Highly enantioselective introduction of bis(alkoxycarbonyl)methyl group into the 2-position of piperidine skeleton

Article abstract of DOI:10.1016/j.jorganchem.2006.04.039

Copper ion catalyzed carbon-carbon bond forming reaction of N-acyliminium ions with diaryl malonates was achieved with high enantioselectivity. The key intermediates in the method were 2-methoxy-3,4-didehydropiperidines, which were easily prepared through

Full text of DOI:10.1016/j.jorganchem.2006.04.039

Journal of Organometallic Chemistry 692 (2007) 654–663
www.elsevier.com/locate/jorganchem
Highly enantioselective introduction of bis(alkoxycarbonyl)methyl
group into the 2-position of piperidine skeleton
*
Yoshihiro Matsumura , Diashirou Minato, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 18 February 2006; received in revised form 3 April 2006; accepted 3 April 2006
Available online 30 August 2006
Abstract
Copper ion catalyzed carbon–carbon bond forming reaction of N-acyliminium ions with diaryl malonates was achieved with high
enantioselectivity. The key intermediates in the method were 2-methoxy-3,4-didehydropiperidines, which were easily prepared
through electrochemical oxidation of 1-(p-methoxybenzoyl)piperidine in methanol followed by the conversion of the oxidation prod-
uct to didehydropiperidine derivative, which was subjected to a chiral Cu(II) catalyzed coupling reaction with diaryl malonates
affording diaryl 2-piperidylmalonates. The maximum % ee (ee, enantiomeric excess) was 97% when di-p-chlorophenyl malonate
was used as a nucleophile.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Optically active 2-alkylpiperidines; 2-Methoxy-3,4-didehydropiperidines; Electrochemical oxidation; Catalytic asymmetric reaction; Copper
ion-catalyzed
1. Introduction
through 1-protected 2-methoxy-3,4-didehydropiperidines
E (Scheme 2) [4].
Asymmetric introduction of alkyl nucleophiles (NuH) to
the 2-position of 1-protected piperidinium ions C (PG: pro-
tecting group) may be one of the most convenient and sim-
ple routes for optically active 2-alkylpiperidines D, key
synthetic intermediates for a variety of chiral piperidine
alkaloids since piperidinium ions C can be generated from
easily available 1-protected piperidines A through electro-
chemical oxidation of A followed by acid treatment of
the oxidation products B (Scheme 1) [1]. However, there
have been very few reports for such asymmetric introduc-
tion in such cases that piperidinium ions C have a chiral
protecting group [2] or a chiral NuH is used [3].
However, the highest enantioselectivity so far reported
in our study was 71% ee in a case that dimethyl malonate
(2p) as NuH was used toward F. Since then, we have sur-
veyed both PG of E (R of 1a–e) and NuH (R0 of 1p–w)
to improve the % ee of G (3ap–ez) Eq. (1) and, as the result,
succeeded in achieving 97% ee of G. This paper describes
the detail of those results.
CO2R'
CO2R'
2p-z
*
CO2R'
CO2R'
N
Cu2+
chiral
ligand
N
OMe
O
R
O
R
3ap-ez
up to 97%e.e.
1a-e
We have already found an asymmetric introduction of
NuH onto the 2-position of 1-protected 3,4-didehydropipe-
ridinium ions F, which are also easily prepared from B
z : R'=o-ClPh
u : R'=
p
-MePh
p : R'=Me
q : R'=Et
r : R'= -Bu
s : R'=Ph
t : R'= -MeOPh
a : R=
p
-MeOPh
v : R'=
w : R'=
x : R'=
p-BrPh
b : R=MeO
c : R=Ph
d : R=
t
p
-ClPh
p
-FPh
p-ClPh
y : R'=m-ClPh
p
e : R=PhO
*
Corresponding author.
ð1Þ
E-mail address: matumura@net.nagasaki-u.ac.jp (Y. Matsumura).
0022-328X/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.04.039

Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
655
electrochemical
acid
NuH
oxidation
treatment
*
-H+
N
N
N
Nu
OMe
N
in MeOH
PG
PG
PG
PG
PG: protecting group
NuH:nucleophile
D
A
B
C
Scheme 1. Asymmetric introduction of alkyl nucleophile (NuH) onto the 2-position of 1-protected piperidinium ions C.
NuH
-H+
acid
treatment
*
B
N
N
Nu
OMe
N
PG
PG
PG
G
E
F
Scheme 2. Asymmetric introduction of alkyl nucleophile (NuH) onto the 2-position of 1-protected 3,4-didehydropiperidinium ions F.
2. Results and discussion
2.2. Chiral ligands
2.1. Preparation of 1-protected 2-methoxy-3,4-
didehydropiperidines 1a–e
Some known chiral bisoxazoline ligands L1–L6 (Fig. 1)
[7] were examined in the coupling reaction of 1a–e with 2p–
z.
Substrates 1a–e were prepared from 1-acylated piperi-
dines 4a–e according to the procedures indicated in Eq.
(2) [5], the first step of which was electrochemical oxida-
tion of 1a–e in methanol to afford 2-methoxylated com-
pounds 5a–e [6]. The conversion of 5a–e into 1a–e was
achieved by elimination of methanol, bromomethoxyla-
tion followed by dehydrobromination according to the
reported method [5]. In a case of 1a, the yields of 5a
and 1a were 91% at 5 F/mol and 70%, respectively.
2.3. Coupling reaction of 1a with dialkyl malonates 2p–s
First, the coupling reaction between 1a and dialkyl mal-
onates 2p–s as NuH was examined in the presence of a chi-
ral bisoxazoline ligand L1.
CO2R'
CO2R'
CO2R'
*
N
CO2R'
2p-s (1.5 equiv)
1a
ð3Þ
O
Cu(OTf)2
(0.05 equiv)
(0.06 equiv)
1) NH4Cl
-2e
MeOH
chiral ligand
OMe
N
OMe
N
N
OMe
2) Br2, NaOMe,
MeOH
L1
O
O
3ap-as
R
R
O
in THF, at rt, 12hrs
R
3) DBU
1a-e
5a-e
4a-e
The results are shown in Table 1. Although the reaction of
ð2Þ
1a with dimethyl malonate (2p) gave the coupling product
O
O
N
O
O
O
O
N
N
N
N
N
L1
L2
L3
N
t-Bu
t-Bu
O
O
O
O
O
O
N
N
N
N
N
N
t
-Bu
t-Bu
L4
L5
Fig. 1. Bisoxazolines as chiral ligands.
L6

656
Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
Table 1
phenyl malonate (2u) or (2v) afforded the corresponding
2-substituted piperidines 3au or 3av with high enantioselec-
tivity (entries 3 and 4) similar to that of using 2s (entry 1).
Di-p-chlorophenyl and di-p-fluorophenyl malonates (2w)
and (2x), which were more acidic than 2s, coupled with
1a to give the carbon–carbon bond forming products 3aw
and 3ax with higher enantioselectivity than 2s (entries 5
and 6). However, di-(m- and o-chlorophenyl) malonates
(2y) and (2z), which seemed to be a more bulky than 2s,
did not always work well (entries 7 and 8).
Coupling reactions between 1a and some malonates 2p–sa
Entry
Malonic acid
Ester
Product
R0
Yield (%) [% ee]b
CO2Me
CO2Me
1
2p
3ap
Me
78 [41]
CO2Et
CO2Et
2
3
2q
2r
3aq
3ar
Et
0 [–]
0 [–]
CO2t-Bu
CO2t-Bu
t-Bu
CO2Ph
CO2Ph
4
2s
3as
Ph
50 [89]
2.5. Coupling reaction of 1-protected 2-methoxy-3,4-
didehydropiperidines 1a–e with dimethyl or diaryl malonate
(2p or 2s,w)
a
The reaction conditions: 1a (0.5 mmol), 2p–s (0.75 mmol), Cu(OTf)2
(0.025 mmol), and L1 (0.03 mmol) in THF (2.5 mL) at RT for 12 h under
nitrogen atmosphere.
b
Determined by chiral HPLC.
The effect of 1-protecting group of 2-methoxy-3,4-dide-
hydropiperidines 1a–e on their asymmetric coupling reac-
tion with malonates 2p,s,w in the presence of chiral
ligand L1 was examined.
3ap in good yield (entry 1), using diethyl and di-tert-butyl
malonates (2q) and (2r) in place of 2p did not afford the
corresponding coupling products 3aq,ar (entries 2 and 3).
On the other hand, the coupling reaction of 1a with diphe-
nyl malonate (2s) proceeded to give the 2-substituted piper-
idine 3as with higher enantioselectivity than that using 2p
(entry 4).
CO2R'
CO2R'
CO2R'
*
N
CO2R'
2p,s,w (1.5 equiv)
N
OMe
O
R
ð5Þ
O
R
Cu(OTf)2
(0.05 equiv)
(0.06 equiv)
chiral ligand
L1
2.4. Coupling reaction of 1a with diaryl malonates 2s–z
3ap-ew
1a-e
in THF, at rt, 12hrs
The results are summarized in Table 3. Enhanced enanti-
oselectivity by using diaryl malonates 2s,w in place of di-
methyl malonate (2p) was observed in the reactions using
1-methoxycarbonylated, 1-benzoylated, and 1-p-chloro-
benzoylated piperidines 1b–d. Although an asymmetric
coupling reaction of 3,4-didehydro-2-methoxy-1-meth-
oxycarbonylpiperidine (1b) with 2p, which was prepared
from 2-methoxy-1-methoxycarbonylpiperidine (5b) [8],
On the basis of the results in Table 1, the coupling reac-
tion of 1a with bis(monosubstituted phenyl) malonates 2s–
z as NuH in the presence of a chiral bisoxazoline ligand L1
was examined.
CO2Ar
CO2Ar
*
CO2Ar
CO2Ar
N
2s-z (1.5 equiv)
1a
O
ð4Þ
Cu(OTf)2
(0.05 equiv)
(0.06 equiv)
chiral ligand
OMe
L1
3as-az
Table 3
in THF, at rt, 12hrs
Coupling reactions between 1a–e and malonates 2p,s,wa
The results are shown in Table 2. Although using di-p-
methoxyphenyl malonate (2t) did not afford the coupling
product 3at (entry 2), di-p-methylphenyl or di-p-bromo-
Entry Substrate
R
Malonate
R1
Product Yield (%) % Eeb
1
2
3
p-MeOPh 1a Me
1a Ph
2p
2s
3ap
3aa
78
50
61
41
89
93
Table 2
1a p-ClPh 2w 3aw
Coupling reactions between 1a and diaryl malonates 2s–za
% Eeb
4
5
6
MeO
1b Me
1b Ph
1b p-ClPh 2w 3bw
2p
2s
3bp
3bs
36
48
86
21
49
68
Entry
Diaryl malonate
Ar
Product
Yield (%)
1
2
3
4
5
6
7
8
a
Ph
2s
3as
3at
50
0
89
–
7
8
Ph
1c Me
1c p-ClPh 2w 3cw
2p
3cp
36
51
46
94
p-MeOPH
p-MePh
p-BrPh
p-ClPh
p-FPh
2t
2u
2v
2w
2x
2y
2z
3au
3av
3aw
3ax
3ay
3az
57
56
61
59
30
16
88
88
93
92
90
35
9
10
p-ClPh
PhO
1d Me
1d p-ClPh 2w 3dw
2p
3dp
38
71
49
91
m-ClPh
o-ClPh
11
1e p-ClPh 2w 3ew
73
77
a
The reaction conditions: 1a–e (0.5 mmol), 2p,s,w (0.75 mmol),
The reaction conditions: 1a (0.5 mmol), 2s–z (0.75 mmol), Cu(OTf)2
(0.025 mmol), and L1 (0.03 mmol) in THF (2.5 mL) at RT for 12 h under
nitrogen atmosphere.
Cu(OTf)2 (0.025 mmol), and L1 (0.03 mmol) in THF (2.5 mL) at RT for
12 h under nitrogen atmosphere.
b
b
Determined by chiral HPLC.
Determined by chiral HPLC.

Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
657
proceeded with low efficiency (entry 4), that of 1b with 2w
afforded the coupling product 3bw in good enantioselectiv-
ity (entry 6). Also, the reaction of 1-benzoylated and 1-p-
chlorobenzoylated piperidines 1c and 1d with 2w as NuH
gave the corresponding 2-substituted piperidines 3cw and
3dw in high enantioselectivities (entries 8 and 10). The reac-
tion of 1-phenoxycarbonylated piperidine 1e with 2w affor-
ded the coupling product 3ew in a reasonable optical purity
(entry 11).
are summarized in Table 5. THF afforded the best result
(entry 1), while dichloromethane, diethyl ether, toluene,
ethyl acetate, and 1,2-dimethoxyethane were a little bit
ineffective than THF (entries 2–6).
2.8. Effect of chiral ligand on the coupling reaction of 1a with
2w
The coupling reaction of 1a with 2w in THF was carried
out in the presence of chiral bisoxazoline ligands L1–L6.
The results are summarized in Table 6. Among the exam-
ined chiral ligands L1–L6 (entries 1–4), L1 gave the best
result for 1a to give 3aw with 93% ee (entry 1). Ligand
2.6. Temperature effect on the coupling reaction of 1a,c with
2p,w
With having those data in hand, we then examined a
temperature effect on an enantioselective carbon–carbon
bond formation at the 2-position of 1a,c with 2p,w in the
presence of chiral ligand L1.
Table 5
Solvent effect on the coupling reaction of 1a with 2wa
Entry
Solvent
Yield (%) of 3aw
% Eeb of 3aw
CO2R'
CO2R'
1
2
3
4
5
6
a
THF
CH2Cl2
Et2O
Toluene
AcOEt
DME
61
43
37
63
51
45
93
81
83
88
82
75
CO2R'
*
N
CO2R'
2p,w (1.5 equiv)
N
OMe
O
R
ð6Þ
O
R
Cu(OTf)2
(0.05 equiv)
(0.06 equiv)
chiral ligand
L1
3ap-cw
The reaction conditions: 1a (0.5 mmol), 2w (0.75 mmol), Cu(OTf)2
(0.025 mmol), and L1 (0.03 mmol)in solvent (2.5 mL) at RT for 12 h under
nitrogen atmosphere.
1a,c
in THF, 12hrs
The results are summarized in Table 4. Although in a case
of using dimethyl malonate (2p) (0.75 mmol) the coupling
reaction of 1a (0.5 mmol) did not occurred at all at 0 ꢁC
in THF (2.5 mL) (entry 2), the reaction between 1a and
di-p-chlorophenyl malonate (2w) proceeded well at 0 ꢁC
to afford the coupling product 3aw in 95% ee (entry 4).
The reaction of 1a (5 mmol) with 2w (7.5 mmol) in the lar-
ger scale than entry 4 at 0 ꢁC also gave 3aw in 97% ee (entry
5), while the reactions of 1a (0.5 mmol) with 2w
(0.75 mmol) at ꢀ20 ꢁC, and of 1c (0.5 mmol) with 2w
(0.75 mmol) at 0 ꢁC proceeded slowly (entries 6 and 8).
b
Determine by chiral HPLC.
Table 6
Effect of ligand on the coupling reaction of 1a with 2wa
Entry
Ligand
Yield (%) of 3aw
% Eeb of 3aw
1
2
3
4
5
6
a
L1
L2
L3
L4
L5
L6
61
72
54
52
52
0
93
92
86
71
ꢀ65c
–
The reaction conditions: 1a (0.5 mmol), 2w (0.75 mmol), Cu(OTf)2
(0.025 mmol), and L1–L6 (0.03 mmol) in THF (2.5 mL) at RT for 12 h
under nitrogen atmosphere.
2.7. Solvent effect on the coupling reaction of 1a with 2w
b
Solvent effect on the coupling reaction of 1a with 2w was
examined in the presence of chiral ligand L1. The results
Determined by chiral HPLC.
Antipode of 3aw was obtained.
c
Table 4
Temperature effect on coupling reactions between 1a,c and malonates 2p,wa
Entry
Substrate
R
Malonate
R1
Temperature
Product
Yield (%)
% Eeb
1
2
3
4
5c
6
p-MeOPh
1a
1a
1a
1a
1a
1a
me
2p
2p
RT
0 ꢁC
RT
0 ꢁC
0 ꢁC
ꢀ20 ꢁC
3ap
3ap
3aw
3aw
3aw
3aw
78
0
61
65
57
23
41
–
93
95
97
93
p-ClPh
2w
2w
2w
2w
7
8
a
Ph
1c
1c
2w
2w
RT
0 ꢁC
3cw
3cw
51
24
94
95
The reaction conditions: 1a,c (0.5 mmol), 2p,w (0.75 mmol), Cu(OTf)2 (0.025 mmol), and L1 (0.03 mmol) in THF (2.5 mL) for 12 h under nitrogen
atmosphere.
b
Determined by chiral HPLC.
c
The reaction conditions: 1a (7.5 mmol) Cu(OTf)2 (0.025 mmol), and L1 (0.03 mmol) in THF (25 mL) for 12 h under nitrogen atmosphere.

658
Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
L2 showed almost similar effect to L1 (entry 2), while
ligands L3–L5 were a little ineffective than L1 (entries 3–
5). PyBOX L6 did not work at all (entry 6).
Cu(OTf)2 (entries 8–10), while CuCl2 and Cu(PF6)2 did not
work at all (entries 7 and 11).
2.10. Identification of absolute stereochemistry of the
coupling products
2.9. Effect of Lewis acid on the coupling reaction of 1a with
2w
In order to propose a reaction mechanism, the absolute
configuration of the coupling products was identified as
shown in Eq. (7). Thus, 3aw (95% ee) were easily converted
by the reaction with NaOMe to 3ap (95% ee) in 85% yield.
The comparison of the optical rotation of 3ap with authen-
tic sample indicated that enantiomerically enriched isomer
of 3aw had a R-configuration.
Next, we examined a variety of Lewis acid catalysts in
the reaction of 1a with di-p-chlorophenyl malonate (2w)
to disclose the counter ion effect. The results are shown
in Table 7.
Among metal trifluoromethanesulfonates, Cu(OTf)2
gave the best result (entry 1), while Zn(OTf)2, Mg(OTf)2,
and La(OTf)3 were ineffective than Cu(OTf)2 (entries 1–3,
and 6). Sc(OTf)3 and Hf(OTf)4 did not work as the catalyst
(entries 4 and 5). Also, examined copper salts did not give
better result than Cu(OTf)2. Namely, Cu(ClO4)2,
Cu(BF4)2, and Cu(SbF6)2 were 6–26% ee less effective than
CO2p-ClPh
CO2p-ClPh
CO2Me
CO2Me
N
NaOMe
MeOH
N
ð7Þ
O
O
OMe
OMe
3aw: 95%e.e.
3ap: 95%e.e.
Table 7
Effect of Lewis acid catalysts on the reaction of 1a with 2wa
2.11. Reaction mechanism
Entry
Lewis acid
Yield (%) of 3aw
% Ee of 3awb
The reaction mechanism for the coupling reaction of 1
with dialkyl malonates 2 is not clear, but it may be tenta-
tively supposed as shown in Schemes 3–5 which are exem-
plified by the reaction of 1a with 2w. At the initiation step,
a copper enolate Pw may be generated from 2w and
Cu(OTf)2 with a loss of a proton which attacks on 1a to
generate an iminium ion 6a. The iminium ion is trapped
with Pw to afford a coupling product 3aw with a regenera-
tion of Cu(II). Thus, a catalytic cycle of Cu(II) for a forma-
tion of 3aw from 1a is achieved.
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Zn(OTf)2
Mg(OTf)2
Sc(OTf)2
Hf(OTf)2
La(OTf)2
CuCl2
Cu(ClO4)2
Cu(BF4)2
Cu(SbF6)2
Cu(PF6)2
61
68
42
Trace
0
78
0
58
54
36
0
93
24
0
8
–
ꢀ8c
–
87
84
67
–
10
11
a
The reaction conditions: 1a (0.5 mmol), 2w (0.75 mmol), Lewis acid
(0.025 mmol), and L1 (0.03 mmol) in THF (2.5 mL) at RT for 12 h under
nitrogen atmosphere.
The stereochemical outcome is hypothetically explain-
able using a mechanism described in Schemes 4 and 5, in
which iminium ion 6a approaches on a copper enolate
Pw through four paths 1–4. Paths 1 and 2 represent
b
Determined by chiral HPLC.
The reverse stereochemistry was observed.
c
O
O
ArO
OAr
H+ + TfO-
2w
Cu2+
O
O
Cu(OTf)2
ArO
OAr
-
-OTf
H+ + TfO-
Copper enolate
Pw
N
OMe
CO2Ar
CO2Ar
N
N
O
R
-OTf
O
R
O
R
MeOH
1a
Iminium ion
3aw
6a
R=
p
-MeOPh
Ar=
p
-ClPh
Scheme 3. A plausible reaction mechanism.

Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
659
iminium ion
MeO
OMe
6a
2
CO2
CO2
p
-ClPh
CO2
CO2
p
-ClPh
2
N
N
6
5
5
6
p-ClPh
p-ClPh
O
O
+
+
N
N
O
O
2
2
MeO
MeO
(S)-3aw
(R)-3aw
Path 2
Path 1
O
-
O
Cl
O
O
Cu
Me
N
Cl
N
O
O
Me
Copper enolate
Pw
Scheme 4. Stereochemical outcome 1.
MeO
OMe
iminium ion
2
CO2p-ClPh
CO2p-ClPh
6a
CO2p-ClPh
CO2p-ClPh
N
2
N
O
2
2
O
+
N
+
N
MeO
O
O
6
5
5
6
MeO
(R)-3aw
(S)-3aw
Path 4
Path 3
O
-
O
Cl
O
O
Cu
Me
N
Cl
N
O
O
Me
Copper enolate
Pw
Scheme 5. Stereochemical outcome 2.
approaches with minimizing an overlap between the C5,6
methylene groups of 6a and Pw (Scheme 4), while paths
3 and 4 represent approaches in which the C5,6 methylene
groups of 6a overlap Pw (Scheme 5).
3. Conclusion
We have presented a facile method for asymmetric intro-
duction of bis(alkoxycarbonyl)methyl group into the 2-
position of a piperidine skeleton. The key intermediates
were 2-methoxy-3,4-didehydropiperidines 1a–e, which were
prepared through electrochemical oxidation of easily avail-
able 1-protected piperidines 4a–e in methanol. The highest
enantioselectivity (97% ee) was observed in a coupling reac-
tion between 1-(p-methoxybenzoyl)-3,4-didehydro-2-meth-
oxypiperidine (1a) and di-p-chlorophenyl malonate (2w)
with a catalytic amount of Cu(OTf)2 and a chiral ligand
L1 in THF at 0 ꢁC. Further study to improve the stereose-
lectivity is under investigation.
Among those paths, path 1 seems more likely than the
other paths because of a steric repulsion between Ph group
of Pw and an aryloyl group of 6a in path 2 and between the
C5,6 methylene groups of 6a and Pw in paths 3 and 4.
The steric factor may be primarily important for the
stereoselectivity, but the result is not always explained
only by the steric factor since diaryl malonates 2s,u–x
afforded the different % ee of the coupling products
(entries 1, 3–6 in Table 2) and more bulky L3 gave a less
stereoselective result than less bulky L1, L2 did (entries 1–
3 in Table 6). A strength of the coordination (a tightness)
between copper ion and the carbonyl oxygen in Pw may
depend on Ar group of diaryl malonates, and it may be
responsible to some extent for the stereoselectivity. Also,
a substituent on the 4-phenyl group of the oxazolidine
ring may affect to the tightness by its electronic or steric
reason.
4. Experimental
4.1. General
HPLC analyses were achieved by using a LC-10AT VP
and a SPD-10A VP of Shimadzu Seisakusho Inc. Specific

660
Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
1
rotations were measured with Jasco DIP-1000. H NMR
spectra were measured on a Varian Gemini 300 spectrom-
eter with TMS as an internal standard. IR spectra were
obtained on a Shimadzu FTIR-8100A. Mass spectra were
obtained on a JEOL JMS-700N instrument. Melting points
are uncorrected.
NMR (CDCl3) d 3.86 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H),
7.20 (s, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.1 Hz,
2H); HRMS (M, EI) calcd for C15H10Cl2O6 323.9956;
found 323.9937.
4.3.3. Di-o-chlorophenyl malonate (2z)
Colorless oil; IR (neat) 3073, 2950, 1782, 1763, 1584,
All solvents were dried by standard techniques. The
preparation of 2-methoxy-3,4-didehydropiperidines 1a,c,d
[4b], 1b [3c] and chiral ligands L2, L3 [4c] were already
reported by us. Malonate 2s [9], 2u,w [10], 2v [11], and 2x
[12] are known compounds. Malonates 2p–r, chiral ligands
L1,L4–L6, and Cu(OTf)2, Mg(OTf)2, Sc(OTf)3, La(OTf)2,
Hf(OTf)4, Zn(OTf)2 were commercially available.
Cu(PF6)2 and Cu(SbF6)2 were prepared according to the
reported method [13].
1
1478, 1217, 1063, 752 cmꢀ1; H NMR (CDCl3) d 3.98 (s,
2H), 7.20–7.35 (m, 6H), 7.448 (d, J = 8.1 Hz, 2H); HRMS
(M, EI) calcd for C15H10Cl2O4 323.9956; found 323.9932.
4.4. Asymmetric coupling reaction of 1 with 2: a typical
experimental procedure
A
solution of di-p-chlorophenyl malonate (2w)
(0.75 mmol), Cu(OTf)2 (0.025 mmol) and L1 (0.03 mmol)
in THF (1 mL) was stirred for 5 min at room temperature
under a nitrogen atmosphere. Into the solution was added
a solution of 1a (0.5 mmol) in THF. After stirring for12 h,
the resulting mixture was poured into aqueous NaHCO3
(5 mL). The organic portion was extracted with AcOEt
(10 mL · 3) and dried over MgSO4. The resulting solution
was concentrated in vacuo. The residue was chromato-
graphed on silica gel (hexane/AcOEt = 5/1) to afford 3aw
(61% yield, 93% ee). The spectroscopic data of products
3ap,bp,cp,dp were also described in the report [4b].
4.2. Preparation of 1-phenoxycarbonyl-2-methoxy-3,4-
didehydropiperidine (1e)
1-Phenoxycarbonyl-2-methoxy-3,4-didehydropiperidine
(1e) was easily prepared by our reported procedure [3c–5].
Namely, electrochemical oxidation of 1-phenoxycarbonyl-
piperidine (4e) in methanol afforded 2-methoxylated com-
pound 5e [14], which was successively transformed into
the corresponding enecarbamate [15] by acid-catalyzed
elimination of methanol. Bromomethoxylation of the enec-
arbamate afforded 3-bromo-2-methoxylated compound
[15], which was transformed into 1e by a base-catalyzed
elimination of hydrobromic acid.
4.4.1. Di-p-chlorophenyl [1-(p-methoxybenzoyl)-3,4-
didehydro-2-piperidyl]malonate (3aw) (93% ee)
25
Colorless oil; ½aꢁD +53.7ꢁ (c = 0.5, CHCl3); IR (neat)
4.2.1. 1-Phenoxycarbonyl-2-methoxy-3,4-
didehydropiperidine (1e)
2934, 2840, 1752, 1624, 1608, 1487, 1429, 1304, 1250,
1
1192, 1134, 1090, 1015 cmꢀ1; H NMR (CDCl3) d 2.00–
Colorless oil; IR (neat) 3044, 2936, 1736, 1651, 1593,
2.17 (m, 1H), 2.20–2.40 (m, 1H), 3.25–3.45 (m, 1H),
3.75–3.95 (m, 1H), 3.83 (s, 3H), 4.24 (d, J = 8.4 Hz, 1H),
5.75–5.90 (m, 1H), 6.00–6.20 (m, 2H), 6.90 (d,
J = 8.7 Hz, 2H), 7.05–7.20 (m, 4H), 7.27–7.40 (m, 6H);
HRMS (M, EI) calcd for C28H23Cl2NO6 539.0902; found
539.0921.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 9 min for minor enantio-
mer and 24 min for major enantiomer.
1424, 1368, 1235, 754 cmꢀ1 1H NMR (CDCl3) d 2.00–
;
2.12 (m, 1H), 2.25–2.40 (m, 1H), 3.15–3.50 (m, 1H), 3.45
and 3.49 (2s, 3H), 4.18–4.28 (m, 1H), 5.50 and 5.60 (2br
s, 1H), 5.80–5.88 (m, 1H), 6.00–6.15 (m, 1H), 7.12 (d,
J = 8.1 Hz, 2H), 7.22 (t, J = 8.1 Hz, 1H), 7.38 (t,
J = 8.1 Hz, 2H); HRMS (M, EI) calcd for C13H15NO3
233.1052; found 233.1042.
4.3. Preparation of diaryl malonates 2t–z
Diaryl malonates 2t–z were prepared from malonic acid
and the corresponding phenols in the presence of POCl3
according to a reported method [9].
4.4.2. Diphenyl [1-(p-methoxybenzoyl)-3,4-didehydro-2-
piperidyl]malonate (3as) (89% ee)
22
Colorless oil; ½aꢁD +86.2ꢁ (c = 0.5, CHCl3); IR (neat)
3044, 2936, 2840, 1752, 1628, 1512, 1493, 1427, 1304,
1
4.3.1. Di-p-methoxyphenyl malonate (2t)
Pale brown solid; mp 77–80 ꢁC; IR (neat) 2950, 2840,
1250, 1186, 1136, 1026 cmꢀ1; H NMR (CDCl3) d 1.90–
2.15 (m, 1H), 2.15–2.40 (m, 1H), 3.25–3.50 (m, 1H),
3.75–3.95 (m, 1H), 3.83 (s, 3H), 4.30 (d, J = 7.8 Hz, 1H),
5.80–5.95 (m, 1H), 6.00–6.20 (m, 2H), 6.90 (d,
J = 9.0 Hz, 2H), 7.10–7.45 (m, 12H); HRMS (M, EI) calcd
for C28H25NO6 471.1682; found 471.1664.
1
1767, 1752, 1514, 1472, 1300, 1186, 1102, 1034 cmꢀ1; H
NMR (CDCl3) d 3.80 (s, 6H), 3.82 (s, 2H), 6.90 (d,
J = 9.0 Hz, 4H), 7.07 (d, J = 8.7 Hz, 1H); HRMS (M,
EI) calcd for C17H16O6 316.0947; found 316.0929.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 ml/min, detection at 210 nm, 25 min for minor enantio-
mer and 39 min for major enantiomer.
4.3.2. Di-m-chlorophenyl malonate (2y)
Pale brown solid; mp 67–69 ꢁC; IR (neat) 3073, 2940,
1
1773, 1752, 1590, 1474, 1431, 1197, 1134, 1070 cmꢀ1; H

Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
661
4.4.3. Di-p-methylphenyl [1-(p-methoxybenzoyl)-3,4-
didehydro-2-piperidyl]malonate (3au) (88% ee)
6.91 (d, J = 8.5 Hz, 2H), 7.05–7.40 (m, 10H); HRMS
(M, EI) calcd for C28H23Cl2NO6 539.0902; found
539.0912.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 8 min for minor enantio-
mer and 15 min for major enantiomer.
21
Colorless oil; ½aꢁD +70.9ꢁ (c = 0.5, CHCl3); IR (neat)
2932, 2840, 1750, 1628, 1609, 1507, 1426, 1304, 1252,
1
1136, 843 cmꢀ1; H NMR (CDCl3) d 1.95–2.15 (m, 1H),
2.15–2.40 (m,1H), 2.33 (s, 3H), 2.35 (s, 3H), 3.30–3.45
(m, 1H), 3.75–3.95 (m, 1H), 3.82 (s, 3H), 4.27 (d,
J = 8.1 Hz, 1H), 5.80–5.90 (m, 1H), 6.00–6.20 (m, 2H),
6.89 (d, J = 8.7 Hz, 2H), 7.03 and 7.06 (2d, J = 9.0 Hz,
4H), 7.16 and 7.19 (2d, J = 9.0 Hz, 4H), 7.36 (d, J =
8.7 Hz, 2H); HRMS (M, EI) calcd for C30H29NO6
499.1995; found 499.1986.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 10 min for minor enan-
tiomer and 20 min for major enantiomer.
4.4.7. Di-o-chlorophenyl [1-(p-methoxybenzoyl)-3,4-
didehydro-2-piperidyl]malonate (3az) (35% ee)
20
White solid; mp 143–144 ꢁC; ½aꢁD +38.8ꢁ (c = 0.5,
CHCl3); IR (neat) 2936, 2840, 1759, 1628, 1609, 1512,
1478, 1428, 1304, 1254, 1136, 1061 cmꢀ1 1H NMR
;
(CDCl3) d 2.00–2.15 (m, 1H), 2.20–2.40 (m,1H), 3.30–
3.50 (m, 1H), 3.80–3.95 (m, 1H), 3.82 (s, 3H), 4.42 (d,
J = 8.7 Hz, 1H), 5.85–6.00 (m, 1H), 6.00–6.25 (m, 2H),
6.90 (d, J = 8.7 Hz, 2H), 7.20–7.50 (m, 10H); HRMS (M,
EI) calcd for C28H23Cl2NO6 539.0902; found 539.0920.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 12 min for minor enan-
tiomer and 19 min for major enantiomer.
4.4.4. Di-p-bromophenyl [1-(p-methoxybenzoyl)-3,4-
didehydro-2-piperidyl]malonate (3av) (88% ee)
22
Colorless oil; ½aꢁD +38.6ꢁ (c = 0.5, CHCl3), IR (neat)
2936, 2838, 2249, 1752, 1640, 1508, 1458, 1304, 1254,
1134, 1068, 1012 cmꢀ1 1H NMR (CDCl3) d 2.00–2.15
;
(m, 1H), 2.20–2.40 (m, 1H), 3.25–3.45 (m, 1H), 3.75–3.95
(m, 1H), 3.83 (s, 3H), 4.23 (d, J = 8.3 Hz, 1H), 5.75–5.90
(m, 1H), 6.00–6.15 (m, 2H), 6.90 (d, J = 8.5 Hz, 2H),
7.00–7.15 (m, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.45–7.55
(m, 4H); HRMS (M+H, FAB) calcd for C28H24Br2NO6
627.9971; found 627.9985.
4.4.8. Diphenyl (1-methoxycarbonyl-3,4-didehydro-2-
piperidyl)malonate (3bs) (49% ee)
21
Colorless oil; ½aꢁD +88.1ꢁ (c = 0.5, CHCl3); IR (neat)
3044, 2955, 2840, 1752, 1701, 1591, 1491, 1447, 1410,
1
1300, 1188 cmꢀ1; H NMR (CDCl3) d 2.00–2.42 (m, 2H),
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 10 min for minor enan-
tiomer and 26 min for major enantiomer.
3.05–3.20 (m, 1H), 3.71 and 3.75 (2s, 3H), 4.10–4.42 (m,
2H), 5.25–5.42 (m, 1H), 5.98–6.10 (m, 2H), 7.14 (d,
J = 7.8 Hz, 4H), 7.20–7.32 (m, 2H), 7.35–7.45 (m, 4H);
HRMS (M, EI) calcd for C22H21NO6 395.1369; found
395.1357.
4.4.5. Di-p-fluorophenyl [1-(p-methoxybenzoyl)-3,4-
didehydro-2-piperidyl]malonate (3ax) (92% ee)
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (10/1) (v/v),
1.0 mL/min, detection at 210 nm, 9 min for minor enantio-
mer and 10 min for major enantiomer.
22
Colorless oil; ½aꢁD +110.1ꢁ (c = 0.5, CHCl3); IR (neat)
3078, 2936, 2840, 1754, 1628, 1611, 1507, 1429, 1306,
1254, 1136, 1030, 843 cmꢀ1 1H NMR (CDCl3) d 2.00–
;
2.15 (m, 1H), 2.20–2.40 (m,1H), 3.25–3.45 (m, 1H),
3.75–3.95 (m, 1H), 3.83 (s, 3H), 4.24 (d, J = 8.1 Hz,
1H), 5.80–5.95 (m, 1H), 6.00–6.20 (m, 2H), 6.90 (d,
J = 8.7 Hz, 2H), 7.00–7.20 (m, 8H), 7.33 (d, J = 8.7 Hz,
2H); HRMS (M, EI) calcd for C28H23F2NO6 507.1493;
found 507.1490.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 9 min for minor enantio-
mer and 22 min for major enantiomer.
4.4.9. Di-p-chlorophenyl (1-methoxycarbonyl-3,4-
didehydro-2-piperidyl)malonate (3bw) (68% ee)
21
Colorless oil; ½aꢁD +82.2ꢁ (c = 0.5, CHCl3); IR (neat)
2955, 1754, 1701, 1487, 1300, 1200, 1196, 1092,
1015 cmꢀ1
;
1H NMR (CDCl3) d 2.00–2.12 (m, 1H),
2.20–2.38 (m, 1H), 3.00–3.15 (m, 1H), 3.68 and 3.72
(2s, 3H), 4.10–4.42 (m, 2H), 5.20–5.40 (m, 1H), 5.90–
6.10 (m, 2H), 7.07 (d, J = 8.8 Hz, 4H), 7.30–7.40 (m,
4H); HRMS (M, EI) calcd for C22H19Cl2NO6 463.0589;
found 463.0570.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (50/1) (v/v),
1.0 mL/min, detection at 210 nm, 12 min for minor enan-
tiomer and 16 min for major enantiomer.
4.4.6. Di-m-chlorophenyl [1-(p-methoxybenzoyl)-3,4-
didehydro-2-piperidyl]malonate (3ay) (90% ee)
22
Colorless oil; ½aꢁD +61.6ꢁ (c = 0.25, CHCl3); IR (neat)
3069, 2934, 2838, 1754, 1624, 1591, 1512, 1471, 1427,
1304, 1248, 1192, 1129 cmꢀ1
;
1H NMR (CDCl3) d
4.4.10. Di-p-chlorophenyl (1-benzoyl-3,4-didehydro-2-
piperidyl)malonate (3cw) (94% ee)
2.05–2.15 (m, 1H), 2.25–2.45 (m,1H), 3.25–3.45 (m,
1H), 3.75–3.95 (m, 1H), 3.83 (s, 3H), 4.27 (d,
J = 8.0 Hz, 1H), 5.75–5.90 (m, 1H), 6.00–6.20 (m, 2H),
22
White solid; mp 111–113 ꢁC; ½aꢁD +60.0ꢁ (c = 0.25,
CHCl3); IR (neat) 2932, 1753, 1632, 1487, 1429, 1306,

662
Y. Matsumura et al. / Journal of Organometallic Chemistry 692 (2007) 654–663
1
1192, 1090, 1015 cmꢀ1; H NMR (CDCl3) d 2.00–2.12 (m,
1H), 2.2.0–2.38 (m, 1H), 3.25–3.40 (m, 1H), 3.70–3.85 (m,
1H), 4.23 (d, J = 8.4 Hz, 1H), 5.88 (br d, J = 6.9 Hz,
1H), 6.05–6.15 (m, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.15 (d,
J = 8.9 Hz, 2H), 7.30–7.45 (m, 9H); HRMS (M, EI) calcd
for C27H21Cl2NO5 509.0797; found 509.0786.
1.0 mL/min, detection at 210 nm, 41 min for (S)-3ap and
53 min for (R)-3ap.
Acknowledgements
This study was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (No. 420: Reaction Con-
trol of Dynamic Complexes) from the Ministry of
Education, Science, Sports and Culture, Japan and by a
Grant-in-Aid for Scientific Research (C) (No. 15550094)
from Japan Society for the Promotion of Science.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 8 min for minor enantio-
mer and 15 min for major enantiomer.
4.4.11. Di-p-chlorophenyl [1-(p-chlorobenzoyl)-3,4-
didehydro-2-piperidyl]malonate (3dw) (91% ee)
References
19
White solid; mp 31–33 ꢁC; ½aꢁD +40.3ꢁ (c = 0.25,
CHCl3); IR (neat) 2930, 1752, 1632, 1487, 1431, 1306,
[1] (a) T. Shono, Y. Matsumura, K. Tsubata, Org. Synth. 63 (1984)
206;
1194, 1090, 1015 cmꢀ1 1H NMR (CDCl3) d 2.00–2.40
;
(aa) T. Shono, Y. Matsumura, K. Tsubata, Org. Synth. Coll. VII
(1990) 307;
(m, 2H), 3.15–3.42 (m, 1H), 3.71 and 3.76 (2d, J = 5.4
and 5.4 Hz, 1H), 4.20 (d, J = 8.4 Hz, 1H), 5.85 (d,
J = 8.4 Hz, 1H), 6.09 (br s, 2H), 7.10 (d, J = 9.0 Hz, 2H),
7.14 (d, J = 9.0 Hz, 2H), 7.20–7.52 (m, 8H); HRMS (M,
EI) calcd for C27H2035Cl237ClNO5 545.0378; found
545.0394.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 7 min for minor enantio-
mer and 12 min for major enantiomer.
(b) W.N. Speckamp, M.J. Moolenaar, Tetrahedron 56 (2000) 3817.
[2] (a) K.T. Wanner, A. Kaetner, Heterocycles 26 (1987) 921;
(b) S.S. Kinderman, J.H. van Maarseveen, H.E. Schoemaker, H.
Hiemstra, F.P.J.T. Rutjes, Synthesis (2004) 1413.
[3] (a) Y. Matsumura, Y. Kanda, K. Shirai, O. Onomura, T. Maki, Org.
Lett. 1 (1999) 175;
(b) R.A. Pilli, C.F. Alves, M.A. Bockelmann, Y.P. Mascarenhas,
J.G. Nery, I. Vencato, Tetrahedron Lett. 40 (1999) 2891;
(c) Y. Matsumura, Y. Kanda, K. Shirai, O. Onomura, T. Maki,
Tetrahedron 56 (2000) 7411.
[4] (a) O. Onomura, Y. Kanda, Y. Nakamura, T. Maki, Y. Matsumura,
Tetrahedron Lett. 43 (2002) 3229;
4.4.12. Di-p-chlorophenyl (1-phenoxycarbonyl-3,4-
didehydro-2-piperidyl)malonate (3ew) (77% ee)
(b) Y. Kanda, O. Onomura, T. Maki, Y. Matsumura, Chirality 15
(2003) 89;
(c) O. Onomura, Y. Kanda, E. Imai, Y. Matsumura, Electrochim.
Acta 50 (2005) 4926.
24
Colorless oil; ½aꢁD +89.6ꢁ (c = 0.7, CHCl3); IR (neat)
3046, 2936, 1755, 1719, 1489, 1424, 1209, 1092,
1
1015 cmꢀ1; H NMR (CDCl3) d 21.0–2.25 (m, 1H), 2.35–
[5] T. Shono, Y. Matsumura, O. Onomura, Y. Yamada, Tetrahedron
Lett. 28 (1987) 4073.
[6] T. Shono, H. Hamaguchi, Y. Matsumura, J. Am. Chem. Soc. 97
(1975) 4264.
[7] (a) Recent representative asymmetric carbon-carbon bond forming
reactions using chiral bisoxazoline ligand: D.A. Evans, D.M. Fitch,
T.E. Smith, V.J. Cee, J. Am. Chem. Soc. 122 (2000) 10033;
(b) M.A. Pericas, C. Puigjaner, A. Riera, A. Vidal-Ferran, M.
Gomez, F. Jimenez, G. Muller, M. Rocamora, Chem. Eur. J. 8
(2002) 4164;
2.50 (m, 1H), 3.12–3.35 (m, 1H), 4.11 and 4.21 (2d,
J = 7.8 and 7.8 Hz, 1H), 4.35–4.45 (m, 1H), 5.38–5.56 (m,
1H), 6.00–6.18 (m, 2H), 6.98–7.42 (m, 13H); HRMS (M,
EI) calcd for C27H21Cl2NO6 525.0746; found 525.0741.
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (5/1) (v/v),
1.0 mL/min, detection at 210 nm, 7 min for minor enantio-
mer and 9 min for major enantiomer.
(c) N. Halland, T. Velgaard, K.A. Jorgensen, J. Org. Chem. 68 (2003)
5067;
(d) M. Marigo, A. Kjaersgaard, K. Juhl, N. Gathergood, K.A.
Jorgensen, Chem. Eur. J. 9 (2003) 2359;
4.5. Transformation of 3aw into (R)-3ap
(e) D.A. Evans, D. Seidel, M. Rueping, H.W. Lam, J.T. Shaw, C.W.
Downey, J. Am. Chem. Soc. 125 (2003) 12692;
(f) V.K. Aggarwal, A.J. Belfield, Org. Lett. 5 (2003) 5075;
(g) M.P. Sibi, G. Petrovic, J. Zimmerman, J. Am. Chem. Soc. 127
(2005) 2390;
A solution of NaOMe (95 mg, 1.77 mmol) in MeOH
(7 mL) was added into a solution of 3aw (95% ee,
318 mg, 0.59 mmol) in MeOH (3 mL), and the resulting
solution was allowed to be stirred at 0 ꢁC to room temper-
ature. After 12 h, solvent of the reaction mixture was
removed in vacuo. Into the residue was added water. The
organic portion was extracted with AcOEt (10 mL · 3)
and dried over MgSO4. The resulting solution was concen-
trated in vacuo to afford a crude (R)-3ap [1], which was
purified by silica gel chromatography (hexane/AcOEt =
(h) M. Ma, L. Peng, C. Li, X. Zhang, J. Wang, J. Am. Chem. Soc.
127 (2005) 15016.
[8] (a) T. Shono, Y. Matsumura, K. Uchida, H. Kobayashi, J. Org.
Chem. 50 (1985) 3243;
(b) T. Shono, Y. Matsumura, K. Tsubata, J. Am. Chem. Soc. 103
(1981) 1172;
(c) T. Shono, Y. Matsumura, K. Uchida, K. Tagami, Chem. Lett.
(1987) 919;
25
5/1) to afford (R)-3ap (85% yield, 95% ee). ½aꢁD +172.4ꢁ
(d) T. Shono, Y. Matsumura, K. Tsubata, Y. Sugihara, S. Yamane,
T. Kanazawa, T. Aoki, J. Am. Chem. Soc. 104 (1982) 6697.
[9] I. Jabin, G. Revial, N. Monnier-Benoit, P. Netchitailo, J. Org. Chem.
66 (2001) 256.
(c = 0.25, CHCl3).
The ee was obtained by DAICEL Chiralcel OD
(B4.6 mm, 250 mm) hexane/isopropanol (9/1) (v/v),

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663
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