An efficient synthetic methodology of chiral isoquinuclidines by the enantioselective Diels-Alder reaction of 1,2-dihydropyridines using chiral cationic palladium-phosphinooxazolidine catalyst

Article abstract of DOI:10.1016/j.tet.2006.08.099

High purity chiral isoquinuclidines (97% ee) were obtained from the enantioselective Diels-Alder reaction of 1-phenoxycarbonyl-1,2-dihydropyridine with 1-benzyl-2-acryloylpyrazolidin-3-one using chiral cationic palladium-phosphinooxazolidine (Pd-POZ) catalyst. The obtained DA adduct was easily converted to the chiral piperidine derivative bearing three stereogenetic centers in the structure.

Full text of DOI:10.1016/j.tet.2006.08.099

Tetrahedron 62 (2006) 10879–10887
An efficient synthetic methodology of chiral isoquinuclidines by
the enantioselective Diels–Alder reaction of 1,2-dihydropyridines
using chiral cationic palladium–phosphinooxazolidine catalyst
*
Hiroto Nakano, Natsumi Tsugawa, Kouichi Takahashi, Yuko Okuyama and Reiko Fujita
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 6 July 2006; revised 27 August 2006; accepted 30 August 2006
Available online 20 September 2006
Abstract—High purity chiral isoquinuclidines (97% ee) were obtained from the enantioselective Diels–Alder reaction of 1-phenoxycarbonyl-
1,2-dihydropyridine with 1-benzyl-2-acryloylpyrazolidin-3-one using chiral cationic palladium–phosphinooxazolidine (Pd–POZ) catalyst.
The obtained DA adduct was easily converted to the chiral piperidine derivative bearing three stereogenetic centers in the structure.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
isoquinuclidines are also valuable intermediates in the syn-
thesis of other alkaloids4 and in medicinal chemistry.5
Therefore, it is important to establish an effective asymmet-
ric synthetic methodology for chiral isoquinuclidines. A
well-established route to this ring system is through the
Diels–Alder (DA) reaction of 1,2-dihydropyridines with
dienophiles. However, little research on the asymmetric
version of this reaction has been reported, and most reports
are of diastereoselective versions of the reaction, which used
1,2-dihydropyridines or dienophiles attached to a chiral
auxiliary.6 Despite the obvious advantages of its catalytic
enantioselective version, to the best of our knowledge,
The 2-azabicyclo[2.2.2]octanes (isoquinuclidines) are found
widely in natural products such as iboga-type indole
alkaloids, which have varied and interesting biological
properties (Fig. 1).1 Typical iboga-alkaloids include cathar-
anthine 1, which is the precursor of pharmacologically
important vinca alkaloids such as vinblastine 3a and vincris-
tine 3b.2 Most recently, it was also indicated that ibogaine 2
reduces cravings for alcohol and other drugs by means of its
ability to boost the levels of a growth factor known as glial
cell line-derived neurotrophic factor (GDNF).3 Furthermore,
R
N
MeO
N
N
+
X
N
N
H
N
H
O
O
R
X
CO2Me
1,2-dihydropyridines
1
2
isoquinuclidines
2+
N
Ph
O
3a: R=Me: vinblastine
3b: R=CHO: vincristine
Ph
N
H
N
+2X
Pd
Ph
OH
N
MeO2C
P
Ph
A
OH
cationic Pd-POZ catalyst
MeO
N
R
OAc
H
CO2Me
Figure 1.
Keywords: Enantioselective Diels–Alder reaction; 1,2-Dihydropyridine; Chiral cationic palladium–phosphinooxazolidine catalyst; Chiral isoquinuclidines;
Chiral piperidines.
* Corresponding author. Tel.: +81 22 727 0147; fax: +81 22 275 2013; e-mail: hnakano@tohoku-pharm.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.099

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H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
Table 1. Enantioselective DA reactions of 1,2-dihydropyridines 6a,b with
2-acryloyl-1,3-oxazolidine-2-one 7
only one example employing a Cr–BINAM catalyst has
been reported to date by Rawal et al. for the catalytic
enantioselective version of the DA reaction. However, the
reaction afforded only modest asymmetric induction (up to
85% ee).7 Most recently, we have reported that the enan-
tioselective DA reaction of 1,2-dihydropyridines with
1-substituted acryloylpyrazolidin-3-ones using a Pd–POZ
catalyst is an efficient synthetic methodology for obtaining
chiral isoquinuclidines at synthetically useful levels of
enantiomeric excess (ee).8
RO2C
chiral cationic
N
Pd-catalysts 5a-d
O
O
(10 mol%)
+
N
O
O
N
CH2Cl2
O
N
CO2R
O
7
6a,b
(7R)-8a,b
a: R=Ph
b: R=PhCH2
a: R=Ph
b: R=PhCH2
Entry Diene Catalyst Temp Time DA
(ꢀC)
Yield ee
In this paper, we describe the details of the first successful
enantioselective DA reaction of 1,2-dihydropyridines with
1-substituted acryloylpyrazolidin-3-ones using a Pd–POZ
catalyst,8 and also the convenient transformation of the
obtained DA adduct to the chiral piperidine derivative bear-
ing three chiral carbon centers in the structure.
(h)
adduct (%)a (%)b
1
2
3
4
6a
6a
6a
6a
5a
5b
5c
5d
0
0
0
0
24
24
24
24
8a
8a
8a
8a
98
90
46
37
76
84
88
74
5
6
6a
6a
5a
5b
ꢁ25
ꢁ25
48
48
8a
8a
84
73
82
82
7
6b
5a
0
24
8b
90
74
2. Results and discussion
a
Isolated yields.
Enantiomeric excess of endo-isomer was determined by chiral HPLC
using a Daicel AD or AD-H column.
b
2.1. Diels–Alder reaction with acryloyl-1,3-oxazolidine-
2-one
We first tested the DA reaction of 1-phenoxycarbonyl-1,2-
dihydropyridine 6a or 1-benzyloxycarbonyl-1,2-dihydro-
pyridine 6b with common 2-acryloyl-1,3-oxazolidine-2-one
7. The reaction was carried out at 0 ꢀC or ꢁ25 ꢀC in
CH2Cl2 in the presence of 10 mol % of the cationic Pd–POZ
catalysts 5a–d that were prepared by the reactions of PdCl2–
POZ complex 4 and the corresponding AgX (X¼SbF6,
ClO4, BF4, OTf) using our previously reported procedure
(Scheme 1).9 As a result, antimonate catalyst 5a at ꢁ25 ꢀC
and perchlorate catalyst 5b at 0 ꢀC gave the endo-DA adduct
8a in good chemical yields and enantioselectivities (entries 2
and 5, Table 1). The other 1,2-dihydropyridine, 1-benzyl-
oxycarbonyl-1,2-dihydropyridine 6b, was also used in the
same reaction. Although the reaction proceeded with an
excellent chemical yield to afford 8b, the enantioselectivity
was moderate. In both reactions, enantioselectivity over
90% ee was not achieved as in the results of Rawal et al.7
reaction with cyclopentadiene as a diene. However, a fairly
high level of catalytic loading (50 mol %) was needed for
the achievement of satisfactory enantioselectivity in the
reaction. We applied the 1-substituted 2-pyrazolidin-3-one
dienophile to the DA reactions of 1,2-dihydropyridines
6a–c using cationic Pd–POZ catalysts 5a–d.
Although Sibi et al. used 1-substituted 2-crotonylpyrazoli-
din-3-ones as a dienophile, we applied the simplest
1-substituted 2-acryloylpyrazolidin-3-ones to our DA reac-
tion. 2-Acryloylpyrazolidin-3-ones 12a–c were prepared
following the procedure reported by Sibi et al.10 and Perri
et al.11 (Scheme 2). Thus, 3,3-dimethylacrylate 9 was con-
verted to 5,5-dimethylpyrazolidin-3-one 10 by the reaction
with hydrazine monohydrate. N-Alkylation of 10, followed
by the reactions of 11a,b with acryloyl chloride, afforded
the dienophiles 12a10 and b in moderate to good yields.
On the other hand, dienophile 12c was obtained from the
condensation of 10 with acetaldehyde, followed by the re-
duction of the imino moiety and then the reaction of the
obtained 11c with acryloyl chloride in a moderate yield.
2+
Ph
O
Ph
O
Ph
Ph
N
N
Cl
Cl
Ph
Ph
1) PdCl2
+2X
Pd
Pd
2) AgX
CH2Cl2
rt
P
P
Ph
Ph
CO2Et
a: X=SbF6
b: X=ClO4
c: X=BF4
d: X=OTf
9
5a-d
4
•
NH2NH2 H2O, abs.ethanol
reflux, 4 h, 64%
Scheme 1. Preparations of cationic POZ complexes 5a–d.
O
O
O
O
O
2.2. Diels–Alder reaction with 1-substituted
2-acryloylpyrazolidin-3-ones
alkylBr
Cl
N
N
NaI, K2CO3
HN
N
acrylic acid
HN
HN
X
X
2-butanone
reflux, 3 h
Et3N, LiCl
THF, 0 °C
In order to improve the enantioselectivity of the reaction, we
explored the possibilities presented in a report by Sibi
et al.,10 who examined a novel 1-substituted 2-crotonyl-
pyrazolidin-3-one as a dienophile based on the concept of
‘chiral relay’, and reported that the combination of this dien-
ophile and nonoptimized Cu–bis-oxazoline catalyst can
bring about an excellent asymmetric induction in the DA
12a : X=Ph, 12 h, 65%
12b : X=1-Naph, 5 h, 61%
12c : X=Et, 6 h, 69%
10
11a : X=Ph, 85%
1)
CH3CHO
abs.methanol
11b : X=1-Naph, 65%
11c : X=Me, 72%
2) NaBH4
0 °C rt
30 min
Scheme 2. Preparations of dienophiles 12a–c.

H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
10881
First, we examined the effectiveness of dienophiles 12a–c
using superior antimonate catalyst 5a. The reactions of diene
6a with dienophiles 12a–c were carried out at 0 ꢀC in the
presence of 10 mol % of the prepared Pd–POZ catalysts
5a–d to give the corresponding endo-DA adducts 13a–c.
The results are summarized in Table 2. A significant differ-
ence was observed in chemical yield and enantioselectivity
corresponding to the different substituent groups on the
nitrogen at the 1-position. A dramatic increase in enantio-
selectivity to 97% ee was accomplished with good chemical
yield when 1-benzyl substituted derivative 12a was used as
a dienophile (80%, entry 1). Despite our expectations, the
bulkier 1-naphthylmethyl derivative 12b brought about a de-
crease in both chemical yield and enantioselectivity (entry 2).
Similarly, the reactionusing the less bulky1-ethyl substituted
derivative 12c was also sluggish, although the reasons for this
remain unclear (entry 3). Next, we examined the effects of
other counterions such as perchlorate, tetrafluoroborate,
and triflate on the reaction with superior dienophile 12a. As
aresult, cationic perchlorate catalyst 5b and tetrafluoroborate
catalyst 5c afforded the DA adduct 13a in high enantioselec-
tivities with good chemical yields (entries 4 and 5). In partic-
ular, 5c showed the best enantioselectivity (97% ee) with
76% yield (entry 5), the results are almost identical to those
achieved with antimonate catalyst 5a. However, triflate cata-
lyst 5d did not give satisfactory reactivity and enantioselec-
tivity (60%, 89% ee, entry 6). The reactions with superior
cationic catalysts 5a and c at ꢁ25 ꢀC did not afford better
results for chemical yields and enantioselectivities than the
results at 0 ꢀC (entries 7 and 8). Furthermore, the effect of
reducing the molar ratio of catalyst 5a was examined. At
low catalytic loading to 5 mol % of 5a, equally satisfactory
results (78%, 95% ee) were obtained, but the use of
2.5 mol % greatly decreased both the chemical yield and
enantioselectivity (59 and 84% ee, entries 9 and 10). These
results indicate that the antimonate POZ catalyst 5a and
1-benzylpyrazolidin-3-one dienophile 12a were most effec-
tive in obtaining chiral isoquinuclidines 13a with excellent
enantioselectivity. Other 1,2-dihydropyridines 6b6g and c6g
were also examined using superior antimonate catalyst 5a
and dienophile 12a (entries 11 and 12). The reactions were
carried out at 0 ꢀC in the presence of 10 mol % of the
prepared Pd–POZ catalysts 5a to give the corresponding
endo-DA adducts 13d and e, respectively. However, the
results of both reactions did not exceed the result of diene 6a.
Based on the X-ray structure of PdCl2–POZ complex 49a and
the high enantiopurity (97% ee) of the chiral DA adduct
(7R)-13a that was obtained from the reaction of diene 6a
with dienophile 12a, a model of the enantioselective reaction
course was proposed as follows (Scheme 3). Thus, the
reaction might be through the intermediate I-1 that has
a less steric interaction between the diphenylphosphino
substituent on the phenyl group in the catalyst and the olefin
part of the dienophile. Then, the diene might attack from the
si-face of the acryloyl group on the dienophile rather than
the re-face that was masked by the 1-benzyl group on the
dienophile to afford (7R)-13a.
Ph
Ph
Ph
Ph
Ph
N
N
O
O
N
O
H
O
O
N
N
Pd
H
Pd
N
O
P
Table 2. Enantioselective DA reactions of dienes 6a–c with 12a–c
P
Ph
Ph
Ph
Ph
Ph
R1O2C
N
12a
O
O
catalysts
5a-d
I-1
I-2
7
+
N
N
O
CH2Cl2
N
O
X
N
N
CO2R
X
6a-c
12a-c
[7R ]-13a-e
H
si-face
O
N
a: R=Ph, X=Ph
a: X=Ph
b: X=1-Naph
c: X=Me
a: R=Ph
b: R=Ph, X=1-Naph
c: R=Ph, X=Me
b: R=CH2Ph
6a
c: R=But
97% ee
P
Pd
O
(7R)-13a
O
N
d: R=CH2Ph, X=Ph
O
e: R=But, X=Ph
PhO
N
Entry Diene Dienophile Cat.
Temp Time DA
adduct (%)
Yielda eeb
(%)
N
(mol %) (ꢀC) (h)
re-face
1
2
3
6a
6a
6a
12a
12b
12c
5a (10)
5a (10)
5a (10)
0
0
0
24
72
72
13a
13b
13c
80
47
44
97
33
43
Scheme 3. Plausible reaction course for DA reaction of 6a with 12a.
The absolute stereochemistry assignments of the new DA
adducts 13a–e were carried out as follows (Scheme 4). For
the assignments of 13a–c, both 13a–c and the known (7R)-
8a were converted to benzyl ester 14. Thus, the reactions
of 13a–c or (7R)-8 with BnOH using n-BuLi as a base in
THF afforded (7R)-benzyl ester 14 in moderate yields
(13a: 60%; 13b: 64%; 13c: 64%; 7: 38%). Furthermore,
both the DA adducts 13d and (7R)-13a were converted to
methyl esters 15 and (7R)-16, respectively, by the reactions
with LiOMe for the assignment of 13d. And then, the reduc-
tion of the olefin moiety in 15, followed by the exchange
from the benzyloxycarbonyl group to the phenoxycarbonyl
4
5
6
6a
6a
6a
12a
12a
12a
5b (10)
5c (10)
5d (10)
0
0
0
24
24
24
13a
13a
13a
87
76
60
94
97
89
7
8
6a
6a
12a
12a
5a (10) ꢁ25 48
5c (10) ꢁ25 48
5a (5)
5a (2.5)
13a
13a
76
76
95
89
9
10
6a
6a
12a
12a
0
0
24
24
13a
13a
78
59
95
84
11
12
6b
6c
12a
12a
5a (10)
5a (10)
0
0
24
24
13d
13e
74
85
89
67
a
Isolated yields.
Enantiomeric excess of endo-isomer was determined by HPLC analysis
using a DAICEL Chiralcel AD-H column.
b

10882
H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
PhO2C
O
PhO2C
PhO2C
N
N
N
n-BuLi
BnOH
n-BuLi
BnOH
THF
0 °C
7
CH2Cl2
0 °C, 4h
38%
O
O
O
O
N
N
OBn
O
N
X
(7R)-14
(7R)-8
(7R)-13a-c
from 13a: 7 h, 60%,
from 13b: 24h, 64%,
from 13c: 9h, 64%
1)
H2
10% Pd-C
MeOH
BnO2C
N
BnO2C
N
n-BuLi
LiOMe
rt, 2 h
7
2) ClCO2Ph
NaHCO3
CH3CN
rt, 15 h
THF
O
O
0 °C, 6 h
77%
O
N
OMe
PhO2C
N
N
26%
7
(7R)-15
(7R)-13d
O
OMe
PhO2C
N
PhO2C
N
H2
5% Pd-C
n-BuLi
LiOMe
(7R)-17
7
MeOH
THF
O
0 °C, 6
h
O
O
N
rt, 12 h
OMe
80%
83%
N
(7R)-13a
(7R)-16
1) TFA
CH2Cl2
rt, 12 h
t-BuO2C
N
2) ClCO2Ph
NaHCO3
CH3CN
rt, 18 h
O
O
N
N
58%
(7R)-13e
Scheme 4. Absolute configurations of DA adducts 13a–e.
group on nitrogen at the 2-position afforded the compound
(7R)-17 in 26% yield. Similarly, (7R)-16 was also trans-
formed to (7R)-17 in a good yield. In addition, the DA adduct
13e was converted to (7R)-13a by the decarboxylation and
the phenoxycarboxylation on nitrogen at the 2-position in
a moderate yield.
pyrrolidine ring system (entry 3). The effective catalyst 20
in Sibi’s experiment10 did not show catalytic activity when
10 mol % of 20 was used (entry 4). Catalyst 21, acting as
a superior catalyst in many reactions, had low reactivity
and afforded only moderate chemical yield (57%) even at
72 h of reaction time, although it gave excellent enantio-
selectivity (96% ee, entry 5). Furthermore, catalyst 22
gave DA adduct 13a in a low chemical yield (31%), but
with 85% ee (entry 6). These results indicated that the com-
bination of the POZ catalyst 8a and dienophile 12a was the
most effective combination for this reaction.
We also examined the effectiveness of six kinds of chiral
catalysts (Pd–hydroxyPOZ-18a and 18b,9b 2-azanorbor-
nane-based Pd–POZ-19,9b Cu–bis-oxazoline-20,10 Pd–
BINAP-21,12 and phosphinooxazoline-2213 catalysts) in
the DA reaction of superior diene 6a with dienophile 12a.
The reactions were carried out at 0 ꢀC in the presence of
10 mol % of catalysts 18–22 to give the corresponding DA
adduct 13a. The results are shown in Table 3. The catalytic
abilities of our developed 7-hydroxy-POZ catalysts 18a
and b in this reaction were contrastive. Thus, the reaction us-
ing the 2,7-cis-catalyst 18a proceeded with 82% yield and
91% ee (entry 1). On the other hand, 2,7-trans-catalyst
18b gave only low chemical and moderate enantioselectivity
(44%, 79% ee, entry 2). The contrast of the results between
18a and b might be due to the steric factor of the 7-hydroxy
group. The more conformationally constrained cationic POZ
catalyst 19, fusing the 2-azanorbornane ring system, was ap-
plied in this reaction. Unfortunately, the catalyst 19 did not
afford a better result than the result of 5a in fusing the
2.3. Transformation from isoquinuclidines to
piperidines
Many medicines and biologically active compounds include
a piperidine skeleton14 in their structures. Therefore, it is
important to develop an effective and convenient synthetic
methodology for chiral piperidines bearing two or more chi-
ral carbon centers in the structure. In order to develop such
a methodology, we attempted to obtain the chiral piperidine
derivative bearing three carbon centers by means of the
ozonolysis of DA adduct 16 converted from 13a (Scheme
5). The desired chiral piperidine derivative 23 bearing three
chiral carbon centers at 2,3,5-positions was obtained with
good yield, as well as we expected.

H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
10883
PhO2C
O
N
PhO2C
CO2Me
CHO
OHC
1) O3, MeOH/CH2Cl2
N
LiOMe
*
*
*
-78°C, 10 min
n-BuLi
O
N
2) DMS, rt, 14 h
86%
THF
0 °C, 4 h
80%
N
N
CO2Ph
(2S,3R,5S)-23
O
OMe
(7R)-13a
(7R)-16
Scheme 5. Transformation from 13a to piperidine 23.
Table 3. Catalyst screen
intermediate of the pharmacologically important chiral
piperidines and other alkaloids. In addition, these results
indicate that the combination of Pd–POZ catalyst 5 with
1-substituted pyrazolidin-3-one dienophile 12 is useful not
only in the DA reaction of 1,2-dihydropyridine but also in
other asymmetric processes.
catalysts
(10 mol%)
+
6a
12a
13a
CH2Cl2
0 °C
Entry
Catalyst
Time (h)
Yielda (%)
eeb (%)
Config.c
1
2
3
18a
18b
19
24
24
24
82
44
54
91
79
10
7R
7R
7S
4. Experimental
4
5
6
20
21
22
72
72
24
No reaction
57
31
—
96
85
—
7S
7S
4.1. General information
Melting points are uncorrected. IR spectra were recorded as
KBr pellets (solids) or thin films (liquids). 1H NMR spectra
were recorded at 270 and 400 MHz. 13C NMR spectra were
recorded at 67.5 and 100 MHz. The chemical shifts are
reported in parts per million downfield to TMS (d¼0) for
1H NMR and relative to the central CDCl3 resonance
(d¼77.0) for 13C NMR. Mass spectra were obtained by EI.
The enantiomeric excess (ee) of the products was deter-
mined by chiral HPLC. Optical rotations were recorded at
the sodium D line with a polarimeter at room temperature.
Commercially available compounds were used without fur-
ther purification. Solvents were dried according to standard
procedures. Chromatography refers to flash chromatography
on silica gel (230–400 mesh), unless otherwise noted.
a
Isolated yields.
Enantiomeric excess of endo-isomer was determined by HPLC analysis
using a DAICEL Chiralcel AD column.
After conversion to benzyl ester [7R]-14, the absolute configuration was
determined.
b
c
R1
2+
7
Ph
R2
Ph
18a: R1=OH, R2=H
18b: R1=H, R2=OH
-
N
O
+2SbF6
2
Pd
P
Ph
Ph
18
2+
2+
Ph
Ph
O
O
O
+2OTf2
N
+2SbF6
N
N
Pd
Cu
4.2. General procedure for the DA reaction of 1,2-di-
hydropyridines 6a,b with 2-acryloyl-1,3-oxazolidine-2-
one 7 catalyzed by cationic Pd–POZ complexes 5a–d
P
Ph
Ph
20
19
A suspension of PdCl2–POZ complex 4 (0.07 mmol) and
AgX (X¼SbF6, ClO4, BF4, OTf) (2 equiv) in CH2Cl2
(1 mL) was stirred at room temperature for 1 h under Ar.
The suspension was cooled to 0 ꢀC and diene 6a or b
(3.5 mmol) and dienophile 7 (0.7 mmol) were added. The
reaction mixture was stirred under Ar. The mixture was
then quenched with satd NaHCO3 solution and extracted
with CHCl3. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtrated, and con-
centrated under a reduced pressure. The residue was purified
by flash chromatography (hexane/AcOEt, 1/1) to afford 8.
The reaction conditions, chemical yields, and optical yields
are shown in Table 1.
2+
+2SbF6
2+
Ph
P
Ph
N
O
Pd
+2SbF6
Pd
P
P
Ph
Ph
Ph
Ph
21
22
3. Conclusion
In conclusion, we have developed an efficient methodology
for obtaining the chiral isoquinuclidines that are the precur-
sor of pharmacologically important compounds. Thus, the
DA reaction of 1-phenoxycarbonyl-1,2-dihydropyridine 6a
with 1-benzyl-2-acryloylpyrazolidin-3-one 12a as a dieno-
phile using cationic antimonate Pd–POZ catalyst 5a
afforded the corresponding DA adduct 13a at 97% ee with
good chemical yield. Furthermore, the obtained DA adduct
13a was easily transformed to the chiral piperidine 23 that
bears three chiral carbon centers in the structure. Compound
23 might have a high potential utility as the synthetic
4.2.1. (1R,4R,7R)-7-(20-Oxo-oxazolidine-30-carbonyl)-2-
azabicyclo[2.2.2]oct-5-ene-1-carboxylic acid benzyl ester
(8b). Yield 118 mg, 90%; white solid (n-hexane), mp 37–
1
38 ꢀC; IR (KBr) 2929, 2342, 1781, 1694, 697 cmꢁ1; H
NMR (DMSO-d6, 100 ꢀC) d 1.54–1.63 (m, 1H), 2.05 (ddd,
J¼2.6, 9.8, 12.6 Hz, 1H), 2.84 (m, 1H), 2.92 (dt, J¼2.7,
10.2 Hz, 1H), 3.28 (d, J¼10.1 Hz, 1H), 3.80–3.89 (m, 2H),
4.00 (ddd, J¼2.7, 5.4, 9.8 Hz, 1H), 4.32–4.38 (m, 2H),

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H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
4.92 (m, 1H), 5.08 (s, 2H), 6.32–6.44 (m, 2H), 7.28–7.36 (m,
5H); 13C NMR (DMSO-d6, 100 ꢀC) d 26.88, 29.72, 42.13,
43.33, 46.24, 46.37, 61.84, 65.54, 126.80 (2C), 127.06,
127.73 (2C), 130.66, 133.44, 152.50, 153.69, 163.65,
171.59; MS m/z 356 (M+); HRMS (EI) calcd for
C19H20N2O5 (M+) 356.1372, found 356.1365. Anal. Calcd
for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C,
64.12, H, 5.70; N, 7.72. The enantiomeric excess (ee) was
determined by HPLC (DAICEL Chiralcel AD-H, 0.5 mL/
min; n-hexane/2-propanol, 1/1; tR (minor)¼28.5 min,
tR (major)¼35.4 min).
room temperature for 1 h under Ar. The suspension was
cooled to 0 ꢀC and diene 6a (402 mg, 2.0 mmol) and pyrrazo-
lidin-3-ones 12a–c (0.4 mmol) in CH2Cl2 (1 mL) were added
under Ar. The reaction mixture was stirred under Ar. The
reaction was then quenched with satd NaHCO3 solution and
extracted with CHCl3. The combined organic layers were
washed with brine, dried with anhydrous MgSO4, filtrated,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (n-hexane/AcOEt, 1/1) to
afford 13a–c. The reaction conditions, chemical yields, and
optical yields are shown in Table 2.
4.3. General procedure for the preparation of
pyrazolidin-3-ones 12b,c
4.4.1. (1R,4R,7R)-7-(10-Benzyl-50,50-dimethyl-30-oxo-pyr-
azolidin-20-carbonyl)-2-azabicyclo[2.2.2]oct-5-ene-1-carb-
oxylic acid phenyl ester (13a). White solid (AcOEt/
n-hexane), mp 165–168 ꢀC; [a]D20 ꢁ52.94 (c 0.68, CHCl3);
IR (KBr) 1216, 1524, 1644, 3020 cmꢁ1; 1H NMR (CDCl3)
d 1.12–1.24 (m, 6H), 1.59 (m, 1H), 2.06 (m, 1H), 2.58 (m,
1H), 2.67 (m, 1H), 2.84 (br s, 1H), 3.06 (d, J¼10.6 Hz,
0.5H), 3.18 (d, J¼10.3 Hz, 0.5H), 3.35 (d, J¼10.6 Hz,
0.5H), 3.50 (d, J¼10.3 Hz, 0.5H), 4.00 (br s, 1H), 4.03 (br
s, 2H), 5.07 (br s, 1H), 6.39–6.44 (m, 2H), 7.13 (m, 1H),
7.13–7.38 (m, 7H), 7.43–7.45 (m, 2H); 13C NMR (CDCl3)
d 25.80, 26.65, 27.51, 30.76, 43.50, 45.54, 46.79, 47.20,
57.10, 60.93, 121.78, 121.83, 125.13, 127.45, 127.50,
128.37, 128.88, 128.99, 129.18, 129.23, 130.84, 133.65,
137.58, 151.36, 153.38, 169.68, 173.91; MS m/z 459 (M+);
HRMS (EI) calcd for C27H29N3O4 (M+) 459.2158, found
459.2176. Anal. Calcd for C27H29N3O4: C, 70.57; H, 6.36;
N, 9.14. Found: C, 70.62; H, 6.21; N, 9.25. The ee was de-
termined by HPLC (DAICEL Chiralcel AD-H, 0.5 mL/
min; n-hexane/2-propanol, 1/1; tR (minor)¼12.70 min,
tR (major)¼14.38 min).
To a solution of acrylic acid (1.53 mmol) and Et3N
(2.95 mmol) in THF (10 mL) was added acryloyl chloride
(1.60 mmol) at ꢁ25 ꢀC and the mixture was stirred for 1 h
under Ar. Lithium chloride (1.30 mmol) was added,
followed by the pyrazolidin-3-ones, 11b (1.18 mmol) or
11c (1.18 mmol). The mixture was allowed to warm to
room temperature and stirred for 6 h. The reaction was
quenched by satd NaCl and THF was removed under a re-
duced pressure. The residue was partitioned between AcOEt
and satd NaCl. The organic layer was washed with satd
Na2CO3. The organic layers were then dried over anhydrous
MgSO4, filtrated, and concentrated under a reduced pres-
sure. The residue was purified by flash chromatography
(n-hexane/AcOEt, 1/1) to afford 12b and 12c, respectively.
4.3.1. 2-Acryloyl-1-(1-naphthylmethyl)-5,5-dimethylpyr-
azolidin-3-one (12b). Yield 223 mg, 61%; white solid
(n-hexane), mp 120–122 ꢀC; IR (KBr) 1599, 1669,
1
1766 cmꢁ1; H NMR (CDCl3) d 1.42 (s, 6H), 2.75 (s, 2H),
4.45 (br s, 2H), 5.01 (m, 1H), 5.84 (d, J¼15.9 Hz, 1H),
6.36 (m, 1H), 7.36 (t, J¼4.2 Hz, 1H), 7.48 (t, J¼1.2 Hz,
2H), 7.56 (t, J¼1.5 Hz, 1H), 7.77 (d, J¼8.3 Hz, 1H), 7.82
(d, J¼8.3 Hz, 1H), 8.17 (d, J¼8.5 Hz, 1H); 13C NMR
(CDCl3) d 25.93, 30.89, 43.00, 55.20, 61.45, 123.22,
125.33, 125.59, 126.29, 127.54, 128.72, 128.74, 129.31,
129.41, 133.63, 163.38, 173.96; MS m/z 308 (M+); HRMS
(EI) calcd for C19H20N2O2 (M+) 308.1525, found
308.1539. Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54;
N, 9.08. Found: C, 74.12; H, 6.51; N, 8.87.
4.4.2. (1R,4R,7R)-7-(10-Naphthylmethyl-50,50-dimethyl-
30-oxo-pyrazolidin-20-carbonyl)-2-azabicyclo[2.2.2]oct-
5-ene-1-carboxylic acid phenyl ester (13b). White solid
(AcOEt/n-hexane), mp 170–172 ꢀC; [a]D20 ꢁ20.13 (c 1.49,
CHCl3); IR (KBr) 1238, 1596, 1717, 2969 cmꢁ1; 1H NMR
(CDCl3) d 1.35–1.41 (m, 6H), 1.58 (m, 1H), 2.18 (m, 1H),
2.63–2.71 (m, 2H), 2.83 (m, 1H), 3.00–3.13 (m, 2H), 3.54
(m, 1H), 4.32 (m, 1H), 4.57 (m, 1H), 4.87 (m, 1H), 6.10 (t,
J¼6.5 Hz, 0.5H), 6.18 (t, J¼6.7 Hz, 0.5H), 6.28 (m, 1H),
7.12 (d, J¼7.6 Hz, 1H), 7.17–7.22 (m, 2H), 7.35–7.40 (m,
3H), 7.42–7.58 (m, 2H), 7.65 (m, 1H), 7.78 (t, J¼7.4 Hz,
1H), 7.86 (t, J¼7.9 Hz, 1H), 8.21 (t, J¼9.8 Hz, 1H); 13C
NMR (CDCl3) d 26.92, 27.22, 30.33, 30.58, 43.22, 46.50,
46.90, 47.44, 54.98, 55.18, 121.72, 121.74, 123.25,
123.33, 125.13, 125.15, 125.35, 125.45, 125.74, 125.85,
126.39, 128.48, 128.76, 129.23, 129.27, 131.77, 133.71,
151.40, 151.43, 153.15, 173.85; MS m/z 509 (M+); HRMS
(EI) calcd for C31H31N3O4 (M+) 509.2315, found
509.2336. Anal. Calcd for C31H31N3O4: C, 73.06; H, 6.13;
N, 8.25. Found: C, 73.11; H, 6.01; N, 8.36. The ee was
determined by HPLC (DAICEL Chiralcel AD-H, 0.5 mL/
min; n-hexane/2-propanol, 1/1; tR (minor)¼15.00 min,
tR (major)¼17.98 min).
4.3.2. 2-Acryloyl-1-ethyl-5,5-dimethylpyrazolidin-3-one
(12c). Yield 158 mg, 72%; pale yellow oil; IR (NaCl)
1
1694, 1749 cmꢁ1; H NMR (CDCl3) d 1.08 (t, J¼7.2 Hz,
3H), 1.33 (s, 6H), 2.60 (s, 2H), 3.01 (q, J¼7.1 Hz, 2H),
5.86 (d, J¼12.2 Hz, 1H), 6.55 (d, J¼17.1 Hz, 1H), 7.27
(m, 1H); 13C NMR (CDCl3) d 12.79, 25.75, 43.79, 47.31,
60.67, 128.57, 131.30, 163.76, 175.11; MS m/z 196 (M+);
HRMS (EI) calcd for C10H16N2O2 (M+) 196.1212, found
196.1226. Anal. Calcd for C10H16N2O2: C, 61.20; H, 8.22;
N, 14.27. Found: C, 61.28; H, 8.31; N, 14.16.
4.4. General procedure for the DA reaction of 1,2-di-
hydropyridine 6a with 2-acryloylpyrazolidin-3-ones
12a–c using cationic Pd–POZ complexes 5a–d
4.4.3. (1R,4R,7R)-7-(10-Ethyl-50,50-dimethyl-30-oxo-pyra-
zolidin-20-carbonyl)-2-azabicyclo[2.2.2]oct-5-ene-1-carb-
oxylic acid phenyl ester (13c). White solid (AcOEt/
n-hexane), mp 130–133 ꢀC; [a]D20 ꢁ33.98 (c 1.53, CHCl3);
IR (KBr) 1207, 1596, 1711, 2979 cmꢁ1; 1H NMR (CDCl3)
A suspension of PdCl2–POZ complex 4 (10 mol %: 28 mg,
5 mol %: 14 mg, 2.5 mol %: 7 mg) and AgX (X¼SbF6,
ClO4, BF4, OTf) (2 equiv) in CH2Cl2 (1 mL) was stirred at

H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
10885
d 1.02–1.07 (m, 3H), 1.24–1.31 (m, 6H), 1.70 (m, 1H), 2.21
(m, 1H), 2.53–2.64 (m, 2H), 2.89 (br s, 1H), 2.90–3.01 (m,
2H), 3.09 (d, J¼10.5 Hz, 0.5H), 3.22 (d, J¼10.2 Hz,
0.5H), 3.40 (d, J¼10.5 Hz, 0.5H), 3.55 (d, J¼10.2 Hz,
0.5H), 4.12 (m, 1H), 5.17 (m, 0.5H), 5.19 (m, 0.5H), 6.44–
6.54 (m, 2H), 7.11–7.21 (m, 3H), 7.31–7.38 (m, 2H); 13C
NMR (CDCl3) d 12.95, 25.77, 25.99, 30.84, 44.04, 45.70,
45.87, 47.03, 47.94, 121.78, 121.90, 125.09, 125.18,
129.15, 129.22, 132.19, 133.53, 134.36, 151.40, 152.96,
153.37; MS m/z 397 (M+); HRMS (EI) calcd for
C22H27N3O4 (M+) 397.2002, found 397.1996. Anal. Calcd
for C22H27N3O4: C, 66.48; H, 6.85; N, 10.57. Found:
C, 66.57; H, 6.94; N, 10.38. The ee was determined
by HPLC (DAICEL Chiralcel AD-H, 0.5 mL/
min; n-hexane/2-propanol, 1/1; tR (minor)¼9.96 min,
tR (major)¼11.75 min).
1H), 2.01 (m, 1H), 2.54–2.66 (m, 2H), 2.72 (d, J¼1.8 Hz,
1H), 2.90 (d, J¼10.3 Hz, 0.5H), 2.94 (d, J¼10.6 Hz,
0.5H), 3.23 (t, J¼5.1 Hz, 1H), 3.90 (br s, 1H), 4.03 (d,
J¼1.7 Hz, 2H), 4.80 (br s, 0.5H), 5.00 (br s, 0.5H), 6.28–
6.37 (m, 2H), 7.22–7.31 (m, 3H), 7.45 (d, J¼7.7 Hz, 2H);
13C NMR (CDCl3) d 25.99, 26.50, 27.63, 28.50, 28.54,
30.63, 30.90, 31.23, 43.54, 45.84, 46.58, 47.10, 60.81,
127.34, 128.31, 128.35, 128.77, 128.82, 131.23, 133.42,
134.00, 137.80, 154.23, 154.46; MS m/z 439 (M+); HRMS
(EI) calcd for C25H33N3O4 (M+) 439.2471, found
439.2452. Anal. Calcd for C25H33N3O4: C, 68.31; H, 7.57;
N, 9.56. Found: C, 70.48; H, 7.65; N, 9.78. The ee was
determined by HPLC (DAICEL Chiralcel AD-H, 0.5 mL/
min; n-hexane/2-propanol, 1/1; tR (minor)¼7.89 min,
tR (major)¼12.97 min).
4.6. Determinations of the absolute stereochemistries
of 13a–c, d, and e
4.5. General procedure for the DA reaction of 1,2-di-
hydropyridines 6b,c with 2-acryloylpyrazolidin-3-one 12a
4.6.1. General procedure for the conversion of DA ad-
ducts 8 or 13a–c to benzyl ester 14. To a stirred solution
of benzyl alcohol (0.1 mL, 1.0 mmol) in anhydrous THF
(6 mL) was added n-BuLi (1.0 M in n-hexane, 0.73 mL,
0.78 mmol) at ꢁ78 ꢀC under Ar. The reaction mixture was
stirred for 5 min and then the solution of (7R)-8 or 13a–c
(0.52 mmol) in THF was added to the mixture at 0 ꢀC. After
being stirred for 3 h, the reaction was quenched by satd
NH4Cl and the solvent was removed under a reduced pres-
sure, diluted with water, and extracted with CHCl3. The
combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under a reduced pressure.
The residue was purified by flash chromatography (CHCl3/
AcOEt, 1/3) to afford (7R)-14 (8: 75 mg, 38%; 13a:
113 mg, 57%; 13b: 121 mg, 61%; 13c: 127 mg, 64%). The
absolute stereochemistries of 13a–c were determined in
comparison with the optical rotation of (7R)-14 derived
from (7R)-8.
A suspension of PdCl2–POZ complex 4 (0.03 mmol) and
AgSbF6 (0.06 mmol) in CH2Cl2 (1 mL) was stirred at
room temperature for 1 h under Ar. The suspension was
cooled to 0 ꢀC and the solution of dienophile 12a
(0.26 mmol) in CH2Cl2 (1 mL) and 6b (1.30 mmol) or 6c
(1.30 mmol) was added at that temperature. The reaction
mixture was stirred under Ar for 24 h. The mixture was
then quenched with satd NaHCO3 and extracted with
CHCl3. The combined organic layers were washed with
brine, dried with anhydrous MgSO4, and concentrated under
a reduced pressure. The residue was purified by flash
chromatography (n-hexane/AcOEt, 1/1) to afford the corre-
sponding DA adducts 13d and 13e, respectively. The reac-
tion conditions, chemical yields, and optical yields are
shown in Table 2.
4.5.1. (1R,4R,7R)-7-(10-Benzyl-50,50-dimethyl-30-pyrazo-
lidin-20-carbonyl)-2-azabicyclo[2.2.2]oct-5-ene-1-carb-
oxylic acid benzyl ester (13d). White solid (AcOEt/
n-hexane), mp 158–162 ꢀC; [a]D20 ꢁ25.20 (c 1.23, CHCl3);
4.6.2. (1R,4R,7R)-1-Phenoxycarbonyl-2-azabi-
cyclo[2.2.2]oct-5-ene-7-benzylcarboxylate (14). Colorless
oil [14 (from 8, 76% ee): [a]2D1 ꢁ47.77 (c 0.90, CHCl3); 14
(from 13a, 97% ee): [a]D21 ꢁ59.92 (c 2.52, CHCl3); 14 (from
13b, 33% ee): [a]2D1 ꢁ12.50 (c 0.64, CHCl3); 14 (from 13c,
43% ee): [a]2D1 ꢁ33.33 (c 0.75, CHCl3)]; IR (NaCl) 1216,
1
IR (KBr) 1232, 1495, 1689, 1755, 2957 cmꢁ1; H NMR
(CDCl3) d 1.81–1.27 (m, 6H), 1.54 (m, 1H), 2.05 (br s,
1H), 2.52–2.67 (m, 2H), 2.77 (m, 1H), 3.01 (m, 1H), 3.31
(m, 1H), 3.99 (d, J¼6.6 Hz, 1H), 4.01–4.08 (m, 2H), 5.05
(m, 1H), 5.11–5.17 (m, 2H), 6.28–6.37 (m, 2H), 7.21–7.33
(m, 4H), 7.35–7.39 (m, 5H), 7.44 (m, 1H); 13C NMR
(CDCl3) d 25.87, 26.60, 26.63, 27.55, 30.73, 43.52, 45.57,
46.65, 46.78, 57.00, 66.81, 127.39, 127.47, 127.66,
127.83, 127.89, 127.94, 128.01, 128.34, 128.36, 128.45,
128.84, 128.91, 131.65, 133.67, 136.91, 137.69, 154.96;
MS m/z 473 (M+); HRMS (EI) calcd for C28H31N3O4 (M+)
473.2315, found 473.2320. Anal. Calcd for C28H31N3O4:
C, 71.01; H, 6.60; N, 8.87. Found: C, 71.18; H, 6.72; N,
8.98. The ee was determined by HPLC (DAICEL Chiralcel
AD-H, 0.5 mL/min; n-hexane/2-propanol, 1/1; tR (minor)¼
12.97 min, tR (major)¼14.55 min).
1595, 1713, 3019 cmꢁ1 1H NMR (CDCl3) d 1.91–2.07
;
(m, 2H), 2.91 (br s, 1H), 3.05 (d, J¼10.6 Hz, 0.5H), 3.16
(d, J¼10.3 Hz, 0.5H), 3.24 (m, 1H), 3.35 (d, J¼10.6 Hz,
0.5H), 3.49 (d, J¼10.3 Hz, 0.5H), 5.07–5.16 (m, 2H), 5.26
(m, 1H), 6.36 (m, 1H), 6.52 (m, 1H), 7.04–7.13 (m, 2H),
7.19 (m, 1H), 7.30–7.41 (m, 7H); 13C NMR (CDCl3)
d 26.00, 30.67, 43.87, 46.96, 47.58, 66.61, 121.69, 121.76,
125.22, 128.11, 128.20, 128.25, 128.55, 128.59, 129.21,
129.25, 130.15, 135.26, 151.27, 153.06, 153.62, 172.36;
MS m/z 363 (M+); HRMS (EI) calcd for C22H21NO4 (M+)
363.1471, found 363.1471.
4.6.3. (1R,4R,7R)-1-Benzyloxycarbonyl-2-azabi-
cyclo[2.2.2]oct-5-ene-7-methylcarboxylate (15). To the
solution of lithium methoxide (1.0 M in methanol, 0.6 mL,
0.6 mmol) in THF (3 mL) at ꢁ78 ꢀC was added n-BuLi
(1.0 M in n-hexane, 0.42 mL, 0.45 mmol) and the solution
of 13d (89% ee, 140 mg, 0.3 mmol) in THF (8 mL) was
added at that temperature. The mixture was stirred at 0 ꢀC
4.5.2. (1R,4R,7R)-7-(10-Benzyl-50,50-dimethyl-30-oxo-pyr-
azolidin-20-carbonyl)-2-azabicyclo[2.2.2]oct-5-ene-1-carb-
oxylic acid-tert-butyl ester (13e). White solid (AcOEt/
n-hexane), mp 155–158 ꢀC; [a]D20 ꢁ30.98 (c 1.42, CHCl3);
1
IR (KBr) 1236, 1496, 1688, 1756, 2981 cmꢁ1; H NMR
(CDCl3) d 1.19–1.23 (m, 6H), 1.45–1.48 (m, 9H), 1.53 (m,

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H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
for 6 h. The reaction was quenched by satd NH4Cl and ex-
tracted with CHCl3. The organic layers were dried over an-
hydrous MgSO4. The solvent was removed under a reduced
pressure. The residue was purified by flash chromatography
(CHCl3/AcOEt, 3/1) to afford (7R)-15 (70 mg, 77% yield).
Colorless oil; [a]2D0 ꢁ74.75 (c 1.03, CHCl3); IR (NaCl)
287 (M+); HRMS (EI) calcd for C16H17NO4 (M+)
287.1158, found 287.1176.
4.6.6. Conversion of 16 to 17. The suspension of 16
(103 mg, 0.36 mmol) and 5% Pd–C (8 mg, 0.36 mmol) in
methanol (12 mL) was stirred under H2 at room temperature
for 12 h. Pd–C (5%) was filtered off and the solvent was
removed under a reduced pressure to give the (7R)-17
[86 mg, 83% yield, [a]2D0 ꢁ61.03 (c 1.00, CHCl3)].
1216, 1587, 1692, 1732, 3019 cmꢁ1 1H NMR (CDCl3)
;
d 1.85–1.87 (m, 2H), 2.84 (m, 1H), 3.00 (m, 1H), 3.09 (m,
1H), 3.31 (m, 1H), 3.66 (s, 3H), 5.09 (m, 1H), 5.12–5.20
(m, 2H), 6.35 (m, 1H), 6.45 (m, 1H), 7.28–7.38 (m, 5H);
13C NMR (CDCl3) d 25.98, 30.61, 43.73, 46.73, 47.09,
51.95, 66.88, 127.84, 127.91, 127.95, 127.99, 128.46,
128.50, 130.23, 130.63, 135.14, 135.45; MS m/z 301 (M+);
HRMS (EI) calcd for C17H19NO4 (M+) 301.1314, found
301.1288.
4.6.7. Conversion of 13e to 13a. To the solution of 13e (67%
ee, 33 mg, 0.08 mmol) in CH2Cl2 (1 mL) was added
trifluoroacetic acid (TFA) (0.01 mL, 0.11 mmol), and the
mixture was stirred at room temperature for 12 h. The reac-
tion was quenched by 1 N HCl and extracted with CHCl3.
The organic layers were dried over anhydrous MgSO4 and
the solvent was removed under a reduced pressure. The
obtained residue was dissolved in CH3CN, phenyl chloro-
formate (0.01 mL, 0.08 mmol) and NaHCO3 (21 mg,
0.25 mmol) were added to the solution. The solution was
stirred at room temperature for 18 h. The reaction was
quenched by satd NH4Cl and extracted with CHCl3. The
organic layers were dried over anhydrous MgSO4 and the
solvent was removed under a reduced pressure. The residue
was purified by flash chromatography (n-hexane/AcOEt,
2/1) to afford (7R)-13a [23 mg, 38% yield, [a]2D0 ꢁ24.99
(c 1.36, CHCl3)].
4.6.4. (1R,4R,7R)-1-Phenoxycarbonyl-2-azabicyclo-
[2.2.2]octane-7-methylcarboxylate (17). A suspension of
15 (50 mg, 0.17 mmol) and 10% Pd–C (18 mg,
0.17 mmol) in methanol (5 mL) was stirred under H2 at
room temperature for 2 h. Pd–C (10%) was filtered off and
the filtrate was concentrated under a reduced pressure. The
obtained residue without purification was dissolved in
CH3CN (1.5 mL). To the solution, phenyl chloroformate
(0.02 mL, 0.17 mmol) and NaHCO3 (43 mg, 0.51 mmol)
were added and the mixture was stirred at room temperature
for 15 h under Ar. The reaction was quenched by satd NH4Cl
and extracted with CHCl3. The organic layers were dried
over anhydrous MgSO4 and concentrated under a reduced
pressure. The residue was purified by flash chromatography
(n-hexane/AcOEt, 3/2) to afford (7R)-17 (13 mg, 26%
yield). White solid (AcOEt/n-hexane), mp 68–70 ꢀC; [a]D20
ꢁ56.80 (c 1.02, CHCl3); IR (KBr) 1202, 1591, 1704,
4.7. General procedure for the DA reaction of 1,2-di-
hydropyridine 6a with 2-acryloylpyrazolidin-3-one 12a
using cationic Pd–POZ complexes 18a,b and 19
A suspension of PdCl2–POZ complexes (0.04 mmol) and
AgSbF6 (0.08 mmol) in CH2Cl2 (1 mL) was stirred at
room temperature for 1 h under Ar. To the suspension of
the obtained catalysts 18a,b or 19 was added the solution
of 12a (0.4 mmol) in CH2Cl2 (1 mL) and 6a (2.0 mmol) at
0 ꢀC. The reaction was stirred at that temperature for 24 h
under Ar. The mixture was then quenched with satd
NaHCO3 solution and extracted with CHCl3. The combined
organic layers were washed with brine, dried with anhydrous
MgSO4, and concentrated under a reduced pressure. The
residue was purified by flash chromatography (n-hexane/
AcOEt, 1/1) to afford 13a. The reaction conditions, chemical
yields, and optical yields are shown in Table 3.
1
1737 cmꢁ1; H NMR (CDCl3) d 1.59–1.79 (m, 3H), 1.85–
2.09 (m, 2H), 2.22 (m, 1H), 3.07 (m, 1H), 3.45 (s, 1H),
3.58 (m, 1H), 3.68–3.74 (m, 3H), 4.47 (br s, 0.5H), 4.53
(br s, 0.5H), 7.09–7.21 (m, 3H), 7.32–7.38 (m, 2H); 13C
NMR (CDCl3) d 23.0, 23.3, 23.7, 25.9, 42.7, 45.5, 46.5,
49.2, 121.7, 121.8, 125.1, 129.2 (2C), 129.3, 151.4, 153.6;
MS m/z 289 (M+); HRMS (EI) calcd for C16H19NO4 (M+)
289.1314, found 289.1290.
4.6.5. (1R,4R,7R)-1-Phenoxycarbonyl-2-azabicyclo-
[2.2.2]oct-5-ene-7-methylcarboxylate (16). To a solution
of lithium methoxide (1.0 M in methanol, 1.70 mL,
1.70 mmol) in THF (10 mL) were added n-BuLi (1.0 M in
n-hexane, 1.20 mL, 1.30 mmol) and the solution of 13a
(>99% ee, 400 mg, 0.87 mmol) in THF (23 mL) at
ꢁ78 ꢀC. The mixture was stirred at 0 ꢀC for 4 h. The reaction
was quenched by satd NH4Cl and extracted with CHCl3. The
organic layer was dried over anhydrous MgSO4 and concen-
trated under a reduced pressure. The residue was purified by
flash chromatography (AcOEt/CHCl3, 1/3) to afford (7R)-16
(199 mg, 80% yield). White solid (AcOEt/n-hexane), mp
76–78 ꢀC; [a]D20 ꢁ68.18 (c 1.98, CHCl3); IR (KBr) 1204,
4.8. General procedure for the DA reaction of 1,2-di-
hydropyridine 6a with 2-acryloyl-1,3-oxazolidine-2-one
12a using cationic Pd–POZ complexes 20–22
To a suspension of chiral catalysts 20–22 (0.04 mmol) pre-
pared by the previous reported methods6g,12,13 in CH2Cl2
(1 mL) was added the solution of 12a (0.4 mmol) in
CH2Cl2 (1 mL) and 6a (2.0 mmol) at 0 ꢀC and the suspen-
sion was stirred at that temperature under Ar. The reaction
conditions are shown in Table 3. The mixture was then
quenched with satd NaHCO3 solution and extracted with
CHCl3. The combined organic layers were washed with
brine, dried with anhydrous MgSO4, and concentrated under
a reduced pressure. The residue was purified by flash
chromatography (n-hexane/AcOEt, 1/1) to afford 13a. The
reaction conditions, chemical yields, and optical yields are
shown in Table 3.
1570, 1703, 1715 cmꢁ1 1H NMR (CDCl3) d 1.90–1.98
;
(m, 2H), 2.92 (br s, 1H), 3.05 (d, J¼10.6 Hz, 0.5H), 3.16–
3.22 (m, 1.5H), 3.5 (d, J¼10.3 Hz, 0.5H), 3.48 (m, 0.5H),
3.67–3.71 (m, 3H), 5.21 (m, 0.5H), 5.27 (m, 0.5H), 6.42
(m, 1H), 6.52 (m, 1H), 7.07–7.14 (m, 2H), 7.19 (m, 1H),
7.31–7.37 (m, 2H); 13C NMR (CDCl3) d 25.96, 30.61,
30.87, 43.61, 46.85, 47.50, 51.95, 121.64, 121.69, 125.15,
125.22, 129.16, 129.21, 135.19, 135.69, 151.23; MS m/z

H. Nakano et al. / Tetrahedron 62 (2006) 10879–10887
10887
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Chem. 1987, 109, 442–446; (d) Redding, M. T.; Fukuyama, T.
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4.9. Transformation of 16 to chiral piperidine derivative
23
3. He, D. Y.; McGough, N. N.; Ravindranathan, A.; Jeanblanc, J.;
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4.9.1. (2S,3R,5S)-2,5-Diformyl-1-phenoxycarbonyl-
piperidin-3-methylcarboxylate (23). O3 was bubbled
through a MeOH/CH2Cl2 (1/1) (6 mL) of DA adduct 16
(115 mg, 0.4 mmol) at ꢁ78 ꢀC. After 10 min, the ozone
stream from the blue solution was immediately removed
from the mixture, which was then purged with N2 for
5 min. Excess dimethyl sulfide (1 mL) was quickly added
and the solution was allowed to reach room temperature
slowly (12 h), and then quenched with brine and extracted
with AcOEt. The organic layers were washed with brine,
dried with anhydrous MgSO4, and concentrated under a
reduced pressure. The residue was purified by flash chroma-
tography (n-hexane/AcOEt, 2/1) to give the product 23
(110 mg, 86%). Pale yellow solid (AcOEt/n-hexane), mp
63–65 ꢀC; [a]D20 ꢁ54.37 (c 1.84, CHCl3); IR (KBr) 1413,
5. (a) Mitch, C. H. U.S. Patent 5,834,458, 1998; Chem. Abstr.
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1
1594, 1719, 2954, 3446 cmꢁ1; H NMR (CDCl3) d 1.61–
1.71 (m, 1H), 2.57–2.60 (m, 2H), 2.63–3.00 (m, 2H),
3.78–3.81 (m, 3H), 4.63 (m, 1H), 5.51 (d, J¼5.1 Hz,
1H), 7.12–7.16 (m, 2H), 7.25 (m, 1H), 7.38–7.42 (m, 2H),
9.68 (s, 2H); 13C NMR (CDCl3) d 23.28, 42.03, 47.78,
52.44, 60.40, 60.63, 121.45, 121.52, 125.93, 125.99,
128.70, 129.50, 129.78, 197.97, 199.77; MS m/z 319 (M+);
HRMS (EI) calcd for C16H17NO6 (M+) 319.1056, found
319.1049.
8. The preliminary results were partially reported, see: Nakano,
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References and notes
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