Chiral Zn(II)-bisamidine complex as a lewis-bronsted combined acid catalyst: Application to asymmetric mukaiyama aldol reactions of α-ketoesters

Article abstract of DOI:10.3390/molecules17089010

Focusing on the steric and electronic properties of the resonance-stabilized amidine framework, a cationic metal-bisamidine complex was designed as a conjugated combined Lewis-Bronsted acid catalyst. The chiral Zn(II)-bisamidine catalyst prepared from the 2,2'-bipyridyl derived bisamidine ligand, ZnCl₂, and AgSbF₆ promoted asymmetric Mukaiyama aldol reaction of α-ketoester and α,α-disubstituted silyl enol ether to afford the α-hydroxyester having sequential quarternary carbons in good yield, albeit with low enantioselectivity. Addition of 1.0 equivalent of the fluoroalcohol having suitable acidity and bulkiness dramatically increased the enantioselectivity (up to 68% ee). DFT calculations suggested that this additive effect would be caused by self-assembly of the fluoroalcohol on the Zn(II)-bisamidine catalyst.

Full text of DOI:10.3390/molecules17089010

Molecules 2012, 17, 9010-9022; doi:10.3390/molecules17089010
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Chiral Zn(II)-Bisamidine Complex as a Lewis-Brønsted
Combined Acid Catalyst: Application to Asymmetric
Mukaiyama Aldol Reactions of α-Ketoesters
Ryo Gotoh and Masahiro Yamanaka *
Department of Chemistry and Research Center for Smart Molecules, Rikkyo University,
Toshima-Ku, Tokyo 171-8501, Japan
* Author to whom correspondence should be addressed; E-Mail: myamanak@rikkyo.ac.jp;
Tel./Fax: +81-3-3985-2395.
Received: 11 July 2012; in revised form: 21 July 2012 / Accepted: 21 July 2012 /
Published: 30 July 2012
Abstract: Focusing on the steric and electronic properties of the resonance-stabilized
amidine framework, a cationic metal-bisamidine complex was designed as a conjugated
combined Lewis-Brønsted acid catalyst. The chiral Zn(II)-bisamidine catalyst prepared
from the 2,2'-bipyridyl derived bisamidine ligand, ZnCl2, and AgSbF6 promoted
asymmetric Mukaiyama aldol reaction of α-ketoester and α,α-disubstituted silyl enol ether
to afford the α-hydroxyester having sequential quarternary carbons in good yield, albeit
with low enantioselectivity. Addition of 1.0 equivalent of the fluoroalcohol having suitable
acidity and bulkiness dramatically increased the enantioselectivity (up to 68% ee). DFT
calculations suggested that this additive effect would be caused by self-assembly of the
fluoroalcohol on the Zn(II)-bisamidine catalyst.
Keywords: Lewis-Brønsted combined acid; bisamidine; asymmetric Mukaiyama aldol
reaction; α-ketoester
1. Introduction
Lewis-Brønsted combined acid catalysts promote higher catalytic activity and stereoselectivity than
the individual acid catalysts through the dual effects of enhancement of Lewis acidity and the
intramolecular hydrogen-bonding interaction of additional Brønsted acid sites (Figure 1a) [1]. Since
the late 1990s, various types of Brønsted acid-assisted chiral Lewis acid catalysts have been developed

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and are regarded as an efficient catalyst design for asymmetric reactions [2–14]. Based on Yamamoto’s
combined acid concept, we proposed double activation phenomena of carbonyl compounds caused by
simultaneous coordination of Lewis acid and Brønsted acid sites of the combined acid catalyst. In
contrast to the previously reported combined acid catalysts, in which doubly coordination of both acid
sites would form a labile four-membered complex (Figure 1b), the three-centered conjugated scaffold
would form a more stable six-membered complex (Figure 1c).
Figure 1. (a) Schematic concept of Lewis-Brønsted combined acid catalyst; (b) Double
activation by the normal combined acid; (c) Double activation by the conjugated
combined acid.
Focusing on the steric and electronic properties of the the resonance-stabilized amidine framework,
we designed a novel conjugated Lewis-Brønsted combined acid catalyst. Amidinium cation is
significantly stabilized by delocalization of positive charge on two N atoms. The electronic flexibility
of the amidine framework should induce similar electronic delocalization in the cationic metal amidine
complex. When coordinating of cationic metal ions (Mn+) instead of proton (H+), positive charge in the
metal amidine complex could be delocalized to enhance Brønsted acidity of the NH moiety in the
parent amidine. We eventually designed the cationic metal bisamidine catalyst, which should be
thermodynamically stabilized by bidentate coordination of two amidine moieties (Figure 2).
Figure 2. Design of the metal bisamidine complex as a Lewis-Brønsted combined acid catalyst.
Various chiral bisamidines have been recently developed as chiral Brønsted acid catalysts [15–19]
and chiral ligands [20]. To our best knowledge, however, there has been no report of bisamidine-based
combined acid catalysis. For our initial studies, our designed cationic Zn(II)-bisamidine catalyst was
applied in the reaction of an α-ketoester and an α,α-disubstituted silyl enol ether to overcome the
present limitations of the asymmetric Mukaiyama aldol reaction [21]. The catalytic asymmetric
Mukaiyama aldol reaction of α-ketoesters has been recently identified as an efficient synthetic tool for

Molecules 2012, 17
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making a chiral quaternary carbon center. Evans has reported pioneering studies of asymmetric
addition of thioester-derived enolsilanes to pyruvate esters catalyzed by the chiral Cu(II)-bisoxazoline
complexes [22–24]. Bolm has also reported highly enantioselective additions of various ketone-derived
enolsilanes to methyl pyruvate catalyzed by a chiral Cu(II)-oxazolinyl sulfoximine [25,26]. However,
the use of aryl substituted α-ketoesters or ester-derived enolsilanes is still rather limited. Hoveyda
developed the chiral AgF2-pyridyl Schiff base catalyzed reaction of alkyl/aryl substituted
α-ketoesters [27]. Pagenkopf reported a significant expansion in substrate scope to include ester-derived
enolsilanes and alkyl/aryl substituted α-ketoesters [28]. Despite the synthetic value of α-hydroxyesters
having sequential quarternary carbons, the reactions of α-ketoesters and α,α-disubstituted silyl enol
ethers have been quite rare [29,30].
2. Results and Discussion
As a preliminary computational study, we investigated the dual effects of Lewis and Brønsted acids
on the cationic metal bisamidine complex by DFT calculations (Figure 3) [31]. In spite of the
structurally stable aromatic ring in the 2,2'-bipyridine framework, the difference of the bond lengths
between a and b in the amidine moiety becomes smaller upon coordination of the Zn(II) cation.
The natural charge of the NH moiety in Zn2+-L (−0.171) was more positive than in L (−0.206).
Furthermore, Zn2+-Bipy exhibited a greater degree of the positive charge on the Zn(II) center (+1.545)
than Zn2+-L (+1.433). These natural charge differences suggested delocalization of the positive charge
via the amidine framework to increase Brønsted acidity of the NH proton. In a manner similar to the
amidinium complex, the efficient charge delocalization in the amidine moiety was also induced in
Zn2+-L. These DFT calculations predicted that the cationic Zn(II)-bisamidine complex such as Zn2+-L
would have a unique catalytic ability incorporating Lewis acid and Brønsted acid functions.
Figure 3. DFT calculations of bisamidine ligand (L), Zn(II)-bisamidine (Zn2+-L), and
Zn(II)-bipyridine (Zn2+-Bipy) complexes (B3LYP/LANL2DZ for Zn, 6-31G* for the rest).
Bond lengths are shown in Å. NBO charges are shown in italics.
First, we compared the catalytic activities of the cationic metal complex prepared with L1 and L2,
ZnCl2, and 2.0 equivalents of AgSbF6 under stoichiometric conditions (Table 1). In the Zn(II), Cu(II),
and Fe(II)-catalyzed Mukaiyama aldol reaction of methyl benzoylformate (1a) and dimethylketene
methyl trimethylsilyl acetal (2), L1 derived catalysts gave the product 3a in better yields than the
corresponding L2 derived catalyst. This indicates that the presence of the amidine unit is essential for

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the higher catalytic activity, which would be caused by the Brønsted acid function at the NH moiety.
−
−
Based on the promising results of the Zn(II)-L1 catalyst, various counteranions, SbF6 , BF4 , and TfO−
were explored under catalytic conditions (the reaction was carried out in CH2Cl2 at −78 °C for 15 h in
−
−
the presence of 10 mol% Zn(II)-L1). The highest yield of 89% was achieved by use of SbF6 (BF4 :
68%, TfO−: 57%).
Table 1. Metal-bisamidine catalyzed reaction of 1a and 2 under stoichiometric condition.
Entry
MX2
CuCl2
ZnCl2
FeCl2
Ligand Yield (%) a Ligand
Yield (%) a
1
2
3
L1
L1
L1
28
51 (89) b
48
L2
L2
L2
13
30
15
Notes: a Determined by 1H-NMR analysis of crude mixture; b 10 mol% of Zn(II)-L1 catalyst was
used for 15 h.
The (R)-DABN derived chiral bisamidine ligand L3 was developed for the catalytic asymmetric
version (Table 2). The asymmetric Mukaiyama aldol reaction of 1a and 2 was catalyzed by 10 mol%
of Zn(II)-L3 to afford 3a in moderate yield with 26% ee (Entry 1). On the other hand, both Zn(II)-L4
and Zn(II)-L5 catalysts proved much less selective (Entries 2 and 3). The NMe2 group in the DABN
moiety performed better than either smaller or larger amino groups. In some cases, it has been
recognized that achiral additives can be beneficial for catalytic activity and the stereocontrol ability of
chiral catalysts [32]. Fluoroalcohol, in particular, has emerged as an efficient additive for promoting
catalyst turnover in addition reactions of enolsilanes [26,33–35]. These reports encouraged us to
examine the additive effect of trifluoroethanol (TFE), which acts as a proton source to regenerate the
active catalyst or coordinates on the active catalyst to form a more efficient chiral environment at the
reaction centre. Addition of 20 mol% of TFE slightly improved yield (71%) and enantioselectivity
(35% ee, Entry 4). The enantioselectivity was increased with increasing of the amount of the additional
TFE. Addition of 1.0 equivalent of TFE provided the optimal enantoselectivity of up to 50% ee (Entry 5),
while an excess amount of TFE would affect solvent polarity to decrease the enantioselectivity (Entry 6).
We predicted that the present additive effect would be caused by self-assembly of the fluoroalcohol on
the Zn(II)-L3 catalyst. To investigate our prediction, DFT calculations for the reactive complex models
of the Zn(II)-L3 and α-ketoester with/without TFE were carried out (Figures 4 and 5).

Molecules 2012, 17
Figure 4. Schematic geometries for the assembled complex models (A–F) of Zn(II)-L3
9014
and α-ketoester with TFE and the relative energies (B3LYP/LANL2DAZ for Zn, 6-31G*
for the rest).
Figure 5. DFT calculations for the TFE addition effect in the complex of Zn(II)-L3 and
α-ketoester (B3LYP/LANL2DAZ for Zn, 6-31G* for the rest). Bond lengths are shown in Å.

Molecules 2012, 17
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Focusing on the TFE coordination to Zn(II)-L3 and α-ketoester, methyl pyruvate was used in the
chemical models to reduce the computational costs. Six assembled complex models (A–F) were
optimized (B3LYP/LANL2DAZ for Zn, 6-31G* for the rest). The assembled complex A found to be
most stable (Figure 4). The structural properties of the parent complex G were dramatically changed
by coordination with two molecules of TFE (Figure 5). Whereas G has the tetrahedral Zn(II) centre, an
octahedral hexacoordinated Zn(II) centre was formed in A. The hydrogen-bonding between F and
binaphthyl hydrogen atoms (2.42 Å, 2.47 Å) and the Zn-O interaction (2.24 Å, 2.27 Å) stabilized A
by 7.4 kcal/mol in Gibbs free energy. These structural changes would enhance enantiofacial
differentiation at the carbonyl group (dotted purple circles in Figure 5). There is no enantiofacial
differentiation at the carbonyl group in G. In contrast, Si-facial attack of 2 in A would be prevented by
the steric hindrance of TFE to increase the enantioselectivity. This computational prediction was
supported by the stoichiometric reaction with 2.0 equivalents of TFE yielding 3a with 46% ee (almost
the same enantioselectivity under catalytic condition, Entry 5 in Table 2). To further improve the
enantioselectivity, other alcohol additives were examined (Scheme 1).
Table 2. Metal-bisamidine catalyzed reaction of 1a and 2 under stoichiometric conditions.
Entry
Ligand
L3
Y eq. of TFE
Yield (%) a
ee (%) b
1
2
3
4
5
6
-
-
-
0.2
1.0
5.0
60
81
53
71
69
68
26
1
0
35
50
33
L4
L5
L3
L3
L3
a
1
b
Notes: Determined by H-NMR analysis of the reaction crude mixtures. Determined by chiral
HPLC analysis.
Whereas ethanol (b), trichloroethanol (c), and phenol derivatives (d and e) exhibited no positive
impact on the enantioselectivity, 2,2,3,3,3-pentafluoro-1-propanol (f) slightly increased the
enantioselectivity (40% ee). Aliphatic fluorinated alcohols yielded promising results in the initial
screening. After investigation of various aliphatic fluorinated alcohols, hexafluoroisopropyl alcohol
(HFIP, g) was found to be the most efficient alcohol additive and the highest enantioselectivity was
achieved (68% ee). A more sterically demanding alcohol, 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol

Molecules 2012, 17
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(h), exhibited lower enantioselectivity than HFIP (34% ee). The more bulky and acidic alcohol
tris(trifluoromethyl)methanol (i), promoted the achiral pathway to exhibit no enantioselectivity.
Therefore, aliphatic fluorinated alcohols having suitable acidity and bulkiness exerted a significant
impact on the enantiofacial control of Zn(II)-L3. A similar additive effect was observed when methyl
pyruvate (1b) was used as electrophile. The Zn(II)-L3 catalyzed reaction of 1b and 2 readily proceeds
at −78 °C to afford 3b in 95% yield with 11% ee. Addition of 1.0 equivalent of HFIP led to the same
yield (95%) and an increase in the enantioselectivity to 41% ee (Scheme 2). The lower ee value of 3b
than 3a indicates that Me group would be too small to achieve the enantiofacial discrimination
controlled by the Zn(II)-L3 catalyst.
Scheme 1. Screening of alcohol additives.
Scheme 2. Zn(II)-L3 catalyzed reaction of 1b and 2 with or without HFIP.
3. Experimental
3.1. General
All reactions were performed under nitrogen atmosphere with magnetic stirring in dried glassware.
AgOTf, AgBF4, ZnCl2, CuCl2, FeCl2·4H2O, were purchased from Sigma-Aldrich Japan K. K. (Tokyo,

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Japan). Dimethylketene methyl trimethylsilyl acetal was purchased from Tokyo Chemical Industry Co.,
Ltd. (Tokyo, Japan). (R)-1,1'-binaphthyl-2,2'-diamine ((R)-DABN), methyl phenylglyoxylate, methyl
pyruvate were purchased from Wako Pure Chemical Industries, Ltd. (Tokyo, Japan) All dehydrated
solvents were purchased from Kanto Chemical Co., Inc. (Tokyo, Japan) Enantiomeric excess was
determined on a Shimadzu HPLC system with UV detection or a Shimadzu GC system. 1H-NMR and
13C-NMR spectra were recorded on a JEOL JNM-ECX400 spectrometer. Chemical shifts in CDCl3
1
were reported in ppm from tetramethylsilane as the internal standard (CDCl3: δ = 0) for H-NMR and
13
from the solvent resonance (CDCl3: δ = 77.0) for C-NMR. Infrared (IR) spectra were recorded on a
JASCO FT/IR-230 Fourier transform infrared spectrophotometer. High resolution mass was performed
by JEOL JMS-GC mate II. Purification of the products was performed by column chromatography on
silica gel 60N (spherical, neutral, Kanto Chemical Co., Inc), Wakogel 50NH2 (Wako Pure Chemical
Industries, Ltd.) or activated alumina (about 75 μm).
3.2. Synthesis of the 2,2'-Bipyridyl Derived Bisamidine Ligands
3.2.1. Synthesis of 6,6'-Dibromo-2,2'-dipyridyl
To a solution of 2,6-dibromopyridine (1.17 g, 5.0 mmol) in Et2O (10 mL), n-BuLi (1.67 M solution
in hexane, 6.6 mL, 11 mmol) was added dropwise at −78 °C over 1 h, and then CuCl2 (1.01 g, 7.5 mmol)
was added to the reaction mixture. After stirring for 30 min, the reaction mixture was bubbled by O2
for 24 h at −78 °C. To the reaction mixture 6 N HCl aq. (15 mL) was added, and then filtered through
B üchner funnel. The residue was purified by recrystallization from AcOEt gave 6,6'-dibromo-2,2'-
dipyridyl as a white powder in 28% yield.
3.2.2. Synthesis of the (R)-DABN Derivatives
(R)-N,N-Dimethyl-1,1'-binaphthalene-2,2'-diamine [(R)-NMe2-DABN] was prepared according
to the previously reported method [36]. To a solution of (R)-1,1'-binaphthalene-2,2'-diamine
[(R)- DABN] (516.0 mg, 2.0 mmol) and AcOH (1.2 mL, 20 mmol) in CH2Cl2 (10 mL) was added
acetic anhydride (0.2 mL, 2.0 mmol) at 0 °C under N2. The reaction mixture was stirred for 20 h at
room temperature, and then 1 N NaOH aq. was added to adjust the solution to pH > 7. The solution
was extracted by CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4,
and then concentrated under reduced pressure. The crude mixture was purified by column
chromatography on silica gel 60N (AcOEt/hexane = 2/1) to afford N-[(1R)-2'-amino-1,1'-binaphthalen-
2-yl]acetamide [(R)-Ac-DABN] as a colorless oil in 75% yield. To a solution of (R)-Ac-DABN
(0.49 g, 1.5 mmol) and aqueous formaldehyde (37%, 1.48 mL, 17.5 mmol) in THF (19 mL) was added
NaBH3CN (0.19 mg, 10.3 mmol). The reaction mixture was stirred for 15 min at room temperature
followed by addition of AcOH (1.9 mL). After stirring for 4 h at room temperature, 1 N NaOH aq. was
added to adjust the solution to pH > 7. The solution was extracted by CH2Cl2 and the combined organic
layers were washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The
crude mixture was purified by column chromatography on silica gel 60N (AcOEt/hexane = 1/5) to
afford the N-[(1R)-2'-(dimethylamino)-1,1'-binaphthalen-2-yl]acetamide [(R)-Ac-NMe2-DABN] as a
brown powder in quantitative yield. To a solution of (R)-Ac-NMe2-DABN (529 mg, 1.5 mmol) in EtOH

Molecules 2012, 17
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(5 mL) was added 4 N HCl (5 mL). The reaction mixture was stirred for 24 h at 75 °C, and then 1 N
NaOH aq. was added to adjust the solution to pH > 7. The solution was extracted by CH2Cl2 and the
combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under
reduced pressure. The crude mixture was purified by column chromatography on silica gel 60N
(AcOEt/hexane = 1/10) to afford (1R)-N,N-dimethyl-1,1'-binaphthalene-2,2'-diamine [(R)-NMe2-
DABN] as a white powder in 90% yield.
To a solution of (R)-Ac-DABN (93 mg, 0.29 mmol) in DMF (1.5 mL), 1,5-dibromopentane (345 mg,
1.5 mmol) and Et3N (0.3 mL, 3.0 mmol) were added. The reaction mixture was stirred for 2 ddy at
150 °C followed by addition of water (5 mL). The solution was extracted by CH2Cl2 and the combined
organic layers were washed with brine, dried over Na2SO4, and then concentrated under reduced
pressure. To a solution of the crude residue in EtOH (2 mL) was added 6 N HCl aq. (2 mL). After
stirring for 24 h at 85 °C, 1 N NaOH aq. was added to adjust the solution to pH > 7. The solution was
extracted by CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, and
then concentrated under reduced pressure. The crude mixture was purified by column chromatography
on silica gel 60N (AcOEt/hexane = 1/10) to afford (1R)-2'-(1-piperidinyl)-1,1'-binaphthalen-2-amine
[(R)-C5H10N-DABN] as a white powder in 66% yield.
3.2.3. Synthesis of L1, L3, L4, and L5
2,2'-Bipyridyl linked bisamidines L1, L3, L4, and L5 were prepared according to the C-N coupling
method reported by Buchwald [37]. A solution of Pd(dba)2 (6.8 mg, 0.012 mmol) and racemic-BINAP
(14.8 mg, 0.024 mmol) in toluene (2 mL) under N2 was stirred for 20 min at room temperature.
t
6,6'-Dibromo-2,2'-dipyridyl (153.5 mg 0.49 mmol), BuONa (119.5 mg, 1.25 mmol) and the primary
amine (L1: BnNH2, L3: (R)-NMe2-DABN, L4: (R)-Ac-DABN, L5: (R)-C5H10N-DABN, 1.0 mmol)
were added to the solution at room temperature followed by stirring or 24 h at 110 °C. The solution
was filtered through Celite and concentrated under reduced pressure.
For L1, L3, and L5: The crude mixture was purified by column chromatography on activated
alumina (L1: AcOEt/CH2Cl2 = 1/1, L3: AcOEt/hexane = 1/3) or silica gel 60N (L5: AcOEt/hexane = 1/15)
to afford the 2,2'-bipyridyl linked bisamidine as a white powder (L1: 99%, L3: 99%, L5: 51%).
For L4: To a solution of the crude residue in EtOH (2 mL) was added 6 N HCl aq. (2 mL). After
stirring for 24 h at 85 °C, 1 N NaOH aq. was added to adjust the solution to pH > 7. The solution was
extracted by CH2Cl2 and the combined organic layers were washed with brine and dried over Na2SO4.
The crude mixture was purified by column chromatography on silica gel 60N (AcOEt/ hexane = 1/3)
to afford L4 as a white powder in 99% yield.
1
L1: H-NMR (400 MHz, CDCl3): δ 7.64 (d, J = 7.6 Hz, 2H), 7.50 (m, 2H) 7.40 (d, J = 7.2 Hz, 4H),
7.34 (m, 4H), 7.28 (m, 2H), 6.38 (d, J = 7.6 Hz, 2H), 4.97 (br, 2H), 4.60 (s, 4H); 13C-NMR (100 MHz,
CDCl3): δ 158.3, 139.9, 138.5, 128.9, 127.8, 127.8, 127.4, 110.8, 107.2, 46.7; IR ν 3392, 3055, 2831,
2785, 1572, 1500, 1429, 1335 cm−1; HRMS Calcd for C24H23N4 [M+H]: 367.1923; Found: 367.1948.
1
L3: H-NMR (400 MHz, CDCl3): δ 8.28 (d, J = 9.2 Hz 2H), 7.90 (m, 6H), 7.81 (d, J = 8.4 Hz, 2H),
7.67 (m, 2H), 7.47 (m, 4H), 7.33(m, 2H), 7.27 (m, 2H), 7.20 (m, 2H), 7.12 (m, 6H), 6.68 (s, 2H), 6.63
13
(d, J = 8.0 Hz, 2H), 2.51 (s, 12H); C-NMR (100 MHz, CDCl3): δ 155.6, 155.0, 150.4, 138.3, 137.2,

Molecules 2012, 17
9019
134.4, 134.2, 130.5, 130.0, 129.9, 128.4, 128.3, 128.2, 126.8, 126.6, 126.4, 125.6, 124.3, 124.1, 124.0,
122.6, 121.7, 119.6, 112.6, 109.5, 43.6; IR ν 3395, 3054, 2930, 2867, 2831, 2784, 1571, 1501, 1442,
1428, 1334 cm−1; HRMS Calcd for C54H45N6 [M+H]: 777.3706; Found: 777.3377.
1
L4: H-NMR (400 MHz, CDCl3): δ 8.57 (d, J = 8.8 Hz 2H), 7.98 (d, J = 8.8 Hz, 2H) 7.88 (d,
J = 8.0 Hz, 2H), 7.80 (m, 4H), 7.74 (m, 2H), 7.48 (m, 2H), 7.34 (m, 2H), 7.24–7.04 (m, 12H), 6.53 (d,
J = 7.6 Hz, 2H), 6.36 (s, 2H), 3.67 (s, 4H); 13C-NMR (100 MHz, CDCl3): δ 154.8, 154.6, 142.9, 138.2,
137.9, 133.9, 133.3, 130.2, 129.9, 128.7, 128.3, 128.2, 128.1, 127.0, 126.7, 125.0, 124.0, 123.9, 122.5,
120.5, 119.0, 118.2, 113.0, 111.6, 110.5; IR ν 3470, 3381, 3051, 1617, 1463, 1335, 1310, 1270 cm−1;
HRMS Calcd for C50H37N6 [M+H]: 721.3080; Found: 721.3436.
1
L5: H-NMR (400 MHz, CDCl3): δ 8.30 (d, J = 8.8 Hz, 2H), 7.93 (m, 4H) 7.84 (m, 4H), 7.69 (d,
J = 7.6 Hz, 2H), 7.48 (m, 4H), 7.32 (m, 4H), 7.20–7.05 (m, 8H), 7.00 (d, J = 4.0 Hz, 2H), 6.65 (d,
13
J = 8.0 Hz, 2H), 2.85 (m, 8H), 1.26–1.17 (m, 12H); C-NMR (100 MHz, CDCl3): δ 155.1, 154.8,
150.4, 138.0, 136.6, 134.1, 133.8, 130.2, 130.1, 129.6, 127.9, 127.9, 126.3, 126.1, 126.1, 125.7, 125.1,
124.0, 123.6, 123.3, 121.1, 121.1, 120.0, 112.1, 109.3, 52.9, 26.1, 24.1; IR ν 3393, 3054, 2929, 2850,
2796, 1572, 1501, 1443, 1429, 1337 cm−1; HRMS Calcd for C60H53N6 [M+H]: 857.4332; Found:
857.4039.
3.3. General Procedure for Asymmetric Mukaiyama Aldol Reaction of 1a and 2 (Scheme 1)
Under a N2 atmosphere, a solution of ZnCl2 (1.4 mg, 0.01 mmol) and L3 (7.8 mg, 0.01 mmol) in
CH3CN was stirred at room temperature for 20 min. The solvent was removed under reduced pressure
and AgSbF6 (6.9 mg, 0.02 mmol) was added under N2. The residue was stirred in CH2Cl2 (0.5 mL) at
room temperature for 30 min followed by addition of HFIP (16.8 mg, 0.1 mmol). After stirring at room
temperature for 20 min, 1a (16.4 mg, 0.1 mmol), 2 (17.9 mg, 0.1 mmol) were added to the solution and
the mixture was stirred at −45 °C. The reaction was quenched by filtration through silica gel 60N.
After concentration under reduced pressure, the residue was dissolved in THF (0.5 mL). 6 N HCl
aq. was added and the solution was stirred at 65 °C. The solution was extracted by CH2Cl2 and the
combined organic layers were washed with brine, dried over Na2SO4, and then concentration under
reduced pressure. The crude mixture was purified by column chromatography on silica gel 60N
(AcOEt/Hexane = 1/15) to afford 3a as white crystals (63% yield).
Dimethyl-2,2-dimethyl-3-hydroxy-3-phenylbutanedioate (3a) [38]. 3a is a known compound. white
1
crystals: IR  3474, 2955, 1706, 1442, 1356 cm−1; H-NMR (400 MHz, CDCl3): δ 7.57 (d, J = 6.4 Hz,
13
2H), 7.37–7.30 (m, 3H), 4.70 (s, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 1.36 (s, 3H), 1.13 (s, 3H); C-NMR
(100 MHz, CDCl3) δ = 178.7, 174.3, 136.9, 128.0, 127.5, 127.3, 81.9, 52.9, 52.4, 50.4, 22.7, 21.5;
EI-MS m/z = 266 [M]+ for C14H18O5; Enantiomeric excess was determined by chiral HPLC analysis
(68% ee, DAICEL CHIRALPAK OD-H, 2-propanol/n-hexane = 5/95, flow rate 1.0 mL/min,
wavelength = 220 nm, tminor = 5.9 min and tmajor = 7.5 min).
Dimethyl-3-hydroxy-2,2,3-trimethylbutanedioate (3b) [38]. 3b is a known compound. pale yellow oil.:
1
IR  3511, 2954, 1728, 1439, 1374 cm−1; H-NMR (400 MHz, CDCl3): δ 3.94 (s, 1H), 3.77 (s, 3H),

Molecules 2012, 17
9020
3.70 (s, 3H), 1.43 (s, 3H), 1.28 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ = 176.8, 175.9, 78.0, 52.7, 52.2,
49.3, 21.6, 20.9, 20.6; EI-MS m/z = 205 [M+H]+ for C9H16O5; Enantiomeric excess was determined by
chiral GC analysis (41% ee, Cyclodex-β column, 100 °C, tminor = 37.5 min and tmajor = 38.4 min).
4. Conclusions
In summary, we developed asymmetric Mukaiyama aldol reaction of α,α-disubstituted silyl enol
ether and -ketoester promoted by the rationally designed chiral Zn(II)-bisamidine catalyst, which
exhibited an unique catalytic ability incorporating Lewis acid and Brønsted acid functions. Aliphatic
fluorinated alcohols having suitable acidity and bulkiness dramatically enhanced the enantioselectivity.
DFT calculations revealed self-assembly of the fluorinated alcohol exerted a significant impact on
the active catalyst structure to enhance enantiofacial control. Although DFT calculations predicted
Re-facial attack leading to the R configured product would be preferred, the absolute configuration of
the product has not been determined yet. Studies on further improvement of the cationic metal-bisamidine
catalyst system and determination of the absolute configuration of the product are currently underway.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/8//9010/s1.
Acknowledgments
This work was supported by a Grantin-Aid for Young Scientists (B) from JSPS (Grant No.
20750082).
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