldehydes. Adv. Synth. Catal. 2008,
350, 1383.
20
1
Viscous oil; [ꢀ]D = -35.6º(c = 0.36, CHCl3); H NMR
(400 MHz, CDCl3): ꢁ 9.60 (t, J=2.0 Hz, 1H), 7.23-7.16 (m,
2H), 6.88-6.83 (m, 2H), 4.23-4.17 (m, 3H), 4.07 (d, J=10.0
Hz, 1H), 3.91 (q, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.02-2.95 (m,
1H), 2.88-2.82 (m, 1H), 1.26 (t, J=7.2 Hz, 3H), 0.99 (t,
J=7.2 Hz, 3H).
[4]
The corresponding lactone is (S)-ethyl 6-hydroxy
-4-(2-methoxyphenyl)-3,4-dihydro-2H-pyran-5-carboxylate.
HPLC (CHIRALPAK AS, Hexane:i-PrOH = 82:18, flow
rate 0.9 mL/min, ꢂ = 246nm), tR = 7.45 (major), 7.95 (minor)
min. 89% ee.
[5]
[6]
(R)-Dimethyl 2-(2-formyl-1-phenylethyl)malonate (4m) [4]
20
Viscous oil; [ꢀ]D = -26.9º(c = 0.30, CHCl3); 1H NMR
(400 MHz, CDCl3): ꢁ 9.59 (s, 1H), 7.31-7.22 (m, 5H), 4.06-
4.00 (m, 1H), 3.76 (d, J=5.2 Hz, 1H), 3.74 (s, 3H), 3.50 (s,
3H), 2.94-2.90 (m, 2H).
[7]
[8]
Yu, C.; Zheng, F.; Ye, H and Zhong W. Enantioselective synthesis
of functionalized 3,4-dihydropyran derivatives organocatalyzed by
a novel fluorinated-diphenylprolinolether. Tetrahedron 2009, 65,
10016.
The lactones prepared from Michael adducts were enolizable form,
as follows:
The corresponding lactone is (S)-methyl 6-hydroxy-4-
phenyl-3,4-dihydro-2H-pyran-5-carboxylate. HPLC (CHIR
ALPAK AS, Hexane:i-PrOH = 85:15, flow rate 1.0 mL/min,
ꢂ = 246nm), tR =5.30 (minor), 7.20 (major) min. 99% ee.
O
OH
CO2R2
REFERENCE
R1
[1]
(a) Dalko, P. I.; Moisan, L. In the golden age of organocatalysis.
Angew. Chem., Int. Ed. 2004, 43, 5138; (b) List, B.; Seayad, J.
Asymmetric organocatalysis. Org. Biomol. Chem. 2005, 3, 719; (c)
Connon, S. J, Chiral phosphoric acids: powerful organocatalysts for
[9]
Carlone, A.; Cabrera, S.; Marigo, M.; Jøgensen, K. A.. A new
approach for an organocatalytic multicomponent domino asymmet-
ric reaction. Angew. Chem., Int. Ed. 2007, 46, 1101.