Asymmetric Michael addition of malonates to unsaturated ketones catalyzed by rare earth metal complexes bearing phenoxy functionalized chiral diphenylprolinolate ligands

Article abstract of DOI:10.1016/j.tetasy.2016.07.014

A simple, efficient catalytic asymmetric Michael addition of malonates to unsaturated ketones has been successfully developed. This process was promoted by rare earth metal complexes 1–4 bearing a chiral phenoxy functionalized prolinol ligand at room temperature [L¹RE(L¹H) (H₂L¹?=?(S)-2,4-di-tert-butyl-6-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)phenol, RE?=?Yb 1, Y 2, Sc 3 and L²Sc(L²H) 4 (H₂L²?=?(S)-2,4-di-dimethylbenzyl-6-((2-(hydroxydiphenylmethyl)-pyrrolidin-1-yl)methyl)phenol)]. Complex 3 was the best catalyst in the transformation and the products were obtained in up to 99% yield and with 90% ee. In addition, the molecular structures of the catalysts were well characterized, including X-ray determination of complex 3.

Full text of DOI:10.1016/j.tetasy.2016.07.014

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric Michael addition of malonates to unsaturated ketones
catalyzed by rare earth metal complexes bearing phenoxy
functionalized chiral diphenylprolinolate ligands
⇑
⇑
Qinqin Qian, Wenguo Zhu, Chengrong Lu, Bei Zhao , Yingming Yao
College of Chemistry, Chemical Engineering and Materials Science, Dushu Lake Campus, Soochow University, Suzhou 215123, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient catalytic asymmetric Michael addition of malonates to unsaturated ketones has
been successfully developed. This process was promoted by rare earth metal complexes 1–4 bearing a
chiral phenoxy functionalized prolinol ligand at room temperature [L1RE(L1H) (H2L1 = (S)-2,4-di-tert-
butyl-6-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)phenol, RE = Yb 1, Y 2, Sc 3 and L2Sc(L2H)
Received 22 April 2016
Revised 14 July 2016
Accepted 20 July 2016
Available online xxxx
4
(H2L2 = (S)-2,4-di-dimethylbenzyl-6-((2-(hydroxydiphenylmethyl)-pyrrolidin-1-yl)methyl)phenol)].
Complex 3 was the best catalyst in the transformation and the products were obtained in up to 99% yield
and with 90% ee. In addition, the molecular structures of the catalysts were well characterized, including
X-ray determination of complex 3.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
1,4-diketone compounds13 have been used as the Michael accep-
tors. To the best of our knowledge, only a few rare earth metal
Optically active 1,5-dicarbonyl compounds are key intermedi-
ates in organic synthesis,1 which can be simply synthesized by
compounds have been applied to catalyze the asymmetric Michael
addition of malonates and suitable Michael acceptors.8b,9,11 Feng’s
asymmetric Michael addition of 1,3-dicarbonyl compounds to
a,
discovery in 2009 is noteworthy: they employed a catalyst
b-unsaturated carbonyl compounds.2 Malonates are relatively
popular Michael donors in Michael additions because of their high
contents of enolates, which are stabilized by two electron-with-
drawing ester groups under mild conditions. Over the past two
decades, various chiral catalysts, such as organocatalysts,3–7
including chiral ammonium salts4,6 and amino acid salts,5 and
metal complexes,8–13 have been developed to realize the asymmet-
ric Michael addition. In the 1990s, Shibasaki et al. reported a type
of multifunctional heterobimetallic chiral catalyst, which was
successfully applied in the synthesis of chiral 1,5-dicarbonyl
compounds via the addition of malonate with cyclohexenone.9
However, in the first example, the enantioselectivities of the
corresponding adducts were not satisfactory when the chalcone
derivatives were used as the Michael acceptors. 1,5-Dicarbonyl
compounds were obtained with excellent ee values by Maruoka,6
Wang,7 Kobayashi10 and Feng11 using chalcones as substrates.
combination derived from 5 mol % scandium triflate and 6 mol %
N,N0-dioxides to catalyze the conjugate addition of malonates to
chalcones and yielded the corresponding dicarbonyl products
with excellent selectivities (96–99% ee).11 This is the only success-
ful case in which the transformation is catalyzed by rare earth
metal catalysts with excellent yield and excellent enantioselectiv-
ity until now. Hence, more attention was paid to develop new and
high efficient chiral rare earth metal catalysts continuously.
Our group previously developed a set of heterobimetallic rare
earth metal–lithium complexes bearing a chiral phenoxy-function-
alized diphenylprolinolate ligand and successfully introduced
them in the asymmetric epoxidation of
Recently, we addressed the further issue of asymmetric
epoxidation of ,b-unsaturated ketones catalyzed by rare-earth
amides [(Me3Si)2N]3RE( -Cl)Li(THF)3 with a series of phenoxy-
a
,b-unsaturated ketones.14
a
l
functionalized chiral prolinols.15 The ytterbium complex
[L1Yb(L1H)] (H2L1 = (S)-2,4-di-tert-butyl-6-((2-(hydroxydiphenyl-
methyl)pyrrolidin-1-yl)methyl)phenol) was also proved to have
an effect on the epoxidation reaction. All of the results indicated
that the rare earth metal complexes supported by chiral
phenoxy-functionalized prolinolate ligand are high efficient
system in some homogenous asymmetric catalytic reactions. We
Until now, except for some simple ketones,
a,b-unsaturated
cyclohexenones and chalcones,3a,c,4a,6,7,8a,c,h,10,11 2-enoylpyridine
N-oxides,12 b, -ketoesters8b and unsaturated
c-unsaturated a
⇑
Corresponding authors. Tel./fax: +86 512 65880305 (B.Z.).
E-mail addresses: zhaobei@suda.edu.cn (B. Zhao), yaoym@suda.edu.cn (Y. Yao).
http://dx.doi.org/10.1016/j.tetasy.2016.07.014
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Qian, Q.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.014

2
Q. Qian et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
believe that these rare earth metal complexes have potential in
enantioselective Michael additions of malonates to chalcones and
their derivatives.
2. Results and discussion
2.1. Synthesis and characterization of rare earth metal
complexes 1–4
In order to investigate the effects of the central metal and the
ligand of the catalyst on the reaction, four rare earth metal com-
plexes 1–4 stabilized by chiral phenoxy functionalized prolinolate
ligands were synthesized according to the literature15 and well
characterized. As depicted in Scheme 1, treatment of RE[N
(SiMe3)2]3 with 2 equiv of proligand (S)-2,4-di-substituted-6-((2-
(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)phenol in THF
for 3 h, after work-up, gave colorless crystals of complexes 1–4,
which were recrystallized in toluene. Crystals of complex 3 were
suitable for X-ray diffraction and the definite solid-state structure
of it is depicted in Figure 1. The scandium complex has a cen-
trosymmetric structure with two chiral ligands in the unit cell, just
the same as that of the known complex 1.15 One hydrogen atom of
the hydroxyl group in one of the chiral prolinolates remained to
meet the requirement of the common trivalence of the central Sc
atom. The structure of complex 3 was also confirmed by 1H NMR
analysis, in which the signal at 9.38 assigned to the proton of the
free hydroxyl group was observed. Unsatisfactory results from X-
ray diffraction were obtained and only the skeletons of the molec-
ular structures of 2 and 4 could be determined. Fortunately, NMR
spectra of complexes 2 and 4 and the elemental analysis results
of them are informative. It can be deduced that the molar ratio
of the chiral prolinolates to the metal center is 2:1. Therefore, it
is presumed that the solid structures of complexes 1–4 are
isostructural, considering of the atomic radius of Yb (1), Y (2),
and Sc (3 and 4).
Figure 1. Molecular structure of 3 showing 20% probability ellipsoids. Hydrogen
atoms are omitted for clarity. Selected bond lengths (Å) and bond angles (°): Sc(1)–
O(1) 2.013(3), Sc(1)–O(2) 1.974(4), Sc(1)–O(3) 1.947(4), Sc(1)–O(4) 1.955(3), Sc(1)–
N(2) 2.404(4), O(3)–Sc(1)–O(4) 113.01(16), O(3)–Sc(1)–O(2) 127.50(16), O(4)–Sc
(1)–O(2) 115.45(16), O(3)–Sc(1)–O(1) 98.59(14), O(4)–Sc(1)–O(1) 96.29(14), O(2)–
Sc(1)–O(1) 95.10(15), O(3)–Sc(1)–N(2) 73.35(15), O(4)–Sc(1)–N(2) 97.68(15), O(2)–
Sc(1)–N(2) 81.36(16), O(1)–Sc(1)–N(2) 165.76(15).
Table 1
Screening of various rare earth metal catalystsa
O
COOEt
COOEt
O
CH(COOEt)2
Ph
10 mol% Cat.
Tol, RT
+
Ph
Ph
Ph
7a
5a
Entry Cat.
6a
Time
(h)
T
(°C)
Yield
(%)b
ee
(%)c
1
2
3
4
5
1-Yb
1-Yb
24
18
18
18
18
ꢀ20
25
25
25
25
51
90
99
91
88
17
35
5
34
27
Yb[N(SiMe3)2]3 + 2H2L1
[Yb(L1)2][{(THF)3Li}2(
l
-Cl)]
[(Me3Si)2N]3Yb(
l-Cl)Li
R
(THF)3 + 1.5H2L1
6
7
2-Y
18
21
21
21
25
25
25
25
90
82
50
76
33
45
49
40
3-Sc
4-Sc
3-Sc
N
R
8
R
9d
O
O
2
THF
RT
a
Ph
N
Reactions were performed with 5a (0.3 mmol) and the catalyst (10 mol %) in
Ph
RE[N(SiMe3)2]3
+
RE
R
Ph
Tol. (2 mL) under argon for 30 min, then 6a (0.36 mmol) was added.
Ph
b
OH
OH
Isolated yield.
Determined by HPLC analysis.
5 mol % catalyst 3 was used.
HO
Ph
c
O
Ph
d
R
N
H2L1: R = tBu
H2L2: R = CMe2Ph
phenoxy-functionalized chiral prolinol H2L1 were added separately
in a 1:2 molar ratio, the ee value decreased dramatically (Table 1,
entry 3). The effects of two known catalysts, a heterobimetallic
R
R = tBu, RE = Yb 1, Y 2, Sc 3
R = CMe2Ph, RE = Sc 4
Yb–Li complex [Yb(L1)2][{(THF)3Li}2(
l
-Cl)]14 and the combination
Scheme 1. Synthesis of complexes 1–4.
of [(Me3Si)2N]3Yb(
l
-Cl)Li(THF)3 with H2L1 in a 1:1.5 molar ratio15
were also tested and the outcomes were comparable with those
of complex 1 (Table 1, entries 4 and 5). It was found that the metal
centers of the complexes had an influence on the asymmetric addi-
tion. Y-based complex 2 almost had the same effect on the reaction
as that of complex 1, while Sc-based complex 3 gave us higher
enantioselectivity on the addition (Table 1, entries 2, 6 and 7).
Since the substituent group at the aromatic ring in the chiral ligand
had significant effect on the enantioselectivity of the asymmetric
reaction,15 the steric effect of the chiral ligand was also investi-
gated. As a result, the enantioselectivity of the current reaction
was slightly increased in the presence of Sc-based complex 4 with
the bulky ligand H2L2 (cumenyl group instead of tert-butyl group),
although the yield of the Michael adduct was observed to decrease
2.2. Catalytic asymmetric Michael addition of malonates to
unsaturated ketones
Inspired by our previous studies,14,15 we started with the model
asymmetric Michael addition of chalcone 5a with diethyl malonate
6a to investigate the effects of various rare earth metal complexes.
The known complex 1 was first tested in the reaction at -20 °C in
toluene for 24 h. The yield of the product was 51%, however, the
ee value was only 17% (Table 1, entry 1). When the reaction was
conducted at room temperature, both the yield and ee value of
the product were almost doubled after 18 h (Table 1, entry 2). If
the catalyst ytterbium amide [(Me3Si)2N]3Yb and the
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Q. Qian et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
under the same conditions (Table 1, entry 8). If the catalytic
amount of complex 3 was reduced by half, both the yield and the
ee value decreased (Table 1, entry 9). After screening of the cata-
lysts in hand, Sc-based complex 3 was found to be ideal in the fol-
lowing experiments. Using the complex 3 as the catalyst, the
reaction conditions, including solvent, reaction time and the
amount of malonate were screened. Among the various solvents
used, a high yield of the Michael adduct (82%) was obtained in
toluene, but the enantioselectivity was still poor (Table 2, entry
1). In dichloromethane (DCM), the enantioselectivity of the pro-
duct was at its best (up to 77% ee), but the yield was medium
and unsatisfactory (Table 2, entry 2). Coordinated solvents, such
as THF, diethyl ether and 1,4-dioxane, and aprotic solvent DMSO
gave poor results (Table 2, entries 3–6). 1.2 equiv of diethyl malo-
nate proved to be optimal (Table 2, entries 7–9). When the reaction
time was prolonged to 50 h and the dosage of DCM was lowered to
1 mL, 7a was obtained in 95% yield, while the ee value was main-
tained (Table 2, entry 10). An ester group effect of malonates was
studied for the enantioselective Michael addition as well (Table 2,
entries 10–12). Diisopropyl malonate turned out to be an outstand-
ing Michael donor and product 7c was obtained in 97% yield and
with 85% ee (Table 2, entry 12). When 3 Å MS was introduced,
the ee value of 7c was continuously improved to 90% (Table 2,
entry 13).
conjugate reaction and afforded products 7o and 7p in excellent
yields with high enantioselectivities, while 2-enoylpyridine
N-oxide with an electron-deficient heteroaromatic ring directly
attached to the carbonyl group retarded the addition
(Table 3, 7q). Unfortunately, the current catalytic system is not
suitable for the trisubstituted
(Table 3, 7r–7t). Furthermore, the enantiomeric purity of the prod-
ucts improved significantly after recrystallization
a,b-unsaturated ketones
(Table 3, 7i, 7k, and 7p).
3. Conclusions
In conclusion, four rare earth metal complexes 1–4 stabilized by
chiral phenoxy functionalized prolinolate ligands have been syn-
thesized and well characterized. All of the complexes, together
with three known chiral catalysts, were found to be efficient cata-
lysts in the Michael addition of malonates with
a,b-unsaturated
ketones. In particular, complex 3 with the central metal Sc gave
excellent results in the conjugate Michael addition of malonates.
Moreover, enantio-enriched 1,5-ketoesters were obtained in good
yield and with moderate to good enantiomeric excesses from chal-
cone derivatives (77–90% ee). Further studies of the promising
applications of the current catalyst system are underway.
4. Experimental
4.1. General
Table 2
Optimal conditions of the Michael reaction of malonates and chalconea
O
3
COOR
COOR
6a-c
-Sc (10 mol%)
O
CH(COOR)2
Ph
All reagents are commercially available, reagent grade, and used
as received unless otherwise noted. Experiments involving air and
water sensitive components were performed in a glovebox or using
the standard Schlenk techniques. Solvents were distilled before use
from calcium hydride or sodium/benzophenone. 1H and 13C spectra
were obtained on a Bruker AVANCEIII 400 MHz spectrometer using
tetramethylsilane (TMS) as an internal reference. HRMS data were
obtained on a Micromass GCT instrument. Enantiomeric excesses
(ee) were determined by HPLC analysis (Shimadzu LC-20A) using
the Daicel column IA and column ID. Suitable single crystals of
complex 3 were sealed in a thin-walled glass capillary for deter-
mining the single-crystal structure. Intensity data were collected
+
Ph
Ph
RT
Ph
5a
7a-c
Entry
R
Time (h)
Solvent
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
21
21
21
21
21
21
48
48
48
50
50
50
50
50
TOL
82
69
Trace
15
79
Trace
78
70
68
95
85
45
77
—
53
49
—
77
43
74
78
70
85
90
83
DCM
DMSO
THF
Et2O
1,4-Dioxane
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
8d
9e
10f
11
12
with a Rigaku Mercury CCD area detector in
x scan mode using
Mo-K radiation (k = 0.71075 Å). The diffracted intensities were
a
f
Me
corrected for Lorentz polarization effects and empirical absorption
corrections.
iPr
97
95
93
f
f,g
13
iPr
14f
tBu
4.2. Synthesis of L1Yb(L1H) 1
a
Reactions were performed with 5a (0.3 mmol) and the catalyst 3 (10 mol %) in
solvent (2 mL) under argon for 30 min, then 6a (0.36 mmol, 1.2 equiv) was added.
According to our previous work,1 to a THF solution of Yb[N
(TMS)2]3 (2 mmol), a THF solution of H2L1 (4 mmol) (H2L1 = (S)-
2,4-di-tert-butyl-6-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)
methyl)phenol) was added and the mixture was stirred at room
temperature for 12 h. The solvent was evaporated and the mixture
was crystallized in toluene. The colorless crystals were obtained at
room temperature after 1 or 2 days (1.38 g, yield 62% based on
ytterbium). Anal. Calcd for C64H79N2O4Yb: C, 69.04; H, 7.15; N,
2.52; Yb, 15.54. Found: C, 69.32; H, 7.23; N, 2.69; Yb, 15.65.
b
Isolated yield.
Determined by HPLC analysis.
1.0 equiv of malonate was used.
1.5 equiv of malonate was added.
1 mL DCM was used.
3 Å MS (60 mg) was used.
c
d
e
f
g
The optimal reaction conditions were established as follows;
the molar ratio of diisopropyl malonate and chalcone was 1.2:1,
and 10 mol % Sc-based complex 3 as the catalyst, 1 mL DCM, 50
h, at room temperature, in the presence of 3 Å MS.
The substrate scope of the Michael addition catalyzed by com-
plex 3 was investigated, and the results are summarized in Table 3.
It can be seen that most of chalcones, except for the substrates
bearing very strong electron-withdrawing groups, CF3 and NO2,
at the para-position of either phenyl ring, underwent the reactions
smoothly to produce the desired products in high to excellent
yields and with high enantioselectivities (Table 3, 7d–7n).
4.3. Synthesis of L1Y(L1H) 2
The synthesis of complex 2 was carried out in the same way as
that described for complex 1, but Y[N(TMS)2]3 (2 mmol) was used
instead of Yb[N(TMS)2]3. After work-up, colorless crystals were
obtained from Tol-hexane solution (1.09 g, yield 53% based on
yttrium). Anal. Calcd for C64H79N2O4Y: C, 74.69; H, 7.74; N, 2.72;
Y, 8.64. Found: C, 74.81; H, 8.03; N, 2.98; Y, 8.88. 1H NMR
(400 MHz, CDCl3, 25 °C): 7.78 (m, 3H, ArH), 7.72 (m, 2H, ArH),
Similarly,
a,b-unsaturated ketones bearing electron-rich
heteroaromatic rings were also suitable Michael acceptors for the
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Q. Qian et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 3
Scope of
a
,b-unsaturated ketones
COOiPr
O
O
CH(COOiPr)2
Ar'
3-Sc (10 mol%)
+
COOiPr
(1.2 eq.)
6c
Ar
Ar'
DCM, RT
3Å MS, 50 h
Ar
7c-t
CH(COOiPr)2
5
O
CH(COOiPr)2
O
O
CH(COOiPr)2
O
CH(COOiPr)2
Br
Cl
O
7e
7c
7f
7d
yield: 99%
ee: 89%
yield: 95%
ee: 90%
yield: 99%
ee: 87%
yield: 92%
ee: 83%
CH(COOiPr)2
O
CH(COOiPr)2
O
CH(COOiPr)2
O
O
F3C
7g
7h
yield: 82%
ee: 88%
7i
yield: 90% (78%)a
ee: 88% (96%)a
yield: 90%
ee: 64%
CH(COOiPr)2
O
CH(COOiPr)2
O
CH(COOiPr)2
O
NO2
F
Cl
7j
7k
7l
yield: 97%(86%) a
ee: 84%(91%)a
yield: 95%
ee: 86%
yield: 99%
ee: 77%
CH(COOiPr)2
O
CH(COOiPr)2
O
CH(COOiPr)2
O
O
CH(COOiPr)2
O
S
O
Cl
7m
yield: 86%
ee: 81%
7o
7n
7p
yield: 95%(83%)a
ee: 82%(91%)a
yield: 80%
ee: 86%
yield: 97%
ee: 89%
O
CH(COOiPr)2
CH(COOiPr)2
O
O
O
O
CH(COOiPr)2
N
S
CH(COOiPr)2
Ph
Ph
O
7q
7r
7t
trace
7s
trace
yield: 65%
ee: 40%
yield: 30%
ee: 26%
aData in parentheses were obtained after recrystallization
7.52 (m, 3H, ArH), 7.28 (m, 1H, ArH), 7.22 (m, 9H, ArH), 7.12 (m, 4H,
ArH), 6.85 (m, 1H, ArH), 6.77 (m, 1H, ArH), 4.26 (m, 4H, NCH2Ar),
3.71 (m, 2H, NCH), 3.14 (m, 2H, NCH2), 2.81 (m, 2H, NCH2), 2.64
(m, 2H, CH2), 2.01 (m, 2H, CH2), 1.82 (m, 4H, CH2), 1.44 (m, 9H, C
(CH3)3), 1.36 (m, 15H, C(CH3)3), 1.28 (m, 12H, C(CH3)3). 13C NMR
(100 MHz, CDCl3, 25 °C): d 160.6 (Ph), 160.6 (Ph), 153.5 (Ph),
148.4 (Ph), 147.8 (Ph), 146.2 (Ph), 145.9 (Ph), 140.3 (Ph), 136.7
(Ph), 136.0 (Ph), 135.1 (Ph), 128.8 (Ph), 128.6 (Ph), 128.4 (Ph),
128.1 (Ph), 127.8 (Ph), 127.2 (Ph), 126.9 (Ph), 126.5 (Ph), 126.1
(Ph), 125.9 (Ph), 125.6 (Ph), 124.5 (Ph), 123.8 (Ph), 123.4 (Ph),
122.8 (Ph), 122.3 (Ph), 82.4 (OCPh2), 81.6 (OCPh2), 79.9 (NCH2Ar),
77.4 (NCH2Ar), 76.3 (NCH), 72.8 (NCH), 68.1 (NCH2), 67.2 (NCH2),
66.0 (C(CH3)3), 62.0 (C(CH3)3), 61.8 (C(CH3)3), 55.3 (C(CH3)3), 53.5
(CH2), 51.1 (CH2), 35.1 (CH2), 34.0 (CH2), 32.0 (C(CH3)3), 31.8 (C
(CH3)3), 30.5 (C(CH3)3), 30.2 (C(CH3)3), 30.1 (C(CH3)3), 29.6 (C
(CH3)3), 29.5 (C(CH3)3), 28.7 (C(CH3)3), 25.7 (C(CH3)3), 24.4 (C
(CH3)3), 20.6 (C(CH3)3), 15.4 (C(CH3)3).
4.4. Synthesis of L1Sc(L1H) 3
The synthesis of complex 3 was carried out in the same way as
that described for complex 1, but Sc[N(TMS)2]3 (2 mmol) was used
instead of Yb[N(TMS)2]3. After work-up, colorless crystals were
obtained from toluene. (1.62 g, yield 82% based on scandium).
Anal. Calcd for C64H79N2O4Sc: C, 78.02; H, 8.08; N, 2.84; Sc, 4.56.
Found: C, 78.44; H, 8.17; N, 2.97; Sc, 4.84. 1H NMR (400 MHz,
CDCl3, 25 °C): d 9.38 (s, 1H, OH), 7.94 (m, 5H, ArH), 7.52 (m, 5H,
ArH), 7.17 (m, 11H, ArH), 6.82 (m, 3H, ArH), 5.41 (s, 1H, NCH2Ar),
4.64 (s, 1H, NCH2Ar), 4.89 (m, 4H, NCH2Ar, NCH), 2.85 (m, 4H,
NCH2), 2.06 (m, 3H, CH2), 1.74 (s, 9H, C(CH)3), 1.42 (m, 3H, CH2),
1.21 (m, 27H, C(CH)3). 13C NMR (100 MHz, CDCl3, 25 °C): d 161.8
(Ph), 160.2 (Ph), 153.5 (Ph), 152.5 (Ph), 146.2 (Ph), 145.9 (Ph),
145.2 (Ph), 142.7 (Ph), 140.3 (Ph), 138.9 (Ph), 137.2 (Ph), 136.8
(Ph), 135.9 (Ph), 135.1 (Ph), 134.4 (Ph), 128.6 (Ph), 128.4 (Ph),
128.3 (Ph), 128.3 (Ph), 127.9 (Ph), 127.8 (Ph), 127.6 (Ph), 126.1
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Q. Qian et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
(Ph), 125.9 (Ph), 124.1 (Ph), 119.1 (Ph), 83.3 (OCPh2), 82.4 (OCPh2),
82.2(NCH2Ar), 79.9 (NCH2Ar), 79.7 (NCH), 77.4 (NCH), 72.8 (NCH2),
65.0 (NCH2), 62.5 (C(CH3)3), 62.0 (C(CH3)3), 55.3(C(CH3)3), 53.0 (C
(CH3)3CH2), 51.0 (CH2), 35.5 (CH2), 35.0 (CH2), 34.2 (CH2), 34.0 (C
(CH3)3), 32.0 (C(CH3)3), 31.8 (C(CH3)3), 30.4 (C(CH3)3), 29.6 (C
(CH3)3), 25.8 (C(CH3)3), 24.4 (C(CH3)3), 23.0 (C(CH3)3), 19.3 (C
(CH3)3).
127.19, 69.38, 68.98, 58.01, 43.08, 40.89, 21.81, 21.68, 21.47,
21.42; HPLC: Daicel column ID, 90% hexanes, 10% iPrOH,
1.0 mL/min, 18.5 min (major), 21.6 min (minor). HRMS (ESI) calcd
for C24H28O5 [M+H+]: 397.2015, found: 397.2021.
4.7.2. Diisopropyl 2-(3-(4-methoxyphenyl)-3-oxo-1-phenylpro-
pyl)malonate 7d
A white powder; yield 92%, ee 83%; [a]
20 = +17.8 (c 0.449,
D
4.5. Synthesis of L2Sc(L2H) 4
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.94 (m, 2H, Ar), 7.29 (m,
4H, Ar), 7.19 (m, 1H, Ar), 6.92 (m, 2H, Ar), 5.14 (m, 1H, OCH),
4.85 (m, 1H, OCH), 4.02 (td, J1 = 9.8 Hz, J2 = 4.2 Hz, 1H, CH), 4.89
(s, 3H, OCH3), 3.83 (d, J = 10.0 Hz, 1H, CH), 3.54 (dd, J1 = 16.2 Hz,
J2 = 4.2 Hz, 1H, CH2), 3.41 (dd, J1 = 16.1 Hz, J2 = 9.7 Hz, 1H, CH2),
1.29 (dd, J1 = 6.2 Hz, J2 = 1.2 Hz, 6H, CH3), 1.09 (d, J = 6.6 Hz, 3H,
CH3), 1.00 (d, J = 6.3 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
195.68, 167.51, 166.80, 162.88, 140.02, 129.92, 129.51, 127.89,
127.79, 126.53, 113.17, 68.73, 68.32, 57.46, 54.95, 42.16, 40.53,
21.19, 21.06, 20.85, 20.80; HPLC: Daicel column IA, 90% hexanes,
10% iPrOH, 1.0 mL/min, tr (major) = 14.22 min, tr (minor)
= 25.42 min. HRMS (ESI) calcd for C25H30O6 [M+H+]: 427.2115,
found: 427.2121.
The synthesis of complex 4 was carried out in the same way
as that described for complex 3, but H2L2 (2.144 g, 3.6 mmol)
((S)-2,4-di-cumenyl-6-((2-(hydroxydiphenylmethyl)pyrrolidin-1-
yl)methyl)phenol) was used instead of H2L1. After work-up, yellow
solid was obtained from Tol-n-hexane solvent at 0 °C (1.50 g, yield
61% based on scandium). Anal. Calcd for C84H87N2O4Sc: C, 81.79; H,
7.11; N, 2.27; Sc, 3.64. Found: C, 81.83; H, 7.43; N, 2.52; Sc, 3.75. 1H
NMR (400 MHz, CDCl3, 25 °C): d 8.86 (s, 1H, OH), 7.99 (m, 2H, ArH),
7.62 (m, 3H, ArH), 7.47 (m, 6H, ArH), 7.03 (m, 28H, ArH), 6.89 (m,
2H, ArH), 6.73 (m, 1H, ArH), 6.63 (m, 6H, ArH), 6.45 (m, 6H, ArH),
3.89 (m, 1H, NCH2Ar), 3.73 (m, 3H, NCH2Ar), 3.29 (m, 1H, NCH),
3.00 (m, 1H, NCH), 2.62 (m, 3H, NCH2), 2.55 (m, 3H, NCH2, CH2),
1.94 (m, 2H, CH2), 1.78 (m, 2H, CH2), 1.64 (m, 18H, C(CH)3), 1.36
(m, 6H, C(CH)3), 1.13 (m, 2H, CH2). 13C NMR (100 MHz, CDCl3,
25 °C): d 161.6 (Ph), 160.6 (Ph), 152.7 (Ph), 152.3 (Ph), 152.2 (Ph),
152.1 (Ph), 151.9 (Ph), 151.6 (Ph), 151.4 (Ph), 150.7 (Ph), 146.4
(Ph), 145.9 (Ph), 145.2 (Ph), 142.7 (Ph), 140.1 (Ph), 137.9 (Ph),
136.2 (Ph), 135.4 (Ph), 134.5 (Ph), 131.6 (Ph), 128.1 (Ph), 128.0
(Ph), 127.9 (Ph), 127.8 (Ph), 127.7 (Ph), 127.6 (Ph), 126.9 (Ph),
126.9 (Ph), 126.8 (Ph), 126.1 (Ph), 119.8 (Ph), 83.4 (OCPh2), 81.9
(OCPh2), 79.3 (NCH2(Ar)), 78.8 (NCH2(Ar)), 72.1 (NCH), 64.1
(NCH), 61.8 (NCH2), 59.9 (NCH2), 55.0 (C(CH3)2Ph), 52.5
(CC(CH3)2Ph), 50.6 (C(CH3)2Ph), 43.4 (C(CH3)2Ph), 42.6 (CH2), 42.5
(CH2), 42.3 (CH2), 42.1 (CH2), 34.7 (C(CH3)2Ph), 31.3 (C(CH3)2Ph),
28.5 (C(CH3)2Ph), 26.7 (C(CH3)2Ph), 25.5 (C(CH3)2Ph), 24.2
(C(CH3)2Ph), 23.2 (C(CH3)2Ph), 19.2 (C(CH3)2Ph).
4.7.3. Diisopropyl 2-(1-phenyl-3-oxo-3-(4-chlorophenyl)prop-
yl)malonate 7e
A white powder; yield 99%, ee 89%; [a]
20 = +14.5 (c 0.932,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.83 (m, 2H, Ar), 7.40 (m,
2H, Ar), 7.23 (m, 4H, Ar), 7.17 (m, 1H, Ar), 5.07 (m, 1H, OCH),
4.78 (m, 1H, OCH), 4.11 (td, J1 = 9.8 Hz, J2 = 4.0 Hz, 1H, CH), 3.75
(d, J = 9.9 Hz, 1H, CH), 3.50 (dd, J1 = 16.3 Hz, J2 = 4.0 Hz, 1H, CH2),
3.37 (dd, J1 = 16.6 Hz, J2 = 9.7 Hz, 1H, CH2), 1.23 (d, J = 6.2 Hz, 6H,
CH3), 1.03 (d, J = 6.2 Hz, 3H, CH3), 0.96 (d, J = 6.3 Hz, 3H, CH3). 13C
NMR (100 MHz, CDCl3): d 196.69, 168.08, 167.30, 140.27, 139.54,
135.21, 129.70, 128.98, 128.51, 128.42, 127.32, 69.47, 69.04,
57.88, 43.12, 40.96, 21.80, 21.66, 21.45, 21.41; HPLC: Daicel col-
umn IA, 90% hexanes, 10% iPrOH, 1.0 mL/min, tr (major)
= 10.55 min, tr (minor) = 19.08 min. HRMS (ESI) calcd for
C
24H27ClO5 [M+H+]: 431.1619, found: 431.1629.
4.6. General procedure for the asymmetric Michael addition of
malonates to
a
,b-unsaturated ketones
4.7.4. Diisopropyl 2-(1-phenyl-3-oxo-3-(4-bromophenyl)propyl)
malonate 7f
The procedures for the asymmetric Michael addition of
A white powder; yield 99%, ee 87%; [a]
20 = +10.4 (c 0.869,
D
a
,b-unsaturated ketones catalyzed by complexes 1–4 are similar,
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.78 (m, 2H, Ar), 7.57 (m,
2H, Ar), 7.24 (m, 4H, Ar), 7.17 (m, 1H, Ar), 5.07 (m, 1H, OCH),
4.80 (m, 1H, OCH), 4.13 (td, J1 = 9.7 Hz, J2 = 4.0 Hz, 1H, CH), 3.78
(d, J = 9.9 Hz, 1H, CH), 3.55 (dd, J1 = 16.3 Hz, J2 = 4.1 Hz, 1H, CH2),
3.41 (dd, J1 = 16.3 Hz, J2 = 9.7 Hz, 1H, CH2), 1.26 (d, J = 6.2 Hz, 6H,
CH3), 1.06 (d, J = 6.2 Hz, 3H, CH3), 0.98 (d, J = 6.2 Hz, 3H, CH3). 13C
NMR (100 MHz, CDCl3): d 196.87, 168.07, 167.29, 140.32, 135.68,
131.97, 129.81, 128.51, 128.43, 128.28, 127.31, 69.44, 69.03,
57.89, 43.09, 40.97, 21.80, 21.66, 21.45, 21.41; HPLC: Daicel
column IA, 90% hexanes, 10% iPrOH, 1.0 mL/min, tr (major)
= 11.10 min, tr (minor) = 20.29 min. HRMS (ESI) calcd for
and a typical procedure is given as follows. A 10 mL Schlenk flask
was charged with a mixture of chalcone (0.3 mmol), catalyst
(0.03 mmol), molecular sieve 3 Å (60 mg, 30 mg/mmol of starting
material), and 1 mL DCM. After stirring for approximately 30 min.
at room temperature, the malonate (0.36 mmol) was added in
one portion. The reaction system was maintained at 25 °C for
50 h, then quenched by adding water, and the reaction mixture
was purified by flash chromatography (petroleum ether : ethyl
acetate = 20 : 1) on silica gel to afford the desired product. The
enantiomeric excess of the product was determined by chiral
stationary-phase HPLC analysis.
C
24H27BrO5 [M+H+]: 475.1115, found: 475.1110.
4.7. Characterization of the products
4.7.5. Diisopropyl 2-(1-phenyl-3-oxo-3-(4-trifluoromethylphen-
yl)propyl)malonate 7g
4.7.1. Diisopropyl 2-(3-oxo-1,3-diphenylpropyl)malonate 7c
A colorless liquid; yield 90%, ee 64%; [a]
20 = +8.8 (c 0.963,
D
A white powder; yield 95%, ee 90%; [
a
]
D
20 = +18.9 (c 0.925,
CHCl3); 1H NMR (400 MHz, CDCl3): d 8.01 (m, 2H, Ar), 7.69 (m,
2H, Ar), 7.23 (m, 4H, Ar), 7.17 (m, 1H, Ar), 5.11 (m, 1H, OCH),
4.81 (m, 1H, OCH), 4.16 (td, J1 = 9.8 Hz, J2 = 4.0 Hz, 1H, CH), 3.81
(d, J = 9.9 Hz, 1H, CH), 3.64 (dd, J1 = 16.4 Hz, J2 = 4.0 Hz, 1H, CH2),
3.48 (dd, J1 = 16.4 Hz, J2 = 9.7 Hz, 1H, CH2), 1.26 (d, J = 6.3 Hz, 6H,
CH3), 1.06 (d, J = 6.2 Hz, 3H, CH3), 0.98 (d, J = 6.3 Hz, 3H, CH3). 13C
NMR (100 MHz, CDCl3): d 196.92, 168.01, 167.20, 140.20, 139.57,
134.40, 134.07, 133.74, 128.94, 128.53, 128.49, 128.37, 128.07,
127.74, 127.31, 125.67, 125.65, 125.03, 122.32, 119.61, 69.42,
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.88 (m, 2H, Ar), 7.52 (m,
1H, Ar), 7.41 (m, 2H, Ar), 7.24 (m, 4H, Ar), 7.15 (m, 1H, Ar), 5.08
(m, 1H, OCH), 4.79 (m, 1H, OCH), 4.15 (td, J1 = 9.7 Hz, J2 = 4.2 Hz,
1H, CH), 3.78 (d, J = 9.9 Hz, 1H, CH), 3.55 (dd, J1 = 16.5 Hz,
J2 = 3.8 Hz, 1H, CH2), 3.43 (dd, J1 = 16.9 Hz, J2 = 9.6 Hz, 1H, CH2),
1.25 (d, J = 6.3 Hz, 6H, CH3), 1.05 (d, J = 6.2 Hz, 3H, CH3), 0.96 (d,
J = 6.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 197.77, 168.09,
167.39, 140.60, 137.01, 133.10, 128.66, 128.51, 128.45, 128.24,
Please cite this article in press as: Qian, Q.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.014

6
Q. Qian et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
68.99, 57.76, 43.38, 40.86, 21.70, 21.56, 21.36, 21.31; HPLC: Daicel
column IA, 90% hexanes, 10% iPrOH, 1.0 mL/min, tr (major)
= 9.31 min, tr (minor) = 14.04 min. HRMS (ESI) calcd for
21.45; HPLC: Daicel column IA, 90% hexanes, 10% iPrOH,
1.0 mL/min, tr (major) = 10.77 min, tr (minor) = 22.61 min. HRMS
(ESI) calcd for C24H27ClO5 [M+H+]: 431.1619, found: 431.1626.
C
25H27F3O5 [M+H+]: 465.1883, found: 465.1881.
4.7.10. Diisopropyl 2-(1-(4-nitrophenyl)-3-oxo-3-phenylpropyl)
malonate 7l
4.7.6. Diisopropyl 2-(1-(4-methoxyphenyl)-3-oxo-3-phenylpro-
pyl)malonate 7h
A white powder; yield 99%, ee 77%; [a]
20 = +23.6 (c 0.826,
D
A white powder; yield 82%, ee 88%; [
a
]
D
20 = +23.8 (c 0.126, CHCl3);
CHCl3); 1H NMR (400 MHz, CDCl3): d 8.12 (m, 2H, Ar), 7.88 (m,
2H, Ar), 7.55 (m, 1H, Ar), 7.47 (m, 4H, Ar), 5.08 (m, 1H, OCH),
4.84 (m, 1H, OCH), 4.27 (td, J1 = 9.7 Hz, J2 = 4.0 Hz, 1H, CH), 3.80
(d, J = 9.7 Hz, 1H, CH), 3.61 (dd, J1 = 17.1 Hz, J2 = 4.0 Hz, 1H, CH2),
3.48 (dd, J1 = 17.1 Hz, J2 = 9.8 Hz, 1H, CH2), 1.25 (dd, J1 = 6.2 Hz,
J2 = 2.5 Hz, 6H, CH3), 1.07 (d, J = 6.2 Hz, 3H, CH3), 1.01 (d,
J = 6.3 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 196.94, 167.50,
166.94, 148.64, 147.07, 136.53, 133.56, 129.63, 128.84, 128.15,
123.66, 69.84, 69.52, 57.23, 42.44, 40.41, 21.80, 21.65, 21.51; HPLC:
1H NMR (400 MHz, CDCl3): d 7.90 (m, 2H, Ar), 7.52 (m, 1H, Ar), 7.42
(m, 2H, Ar), 7.17 (m, 2H, Ar), 6.77 (m, 2H, Ar), 5.07 (m, 1H, OCH), 4.80
(m, 1H, OCH), 4.10 (td, J1 = 9.9 Hz, J2 = 4.0 Hz, 1H, CH), 3.73 (m, 4H,
OCH3, CH), 3.53 (dd, J1 = 16.4 Hz, J2 = 4.1 Hz, 1H, CH2), 3.40 (dd,
J1 = 16.3 Hz, J2 = 9.8 Hz, 1H, CH2), 1.25 (dd, J1 = 6.4 Hz, J2 = 2.8 Hz,
6H, CH3), 1.06 (d, J = 6.2 Hz, 3H, CH3), 0.98 (d, J = 6.2 Hz, 3H, CH3).
13C NMR (100 MHz, CDCl3): d 197.35, 167.53, 166.82, 158.00,
136.41, 132.46, 131.91, 128.90, 128.04, 127.64, 113.20, 68.72,
68.32, 57.60, 54.67, 42.67, 39.62, 21.21, 21.07, 20.91, 20.86; HPLC:
Daicel column IA, 90% hexanes, 10% iPrOH, 1.0 mL/min,
tr (major) = 13.28 min, tr (minor) = 28.83 min. HRMS (ESI) calcd for
i
Daicel column IC, 90% hexanes, 10% PrOH, 1.0 mL/min, tr (major)
= 16.18 min, tr (minor) = 17.43 min. HRMS (ESI) calcd for
C24H27NO7 [M+H+]: 442.1860, found: 442.1862.
C
25H30O6 [M+H+]: 427.2115, found: 427.2122.
4.7.11. Diisopropyl 2-(1-(2-chlorophenyl)-3-oxo-3-phenylprop-
yl)malonate 7m
4.7.7. Diisopropyl 2-(1-naphthyl-3-oxo-3-phenylpropyl)malon-
ate 7i
A colorless liquid; yield 86%, ee 81%; [a]
20 = +29.1 (c 0.808,
D
A white powder; yield 90%, ee 88%; [
a
]
D
20 = +23.6 (c 0.742,
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.92 (m, 2H, Ar), 7.52 (m,
1H, Ar), 7.41 (m, 2H, Ar), 7.32 (m, 2H, Ar), 7.12 (m, 2H, Ar), 5.06
(m, 1H, OCH), 4.85 (m, 1H, OCH), 4.63 (m, 1H, CH), 4.06 (d,
J = 9.2 Hz, 1H, CH), 3.63 (m, 2H, CH2), 1.24 (d, J = 6.2 Hz, 3H, CH3),
1.18 (d, J = 6.3 Hz, 3H, CH3), 1.06 (m, 6H, CH3). 13C NMR
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.90 (m, 2H, Ar), 7.72 (m,
4H, Ar), 7.51 (m, 1H, Ar), 7.42 (m, 5H, Ar), 5.08 (m, 1H, OCH),
4.74 (m, 1H, OCH), 4.34 (td, J1 = 9.4 Hz, J2 = 4.5 Hz, 1H, CH), 3.88
(d, J = 9.5 Hz, 1H, CH), 3.58 (m, 2H, CH2), 1.24 (dd, J1 = 6.2 Hz,
J2 = 2.2 Hz, 6H, CH3), 1.00 (d, J = 6.3 Hz, 3H, CH3), 0.89 (d,
J = 6.3 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 197.69, 168.10,
167.38, 138.20, 136.98, 133.38, 133.14, 132.70, 128.67, 128.25,
128.17, 127.93, 127.67, 127.41, 126.57, 126.04, 125.78, 69.45,
69.03, 58.04, 43.03, 40.91, 21.82, 21.70, 21.49, 21.39; HPLC: Daicel
column IA, 90% hexanes, 10% iPrOH, 1.0 mL/min, tr (major)
= 12.53 min, tr (minor) = 21.67 min. HRMS (ESI) calcd for
(100 MHz, CDCl3):
d 197.56, 167.90, 167.31, 137.92, 136.81,
134.22, 133.09, 130.04, 129.71, 128.58, 128.25, 128.16, 126.77,
69.28, 69.09, 55.68, 40.85, 37.53, 21.66, 21.58, 21.40, 21.33; HPLC:
i
Daicel column IA, 90% hexanes, 10% PrOH, 1.0 mL/min, tr (major)
= 7.68 min, tr (minor) = 10.16 min. HRMS (ESI) calcd for C24H27ClO5
[M+H+]: 431.1619, found: 431.1622.
C
28H30O5 [M+H+]: 447.2166, found: 447.2167.
4.7.12. Diisopropyl 2-(1-(2-methoxyphenyl)-3-oxo-3-phenylpr-
opyl)malonate 7n
4.7.8. Diisopropyl 2-(1-(4-fluorophenyl)-3-oxo-3-phenylpropyl)
malonate 7j
A colorless liquid; yield 80%, ee 86%; [a]
20 = +18.3 (c 0.601,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.91 (m, 2H, Ar), 7.50 (m,
1H, Ar), 7.40 (m, 2H, Ar), 7.13 (m, 2H, Ar), 6.78 (m, 2H, Ar), 5.07
(m, 1H, OCH), 4.75 (m, 1H, OCH), 4.28 (td, J1 = 10.1 Hz, J2 = 3.8 Hz,
1H, CH), 4.13 (d, J = 10.4 Hz, 1H, CH), 3.80 (s, 3H, OCH3), 3.63 (dd,
J1 = 16.1 Hz, J2 = 9.8 Hz, 1H, CH2), 3.45 (dd, J1 = 16.1 Hz,
J2 = 3.8 Hz, 1H, CH2), 1.24 (d, J = 6.2 Hz, 6H, CH3), 1.02 (d,
J = 6.2 Hz, 3H, CH3), 0.95 (d, J = 6.3 Hz, 3H, CH3). 13C NMR
A white powder; yield 95%, ee 86%; [a]
20 = +22.0 (c 0.726,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.89 (m, 2H, Ar), 7.55 (m,
1H, Ar), 7.44 (m, 2H, Ar), 7.23 (m, 2H, Ar), 6.91 (m, 2H, Ar), 5.07
(m, 1H, OCH), 4.82 (m, 1H, OCH), 4.16 (td, J1 = 9.9 Hz, J2 = 4.0 Hz,
1H, CH), 3.74 (d, J = 9.9 Hz, 1H, CH), 3.54 (dd, J1 = 16.7 Hz,
J2 = 4.0 Hz, 1H, CH2), 3.39 (dd, J1 = 16.6 Hz, J2 = 9.8 Hz, 1H, CH2),
1.25 (dd, J1 = 6.2 Hz, J2 = 3.4 Hz, 6H, CH3), 1.07 (d, J = 6.3 Hz, 3H,
CH3), 0.99 (d, J = 6.3 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
197.65, 167.93, 167.29, 136.89, 133.25, 130.16, 130.09, 128.73,
128.22, 115.40, 115.19, 69.50, 69.12, 57.99, 43.10, 40.20, 21.82,
21.68, 21.51, 21.47; HPLC: Daicel column IA, 90% hexanes,
10% iPrOH, 1.0 mL/min, tr (major) = 9.61 min, tr (minor) =
20.00 min. HRMS (ESI) calcd for C24H27FO5 [M+H+]: 415.1915,
found: 415.1919.
(100 MHz, CDCl3):
d 198.50, 168.55, 167.78, 157.68, 137.24,
132.82, 131.19, 128.52, 128.42, 128.25, 127.78, 120.42, 110.91,
69.08, 68.61, 55.53, 55.33, 41.11, 38.44, 21.81, 21.67, 21.47,
21.38; HPLC: Daicel column IA, 90% hexanes, 10% iPrOH,
1.0 mL/min, tr (major) = 7.55 min, tr (minor) = 8.68 min. HRMS
(ESI) calcd for C25H30O6 [M+H+]: 427.2115, found: 427.2114.
4.7.13. Diisopropyl 2-(3-(furan-2-yl)-3-oxo-1-phenylpropyl)
malonate 7o
4.7.9. Diisopropyl 2-(1-(4-chlorophenyl)-3-oxo-3-phenylpropyl)
malonate 7k
A white powder; yield 97%, ee 89%; [a]
20 = +27.4 (c 0.821,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.52 (m, 1H, Ar), 7.25 (m,
4H, Ar), 7.14 (m, 2H, Ar), 6.47 (m, 1H, Ar), 5.07 (m, 1H, OCH),
4.78 (m, 1H, OCH), 4.13 (td, J1 = 9.8 Hz, J2 = 4.2 Hz, 1H, CH), 3.78
(d, J = 10.0 Hz, 1H, CH), 3.78 (d, J = 7.0 Hz, 2H, CH2), 1.25 (d,
J1 = 6.3 Hz, J2 = 2.4 Hz, 6H, CH3), 1.04 (d, J = 6.2 Hz, 3H, CH3), 0.97
(d, J = 6.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 186.76,
167.96, 167.30, 152.76, 146.36, 140.36, 128.50, 128.45, 127.24,
117.31, 112.30, 69.40, 68.98, 57.92, 42.89, 40.79, 21.80, 21.67,
A white powder; yield 97%, ee 84%; [a]
20 = +17.1 (c 0.703,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.88 (m, 2H, Ar), 7.54 (m,
1H, Ar), 7.43 (m, 2H, Ar), 7.21 (m, 4H, Ar), 5.07 (m, 1H, OCH),
4.81 (m, 1H, OCH), 4.13 (td, J1 = 9.8 Hz, J2 = 4.0 Hz, 1H, CH), 3.73
(d, J = 9.8 Hz, 1H, CH), 3.54 (dd, J1 = 16.7 Hz, J2 = 4.0 Hz, 1H, CH2),
3.41 (dd, J1 = 16.7 Hz, J2 = 9.8 Hz, 1H, CH2), 1.24 (dd, J1 = 6.2 Hz,
J2 = 3.2 Hz, 6H, CH3), 1.08 (d, J = 6.2 Hz, 3H, CH3), 0.99 (d,
J = 6.3 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 197.46, 167.84,
167.20, 139.19, 136.81, 133.27, 132.93, 129.94, 128.72, 128.59,
128.19, 69.53, 69.17, 57.74, 42.83, 40.20, 21.79, 21.65, 21.49,
i
21.45, 21.42; HPLC: Daicel column IA, 90% hexanes, 10% PrOH,
1.0 mL/min, tr (major) = 9.54 min, tr (minor) = 13.87 min. HRMS
(ESI) calcd for C22H26O6 [M+H+]: 387.1802, found: 387.1812.
Please cite this article in press as: Qian, Q.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.014

Q. Qian et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
4.7.14. Diisopropyl 2-(3-(thiophen-2-yl)-3-oxo-1-phenylpropyl)
References
malonate 7p
A white powder; yield 95%, ee 82%; [a]
20 = +14.4 (c 0.766,
D
1. (a) Miyazaki, T.; Maekawa, H.; Yonemura, K.; Yamamoto, Y.; Yamanaka, Y.;
Nishiguchi, I. Tetrahedron 2011, 67, 1598; (b) Somaiah, S.; Sashikanth, S.; Raju,
V.; Reddy, K. V. Tetrahedron: Asymmetry 2011, 22, 1; (c) Fang, H.; Wu, X.; Nie, L.;
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Chem. 2007, 2575.
CHCl3); 1H NMR (4 00 MHz, CDCl3): d 7.73 (m, 1H, Ar), 7.57 (m,
1H, Ar), 7.25 (m, 4H, Ar), 7.17 (m, 1H, Ar), 7.08 (m, 1H, Ar), 5.07
(m, 1H, OCH), 4.78 (m, 1H, OCH), 4.12 (m, 1H, CH), 4.13 (d,
J = 10.1 Hz, 1H, CH), 3.46 (dd, J1 = 15.8 Hz, J2 = 4.2 Hz, 1H, CH2),
3.34 (dd, J1 = 15.8 Hz, J2 = 9.7 Hz, 1H, CH2), 1.25 (d, J1 = 6.3 Hz,
J2 = 1.8 Hz, 6H, CH3), 1.04 (d, J = 6.3 Hz, 3H, CH3), 0.97 (d,
J = 6.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 190.66, 168.03,
167.30, 144.32, 140.21, 13376, 132.23, 128.48, 128.46, 128.19,
127.29, 69.46, 69.02, 57.81, 43.79, 41.29, 21.80, 21.67, 21.45,
21.41; HPLC: Daicel column IA, 90% hexanes, 10% iPrOH,
1.0 mL/min, tr (major) = 9.90 min, tr (minor) = 14.78 min. HRMS
(ESI) calcd for C22H26O5S [M+H+]: 403.1574, found: 403.1572.
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2009, 20, 2651; (j) Tarí, S.; Chinchilla, R.; Nájera, C. Tetrahedron: Asymmetry
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4.7.15. 2-(5-Isopropoxy-4-(isopropoxycarbonyl)-5-oxo-3-phen-
ylpentanoyl)pyridine 1-oxide 7q
A yellow powder; yield 65%, ee 40%; [a]
20 = +13.2 (c 0.088,
D
3. (a) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42,
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CHCl3); 1H NMR (400 MHz, CDCl3): d 8.12 (m, 1H, Ar), 724 (m,
8H, Ar), 5.07 (m, 1H, OCH), 4.74 (m, 1H, OCH), 4.09 (td,
J1 = 10.3 Hz, J2 = 4.2 Hz, 1H; CH), 3.86 (dd, J1 = 17.2 Hz,
J2 = 10.0 Hz, 1H, CH2), 3.67 (d, J = 10.7 Hz, 1H, CH), 3.64 (dd,
J1 = 17.2 Hz, J2 = 4.2 Hz, 1H, CH2), 1.26 (dd, J1 = 9.0 Hz, J2 = 6.3 Hz,
6H, CH3), 1.02 (d, J = 6.2 Hz, 3H, CH3), 0.91 (d, J = 6.3 Hz, 3H, CH3).
13C NMR (100 MHz, CDCl3): d 195.54, 167.70, 167.20, 146.76,
140.53, 140.36, 128.65, 128.33, 127.78, 127.14, 126.83, 125.40,
69.37, 68.83, 58.03, 47.37, 40.96, 21.79, 21.62, 21.42, 21.33; HPLC:
Daicel column IA, 90% hexanes, 10% iPrOH, 1.0 mL/min,
tr (major) = 11.32 min, tr (minor)v12.85 min. HRMS (ESI) calcd for
C
23H27NO6 [M+H+]: 414.1911, found: 414.1920.
4. (a) Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42, 6299; (b) Dere, R.
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Chem. 2003, 68, 1973; (d) Xu, Y.; Ohori, K.; Ohshima, T.; Shibasaki, M.
Tetrahedron 2002, 58, 2585; (e) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N.
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Robinson, J. R.; Fan, X.; Yadav, J.; Carroll, P. J.; Wooten, A. J.; Pericàs, M. A.;
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4.7.16. Diisopropyl 2-(2-benzoyl-3-oxo-1,3-diphenylpropyl)
malonate 7r
A white powder; yield 30%, ee 24%; [a]
20 = +11.2 (c 0.102,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 8.02 (m, 2H, Ar), 7.73 (m,
2H, Ar), 7.51 (m, 1H, Ar), 7.41 (m, 3H, Ar), 7.35 (m, 2H, Ar), 7.28
(m, 2H, Ar), 7.05 (m, 3H, Ar), 6.42 (d, J = 16.1 Hz, 1H, CH), 4.84
(m, 2H, OCH), 4.59 (t, J = 8.6 Hz, 1H, CH), 4.24 (d, J = 8.4 Hz, 1H,
CH), 1.11 (d, J = 6.3 Hz, 3H, CH3), 1.02 (dd, J1 = 6.2 Hz, J2 = 4.4 Hz,
6H; CH3), 0.95 (d, J = 6.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d 195.11, 194.83, 168.20, 168.01, 137.45, 137.13, 136.71, 133.65,
133.20, 130.36, 128.98, 128.95, 128.63, 128.59, 128.05, 127.38,
69.41, 69.09, 59.39, 55.23, 45.67, 21.53, 21.50, 21.41, 21.36; HPLC:
Daicel column IA, 90% hexanes, 10% iPrOH, 1.0 mL/min,
tr (major) = 8.63 min, tr (minor) = 10.93 min. HRMS (ESI) calcd for
C
31H32O6 [M+H+]: 501.2272, found: 501.2266.
Acknowledgments
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We gratefully acknowledge financial supports from the
National Natural Science Foundation of China (Grants 21372172,
and 21572151), PAPD, and the Qing Lan Project.
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Supplementary data
14. Qian, Q.; Tan, Y.; Zhao, B.; Feng, T.; Shen, Q.; Yao, Y. Org. Lett. 2014, 16, 4516.
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.07.
014.
Please cite this article in press as: Qian, Q.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.014