Enantioselective copper-catalyzed 1,4-addition of dialkylzincs to enones using a novel N,N,P-Cu(II) complex

Article abstract of DOI:10.1016/j.tetasy.2012.06.010

Enantioselective copper-catalyzed 1,4-additions of dialkylzincs to enones were carried out in the presence of 1 mol % of Cu(OTf)₂ and 2.5 mol % of an N,N,P-ligand possessing a tert-butyl group at the adjacent position of the nitrogen of pyridin

Full text of DOI:10.1016/j.tetasy.2012.06.010

Tetrahedron: Asymmetry 23 (2012) 959–964
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Tetrahedron: Asymmetry
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Enantioselective copper-catalyzed 1,4-addition of dialkylzincs to enones
using a novel N,N,P–Cu(II) complex
⇑
Yasuhiro Ebisu, Kenjiro Kawamura, Masahiko Hayashi
Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe 657-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective copper-catalyzed 1,4-additions of dialkylzincs to enones were carried out in the pres-
ence of 1 mol % of Cu(OTf)2 and 2.5 mol % of an N,N,P-ligand possessing a tert-butyl group at the adjacent
position of the nitrogen of pyridine to afford the corresponding 1,4-adducts in up to 98% ee.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 April 2012
Accepted 6 June 2012
Available online 19 July 2012
1. Introduction
The conjugate addition (1,4-addition) of organometallic species
to electrophilically activated olefins, such as enones, is one of the
most important asymmetric carbon–carbon bond forming reac-
tions in organic synthesis.1 Since the first report of the copper-cat-
alyzed 1,4-addition of diethylzinc to enones by Alexakis et al.,2,3
many other studies have been carried out, using chiral phosphate
ligands,4 chiral phosphoramidites,5 chiral aminophosphine
ligands,6 chiral phosphines with amino acid moieties,7 N-heterocy-
clic carbene ligands,8 peptide-based ligands,9 chiral bis(oxazoline)
ligands,10 and other types of ligand.11,12 On the other hand, we
have developed O,N,O-tridentate ligands with a Schiff base frame-
work (type I) for use in various asymmetric carbon–carbon
bond-forming reactions, including asymmetric silylcyanations of
aldehydes,13 enantioselective additions of diketenes to alde-
hydes,14 enantioselective addition of dialkylzincs to aldehydes,15
and asymmetric Reformatsky reactions.16 In order to increase the
affinity of the ligands to transition metals such as copper, we
recently reported chiral N,N,P tridentate ligands containing a
quinoline moiety.17 Herein we report the preparation of newly
designed N,N,P-tridentate ligands with a tert-butyl group at the
adjacent position of the nitrogen of pyridine and their application
to copper-catalyzed enantioselective 1,4-additions of dialkylzincs
to enones.
N
R
N
OH
R
N
OH
PPh2
type I
type II
Scheme 1.
The type II ligand was synthesized as shown in Scheme 2
(R = tert-Bu in Scheme 1). The reaction of 2-methylpyridine with
tert-BuLi gave the 2-methyl-4,6-di-tert-butylpyridine (69%), which
when treated with mCPBA afforded the corresponding N-oxide
(54%).18 This N-oxide was converted into the primary alcohol using
trifluoroacetic anhydride (82%). Finally, oxidation using SeO2 gave
the desired aldehyde (80%).19 Condensation of the 2-pyridyl
aldehyde with amino phosphine afforded N,N,P-ligands with a
tert-butyl group at the adjacent position of the nitrogen of pyridine
(71%).
2.2. Enantioselective 1,4-addition using N,N,P-ligand–Cu(OTf)2
complex
Next, we examined the 1,4-addition of dialkylzincs to cyclic
enones using 1.0 mol % of Cu(OTf)2 and 2.5 mol % of ligand 1
(Table 1).
2. Results and discussion
Table 1 lists the optimized reaction conditions for the reactions
of 2-cyclopenten-1-one, 2-cyclohexen-1-one, and 2-cyclohepten-
1-one with dialkylzincs. High enantioselectivity was observed for
the catalyst loading of 1 mol % Cu(OTf)2 and 2.5 mol % ligand, and
the reaction proceeded to afford (S)-3-ethylcyclohexanone (98%
ee) at À40 °C. It should be mentioned that when the N,N,P-ligand
was used without tert-butyl groups on the pyridine ring, the prod-
uct was obtained in 95% yield with only 55% ee (n = 1, R = Et).
2.1. Synthesis of type II ligands
We first designed type II ligands as simple analogues of type I
Schiff base ligands (Scheme 1).
⇑
Corresponding author.
E-mail address: mhayashi@kobe-u.ac.jp (M. Hayashi).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.010

960
Y. Ebisu et al. / Tetrahedron: Asymmetry 23 (2012) 959–964
Table 1
2.3. Proposed catalytic cycle mechanism and the origin of
enantioselection
Enantioselective 1,4-addition of dialkylzincs to cyclic enonesa
1.0 mol% Cu(OTf)2
According to Reiser’s proposed mechanism,10a we suggested
mechanisms for the catalytic cycle and enantioselection as shown
in Scheme 3. In the catalytic cycle, the reaction of the chiral copper
complex and dialkylzinc gives an alkyl-copper species that acts as
an alkyl donor. The enone is then activated by the copper and zinc
species, coordinated to an alkene moiety and a carbonyl oxygen,
respectively.
In order to explain the enantioselectivity, we proposed the
mechanism as shown in Schemes 4–6. Assuming the molecule is
in the plane of the paper, we suggest that the enone attacks from
front side because of the bulkiness of the tert-butyl group at the
stereogenic center. In addition, the plane of the enone itself is also
fixed by the presence of the tert-butyl group at the adjacent posi-
tion of the nitrogen of the pyridine and the PPh2 group to avoid ste-
ric hindrance (Scheme 4). According to Scheme 3, the zinc species
would be coordinated with a carbonyl oxygen as the Lewis acid so
that the carbonyl group became bulky. As a result, the enone ap-
proaches the catalyst plane upward (Scheme 5). Since the copper
center of catalyst would activate the olefin moiety, the sp3 carbons
in 2-cyclohexen-1-one should parry the PPh2 group (Scheme 6).
Thus, we surmised that the enantioselectivity was triply-controlled
by the stereogenic center, the quinoline moiety, and the PPh2
group.
2.5 mol%
t-Bu
N
t-Bu
t-Bu
N
O
O
PPh2
R2Zn
+
CH2Cl2, -40 ºC, 24 h
R
n
n
Entry
n
R
Yieldb (%)
eec,d (%)
1
2
3
4
5
0
1
1
2
2
Et
Me
Et
Me
Et
64
70
70
55
79
98 (S)
98 (S)
97 (S)
92 (S)
80 (S)
a
b
c
All reactions were carried out at À40 °C.
Isolated yield.
Determined by GC analysis.
d
The absolute configuration was determined by comparison of the specific
rotation value compared with that reported in the literature.20
3. Conclusion
We next examined the reaction of acyclic enones, such as
chalcone and substituted chalcone using the same catalyst system
(Table 2). Compared with our previously reported 2-quinolyl
ligand (63% ee), the present catalyst system exhibited higher
enantioselectivity (up to 83% ee).
Our new chiral N,N,P-tridentate ligand possesses a tert-butyl
group at the adjacent position of the nitrogen of pyridine and
promotes highly enantioselective 1,4-additions of dialkylzinc to
enones (up to 98% ee) in combination with Cu(OTf)2.
Table 2
Enantioselective 1,4-addition of diethylzinc to acyclic enonesa
1.0 mol% Cu(OTf)2
2.5 mol%
t-Bu
N
t-Bu
t-Bu
N
R2
O
R2
Et
O
PPh2
Et2Zn
+
CH2Cl2, -40 ºC, 24 h
R1
R2
R1
R2
Entry
R1
R2
Yieldb (%)
eec (%)
1
2
3
4
5
H
H
H
H
H
89
93
56
93
75
83 (R)d
75 (R)e
85 (R)f
85 (R)f
79 (R)f
MeO
NO2
F
H
Me
a
b
c
d
e
f
All reactions were carried out at À40 °C.
Isolated yield.
Determined by HPLC analysis.
Absolute configuration was determined by the specific rotation value as compared with that of the reported one.20
Absolute configuration was determined by the comparison of the specific rotation value compared with that of the literature.21
Absolute configuration was estimated by the order of retention time during HPLC analysis.

Y. Ebisu et al. / Tetrahedron: Asymmetry 23 (2012) 959–964
t-Bu
961
mCPBA (7.0 eq)
t-BuLi (5.0 eq)
CHCl3, r.t., 26 h
hexane, -78 °C, 1 h
then 80 °C, 2.5 h
Me
Me
N
Me
N
t-Bu
69%
t-Bu
t-Bu
TFAA (2.5 eq)
SeO2 (1.0 eq)
N
t-Bu
HO
CH2Cl2, r.t., 24 h
pyridine
N
t-Bu
O
120 °C, 5 h
54%
82%
t-Bu
t-Bu
t-Bu
NH2
N
t-Bu
PPh2
H
t-Bu
N
N
t-Bu
O
PPh2
80%
1
71%
Scheme 2.
N
N
Cu(OTf)2
L*nCu
X
+
N
N
Cu
X
PPh2
P
Ph2
ZnR2
L*nCu
X
L*nCu
R
RZnX
O
+
OZnR
R
O
L*nCu
Zn
R
X
R
Scheme 3.

962
Y. Ebisu et al. / Tetrahedron: Asymmetry 23 (2012) 959–964
4.2. Preparation of N,N,P-ligand 1
4.2.1. 2,4-Di-tert-Butyl-6-methylpyridine18
H
H
t-Bu
t-Bu
(S)
N
N
O
(S)
tert-Butyllithium (62 mL, 100 mmol, 1.6 M solution in pentane)
was added to a solution of 2-methylpyridine (1.86 g, 20.0 mmol) in
dry hexane (40 mL) at À78 °C. The mixture was stirred at this tem-
perature for 1 h, then at reflux for 2.5 h at 80 °C. After cooling to
room temperature the resulting solution was hydrolyzed with 2-
propanol (20 mL) followed by water (20 mL). The aqueous layer
was then extracted with hexane (30 mL Â 3). The combined organ-
ic layer was dried over Na2SO4, filtered, and evaporated. The resi-
due was subjected to column chromatography on silica gel using
hexane/ethyl acetate (10:1) as an eluent to afford a yellow oil.
Yield: 2.81 g (69%). Rf 0.63 (10:1 hexane/ethyl acetate). 1H NMR
(400 MHz, CDCl3) d: 1.13 (s, 9H), 1.20, (s, 9H), 2.48 (s, 3H), 6.88
(s, 1H), 6.96 (s, 1H).
N
O
N
Cu
Et
Cu
Et
P
P
Scheme 4.
R
X
Zn
O
4.2.2. 2,4-Di-tert-butyl-6-methylpyridine-N-oxide18
N
N
m-Chloroperbenzoic acid (70%, 21.4 g, 84.5 mmol) was added to
N
N
a
solution
of
2,4-di-tert-butyl-6-methylpyridine
(2.66 g,
Cu
Et
Cu
Et
O
13.0 mmol) in CHCl3 (300 mL). The mixture was then stirred at
room temperature. After 2 h, more m-chloroperbenzoic acid
(1.64 g, 6.5 mmol) was added, and stirring was continued for
24 h. A saturated aqueous solution of NaHCO3 was then added to
the resulting solution, after which aqueous layer was extracted
with CHCl3 (30 mL Â 3). The combined organic layer was dried
over Na2SO4, filtered, and evaporated. The residue was subjected
to column chromatography on silica gel using hexane/ethyl acetate
(5:1) as an eluent to afford the yellow solid. Yield: 1.55 g (54%). Rf
0.33 (5:1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) d: 1.30
(s, 9H), 1.54 (s, 9H), 2.51 (s, 3H), 7.12 (d, J = 2.8 Hz, 1H), 7.20 (d,
J = 2.8 Hz, 1H).
P
P
t-Bu
t-Bu
Zn R
X
Scheme 5.
H
N
H
N
H
H
t-Bu
t-Bu
t-Bu
t-Bu
N
N
Cu
Et
Cu
Et
4.2.3. (4,6-Di-tert-Butylpyridin-2-yl)methanol19
P
O
P
t-Bu
t-Bu
Ph
Ph
Ph
Ph
O
At first, TFAA (0.17 mL, 1.25 mmol) was added to a solution of
2,4-di-tert-butyl-6-methylpyridine-N-oxide (111 mg, 0.5 mmol)
in dry CH2Cl2 (3 mL) at room temperature. After 1 h the reaction
was hydrolyzed with an Na2CO3 solution and the mixture was stir-
red overnight. The aqueous layer was extracted with CH2Cl2
(10 mL Â 3). The combined organic layer was dried over Na2SO4,
filtered, and evaporated. The residue was subjected to column
chromatography on silica gel using hexane/ethyl acetate (5:1) as
an eluent to afford a yellow oil. Yield: 90 mg (82%). Rf 0.29 (5:1
hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) d: 1.31 (s, 9H),
1.37 (s, 9H), 4.6 (br s, 1H), 4.71 (s, 2H), 6.94 (s, 1H), 7.22 (s, 1H).
favored
O
disfavored
O
Et
S-product
Et
R-product
Scheme 6.
4.2.4. 4,6-Di-tert-butyl-2-pyridylaldehyde19
At first, SeO2 (400 mg, 3.6 mmol) was added to a solution of
(4,6-di-tert-butylpyridin-2-yl)methanol (797 mg, 3.6 mmol) in
dry pyridine (30 mL). The mixture was refluxed for 4 h at 120 °C.
The suspension was filtered and evaporated. The residue was sub-
jected to column chromatography on silica gel using hexane/ethyl
acetate (10:1) as an eluent to afford a white solid. Yield: 634 mg
(80%). Rf 0.51 (10:1 hexane/ethyl acetate). 1H NMR (400 MHz,
CDCl3) d: 1.34 (s, 9H), 1.42 (s, 9H), 7.54 (d, J = 2.0 Hz, 1H), 7.78
(d, J = 2.0 Hz, 1H), 10.06 (s, 1H).
4. Experimental
4.1. General
All reactions were carried out in oven-dried glassware with
magnetic stirring. All starting materials were obtained from com-
mercial sources and used without further purification unless other-
wise stated. 1H and 13C NMR spectra (400 and 100.6 MHz,
respectively) were recorded using Me4Si as an internal standard
(0 ppm). The following abbreviations are used: s = singlet, d = dou-
blet, t = triplet, q = quartet, m = multiplet. Gas chromatographic
(GC) analysis was carried out using an instrument equipped with
4.2.5. (S,E)-N-((4,6-Di-tert-butylpyridin-2-yl)methylene)-1-
(diphenylphosphino)-3,3-dimethylbutan-2-amine 1
A mixture of benzene (5 mL), (S)-2-amino-1-diphenylphoshino-
3,3-dimethylbutane22 (171 mg, 0.6 mmol), 4,6-di-tert-butylpico-
linaldehyde (109 mg, 0.5 mmol), and anhydrous Na2SO4 (1 g) was
stirred at 85 °C for 12 h. The mixture was filtered and the filtrate
was evaporated. The residue was subjected to column chromatog-
raphy on silica gel (pre-neutralized with triethylamine) using hex-
ane/ethyl acetate (5:1) as an eluent to afford a yellow oil. Yield:
an FID detector and a capillary column,
Chiral HPLC was performed using an instrument equipped with a
diode array detector and a chiral column CHIRALPAK AD-H
c-DEX-225, b-DEX-225.
(250 mm  4.6 mm  5
lm). High resolution mass spectra (HRMS)
were measured by JEOL JMS-T100LP AccuTOF LC-Plus (ESI) with
JEOL JMS-700 MStation (FAB).

Y. Ebisu et al. / Tetrahedron: Asymmetry 23 (2012) 959–964
963
173 mg (71%). Rf 0.67 (5:1 hexane/ethyl acetate; TLC plate was pre-
neutralized with triethylamine). IR (KBr) cmÀ1: 2955, 2866, 1646,
1598, 1551, 1478, 1433, 1409, 1392, 1362, 1259, 1214, 1166,
1069, 1026, 999, 959, 898, 880, 805, 738, 694, 635, 524, 516,
509, 505, 501; 1H NMR (400 MHz, CDCl3) d: 0.92 (s, 9H), 1.31 (s,
9H), 1.38 (s, 9H), 2.46 (m, 2H), 3.00 (m, 1H), 7.11–7.19 (m, 3H),
7.29 (d, J = 1.2 Hz, 1H), 7.34–7.37 (m, 5H), 7.45–7.49 (m, 2H),
7.71 (d, J = 1.2 Hz, 1H), 8.13 (s, 1H); 13C NMR (100 MHz, CDCl3) d:
168.2, 162.9, 159.7, 153.4, 139.6, 138.7, 133.7, 132.5, 128.7,
128.4, 127.9, 127.7, 116.6, 114.5, 77.5, 77.0, 37.4, 35.2, 34.9, 30.7,
CHCl3); 1H NMR (400 MHz, CDCl3) d: 0.90 (t, J = 7.2 Hz, 3H), 1.25–
1.42 (m, 4H), 1.58–1.65 (m, 2H), 1.85–1.93 (m, 3H), 2.35–2.50
(m, 4H).
4.3.6. (R)-(À)-1,3-Diphenylpentan-1-one17 (Table 1, entry 1)
83% ee [tR of (S)-isomer, 8.23 min; tR of (R)-isomer, 10.69 min;
HPLC conditions: column, CHIRALCEL AD-H (DAICEL); eluent, hex-
ane/2-propanol (99:1); 1.0 mL minÀ1]. [
a
]
D = À2.0 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) d: 0.81 (t, J = 7.6 Hz, 3H), 1.61–1.70
(m, 2H), 1.76–1.82 (m, 1H), 3.23–3.31 (m, 3H), 7.16–7.31 (m,
4H), 7.41–7.45 (m, 2H), 7.51–7.56 (m, 1H), 7.89–7.92 (m, 2H).
30.3, 26.7; [a]D = +81.3 (c 1.0, CHCl3); HRMS (ESI+) Calcd for
C32H44N2P [M+H]+: 487.3237; found: m/z 487.3237.
4.3.7. (R)-(À)-3-(4-Methoxyphenyl)-1-phenyl-pentan-1-one22
(Table 2, entry 2)
4.3. General procedure for the asymmetric 1,4-addition
75% ee [tR of (S)-isomer, 14.47 min; tR of (R)-isomer, 20.84 min;
HPLC conditions: column, CHIRALCEL AD-H (DAICEL); eluent, hex-
A solution of Cu(OTf)2 (0.01 mmol) and ligand (0.025 mmol) in
dichloromethane (1.5 mL) was stirred under an argon atmosphere
at room temperature for 0.5 h. after which enone (1 mmol) was
added to this catalyst solution. The solution was then cooled to
À40 °C, then it was stirred at À40 °C for 15 min, after which Et2Zn
(1.5 mmol, 0.153 ml) was added slowly. The resulting mixture was
stirred at À40 °C for 24 h and then quenched with a 1 M HCl solu-
tion (2 mL). After warming the reaction mixture to room tempera-
ture, the reaction mixture was extracted with diethyl ether
(10 mL Â 3). The data of the ee values were determined by chi-
ane/2-propanol (95:5); 0.5 mL minÀ1]. [
a
]
D = À5.0 (c 1.1, CHCl3);
1H NMR (400 MHz, CDCl3) d: 0.80 (t, J = 7.2 Hz, 3H), 1.58–1.66
(m, 1H), 1.73–1.79 (m, 1H), 3.17–3.26 (m, 3H), 3.78 (s, 3H), 6.82
(d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7.41–7.45 (m, 2H),
7.51–7.55 (m, 1H), 7.89 (d, J = 8.4 Hz, 2H).
4.3.8. (R)-(À)-3-(4-Nitrophenyl)-1-phenyl-pentan-1-one
(Table 2, entry 3)
85% ee [tR of (S)-isomer, 28.40 min; tR of (R)-isomer, 41.82 min;
HPLC conditions: column, CHIRALCEL AD (DAICEL); eluent, hexane/
ral-phase GC analysis with
(30 m
0.25 mm) or b-DEX-225 (SupelcoÒ) column
a c
-DEX-225 (SupelcoÒ) column
x
2-propanol (99:1); 1.0 mL minÀ1]. [ D = +22.2 (c 1.0, CHCl3); 1H
a]
(30 m  0.25 mm).
NMR (400 MHz, CDCl3) d: 0.83 (t, J = 7.2 Hz, 3H), 1.63–1.74 (m,
1H), 1.79–1.88 (m, 1H), 3.32–3.42 (m, 3H), 7.39–7.46 (m, 4H),
7.56 (t, J = 7.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 2H), 8.15 (d J = 8.8 Hz,
2H).
4.3.1. (S)-(À)-3-Ethylcyclopentan-1-one17 (Table 1, entry 1)
98% ee [tR of (S)-isomer, 29.65 min; tR of (R)-isomer, 30.16 min;
GC conditions: c-DEX-225, initial temp 70 °C, initial time 25 min,
progress time 5 °C minÀ1, final temp 120 °C]. [
a
]
D = À50.1 (c 0.8,
4.3.9. (R)-(À)-3-(4-Fluorophenyl)-1-phenyl-pentan-1-one
(Table 2, entry 4)
CHCl3); 1H NMR (400 MHz, CDCl3) d: 0.95 (t, J = 7.2 Hz, 3H), 1.43–
1.56 (m, 3H), 1.77–1.84 (m, 1H), 2.08–2.16 (m, 2H), 2.27–2.42
(m, 3H).
85% ee [tR of (S)-isomer, 11.68 min; tR of (R)-isomer, 14.82 min;
HPLC conditions: column, CHIRALCEL AD-H (DAICEL); eluent, hex-
ane/2-propanol (99:1); 0.5 mL minÀ1]. [
a
]
D = À2.5 (c 1.1, CHCl3);
4.3.2. (S)-(À)-3-Methylcyclohexan-1-one17 (Table 1, entry 2)
98% ee [tR of (S)-isomer, 34.90 min; tR of (R)-isomer, 36.16 min;
1H NMR (400 MHz, CDCl3) d: 0.80 (t, J = 7.6 Hz, 3H), 1.57–1.65
(m, 1H), 1.76–1.81 (m, 1H), 3.20–3.27 (m, 3H), 6.94–6.96 (m,
2H), 7.16–7.19 (m, 2H), 7.41–7.45 (m, 2H), 7.52–7.56 (m, 1H),
7.87–7.90 (m, 2H).
GC conditions: c-DEX-225, initial temp 70 °C, initial time 30 min,
progress time 5 °C minÀ1, final temp 120 °C]. [
a
]
D = À6.6 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d: 0.99 (d, J = 6.4 Hz, 3H),
1.61–1.69 (m, 2H), 1.81–2.04 (m, 4H), 2.16–2.24 (m, 1H), 2.29–
2.38 (m, 2H).
4.3.10. (R)-(À)-3-(2,6-Dimethylphenyl)-1-phenyl-pentan-1-one
(Table 2, entry 5)
79% ee [tR of (S)-isomer, 5.58 min; tR of (R)-isomer, 6.01 min;
HPLC conditions: column, CHIRALCEL AD-H (DAICEL); eluent, hex-
4.3.3. (S)-(À)-3-Ethylcyclohexan-1-one17 (Table 1, entry 3)
97% ee [tR of (S)-isomer, 36.54 min; tR of (R)-isomer, 37.18 min;
ane/2-propanol (99:1); 1.0 mL minÀ1]. [
a]
D = À23.0 (c 1.1, CHCl3);
GC conditions:
c
-DEX-225, initial temp 80 °C, initial time 40 min,
1H NMR (400 MHz, CDCl3) d: 0.83 (t, J = 7.6 Hz, 3H), 1.77–1.93
(m, 2H), 2.36 (s, 3H), 2.48 (s, 3H), 3.33–3.46 (m, 2H), 3.87–3.94
(m, 1H), 6.95–6.98 (m, 3H), 7.44 (t, J = 7.6 Hz, 2H), 7.54 (t,
J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H).
progress time 10 °C minÀ1, final temp 150 °C]. [
a]
D = À10.0 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d: 0.91 (t, J = 7.2 Hz, 3H), 1.32–
1.39 (m, 3H), 1.61–1.70 (m, 2H), 1.87–2.07 (m, 3H), 2.25–2.45
(m, 3H).
Acknowledgments
4.3.4. (S)-(À)-3-Methylcycloheptan-1-one17 (Table 1, entry 4)
92% ee [tR of (S)-isomer, 34.48 min; tR of (R)-isomer, 36.47 min;
GC conditions: b-DEX-225, initial temp 80 °C, initial time 30 min,
We thank Prof. Atsunori Mori of Kobe University for measure-
ment of HRMS spectrum.
progress time 5 °C minÀ1, final temp 120 °C]. [
a]
D = À62.0 (c 1.0,
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas, MEXT, Japan ‘Molecular Activation
Directed toward Straightforward Synthesis’, No. B23350043 from
the Ministry of Education, Culture, Sports, Science and Technology,
Japan. Special Coordination Funds for Promoting Science and
Technology, Creation of Innovation Centers for Advanced Interdis-
ciplinary Research Areas (Innovative Bioproduction Kobe), MEXT,
Japan is also acknowledged.
CHCl3); 1H NMR (400 MHz, CDCl3) d: 1.00 (d, J = 6.8 Hz, 3H),
1.26–1.46 (m, 2H), 1.81–1.92 (m, 5H), 2.42–2.49 (m, 4H).
4.3.5. (S)-(À)-3-Ethylcycloheptan-1-one17 (Table 1, entry 5)
80% ee [tR of (S)-isomer, 40.05 min; tR of (R)-isomer 41.87 min;
GC conditions: b-DEX-225, initial temp 90 °C, initial time 40 min,
progress time 5 °C minÀ1, final temp 120 °C]. [
a]
D = À50.4 (c 1.0,

964
Y. Ebisu et al. / Tetrahedron: Asymmetry 23 (2012) 959–964
13362; (d) Cesati, R. R., III.; De Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004,
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