Highly enantioselective synthesis of α-stereogenic esters through catalytic asymmetric Michael addition of 4-oxo-4-arylbutenoates

Article abstract of DOI:10.1002/chem.201001129

Highly enantioselective Michael addition of 1,3-dicarbonyl compounds and nitromethane to 4-oxo-4-arylbutenoates catalyzed by N,N'-dioxide-Sc(OTf) ₃ complexes has been developed. Using 0.5-2 mol% catalyst loading, various a-stereogenic esters were obtained regioselectively with excellent yields (up to 97%) and enantioselectivities (up to >99% ee). Moreover, the reaction performed well under nearly solvent-free conditions. The products with functional groups are ready for further transformation, which showed the potential value of the catalytic approach. According to the experimental results and previous reports, a plausible working model has been proposed to explain the origin of the activation and the asymmetric induction.

Full text of DOI:10.1002/chem.201001129

DOI: 10.1002/chem.201001129
Highly Enantioselective Synthesis of a-Stereogenic Esters through Catalytic
Asymmetric Michael Addition of 4-Oxo-4-arylbutenoates
Zhen Wang,[a] Donghui Chen,[a] Zhigang Yang,[a] Sha Bai,[a] Xiaohua Liu,[a]
Lili Lin,[a] and Xiaoming Feng*[a, b]
Abstract: Highly enantioselective Mi-
chael addition of 1,3-dicarbonyl com-
pounds and nitromethane to 4-oxo-4-
arylbutenoates catalyzed by N,N’-diox-
selectivities (up to >99% ee). More-
over, the reaction performed well
under nearly solvent-free conditions.
The products with functional groups
are ready for further transformation,
which showed the potential value of
the catalytic approach. According to
the experimental results and previous
reports, a plausible working model has
been proposed to explain the origin of
the activation and the asymmetric in-
duction.
ide–ScACHTUNGTRENNUNG(OTf)3 complexes has been de-
veloped. Using 0.5–2 mol% catalyst
loading, various a-stereogenic esters
were obtained regioselectively with ex-
cellent yields (up to 97%) and enantio-
Keywords: asymmetric catalysis
chirality enantioselectivity
Michael addition · scandium
·
·
·
Introduction
that chiral HfIV and ZrIV complexes promoted Friedel–Crafts
reaction of indoles to electrophiles including 1,4-diaryl-2-
butene-1,4-diones and 4-oxo-4-arylbutenoates with high
enantioselectivities.[4] Xiao and co-workers reported that
chiral urea derivatives worked well for conjugate addition of
nitroalkanes to 4-oxo-enoates.[5a] Despite these impressive
contributions, simple dialkylmalonates and a-substituted
malonates have not been developed as nucleophiles in con-
jugate additions with 4-oxo-4-arylbutenoates. Therefore, the
development of new and more efficient approaches for the
enantioselective Michael addition of 4-oxo-4-arylbutenoates
is still challenging and in high demand (Scheme 1).[6,7]
The Michael addition of carbon nucleophiles to electron-de-
ficient olefins represents one of the most powerful strategies
for the formation of carbon–carbon bonds in organic synthe-
sis.[1] Recently, 1,4-dicarbonyl but-2-enes have been devel-
oped as Michael acceptors to generate an a-stereogenic
center with respect to one of carbonyl groups, which are
useful building blocks for the synthesis of natural com-
pounds. Tedrow et al. reported that rhodium complexes cat-
alyzed Michael addition of arylboronic acids to 1,4-dicar-
bonyl but-2-enes, such as (E)-4-oxo-4-arylbutenamides and
dialkyl fumarates, with high enantioselectivities.[2a] Tan and
co-workers found that chiral bicyclic guanidines catalyzed
highly enantioselective Michael addition of 1,3-alkylthiomal-
onates with 1,4-dicarbonyl but-2-enes to generate a-stereo-
genic esters, amides, and ketones.[3] Pedro et al. reported
[a] Z. Wang, D. Chen, Z. Yang, S. Bai, Dr. X. Liu, Dr. L. Lin,
Prof. Dr. X. Feng
Scheme 1. Conjugate addition of carbon nucleophiles to 4-oxo-4-arylbute-
noates.
Key Laboratory of Green Chemistry and Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P.R. China)
Fax : (+86)28-8541-8249
ScACTHNUGTRENNG(U OTf)3, which features such advantages as stability, re-
E-mail: xmfeng@scu.edu.cn
covery, and reusability, has shown highly catalytic activity in
[b] Prof. Dr. X. Feng
many transformations.[8] As excellent chiral scaffolds, N,N’-
State Key Laboratory of Oral Diseases
Sichuan University, Chengdu 610064 (P.R. China)
dioxides[9] were able to coordinate with Sc
ACHTNUTRGNE(UNG OTf)3 and exhib-
ited great potential in various reactions such as allylation,[10a]
aza-Diels–Alder reactions,[10b] Michael reactions,[10c] Friedel–
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001129.
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Chem. Eur. J. 2010, 16, 10130 – 10136

FULL PAPER
Crafts reactions,[10d–f] and amination.[10k] Herein we expanded
the scope of this approach in an asymmetric Michael reac-
tion using 1,3-dicarbonyl compounds and nitromethane as
the nucleophiles and (E)-4-oxo-4-arylbutenoates as the Mi-
gands derived from aliphatic amines, such as tert-butylamine
and benzylamine, could achieve higher yields but slight
lower enantioselectivities (up to 83% yields; entries 5 and 6
vs. entry 1). As for the chiral backbone moiety, when (S)-
ramipril-derived N,N’-dioxide L7 was used instead of those
derived from (S)-pipecolic acid, good yield and excellent
enantioselectivity were both achieved (85% yield, 99% ee;
Table 1, entry 7). It was found that the addition of 4 ꢁ mo-
lecular sieves (MS) could further improve the yield without
the loss of enantioselectivity (93% yield, 99% ee; Table 1,
entry 8).
chael acceptors. A chiral N,N’-dioxide–scandiumACTHNUTRGNEUG(N III) com-
plex system also allowed expedient access to functionalized
a-stereogenic esters in high yields with excellent regioselec-
tivities and enantioselectivities (ee values up to >99%) with
a low catalyst loading (as low as 0.5 mol%).
Results and Discussion
Encouraged by the initial results, various solvents were
tested in the presence of L7–ScACHTUNRGTNEUNG(OTf)3 (Table 2). As shown
Initially, we examined the asymmetric Michael addition of
in Table 2, the solvent played an important role in governing
a-chloromalonate (1a) and ethyl (E)-4-oxo-4-phenylbute-
noate (2a) promoted by ScACTHNUTRGNE(NUG OTf)3–N,N’-dioxide complexes
(Table 1). The amide moiety in the N,N’-dioxide ligands had
Table 2. Solvent and concentration effects on the Michael addition of 1a
and 2a.[a]
Table 1. Screening of ligands for the Michael addition of 1a and 2a.[a]
Entry
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
THF
CH3CN
DMF
EtOH
CH2Cl2
toluene
EtOH
EtOH
24
24
24
12
24
48
6
73
65
43
93
88
trace
95
96
96
90
96
99
85
–
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
L7
L7
75
63
52
72
82
83
85
93
98
99
98
99
89
92
99
99
7[d]
8[e]
99
99
2
[a] Unless otherwise noted, reactions were carried out with 2a
(0.1 mmol) and 1a (0.3 mmol) with 5 mol% L7/Sc(OTf)3 (1.1:1) and 4 ꢁ
7
8[d]
AHCTUNGTRENNUNG
molecular sieves (10 mg) in solvents (0.2 mL) under nitrogen at 308C.
[b] Isolated yield. [c] Determined by chiral HPLC analysis. [d] 0.1 mL
EtOH was used. [e] The reaction was carried out on a 0.3 mmol scale
with 4 ꢁ molecular sieves (30 mg) in the presence of EtOH (10 mL).
[a] Unless otherwise noted, reactions were carried out with 2a
(0.1 mmol) and 1a (0.3 mmol) with 5 mol% L/Sc(OTf)3 (1.1:1) in EtOH
(0.2 mL) under nitrogen at 308C for 24 h. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis. [d] In the presence of 4 ꢁ molecular
sieves (10 mg), reaction time: 12 h.
AHCTUNGTRENNUNG
the rate and enantioselectivity of the reaction. Highly polar
solvents such as THF, EtOH, CH3CN, and DMF achieved
good enantioselectivities (Table 2, entries 1–4). Using
CH2Cl2 gave moderate results (Table 2, entry 5). However,
no reaction took place in toluene (Table 2, entry 6). The
concentration of substrate and catalyst were also key factors.
When EtOH (0.1 mL) was used, the product was obtained
in high yield and the enantioselectivity was maintained
(95% yield, 99% ee; Table 2, entry 7 vs. entry 4). Excitingly,
further decreasing the volume of EtOH to 10 mL still led to
an excellent result, and the reaction time was shortened to
2 h (Table 2, entry 8 vs. entry 7).
a significant effect on the enantioselectivity and reactivity
(Table 1, entries 1–6; for screened ligands, see Scheme 2).
N,N’-Dioxides L1–L4 derived from aromatic amines exhibit-
ed excellent enantioselectivities and moderate yields
(Table 1, entries 1–4), and ligands with an electron-donating
substituent at the ortho position of the aromatic ring de-
creased the yields (entries 2 and 3 vs. entry 1). However, li-
To further improve the efficiency of the reaction, the re-
action temperature and catalyst loading were examined. The
results are presented in Table 3. A decrease in the reaction
temperature led to low reactivity (Table 3, entry 1 vs.
entry 2). When the temperature was increased from 30 to
408C, the reactivity increased without any loss of enantiose-
lectivity (Table 3, entry 3 vs. entry 2). The catalyst loading
was then evaluated. A reduction in the catalyst loading
could still result in excellent enantioselectivities; however,
Scheme 2. Ligands screened in this study.
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X. Feng et al.
Table 3. Effects of temperature and catalyst loading on the Michael addi-
(Table 4, entries 2–5). Other a-substituted malonates were
also employed as nucleophiles in the Michael reaction, and
various products that bore a quaternary carbon center were
obtained (Table 4, entries 6–9). a-Methyl malonate 1 f and
a-allyl malonate 1g reacted smoothly with 4-oxo-4-phenyl-
butenoate (2a) to afford the products with excellent results
(Table 4, entries 6 and 7). Unfortunately, the reactions with
a-bromomalonate 1h or a-phenylmalonate 1i gave only
trace products (Table 4, entries 8 and 9). The a-unsubstitut-
ed b-ketoester 1j and a-substituted b-ketoester 1k were
also tolerated in the current system (Table 4, entries 10 and
11).
tion of 1a and 2a.[a]
Entry T [8C] Catalyst loading [mol%] t [h] Yield [%][b] ee [%][c]
1
2
3
4
0
5
5
5
1
0.75
0.5
24
2
1
12
20
30
83
96
95
96
95
86
98
99
99
99
99
99
30
40
40
40
40
5
6[d]
[a] Unless otherwise noted, reactions were carried out with 2a
(0.3 mmol) and 1a (0.9 mmol) in the presence of EtOH (10 mL) with L7/
ScACHTUNGTRENNUNG(OTf)3 (1.1:1) and 4 ꢁ molecular sieves (30 mg) under nitrogen.
[b] Isolated yield. [c] Determined by chiral HPLC analysis. [d] The reac-
tion was carried out with 2a (0.4 mmol) and 1a (1.2 mmol) in the pres-
ence of EtOH (10 mL) and 4 ꢁ molecular sieves (40 mg) with L7/Sc-
Subsequently, the scope of the conjugate addition of a-
chloromalonate 1a to a variety of (E)-4-oxo-4-arylbute-
noates was tested, and the results are summarized in
Table 5. It was noteworthy that either the electronic nature
ACHTUNGTRENNUNG(OTf)3 (1.1:1) under nitrogen at 408C.
Table 5. Enantioselective Michael additions of (E)-4-oxo-4-arylbute-
noates 2 with malonate 1a under the optimal conditions.[a]
the reactivity decreased slightly (Table 3, entries 4–6).
Therefore, the optimal conditions were identified as follows:
L7–ScACHTUNGTRENNUNG(OTf)3 complex (0.75 mol%; L7/ScACHTUNTGERN(NUGN OTf)3 1.1:1), 4 ꢁ
MS (30 mg), (E)-4-oxo-4-arylbutenoate (0.3 mmol), malo-
nate (0.9 mmol), and EtOH (10 mL) at 408C.
Under the optimized conditions, we next examined the
scope of the Michael addition with series of malonates 1a–k
(Table 4, entries 1–9). As shown in Table 4, the ester groups
apparently had little effect on the enantioselectivity of the
reaction, and the large ester groups such as isopropyl and
tert-butyl esters increased the reactivity of the reaction
Entry
Ar
t [h]
Adduct
Yield [%][b]
ee [%][c]
1
2
3
Ph
20
24
24
28
24
24
24
28
32
32
30
26
24
48
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
95
96
96
95
95
97
96
95
86
90
84
92
93
78
99
99
95
99
99
98
99
98
4-MeC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-BrC6H4
4-FC6H4
3-MeOC6H4
4-MeOC6H4
2-furyl
4[d]
5[d]
6[d]
7[d]
8[d]
9
Table 4. Enantioselective Michael additions of 2a with malonates and
ketoesters under the optimal conditions.[a]
90
98
93
10
11
12
13
14
2-thienyl
2-naphthyl
2n[f]
99 (S)[e]
98
98
Entry
1
R1, R3
R2
t [h]
Yield [%][b]
ee [%][c]
[a] Unless otherwise noted, reactions were carried out with 2 (0.3 mmol)
and 1a (0.9 mmol) in the presence of EtOH (10 mL) and 4 ꢁ molecular
sieves (MS; 30 mg) with L7/ScACHTUNTRGNEUNG(OTf)3 (0.75 mol%, 1.1:1) under nitrogen
at 408C for 24–30 h. [b] Isolated yield. [c] Determined by chiral HPLC
analysis. [d] The reaction was carried out with 2 (0.4 mmol) and 1a
(1.2 mmol) in the presence of EtOH (10 mL) and 4 ꢁ molecular sieves
1
1a
1b
1c
1d
1e
1 f
1g
1h
1i
OMe, OMe
OMe, OMe
OEt, OEt
OiPr, OiPr
OtBu, OtBu
OEt, OEt
OEt, OEt
OEt, OEt
OEt, OEt
Me, OiPr
Cl
H
H
H
H
Me
allyl
Br
Ph
H
20
36
36
15
36
26
48
48
48
30
95
72
82
93
90
94
89
trace
trace
85
99
95
98
98
97
98
>99
–
2[d]
3[d]
4
5[d]
6
(40 mg) with L7/ScACTHNUTRGNEUNG(OTf)3 (0.5 mol%, 1.1:1) under nitrogen at 408C.
[e] The absolute configuration was determined by X-ray analysis. [f] (E)-
1,4-Diphenyl-2-butene-1,4-dione was used as the Michael acceptor in
CH2Cl2/EtOH (0.3 mL:0.1 mL) with 2 mol% catalyst at 358C for 48 h.
7
8
9[d]
10[e]
–
1j
90/90
11[d,f]
1k
30
83
95/95
or the position of the substituents at the aromatic ring had
little influence on the enantioselectivity (up to 99% ee;
Table 5, entries 1–10). Substrates that bore a heteroaryl con-
densed ring also proved to be competent candidates for con-
jugate addition (Table 5, entries 11–13; Figure 1). In addi-
tion, (E)-1,4-diphenyl-2-butene-1,4-dione (2n) was used as a
Michael acceptor to generate an a-stereogenic ketone with
excellent enantioselectivity (Table 5, entry 14).
[a] Unless otherwise noted, reactions were carried out with 2a
(0.3 mmol) and
0.75 mol% L7/ScACHTUNGTRENNUNG(OTf)3 (1.1:1) and 4 ꢁ molecular sieves (30 mg) under
nitrogen at 408C. [b] Isolated yield. [c] Determined by chiral HPLC anal-
ysis. [d] The reaction was carried out with 1.5 mol% L7/Sc(OTf)3 (1.1:1)
1
(0.9 mmol) in the presence of 10 mL EtOH with
AHCTUNGTRENNUNG
and 30 mg 4 ꢁ molecular sieves in EtOH (0.1 mL) under nitrogen at
308C. [e] Diastereomeric ratio (d.r.): 56:44. [f] d.r. 67:33.
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Synthesis of a-Stereogenic Esters
FULL PAPER
ditions, thereby giving the corresponding products in good
yields and excellent enantioselectivities (95–99% ee,
Table 7, entries 1–11).
Table 7. Enantioselective Michael additions of (E)-4-oxo-4-arylbute-
noates 2 with nitromethane.[a]
Entry
Ar
Adduct
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4j
85
87
93
85
83
83
78
83
85
88
83
98
99
95
96
99
4-MeC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-BrC6H4
4-FC6H4
4-MeOC6H4
2-thienyl
2-naphthyl
>99
98 (R)[d]
99
Figure 1. X-ray structure of compound 3al.
9
10
11
99
99
99
4l
4m
Encouraged by the success of the conjugate addition of
malonate to (E)-4-oxo-4-arylbutenoates, we also investigat-
ed nitromethane as nucleophile. As shown in Table 6, N,N’-
dioxide L8 derived from aromatic amine exhibited superior
[a] The reactions were carried out with 2 (0.3 mmol) and nitromethane
(0.32 mL) with L8/Sc(OTf)3/DMAP (2 mol%, 1.1:1:1) under nitrogen at
308C for 12 h. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
[d] The absolute configuration was determined by comparison with litera-
ture data.[5a]
AHCTUNGTRENNUNG
Table 6. Optimization of reaction conditions.[a]
To show the synthetic application of the current system, a
gram-scale synthesis of 3aa/4a was tested. As shown in
Scheme 3, using only 0.5 mol% of L7–ScACTHNUTRGENUG(N OTf)3, catalytic
asymmetric Michael addition of a-chloromalonate (1a) with
ethyl (E)-4-oxo-4-phenylbutenoate (2a) was accomplished
with excellent results (1.021 g, 92% yield, 98% ee). Impor-
tantly, the amount of a-chloromalonate 1a was decreased to
1.5 equiv with respect to ethyl (E)-4-oxo-4-phenylbutenoate
(2a; Scheme 3a). In addition, the product 3ea can also be
easily transformed into optically active compound 6 in two
steps (48% yield, 96% ee), which is a versatile building
block (Scheme 3b). The reaction could be performed with
Entry
Ligand
Additive
Yield [%][b]
ee [%][c]
1
2
L7
L8
L8
L8
–
–
17
25
85
82
30
98
98
98
3[d]
4[e]
DMAP
DMAP
[a] Unless otherwise noted, reactions were carried out with 2a
(0.3 mmol) and nitroalkane (0.32 mL) with L/Sc(OTf)3 (1.1:1) under ni-
trogen at 308C for 12 h. [b] Isolated yield. [c] Determined by chiral
HPLC analysis. [d] In the presence of N,N-dimethylpyridin-4-amine
AHCTUNGTRENNUNG
(DMAP; 5 mol%). [e] The catalyst was L8/ScACTHNUTRGENUG(N OTf)3/DMAP (2 mol%,
nitromethane in the presence of 1 mol% L8–ScACTHNUGTRENUNG(OTf)3, thus
1.1:1:1).
giving the desired product 4a with excellent enantioselectiv-
ity. Also, a b2-amino acid[11] derivative could be prepared
from the product 4a by following known procedures (Sche-
me 3c).[5a]
results to L7 based on aliphatic amine with excellent enan-
tioselectivity (Table 6, entry 2 vs. 1). For the improvement of
the yield, the addition of N,N-dimethylpyridin-4-amine
(DMAP) was effective to afford the desired Michael adduct
4a in 85% yield with 98% ee (Table 6, entry 3). The role of
the organic base DMAP is that it might deprotonate the a
proton of nitromethane to generate an ammonium nitronate
and accelerate the reaction rate. Excitingly, the catalyst
loading could be decreased to 2 mol% without affecting the
efficiency of the catalyst (Table 6, entry 4). Under the opti-
mized conditions, the substrate scope was then surveyed.
Various (E)-4-oxo-4-arylbutenoates with electron-withdraw-
ing or -donating groups on the aromatic ring reacted with ni-
tromethane smoothly using 2 mol% catalyst under mild con-
To gain insight into the reaction mechanism,[12] several
control experiments were carried out, and the results are
summarized in Table 8. As shown in Table 8, the ratio of
ligand L7 to Sc
creased remarkably when a 1.5:1 molar ratio of Sc
was used because of the strong background reaction of Sc-
(OTf)3 (Table 8, entry 1). In addition, when the molar ratio
of ligand L7 to Sc(OTf)3 was increased from 1:1 to 2:1, the
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
chemical yields and enantioselectivities were clearly de-
creased (Table 8, entries 2–5). The catalytic composition was
also investigated by using ESIMS, and the results indicated
that an MS peak at 903.2973 (HR-ESIMS: m/z calcd for
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X. Feng et al.
tached to Sc3+ at the favorable
equatorial position.[16] The in-
coming a-chloromalonate (1a)
preferred to attack the Si face
rather than Re face since the
latter was strongly shielded by
the nearby benzyl ring, thereby
giving the S-configured product
(Scheme 4).
Conclusion
We have developed a catalytic
asymmetric Michael addition of
1,3-dicarbonyl compounds and
nitromethane with a wide range
of (E)-4-oxo-4-arylbutenoates
promoted by N,N’-dioxide–Sc-
AHCTUNRTGEG(NNNU OTf)3 complexes. This simple
Scheme 3. Catalytic asymmetric conjugate addition of a-chloromalonate (1a and 1e) and nitromethane to
ethyl (E)-4-oxo-4-phenylbutenoate (2a) on a gram scale, and the transformation of 3ea to 6.
experimental protocol affords
various a-stereogenic esters in
high yields (up to 97%) as well
Table 8. Control experiments for mechanistic studies.[a]
Entry L7 [mol%] ScACTHNUTRGNEUNG
(OTf)3 [mol%] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
1
1
1.2
1.5
2
1.5
15
15
15
24
24
95
94
94
89
85
34
99
98
97
93
1
1
1
1
[a] Unless otherwise noted, reactions were carried out with 2a
(0.3 mmol) and 1a (0.9 mmol) in the presence of EtOH (10 mL) and 4 ꢁ
molecular sieves (30 mg) under nitrogen at 408C. [b] Isolated yield.
[c] Determined by chiral HPLC analysis.
Figure 2. ESIMS spectra of a solution of L7–Sc3+
.
[C35H44F6N4O10S2Sc]+: 903.1962) could be assigned to mono-
ligated complex [L7–ScACHTNUTGRNEUNG
(OTf)2]+ (Figure 2).[13]
Because ligands L1 and L7 showed similar catalytic activi-
ty and enantioselectivity (Table 1, entries 1 and 7), we next
investigated the relationship between the ee value of ligand
L1 and the product 3aa to look for possible nonlinear ef-
fects. As shown in Figure 3, a poor positive nonlinear
effect[14] was observed, thus suggesting that minor oligomeric
aggregates of L7–ScACHTUNTRGNEUNG(OTf)3 might exist in the reaction
system and the major monomeric species was the active cat-
alytic intermediate. In light of the X-ray structure of the
N,N’-dioxide–ScIII complex recently reported by us[10d] and
the above experimental results,
a proposed transition
state[15] that rationalizes the observed sense of asymmetric
induction is provided in Scheme 4. In this transition state,
the N-oxides and amide oxygen atoms of L7 coordinated to
Sc3+ in a tetradentate manner to form two six-membered
chelate rings. Meanwhile, 4-oxo-4-arylbutenoate was at-
Figure 3. Nonlinear effects observed in the L1–Sc
tion of 1a and 2a.
ACHTUNGRTEN(NUGN OTf)3-catalyzed reac-
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Synthesis of a-Stereogenic Esters
FULL PAPER
pyridin-4-amine (DMAP, 0.006 mmol) in nitromethane (0.12 mL) was
added sequentially, and the reaction was stirred at 308C for 12 h. Product
4a was isolated by column chromatography on silica gel (ethyl acetate/
petroleum ether 1:9 to 1:4) in 85% yield with 98% ee. [a]2D0 =À1.16 (c=
0.68 in CHCl3); HPLC (chiral OD-H column; hexane/iPrOH 80:20; flow
rate 1.0 mLminÀ1
; l=254 nm), tR (major)=12.59 min, tR (minor)=
20.46 min; 1H NMR (400 MHz, CDCl3): d=7.88 (d, J=7.6 Hz, 2H), 7.53
(t, J=7.4 Hz, 1H), 7.41 (t, J=7.7 Hz, 2H), 4.75 (qd, J=14.5, 5.7 Hz,
2H), 4.14 (qd, J=7.1, 1.9 Hz, 2H), 3.67 (dd, J=11.8, 5.9 Hz, 1H), 3.53
(dd, J=18.4, 5.1 Hz, 1H), 3.31 (dd, J=18.4, 6.9 Hz, 1H), 1.18 ppm (t, J=
7.1 Hz, 3H).
Scheme 4. Proposed transition-state model.
Acknowledgements
as excellent regioselectivities and enantioselectivities (ee
values up to >99%). Given the low catalyst loading (0.5–
2 mol%), mild reaction conditions, operational simplicity,
and the fact that the diverse functional groups in these ad-
ducts are ready for further conversion, this strategy may
find wide application in organic synthesis. Meanwhile, a pro-
posed transition-state model was put forward to explain the
origin of the asymmetric induction.
We thank the National Natural Science Foundation of China (grant nos.
20732003 and 20872096), Program for Changjiang Scholars and Innova-
tive Research Team (PCSIRT) (no. IRT0846), and the National Basic
Research Program of China (973 Program) (no. 2010CB833300) for fi-
nancial support. We also thank Sichuan University Analytical and Testing
Center for NMR spectroscopic analysis.
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Experimental Section
1
General: H NMR spectra were recorded at 400 or 600 MHz. The chemi-
cal shifts were recorded in ppm relative to tetramethylsilane and with the
solvent resonance as the internal standard. Data are reported as follows:
chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, m=multip-
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comparison with the authentic racemates. Optical rotations were report-
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sealed oven-dried glass tubes under an atmosphere of nitrogen unless
otherwise noted. THF and toluene were distilled from sodium benzophe-
none ketyl. CH2Cl2 was distilled over CaH2. Unless noted, commercial re-
agents were used without further purification. The N,N’-dioxide ligands
were prepared according to the literature.[10]
ˇ
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0.0025 mmol), scandium triflate (1.1 mg, 0.00225 mmol), (E)-4-oxo-4-phe-
nylbutenoate (2a; 71.2 mg, 0.30 mmol), EtOH (10 mL), and 4 ꢁ molecu-
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408C for 10 min, then a-chloromalonate (1a; 110 mL, 0.9 mmol) was
added. The sealed tube was stirred for the time indicated in the tables.
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(petroleum ether/ethyl acetate 12:1 to 5:1) on silica gel to afford the de-
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CHCl3); HPLC (chiral OD-H column; hexane/iPrOH 90:10; flow rate
1.0 mLminÀ1; l=254 nm): tR (major)=9.94 min, tR (minor)=15.61 min;
1H NMR (400 MHz, CDCl3): d=7.99 (d, J=7.5 Hz, 2H), 7.58 (t, J=
7.3 Hz, 1H), 7.48 (t, J=7.7 Hz, 2H), 4.42 (dd, J=9.4, 2.7 Hz, 1H), 4.14
(q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.77 (dd, J=17.7, 9.4 Hz,
1H), 3.36 (dd, J=17.7, 2.8 Hz, 1H), 1.19 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=196.63, 169.43, 166.26, 165.89, 136.47,
133.31, 128.61, 128.14, 71.28, 61.86, 54.13, 54.06, 47.26, 37.17, 13.80 ppm.
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Chem. Eur. J. 2010, 16, 10130 – 10136
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Received: April 29, 2010
Published online: July 19, 2010
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Chem. Eur. J. 2010, 16, 10130 – 10136