Highly enantioselective synthesis of isoquinuclidine by diels-alder reaction of 1,2-dihydropyridine utilizing chiral bisoxazoline-Cu(II) complex

Article abstract of DOI:10.3987/COM-12-S(N)2

The enantioselective Diels-Alder (D-A) reaction between N-phenoxycarbonyl- or N-benzyloxycarbonyl-1,2-dihydropyridine (1a or 1b) and N(2)-acryloyl-N(1)-(1- naphthylmethyl)-5,5-dimethylpyrazolidin-3-one (2b) using (S,S)-bisoxazoline- Cu(II) catalyst (A, B, C or D) has been investigated. Utilizing (S,S)-t-Bu-bisoxazoline-Cu(II) catalyst C, the D-A reaction of 1a and 2 afforded the endo-(7S)-isoquinuclidines (3, 4 or 5) in good chemical yields with high enantioselectivity (up to 99% e.e.).

Full text of DOI:10.3987/COM-12-S(N)2

HETEROCYCLES, Vol. 86, No. 1, 2012
203
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 203 - 217. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 29th February, 2012, Accepted, 15th June, 2012, Published online, 21st June, 2012
DOI: 10.3987/COM-12-S(N)2
HIGHLY ENANTIOSELECTIVE SYNTHESIS OF ISOQUINUCLIDINE
BY DIELS-ALDER REACTION OF 1,2-DIHYDROPYRIDINE UTILIZING
CHIRAL BISOXAZOLINE-Cu(II) COMPLEX
N. D. M. Romauli Hutabarat,1 Chigusa Seki,1* Takashi Shimizu,1
Masafumi Hirama,1 Yoshihito Kohari,1 Hiroto Nakano,1 Koji Uwai,1
Nobuhiro Takano,1 Eunsang Kwon,2 and Haruo Matsuyama1*
1Department of Applied Chemistry, Graduate School of Engineering, Muroran
Institute of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan
2Research and Analytical Center for Giant Molecules, Graduate School of
Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Sendai 980-8578, Japan
e-mail: hmatsuya@mmm.muroran-it.ac.jp and chigusa@mmm.muroran-it.ac.jp
Abstract – The enantioselective Diels-Alder (D-A) reaction between
N-phenoxycarbonyl- or N-benzyloxycarbonyl-1,2-dihydropyridine (1a or 1b) and
N(2)-acryloyl-N(1)-(1-naphthylmethyl)-5,5-dimethylpyrazolidin-3-one (2b) using
(S,S)-bisoxazoline-Cu(II) catalyst (A, B, C or D) has been investigated. Utilizing
(S,S)-t-Bu-bisoxazoline-Cu(II) catalyst C, the D-A reaction of 1a and 2 afforded
the endo-(7S)-isoquinuclidines (3, 4 or 5) in good chemical yields with high
enantioselectivity (up to 99% e.e.).
INTRODUCTION
Syntheses of natural product-like compounds having isoquinuclidine skeleton, 2-azabicyclo[2.2.2]octane
derivatives, via asymmetric synthesis have become one of the most important area of medicinal
chemistry.1,2 For example, catharanthine is the prototypical structure of iboga alkaloid which is known
to be the precursor of anticancer drug, vinblastine.3 Ibogaine is the medicine for alcohol or other drugs
dependence.4 It is also reported that isoquinuclidines are valuable intermediates in the synthesis of
oseltamivir phosphate (Tamiflu) (Figure 1).5 The chiral isoquinuclidine can be accomplished by the
Diels-Alder (D-A) reaction of 1,2-dihydropyridines with dienophiles. In the asymmetric synthesis of
isoquinuclidines, the previous reports have focused on dienophiles having a chiral auxiliary in
Dedicated with respect to Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 1, 2012
diastereoselective process.6 In this paper, we describe the utility of (S,S)-bisoxazoline-Cu(II) catalyst7,8
for the enantioselective Diels-Alder reaction of 1,2-dihydropyridine9
and achiral
1
N(2)-acryloyl-N(1)-arylmethylsubstituted-5,5-dimethylpyrazolidin-3-one 2 to synthesize the chiral
isoquinuclidines in good yields with high enantioselectivity. The R group of pyrazolidinone also can be
easily varied and can be effective for providing the face selection in the D-A reaction.10 We used the
dienophile which has R group such as 1-benzyl, 1-naphthylmethyl or 2-naphthylmethyl group substituted
at N(1) position of pyrazolidinone 2. (S,S)-Bisoxazoline-Cu(II) catalysts (A, B, C and D) were
selected because of their successful application of C2-symmetric bisoxazoline-Cu(II) complexes as chiral
chelating Lewis acids in numerous asymmetric reactions and also due to the possibility of the controlling
selectivity with their structural diversity. The usefulness of bisoxazoline ligand with mild Lewis acid
such as Cu(OTf)2 in the D-A reaction has been reported by Evans et al. in the reaction between
cyclopentadiene and acrylimide in dichloromethane as a solvent and the D-A reaction afforded
endo-cycloadduct with high stereoselectivity (endo/exo = 98:2).7b
N
N
H
N
R
N
OH
N
MeO2C
N
H
R'
OH
CO2Me
MeO
N
OAc
CO2Me
H
Me
isoquinuclidines
catharanthine
vinblastine
CO2Et
OMe
N
O
NH2
NHCOMe
N
H
oseltamivir phosphate
(Tamiflu)
ibogaine
Figure 1. Isoquinuclidine derivatives
RESULTS AND DISCUSSION
We investigated the asymmetric D-A reactions of N-phenoxycarbonyl-1,2-dihydropyridine 1a with the
dienophile, N(2)-acryloyl-N(1)-arylmethylsubstituted-5,5-dimethylpyrazolidin-3-one (2a, 2b or 2c)3 at
C in dichloromethane as a solvent in the presence of chiral (S,S)-bisoxazoline-Cu(II) catalyst (A, B, C
or D). The results are summarized in Table 1. The (S,S)-bisoxazoline catalysts (A, B and D) were
prepared according to the procedure reported by Evans et al.7b The D-A reaction of diene 1a (2 equiv.)
and N(2)-acryloyl-N(1)-benzyl-5,5-dimethylpyrazolidin-3-one 2a (1 equiv.) was carried out at C using

HETEROCYCLES, Vol. 86, No. 1, 2012
205
30 mol% of catalyst A (R2= Me) to give the cycloaddition product endo-3 in 89% yield with moderate
enantioselectivity (72% e.e., Table 1, entry 1). The 2 equiv. (or 3 equiv.) of 1,2-dihydropyridine 1a (or
1b) was used in the D-A reaction because it is reported that 1,2-dihydropyridines (1a and 1b) were
unstable in the presence of Lewis acids.6g The D-A reaction of 1a with N(2)-acryloyl-N(1)-
(1-naphthylmethyl)-5,5-dimethylpyrazolidin-3-one 2b using 30 mol% of catalyst A gave endo-4a in 99%
yield with 85% e.e. (entry 2). The D-A reaction of 1a with N(2)-acryloyl-N(1)-2-naphthylmethyl-
5,5-dimethylpyrazolidin-3-one 2c using catalyst A afforded endo-5 in 96% yield (67% e.e., entry 3).
The result of the D-A reaction of 1a and 2b shows that the stereoselectivity of endo-3, 4a and 5 increased
according to the bulkiness of the group R2 of chiral ligand (A, B or C) as follows (Me < i-Pr < t-Bu);
Table 1, entry 2, chiral catalyst A (R2= Me) 85% e.e.; entry 5, B (R2= i-Pr) 91% e.e.; entry 8, C (R2=
t-Bu) 96% e.e.
However, despite our expectations, the D-A reaction of 1a and 2 using
benzyl-bisoxazoline D (R2= Bn) did not produce better stereoselectivity of endo-4a (entry 11, D, R2= Bn,
83% e.e.). From these enantioselectivities, we found that chiral ligand C (t-Bu-bisoxazoline) was
suitable for this reaction as the catalyst. Among three types of dienophiles (2a, 2b, and 2c), 2b was found
to be effective for providing higher enantioselectivity of the D-A cycloadduct.
CO2Ph
O
O
N
chiral catalyst A-D
2
N
(30 mol%)
N
(7S)
+
3
: R1 = Bn
CH2Cl2, 0 C, 24 h
N
O
CO2Ph
R1
4a : R1 = 1-naphthylmethyl
O
1
N
N
5
: R1 = 2-naphthylmethyl
2
1a
2a : R1 = Bn
2b : R1 = 1-naphthylmethyl
2c : R1 = 2-naphthylmethyl
R1
2 equiv.
1 equiv.
3, 4a, 5
2+
Table 1. Effect of catalyst (A, B, C or D) in cycloaddition of 1,2-dihydropyridine 1a
with pyrazolidinone (2a, 2b or 2c)
O
O
-
2TfO
Yield a) / %
N
N
Entry
2
Catalyst
Product
% e.e. of
endo - 3,4a,5 b)
R2
R2
Cu
endo - 3,4a,5
A: R2 = Me
B: R2 = i-Pr
C: R2 = t-Bu
D: R2 = Bn
1
2
3
4
5
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
A
A
A
B
B
B
C
C
C
D
D
D
3
4a
5
3
4a
5
89
99
96
99
93
91
76
71 (24)
58 (8)
82
95
84
72
85
67
78
91
81
98
96
89
66
83
62
6
7
3
8
9
10
11
12
4a
5
3
4a
5
a) Isolated yields. Recovery of dienophile is shown in parentheses.
b) Enantiomeric excess (% e.e.) was determined by HPLC analysis using a Daicel
Chiralpak AD-H column; eluent, 50% 2-propanol/n-hexane, flow rate 0.5 mL/min,
t R= 14 min (major, 7S), t R= 17 min (minor, 7R).

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We investigated the D-A reaction of 1a and 2b by decreasing the amount of catalyst C (R2= t-Bu) from
30 mol% to 20 mol%, 15 mol% or 10 mol% and the results were summarized in Table 2. Because the
coordination between the copper and the chiral ligand was sensitive to moisture, the addition of activated
molecular sieves 4A may be effective in enhancing the chemical yield and stereoselectivity in the D-A
reaction. The D-A reaction of 1a and 2b using 30 mol% of catalyst C in the presence of MS-4A showed
higher chemical yield and enantioselectivity of endo-4a (Table 2, entry 1, 91% yield with 98% e.e.) than
that in the absence of MS-4A (Table 1, entry 8, 71% yield with 96% e.e.). In the D-A reaction of 1a and
2b using 15 mol% of catalyst C without MS-4A still afforded endo-4a with high streoselectivity but in
low yield (Table 2, entry 3, 46% yield with 92% e.e.). In the D-A reaction with MS-4A, the chemical
yield and enantioselectivity of endo-4a increased to 78% yield with 98% e.e. (Table 2, entry 3).
However, when the amount of catalyst C was reduced to 10 mol% in the presence of MS-4A, the
chemical yield and stereoselectivity of endo-4a was only 44% yield with 90% e.e. (entry 4).
2+
O
O
-
2TfO
CO2Ph
N
N
N
O
O
Cu
t-Bu
2
t-Bu
(7S)
N
chiral catalyst C
+
O
N
N
1
O
N
CH2Cl2, 0 oC, 24 h
(MS 4A)
CO2Ph
N
2b
1 equiv.
1a
2 equiv.
4a
Table 2. Effect of molecular sieves 4A
Without MS-4A
With MS-4A
Yield/% % e.e. of
endo - 4a a) endo - 4a b)
Catalyst C
Entry
Yield/%
% e.e. of
/ mol%
endo - 4a a) endo - 4a b)
91 (4)
82 (10)
78 (10)
44 (33)
30
20
15
10
98
97
98
90
71 (24)
43 (27)
46 (30)
10 (40)
1
2
3
4
96
95
92
40
a) Isolated yields. Recovery of dienophile is shown in parentheses.
b) Enantiomeric excess (% e.e.) was. determined by HPLC analysis using a Daicel
Chiralpak AD-H column; eluent, 50% 2-propanol/n-hexane, flow rate 0.5 mL/min,
t R= 14 min (major, 7S), t R= 17 min (minor, 7R).
In the D-A reaction of 1a and 2b using 15 mol% of Cu(OTf)2 without (S,S)-t-Bu-bisoxazoline, endo-4a
was obtained in 87% yield (Table 3, entry 1). From this result, we considered that the complete
formation of Cu(II)-complex with (S,S)-t-Bu-bisoxazoline is very important. When the excess amount

HETEROCYCLES, Vol. 86, No. 1, 2012
207
of chiral ligand (S,S)-t-Bu-bisoxazoline than the amount of Cu(OTf)2 was used in the presence of MS-4A,
the enantioselectivity of the D-A adduct endo-4a was increased (Table 3). The D-A reaction of 1a and
2b in the presence of 17 mol% of (S,S)-t-Bu-bisoxazoline and 15 mol% of Cu(OTf)2 gave endo-4a in 76%
yield with 99% e.e. (Table 3, entry 2). This result gave slightly higher stereoselectivity than that in the
presence of 15 mol% of t-Bu-bisoxazoline and 15 mol% of Cu(OTf)2, which endo-4a was obtained in
78% yield with 98% e.e. (Table 2, entry 3). Furthermore, the reaction in the presence of 18 mol% of
t-Bu-bisoxazoline and 15 mol% of Cu(OTf)2 gave endo-4a in better yield (Table 3, entry 3, 82% yield
with 99% e.e.). Similarly, in the reaction using 12 mol% of (S,S)-t-Bu-bisoxazoline and 10 mol% of
Cu(OTf)2, the enantiomeric excess of endo-4a was increased to 98% e.e. (Table 3, entry 4), though the
reaction in the presence of 10 mol% of t-Bu-bisoxazoline and 10 mol% of Cu(OTf)2 gave endo-4a in 44%
yield with 90% e.e. (Table 2, entry 4). Next, we examined the effect of counter ion of catalyst in the
D-A reaction. In the reaction using 18 mol% of t-Bu-bisoxazoline and 15 mol% of Cu(ClO4)2, endo-4a
was obtained in 61% yield with 97% e.e. (Table 3, entry 6). Though the reaction was continued for 48 h,
the chemical yield and stereoselectivity of endo-4a was 65% yield with 96% e.e. (Table 3, entry 7).
2+
O
O
-
2X
t-Bu
N
N
Cu
t-Bu
CO2Ph
C: X = OTf
C': X = ClO4
N
O
O
2
(7S)
chiral catalyst C or C'
N
+
O
N
N
O
N
1
CH2Cl2, 0 oC, 24 h
MS 4A
CO2Ph
1a
2 equiv.
N
2b
1 equiv.
4a
Table 3. Effect of excess amount of bisoxazoline and counter ions of catalyst
Yielda) / %
% e.e. of
Counter Bisoxazoline Lewis Acid
Entry
1
endo - 4ab)
/ mol%
ion X
/ mol%
endo - 4a
1a
1a
OTf
OTf
-
17
87
76 (16)
1
2
15
15
0
99
1a
1a
OTf
18
12
17
18
18
82 (14)
69 (17)
45 (34)
61 (23)
65 (14)
3
15
10
15
15
15
99
98
97
97
96
OTf
4
ClO4
ClO4
ClO4
5
1a
1a
6
7c)
1a
a) Isolated yield. Recovery of dienophile is shown in parentheses.
b) Enantiomeric excess (% e.e.) was determined by HPLC analysis using a Daicel
Chiralpak AD-H column; eluent, 50% 2-propanol/n-hexane, flow rate 0.5 mL/min,
t R= 14 min (major, 7S), t R= 17 min (minor, 7R).
c) Reaction time is 48 h.

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HETEROCYCLES, Vol. 86, No. 1, 2012
We also investigated the D-A reaction of N-benzyloxycarbonyl-1,2-dihydropyridine 1b with 2b. In the
D-A reaction of 1b (2 equiv.) with N(2)-acryloyl-N(1)-(1-naphthylmethyl)-5,5-dimethylpyrazolidin-3-one
2b (1 equiv.) was carried out in the presence of 30 mol% of catalyst C gave endo-4b in 42% yield with
99% e.e. (Table 4, entry 1). In the D-A reaction of 1b with 2b, the dropwise addition of 1b (2 equiv.) to
2b (1 equiv.) was carried out in the presence of MS-4A using 30 mol% of catalyst C, and endo-4b was
obtained in better yield (entry 2, 78% yield with 99% e.e.). We also investigated the D-A reaction by
dropwise addition of 1b (3 equiv.) to 2b (1 equiv.) and the endo-4b was obtained in 75% yield with 99%
e.e. (entry 3). The D-A reaction of 1b with 2b for 48 h, afforded endo-4b in 73% yield with 99% e.e.
(entry 4). Since the presence of a small excess amount of (S,S)-t-Bu-bisoxazoline to Cu salt in the
reaction between 1a and 2b improved the chemical yield and stereoselectivity of the cycloadduct endo-4a
as shown in Table 3, we have examined the D-A reaction of 1b (3 equiv.) with 2b (1 equiv.) using 36
mol% of (S,S)-t-Bu-bisoxazoline and 30 mol% of Cu(OTf)2, however, the chemical yield with
stereoselectivity of endo-4b was 72% yield with 99% e.e. (entry 5).
2+
O
O
2TfO-
CO2Bn
N
N
O
O
N
Cu
t-Bu
2
t-Bu
N
(7S)
chiral catalyst C
+
N
N
1
O
O
N
MS-4A, CH2Cl2, 0 oC
CO2Bn
1b
N
2b
1 equiv.
4b
Table 4. Cycloaddition of diene 1b with 2b
Yield a) / %
% e.e. of
endo - 4b b)
Lewis Acid
/ mol%
Bisoxazoline
/ mol%
Entry
1 (equiv.) Time
endo - 4b
1 c)
2
3
4
30
30
30
30
30
99
99
99
99
99
1b (2)
1b (2)
1b (3)
1b (3)
24
24
24
48
24
30
30
30
30
36
42 (26)
78
75
73
72
5
1b (3)
a) Isolated yield. Recovery of dienophile is shown in parentheses.
b) Enantiomeric excess (% e.e.) was determined by HPLC analysis using a Daicel
Chiralpak AD-H column; eluent, 50% 2-propanol/hexane, flow rate 0.5 mL/min,
t R= 20 min (major, 7S), t R= 24 min (minor, 7R).
c) Without MS-4A.
The absolute stereochemistry of D-A adduct 4a was established to be (1S,4R,7S) by comparing the sign of
the optical rotation with the literature value of (7R)-benzyl ester 6, {lit.,3a []D -59.92 (c 2.52, DMSO)} as
follows: the reaction of the endo-4a (98% e.e.) with benzyl alcohol using n-BuLi as a base (PhCH2OLi)

HETEROCYCLES, Vol. 86, No. 1, 2012
209
in THF afforded the corresponding (7S)-benzyl ester 6 {[]D +74.5 (c 0.39, DMSO), 98% e.e.} in 36%
yield (Scheme 1).
CO2Ph
O
CO2Ph
N
N
n-BuLi, BnOH
(7S)
O
THF, 0 C, 4h
36% yield
O
BnO
N
N
6
(7S) []D +74.5(c 0.39, DMSO)
Lit. (7R) []D -59.92(c 2.52, DMSO)
4a
98% e.e.
Scheme 1. Determination of absolute configuration of Diels-Alder adduct 4a
From the absolute stereochemistry and high enentioselectivity (up to 99% e.e.) of (7S)-4a, we considered
the plausible reaction mechanism of the asymmetric D-A reaction of 1a and 2b as shown in Figure 2. It
is well established that the complex of (4S,4’S)-bisoxazoline-Cu(II) catalyst react via distorted square
planar geometries upon complexation to bidentate substrates.7b Sibi et al. have reported the x-ray
structures of pyrazolidinones and possibility of  interactions between aromatic relay groups and the
olefin of the dienophile.10c
O
O
O
O
N
N
N
N
Cu
Cu
O
O
O
O
N
N
N
N
Me
H
H
Me
H
H
H
H
8
7
O
O
H
N
N
Cu
si-face
attack
H
O
N
O
(7S) - 4a
99% e.e.
O
N
N
PhO
re-face
attack
Figure 2. Plausible reaction mechanism of D-A reaction of 1a and 2b using catalyst C

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HETEROCYCLES, Vol. 86, No. 1, 2012
The role of the fluctional N(1) substituent with the bulky 1-naphthylmethyl group of achiral
pyrazolidinone template in conjugation with chiral Lew acid, (4S,4’S)-t-Bu-bisoxazoline catalyst C (R2 =
t-Bu), provided enantioselectivities up to 99% e.e. Some chiral Lewis acids might induce chirality such
that the pyrazolidinone chirality works in concert with the chiral Lewis acid (matched case) and amplify
enantioselectivity. In other cases, the induced chirality might display a mismatched, dissonant effect.
In the complex of dienophile 2b and (4S,4’S)-t-Bu-bisoxazoline catalyst C (R2 = t-Bu), the reaction might
be through the intermediate 7 that has less steric interaction between N(1)-1-naphthylmethyl group and
C-5 methyl hydrogen atoms of dienophile than that of the intermediate 8. Thus, 1,2-dihydropyridine 1a
can approach from the re-face to give (7S)-4a (up to 99% e.e.) since the si-face of the N(2)-acryloyl group
of dienophile 2b is shielded by the N(1)-1-naphthylmethyl group of dienophile 2b and C4-tert-butyl
group of (4S,4’S)-t-Bu-bis(oxazoline) catalyst C.
In conclusion, we have developped the highly enantioselective Diels-Alder reaction of
1,2-dihydropyridine derivatives (1a and 1b) with achiral dienophile N(2)-acryloyl-N(1)-
(1-naphthylmethyl)-5,5-dimethylpyrazolidin-3-one 2b using (S,S)-tert-Bu-substituted bisoxazoline-Cu(II)
catalyst C, which provides an efficient methodology for obtaining the pharmacologically important chiral
isoquinuclidine derivatives in good yield with high enantioselectivity (up to 99% e.e.).
EXPERIMENTAL
General. Melting points were measured using AS ONE ATM-01 melting point apparatus. 1H NMR
spectra and 13C NMR spectra were recorded at 270 MHz on JEOL JNM-EX 270 FT NMR SYSTEM and
500 MHz and 125 MHz on a JEOL JNM-ECA. Chemical shifts of 1H NMR and 13C NMR are reported
in parts per million downfield from tetramethylsilane () as the internal standard and coupling constants
are in hertz (Hz). Specific rotations were recorded at the sodium D line with a polarimeter.
Purification of reaction product was carried out by flash chromatography on silica gel 60 (KANTO
CHEMICALS, 40-100 m). The enantiomeric excess (e.e.) of the cycloaddition products was
determined by high performance liquid chromatography (HPLC) using the Chiralpak AD-H (25 cm).
Bisoxazoline ligands (R2= Me, i-Pr, and Bn) were prepared according to the reported methods.10b
(S,S)-t-Butyl-bisoxazoline ligand was purchased from Tokyo Chemical Ind. Co. Commercially
available compounds were used without further purification.
1.1 Preparation of 1-(phenoxycarbonyl)-1,2-dihydropyridine (1a)9: The compound 1a has been
previously prepared.6b A solution of pyridine (8.00 g, 65 mmol) and NaBH4 (2.06 g, 55 mmol) in 60 mL
of absolute EtOH was stirred together at -78 °C and phenyl chloroformate (10.6 g, 65 mmol) was added

HETEROCYCLES, Vol. 86, No. 1, 2012
211
slowly for l h. The reaction mixture was stirred for 24 h at -78 oC and then quenched with ice-water and
the mixture was stirred until the H2 bubble stopped. The product was extracted with Et2O (100 mL x 3).
The organic layer was dried over sodium sulfate, filtered, and concentrated. The product 1a was
recrystallized from EtOH to give a white solid product in 50% yield (6.60 g, 32.8 mmol). The ratio of
1
1,2-dihydropyridine and 1,4-dihydropyridine (95:5) was measured by H NMR (4.45-4.59 ppm for
1,2-dihydropyridine and 2.89 ppm for 1,4-dihydropyridine): white solid; mp 64-66 °C; 1H NMR [ppm]
(500 MHz, CDCl3)  4.45 (q, J = 4.0, 1.9 Hz, 1.2H), 4.59 (br s, 0.8H), 5.23-5.29 (m, 1H), 5.55-5.61 (m,
1H), 5.89-5.92 (m, 1H), 6.81 (d, J = 7.4 Hz, 0.6 H), 6.88 (d, J = 8.0 Hz, 0.4 H), 7.13 (d, J = 8.0 Hz, 2H),
13
7.23 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H); C NMR [ppm] (125 MHz, CDCl3)  43.82, 105.85,
119.51, 121.57 (2C), 121.84, 125.37, 125.71, 126.06, 129.40 (2C), 150.92.
1.2 Preparation of 1-(benzyloxycarbonyl)-1,2-dihydropyridine (1b)9: To absolute EtOH (8 mL)
solution of pyridine (1.89 g, 24 mmol) and NaBH4 (0.39 g, 10 mmol) was slowly added benzyl
chloroformate (3.41 g, 20 mmol for 1a) for 1 h at -78 °C. The reaction mixture was stirred for 24 h at
-78 °C and then quenched with ice-water and extract with Et2O. The organic layer was dried over
sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica
gel (eluent, n-hexane/AcOEt = 20:1) to afford 1b as pale yellow oil in 54% yield (2.30 g, 10.0 mmol).
1
The ratio of l,2-dihydropyridine and 1,4-dihydropyridine (99:1) was measured by H NMR (4.38 ppm
for 1,2-dihydropyridine and 2.89 ppm for 1,4-dihydropyridine): oil; 1H NMR [ppm] (500 MHz, CDCl3)
δ 4.38 (s, 2H), 5.10 (t, J = 6.3 Hz, 1H), 5.18 (br s, 2H), 5.51-5.53 (m, 1H), 5.80-5.83 (m, 1H), 6.70 (d, J =
8.0 Hz, 0.6H), 6.78 (d, J = 7.4 Hz, 0.4H), 7.32-7.36 (m, 5H); 13C NMR [ppm] (125 MHz, CDCl3)  43.6,
43.85, 67.77, 105.02, 119.18, 121.86, 125.52, 128.10, 128.27, 128.47, 128.54,153.00.
1.3 General procedure for the preparation of bisoxazoline ligand10b: Zinc chloride (5 mmol),
dimethylmalononitrile (10 mmol) and (S)-2-aminopropanol (22 mmol) {for Me-bisoxazoline ligand (R2 =
Me) or L-valinol (22 mol) for i-Pr-bisoxazoline ligand (R2 = i-Pr) or L-alaninol (22 mmol) for
Bn-bisoxazoline ligand (R2 =Bn)} in chlorobenzene (20 mL) was heated at reflux for 72 h. The reaction
solution was cooled to room temperature and the solvent was evaporated. The residue was dissolved
with CH2Cl2 (40 mL) and ammonium hydroxide (5 mL) and then the organic layer was washed with
water (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residual
oil was purified by column chromatography (eluent, MeOH/AcOEt = 1:9).
25
1.3.1 2,2-Bis[2-(4S)-methyl-1,3-oxazolinyl]propane: 31% yield; colorless oil, [α]D -119.0 (c 1.02,

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HETEROCYCLES, Vol. 86, No. 1, 2012
25
1
13
CH2Cl2) (Lit.,7b [α]D -67.7 (c 1.0, CH2Cl2); H NMR and C NMR spectra were identified with the
literature values.10b 1H NMR [ppm] (270 MHz, CDCl3) δ 1.25 (d, J = 6.4 Hz, 6H), 1.51 (s,6H), 3.80 (t, J
13
= 7.5 Hz, 2H) , 4.19 (dd, J = 15.7, 6.8 Hz 2H) , 4.36 (t, J = 8.6 Hz, 2H); C NMR [ppm] (125 MHz,
CDCl3) δ 21.20, 24.26, 38.30, 61.27, 74.35, 168.83.
25
1.3.2 2,2-Bis[2-(4S)-isopropyl-1,3-oxazolinyl]propane: 30% yield; colorless oil, [α]D -126.9 (c
25
1
13
1.02, CH2Cl2) (Lit.,10 [α]D -107.5 (c 1.0, CH2Cl2); H NMR and C NMR spectra were identified with
the literature values.11 1H NMR [ppm] (270 MHz, CDC13) δ 0.85 (d, J = 6.7 Hz, 6H), 0.91 (d, J = 6.7,
6H), 1.51 (s, 6H), 1.77-1.84 (m, 2H), 3.92-4.02 (m, 4H), 4.15-4.22 (m, 2H); 13C NMR [ppm] (125 MHz,
CDCl3) δ 17.29, 18.50, 24.41, 32.14, 38.52, 69.88, 71.43, 168.74.
1.3.3 2,2-Bis[2-(4S)-benzyl-1,3-oxazolinyl]propane: 24% yield; pale yellow oil, [α]D28 -76.6 (c 0.89,
1
13
CH2Cl2); H NMR and C NMR spectra were identified with the literature values.11b 1H NMR [ppm]
(500 MHz, CDCl3) δ 1.45 (s, 6H), 2.63-2.68 (dd, J = 13.7, 8.6 Hz, 2H), 3.09 (dd, J = 13.7, 4.5 Hz, 2H),
3.99-4.02 (m, 2H), 4.17 (t, J = 8.8 Hz, 2H), 4.37-4.42 (m, 4H), 7.18-7.30 (m, 10H); 13C NMR [ppm] (125
MHz, CDCl3) δ 24.14, 38.49, 41.26, 66.89, 71.97, 126.43, 128.40, 129.42, 137.61, 169.40.
1.4 General procedure for the preparation of pyrazolidin-3-ones 2a-c3: To a solution of acrylic
acid (13 mmol) in THF (50 mL) using a 100 mL flask, triethylamine (25 mmol) was added. The
mixture was stirred at -20 °C and acryloyl chloride (12 mmol) was added. The mixture was stirred for
1 h.
LiCl (12.5 mmol) and 1-(1-naphylmethyl)-5,5-dimethylpyrazolidin-3-one (10 mmol) 2a,
1-(2-naphthylmethyl)-5,5-dimethylpyrazolidin-3-one (10 mmol) 2b or 1-benzyl-5,5-dimethyl-
pyrazolidin-3-one 2c was added and the mixture was stirred for l0 min, followed by stirring at room
temperature for 24 h. The reaction was quenched with 0.2 M HCl aq. and THF was removed under a
reduced pressure. The reaction product was extracted with ethyl acetate, and the organic layer was
washed with 0.2 M HCl aq., brine, and 1.0 M NaHCO3 aq. The organic layer was dried over Na2SO4,
filtrated, and concentrated under reduced pressure. The residual oil was purified by dry silica gel
column chromatography (eluent, toluene). n-Hexane was added for crystallization of pyrazolidin-3-one
and the solid was filtered to afford 2a, 2b or 2c, respectively.
1.4.1 N(2)-Acryloyl-N(1)-benzyl-5,5-dimethylpyrazolidin-3-one (2a): 33% yield, white solid; mp
1
81-82 °C (Lit.,10b mp 82-83 oC); H NMR and 13C NMR spectra were identified with the literature
values.10b 1H NMR (500 MHz, CDCl3) δ 1.29 (s, 6H), 2.57 (s, 2H), 4.07 (s, 2H), 5.67 (d, J = 10.9 Hz,
1H), 6.35 (dd, J =17.2, 1.1 Hz, 1H), 7.07 (dd, J = 16.6, 10.3 Hz, 1H), 7.23-7.30 (m, 3H), 7.38 (d, J =6.9

HETEROCYCLES, Vol. 86, No. 1, 2012
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13
Hz, 2H); C NMR (125 MHz, CDCl3) δ 26.04, 43.48, 56.96, 60.98, 127.62, 128.13, 128.39, 129.59,
130.72, 136.85, 162.97, 174.38.
1.4.2 N(2)-Acryloyl-N(1)-(1-naphthylmethyl)-5,5-dimethylpyrazolidin-3-one (2b): 39% yield, white
1
13
solid; mp 129-132 °C (Lit.,10b mp 107-109 oC); H NMR and C NMR spectra were identified with the
literature values.10b 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 6H), 2.75 (s, 2H), 4.44 (s, 2H), 4.99 (d, J =
9.1 Hz, 1H), 5.82 (d, J = 17.4 Hz, 1H), 6.32 (m, 1H), 7.34-7.37 (m, 1H), 7.45-7.50 (m, 2H), 7.55-7.58 (m,
13
1H), 7.77 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H); C NMR (125 MHz,
CDCl3) δ 25.90, 42.94, 55.21, 61.45, 123.19, 125.32, 125.59, 126.29, 127.44, 128.72, 129.37, 129.42,
131.49, 132.30, 133.59, 163.43, 173.99.
1.4.3 N(2)-Acryloyl-N(1)-(2-naphthylmethyl)-5,5-dimethylpyrazolidin-3-one (2c): 64% yield, white
solid; mp l15-116 °C. IR (Nujol) 1507, 1682, 1743 cm-1. 1H NMR (270 MHz, CDCl3) δ 1.30 (s, 6H),
2.61 (s, 2H), 4.23 (s, 2H), 5.65 (d, J = 10.3 Hz, 1H), 6.29 (d, J = 16.6 Hz, 1H), 7.10-7.15 (m, 1H),
13
7.43-7.47 (m, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.78-7.80 (m, 4H); C NMR (125 MHz, CDCl3) δ 26.14,
43.54, 57.17, 61.02, 125.91, 126.04, 127.33, 127.62, 127.79, 128.10, 128.17, 128.23, 130.83, 132.78,
133.16, 134.72, 162.91, 174.33. MS m/z 309.15 [M++1]. Anal. Calcd for: C, 74.00; H, 6.54; N, 9.08.
Found: C, 74.00; H, 6.60; N, 9.17.
1.5 General procedure for D-A reaction of l,2-dihydropyridine (1a or 1b) with N(2)-
acryloyl-N(1)-arylmethyl-5,5-dimethylpyrazolidinone 2a-c using (S,S)-bisoxazoline-Cu(II) (A, B, C,
or D): To the appropriate chiral ligand (0.15 mmol) in anhydrous CH2Cl2 (2 mL), Cu(OTf)2 (0.15
mmol) was added. The reaction mixture was stirred for 2 h at room temperature under nitrogen
atmosphere. Dienophile 2 (0.50 mol) dissolved in anhydrous CH2C12 (2 mL) was added to the above
solution and then diene 1 (1.0 mmol) was added. The reaction mixture was stirred for 24 h at 0 °C.
The reaction was quenched with saturated K2CO3 aq. (2 mL) and the product was extracted with CHCl3.
The organic layer was dried over sodium sulfate, filtered, and concentrated under a reduced pressure.
The residue was purified by flash column chromatography on silica gel (eluent, from n-hexane/AcOEt =
4:1 to n-hexane/AcOEt = 2:1). The reaction conditions, chemical yields and enantioselectivity are
shown in Table 1. In the D-A reaction with molecular sieves 4A, the catalyst and molecular sieves 4A
(230 mg) were stirred together for 2 h in anhydrous CH2C12 (2 mL), followed by the addition of
dienophile 2 and then 1,2-dihydropyridine 1.
The reaction conditions, chemical yields and
enantioselectivity are shown in Table 2. In the reaction using Cu(ClO4)2 as a Lewis acid, a mixture of
chiral t-Bu-oxazoline (0.090 mmol), CuCl2 (0.075 mmol) and AgClO4 (0.15 mmol) was stirred in

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anhydrous CH2Cl2 (2 mL) for 2 h under the dark conditions. The mixture was then filtered though a
syringe filter and the filtrate containing chiral catalyst C’ was added to a solution of dienophile 2. The
reaction conditions, chemical yields and enantioselectivity are shown in Table 3. The enantiomeric
excess (% e.e.) of endo-3, 4a, or 5 was determined by HPLC analysis using a DAICEL Chiralpak AD-H
column; eluent, 50% 2-propanol/n-hexane; flow rate, 0.5 mL/min, detection at 254 nm; retention time, tR
= 14 min (major, 7S), tR= 17 min (minor, 7R). The enantiomeric excess (% e.e.) of endo-4b was
determined by HPLC analysis using a DAICEL Chiralpak AD-H column; eluent, 50%
2-propanol/n-hexane; flow rate, 0.5 mL/min, detection at 254 nm; retention time, tR = 20 min (major, 7S),
tR = 24 min (minor, 7R).
1.5.1 Diels-Alder adduct (7S)-3: White solid (recrystallized from AcOEt/n-hexane), mp 166-169 °C.
20
(Lit.,3b mp 165-168 °C), [α]D +79.0 (c 0.25, CHCl3, 98% e.e.). 1H NMR [ppm] (500 MHz, CDCl3) δ
1.12-1.27 (m, 6H), 1.53-1.64 (m, 1H), 2.04-2.10 (m,1H), 2.53-2.59 (m, 1H), 2.64-2.69 (m,1H), 2.84 (br s,
1H), 3.05 (d, J = 10.3 Hz, 0.5H), 3.18 (d, J = 10.3 Hz, 0.5H), 3.35 (d, J = 9.6 Hz, 0.5H), 3.50 (d, J = 8.6
Hz, 0.5H), 3.99 (br s, 1H), 4.04 (br s, 2H). 5.06 (br s, 1H), 6.33-6.44 (m, 2H), 7.12 (d, J = 7.4 Hz, 1H),
7.16-7.24 (m, 3H), 7.28-7.31 (m, 2H), 7.33-7.38 (m, 2H), 7.43-7.44 (m, 2H); 13C NMR [ppm] (125 MHz,
CDCl3) δ 25.77, 26.64, 27.48, 30.72, 43.47, 45.52, 46.75, 47.22, 57.08, 60.91, 121.77, 121.82, 125.17,
127.43, 127.48, 128.35, 128.85, 128.96, 129.17, 129.22, 130.80, 133.66, 137.56, 151.32, 153.37, 169.67,
173.91.
1.5.2 Diels-Alder adduct (7S)-4a: White solid (recrystallized from AcOEt/n-hexane), mp 134-138 °C.
20
(Lit.,3b mp 170-172 °C), [α]D +92.9 (c 0.25, CHCl3, 99% e.e.). 1H NMR [ppm] (500 MHz, CDCl3) δ
1.28-1.41 (m, 6H), 1.61 (s, 2H), 2.68-2.70 (m, 2H), 2.84 (d, J = 17.2 Hz, 1H), 2.90-3.01 (m, 2H), 3.58 (m,
1H), 4.31 (m, 1H), 4.58 (m, 1H), 4.84-4.88 (m, 1H), 6.10 (t, J = 6.6 Hz, 0.5H), 6.17 (t, J = 6.6Hz, 0.5H),
6.28 (t, J = 7.1Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.17-7.26 (m, 2H), 7.35-7.42 (m, 3H), 7.48-7.57 (m. 2H),
7.64 (m, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.86 (t, J = 8.6 Hz, 1H), 8.18-8.22 (m, 1H); 13C NMR [ppm] (125
MHz,CDCl3) δ 25.44, 26.74, 30.25, 30.50, 43.15, 46.43, 46.84, 47.36, 54.96, 61.26, 121.70, 123.25,
123.38, 125.13, 125.15, 125.33, 125.42, 125.73, 125.84, 126.38, 128.48, 128.74, 129.23, 129.26, 131.75,
133.65, 134.32, 151.40, 151.35, 153.13, 173.87.
1.5.3 Diels-Alder adduct (7S)-4b: White solid (recrystallized from AcOEt/n-hexane), mp 70-72 °C,
20
[α]D +62.7 (c 0.50, CHCl3, 99% e.e.). IR (Nujol) 1225, 1497, 1688, 1743, 2963 cm-1. 1H NMR
[ppm] (500 MHz, CDCl3) δ 1.19-1.39 (m, 6H), 1.65 (s,3H), 2.58 (s, 1H), 2.67 (d, J = 16.6 Hz, 1H),
2.76-2.98 (m, 3H), 4.28-4.29 (m, 0.5H), 4.49-4.56 (m, 1H), 4.64 (s, 1H), 4.87 (s, 1H), 5.10-5.26 (m, 2H),

HETEROCYCLES, Vol. 86, No. 1, 2012
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6.04 (t, J = 6.87Hz, 0.5H), 6.14 (t, J = 6.8Hz, 0.5H), 6.20-6.24 (m, 1H), 7.31-7.42 (m, 6H), 7.43-7.55 (m,
2H), 7.67-7.72 (m, 1H), 7.80 (dd, J = 31.8, 8.3 Hz, 2H), 8.16 (dd, J = 23.7, 8.30 Hz, 1H); 13C NMR [ppm]
(125 MHz, CDCl3) δ 25.47, 26.72, 30.27, 30.52, 43.13, 46.35, 46.42, 46.67, 55.07, 61.24, 66.71, 123.14,
123.24, 125.31, 125.41, 125.68, 125.84, 126.28, 126.38, 127.74, 127.90, 128.07, 128.21, 128.39, 128.71,
131.63, 133.64, 136.78, 136.89, 154.39, 154.75, 173.80. MS m/z 524.25 [M++1]. Anal. Calcd for: C,
73.40; H, 6.35; N, 8.02. Found: C, 73.34; H, 6.11; N, 7.96.
1.5.4 Diels-Alder adduct (7S)-5: White solid (recrystallized from AcOEt/n-hexane), mp 154-156 °C.
[α]D20 +72.1 (c 0.25, CHCl3, 89% e.e.). IR (Nujol) 1205, 1595, 1716, 2969 cm-1. 1H NMR [ppm] (500
MHz, CDCl3) δ 1.12-1.29 (m, 6H), 1.47-1.49 (m, 1H), 2.04 (m, 1H), 2.69 (d, J = 24.6 Hz, 3H), 2.99 (d, J
= 10.8 Hz, 0.5H), 3.12 (d, J = 10.3 Hz, 0.5H), 3.31 (d, J =10.3 Hz, 0.5H), 3.46 (d, J = 9.74 Hz, 0.5H),
3.98 (br s, 1H), 4.13-4.22 (m, 2H), 5.06 (d, J = 23.7 Hz, 1H), 6.09 (t, J =7.4 Hz, 1H), 6.17 (t, J = 6.9 Hz,
0.5H), 6.27 (t, J = 6.6 Hz, 0.5H), 7.11 (d, J = 8.0 Hz, 1H), 7.14-7.20 (m, 2H), 7.32-7.37 (m, 2H),
13
7.44-7.46 (m, 2H), 7.64-7.67 (m, 1H), 7.77-7.82 (m, 4H); C NMR [ppm] (125 MHz, CDCl3) δ 25.97,
27.49, 30.31, 30.61, 43.49, 45.70, 46.64, 47.19, 57.30, 60.01, 121.74, 121.80, 125.12, 125.79, 125.96,
127.08, 127.23, 127.44, 127.58, 127.65, 127.73, 127.94, 129.12, 129.16, 132.28, 134.09, 135.00, 151.27,
153.32, 169.68, 173.86. MS m/z 510.23 [M++1]. Anal. Calcd for: C, 73.06; H, 6.13; N, 8.25. Found:
C, 73.24; H, 6.15; N, 8.14.
1.6 Conversion from Diels-Alder adduct 4a to benzy1 ester (7S)-6: n-BuLi (0.29 mL, 1.65 M in
n-hexane, 0.48 mmol) was added to a cooled (-78 °C) solution of benzy1 alcohol (0.064 mL, 0.62 mmol)
in 5 mL of THF. The resulting solution was strirred for 5 min and a solution of adduct 4a (0.30 mmol,
98% e.e.) in THF (1 mL) was added. The solution was warmed to 0 oC and stirred for 4 h. The
mixture was then quenched with saturated NaHCO3 aq. and the solvent was concentrated under reduced
pressure. Water was added to the residue and extracted with CHCl3. The combined organic layer was
dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column
chromatography on silica gel (eluent, 25% AcOEt in n-hexane) and benzyl ester (7S)-6 was obtained in
36% yield (39 mg, 0.11 mmol). The enantiomeric excess (98% e.e.) of benzyl ester (7S)-6 {[α]D27 +74.5
(c 0.39, DMSO)} as shown in Scheme 1 was determined by HPLC analysis using a DAICEL Chiralpak
AD-H column; eluent, 5% 2-propanol/n-hexane; flow rate, 0.8 mL/min, detection at 254 nm; retention
time, tR= 33.1 min (major, 7S), tR= 38.5 min (minor, 7R). The absolute stereochemistry of Diels-Alder
adduct 4a was established to be (1S,4R,7S) by comparing the sign of the optical rotation with the
literature value of (7R)-benzyl ester 6, { lit.,3a []D -59.92 (c 2.52, DMSO)}.

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HETEROCYCLES, Vol. 86, No. 1, 2012
27
1.6.1 Benzyl ester (7S)-6: yield 39 mg, oil, 36%; [α]D +74.5 (c 0.39, DMSO; 98% e.e.); {Lit.,3a
benzyl ester (7R) [α]D 25-59.92 (c 2.52, DMSO)}; The H NMR and C NMR spectra of (7S)-6 were
identified with the literature values.3a 1H NMR (270 MHz, CDCl3) δ 1.93-1.95 (m, 2H), 2.89 (br s, 1H),
3.04 (d, J = 10.5 Hz, 0.5H), 3.15 (d, J = 10.0 Hz, 0.5H), 3.22-3.25 (m, 1H), 3.34 (d, J = 10.5 Hz, 0.5H),
3.48 (d, J =10.2 Hz, 0.5H), 5.04-5.12 (m, 2H), 5.15-5.24 (m, 1H), 6.31-6.36 (m, 1H), 6.45-6.50(m, 1H),
1
13
13
7.07-7.12 (m, 2H), 7.16-7.19 (m, 1H), 7.24-7.32 (m, 7H); C NMR [ppm] (125 MHz, CDCl3) δ 25.93,
30.60, 44.81, 46.91, 47.52, 66.56, 121.65, 212.72, 125.25, 128.07, 128.16, 128.21, 128.51, 128.55, 129.17,
129.21, 130.54, 135.69, 151.22, 153.58, 153.61, 172.33.
ACKNOWLEDGMENTS
We are grateful to Ms. Yoko Nakano, Ms. Satomi Ahiko, and Mr. Hiroyuki Momma (Research and
Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University) for the
elemental analysis and mass spectra measurements.
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