Asymmetric synthesis of isoquinuclidines by Diels-Alder reaction of 1,2-dihydropyridine utilizing a chiral Lewis acid catalyst

Article abstract of DOI:10.1016/j.tet.2011.12.041

The chiral isoquinuclidine derivative, 2-azabicyclo[2.2.2]octane ring system, endo-(7R)-3 was obtained in good yield with excellent diastereoselectivity (up to 92% de) by Diels-Alder reaction of 1-(phenoxycarbonyl)-1,2-dihydropyridine 1 with N-acryloyl-(4S)-4- benzyloxazolidin-2-one (4S)-2 using titanium-(2R,3R)-TADDOLate 4 as a chiral Lewis acid catalyst in toluene at 0 °C. On the other hand, endo-(7S)-3 was obtained in good yield with excellent diastereoselectivity (up to 97% de) by Diels-Alder reaction of 1 with (4R)-2 using Cu(OTf)₂/(4S,4′S)- bis(oxazoline) catalyst 8 as a chiral Lewis acid catalyst in dichloromethane at 0 °C. In these reactions, the choice of solvent and the combination of titanium-(2R,3R)-TADDOLate 4 {or Cu(II)/(4S,4′S)-bis(oxazoline) 8} and dienophile (4S)-2 {or (4R)-2} are very important. The stereochemistry of endo-(7R)-3 has been established to be (1R,4S,7R) and the reaction mechanism is proposed.

Full text of DOI:10.1016/j.tet.2011.12.041

Tetrahedron 68 (2012) 1774e1781
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Asymmetric synthesis of isoquinuclidines by DielseAlder reaction of
1,2-dihydropyridine utilizing a chiral Lewis acid catalyst
,
a
a
a
a
Chigusa Seki a , Masafumi Hirama , N.D.M. Romauli Hutabarat , Junko Takada , Chonticha Suttibut ,
*
Hideto Takahashi a, Takuya Takaguchi a, Yoshihito Kohari a, Hiroto Nakano a, Koji Uwai a,
Nobuhiro Takano a, Mitsukuni Yasui a, Yuko Okuyama b, Mitsuhiro Takeshita b, Haruo Matsuyama a
,
*
a Department of Applied Chemistry, Graduate School of Engineering, Muroran Institute of Technology, 27-1Mizumoto, Muroran, Hokkaido 050-8585, Japan
b Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The chiral isoquinuclidine derivative, 2-azabicyclo[2.2.2]octane ring system, endo-(7R)-3 was obtained in
good yield with excellent diastereoselectivity (up to 92% de) by DielseAlder reaction of 1-(phenox-
ycarbonyl)-1,2-dihydropyridine 1 with N-acryloyl-(4S)-4-benzyloxazolidin-2-one (4S)-2 using titanium-
(2R,3R)-TADDOLate 4 as a chiral Lewis acid catalyst in toluene at 0 ꢀC. On the other hand, endo-(7S)-3 was
obtained in good yield with excellent diastereoselectivity (up to 97% de) by DielseAlder reaction of 1
with (4R)-2 using Cu(OTf)2/(4S,40S)-bis(oxazoline) catalyst 8 as a chiral Lewis acid catalyst in dichloro-
methane at 0 ꢀC. In these reactions, the choice of solvent and the combination of titanium-(2R,3R)-
TADDOLate 4 {or Cu(II)/(4S,40S)-bis(oxazoline) 8} and dienophile (4S)-2 {or (4R)-2} are very important.
The stereochemistry of endo-(7R)-3 has been established to be (1R,4S,7R) and the reaction mechanism is
proposed.
Received 14 December 2011
Accepted 17 December 2011
Available online 21 December 2011
Keywords:
Alkaloid
DielseAlder reaction
1,2-Dihydropyridine
2-Azabicyclo[2.2.2]octane
Chiral Lewis acid catalyst
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
hafnium tetrachloride, afforded the endo-cycloaddition product
(chiral isoquinuclidine derivatives) in good yield with excellent
Vinblastine extracted from the leaves of the Madagascar peri-
winkle plant (Catharanthus roseus), a natural product in the vinca
alkaloid family, is used for several types of cancer.1 A biosynthetic
pathway of vinblastine is the nucleophilic addition of (ꢁ)-vindo-
line to (þ)-catharanthine, which contains the isoquinuclidine ring
system, 2-azabicyclo[2.2.2]octane ring system. (þ)-Catharanthine
is prototypical structure of Iboga family of alkaloid and (ꢁ)-ibo-
gaine is the medicine for alcohol dependence.1b,2d Furthermore,
isoquinuclidines are valuable intermediates in the synthesis of
other alkaloid,3 and in medicinal chemistry, such as oseltamivir.4,5
The most promising method for the synthesis of isoquinuclidine
derivatives is the DielseAlder (DeA) reaction between 1,2-
dihydropyridine and dienophiles. In the asymmetric synthesis of
isoquinuclidines, the diastereoselective cycloadditions using 1,2-
dihydropyridines or dienophiles having a chiral auxiliary have
been reported.6 The DeA reaction of 1,2-dihydropyridines and N-
acryloyl-(1S)-2,10-camphorsultam in the presence of Lewis acid,
such as titanium tetrachloride, zirconium tetrachloride, and
diastereoselectivity (up to 98% de) in dichloromethane as a sol-
vent.6h Recently, its catalytic enantioselective synthesis was also
reported.2 In order to synthesize the chiral isoquinuclidines, we
adopted the asymmetric DeA reaction catalyzed by a chiral Lewis
acid.7 The commercial availability of optically pure oxazolidi-
nones, and the ease of removal and recovery of these auxiliaries
are valued characteristics in asymmetric synthesis. We report the
study on synthesis of the chiral isoquinuclidine derivatives by
DeA reaction of 1,2-dihydropyridine 1 with chiral dienophile 2
having a chiral auxiliary in the presence of Lewis acid. We in-
vestigated the two ways of the asymmetric DeA reactions. One is
the reaction of 1-(phenoxycarbonyl)-1,2-dihydropyridine 18 and
N-acryloyl-(4S)-4-benzyloxazolidin-2-one (4S)-2 {or N-acryloyl-
(4R)-4-benzyloxazolidin-2-one (4R)-2}9 using Lewis acid and the
other is the reaction of 1 and (4S)-2 {or (4R)-2} using Ti-(2R,3R)-
TADDOLate 4 as a chiral Lewis acid catalyst. Though it is reported
that 1,2-dihydropyridine is unstable for Lewis acid,2c,6g our re-
action system afforded chiral isoquinuclidines in good yields with
high diastereoselectivity (up to 92% de). The absolute stereo-
chemistry of the cycloaddition product endo-(40S)-3 was de-
termined to be (7R) by conversion of endo-(40S)-3 to the known
benzyl ester (7R)-7. We describe the detail of the available method
for the synthesis of the chiral isoquinuclidines (Fig. 1).
* Corresponding authors. E-mail address: hmatsuya@mmm.muroran-it.ac.jp
(H. Matsuyama).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.041

C. Seki et al. / Tetrahedron 68 (2012) 1774e1781
1775
which is the mirror image of (4S)-2 was carried out. The DeA re-
action of 1 (2 equiv) and (4R)-2 (1 equiv) using 2 equiv of Ti(i-
PrO)2Cl2 was carried out at 0 ꢀC for 24 h to afford endo-(40R)-3 in
99% yield with 58% de (entry 7).
2.2. Preparation of Ti-(R,R)-TADDOLate 4 as a chiral Lewis acid
catalyst
Fig. 1. Indole alkaloids.
In order to investigate the additional effect of chiral Lewis acid,
the chiral 1,4-diol (TADDOL)11 {TADDOL: (2R,3R)-2,3-O-iso-
propylidene-1,1,4,4-tetraphenyl-1,2,3,4-butanetetrol, (2R,3R)-2,3-
O-(1-phenylethylidene)-1,1,4,4-tetraphenyl-1,2,3,4-butanetetrol,
2. Results and discussion
and
(4R,5R)-a,a, ,a
a0 0,2,2-O-hexaphenyl-4,5-dimethanol-1,3-
2.1. DielseAlder reaction of 1-(phenoxycarbonyl)-1,2-
dihydropyridine 1 with (4S)-2 {or (4R)-2} in the presence of
Lewis acid
dioxalone14,15}, was employed as a chiral auxiliary (Scheme 2).10,11
We first examined the DeA reaction of 1-(phenoxycarbonyl)-
1,2-dihydropyridine 1 and N-acryloyl (4S)-4-benzyloxazolidin-2-
one (4S)-2 {or N-acryloyl (4R)-4-benzyloxazolidin-2-one (4R)-2}
using Lewis acids, such as dichlorotitanium diisopropoxide, zirco-
nium tetrachloride, hafnium tetrachloride, and scandium tri-
fluoromethanesulfonate (Scheme 1). These DeA reactions were
carried out in dichloromethane at 0 ꢀC for 24 h in the presence of
Scheme 2. Preparation of Ti-(2R,3R)-TADDOLate catalyst.
ꢀ
molecular sieves 4 A, since Lewis acid, such as ZrCl4, HfCl4, and
Sc(OTf)3 could not be dissolved in toluene, and the results are
summarized in Table 1.
Chiral titanium complex Ti-(2R,3R)-TADDOLate
4
{4a
(R1¼R2¼CH3), 4b (R1¼Ph, R2¼CH3), and 4c (R1¼R2¼Ph)} was pre-
pared from TADDOL and dichlorotitanium diisopropoxide (ratio,
ꢀ
1:1) in the presence of molecular sieves 4 A at room temperature
(Scheme 2).11
2.3. DielseAlder reaction of 1-(phenoxycarbonyl)-1,2-
dihydropyridine 1 with N-acryloyloxazolidin-2-one 5 using
chiral Lewis acid catalyst 4b
For the catalytic enantioselective version of the DeA reaction,
we examined the reaction of 1-(phenoxycarbonyl)-1,2-
dihydropyridine 1 and N-acryloyloxazolidin-2-one 59 using chiral
Lewis acid catalyst, Ti-(2R,3R)-TADDOLate 4b.11 The DeA reaction of
diene 1 (2 equiv) with dienophile 2 (1 equiv) was carried out in
dichloromethane at 0 ꢀC for 24 h using 30 mol % of catalyst 4b and
Scheme 1. DeA reaction of 1 and (4S)-2 in the presence of Lewis acid.
Table 1
DeA reaction of 1 and (4S)-2 {or (4R)-2} in the presence of Lewis acid
Entry
Diene
(mol equiv)
Dienophile
(mol equiv)
Lewis acid
(mol equiv)
Yielda/%
endo-3
% de of
endo-3b
ꢀ
molecular sieves 4 A. A clean reaction proceeded to afford exclu-
sively the endo-cycloadduct (7S)-6 in 97% yield with 10% ee (Table 2,
1
2
3
4
5
6
7
8
1 (2)
1 (2)
1 (3)
1 (2)
1 (3)
1 (2)
1 (2)
1 (2)
(4S)-2 (1)
(4S)-2 (1)
(4S)-2 (1)
(4S)-2 (1)
(4S)-2 (1)
(4S)-2 (1)
(4R)-2 (1)
(4R)-2 (1)
Ti(i-PrO)2Cl2 (2)
ZrCl4 (1)
ZrCl4 (1)
HfCl4 (1)
HfCl4 (1)
Sc(OTf)3 (1)
Ti(i-PrO)2Cl2 (2)
Sc(OTf)3 (1)
99
63 (40S)
48 (40S)
57 (40S)
59 (40S)
43 (40S)
52 (40S)
58 (40R)
54 (40R)
42 (24)
72 (10)
73 (21)
94
99
99
Table 2
DeA reaction of 1 and 5 using chiral Lewis acid catalyst 4b
99
a
Isolated yield. Recovery of (4S)-2 is shown in parentheses.
Diastereomeric excess (% de) was determined by HPLC analysis using a TOSOH
b
TSK-GEL Silica-60; 5% 2-propanol/n-hexane, flow rate 0.8 mL/min, 254 nm,
tR¼18 min (minor), 28 min (major).
The DeA reaction of 1,2-dihydropyridine 1 (2 equiv) and (4S)-2
(1 equiv) using 2 equiv of Ti(i-PrO)2Cl2 was carried out in
dichloromethane at 0 ꢀC for 24 h to afford the cycloaddition product
endo-(40S)-3 in 99% yield with 63% de and the product was only
endo isomer (Table 2, entry 1). In the DeA reaction of 1 and (4S)-2
using 1 equiv of ZrCl4, only endo-(40S)-3 was obtained in 42% yield
with 48% de and the recovery of (4S)-2 was 24% yield (entry 2).
However, in the DeA reaction of 1 (3 equiv) and (4S)-2 using
1 equiv of ZrCl4, the yield of endo-(40S)-3 increased to 72% yield
with 57% de (entry 3). As a result, the chemical yield of endo-(40S)-3
in the DeA reaction of 1 and (4S)-2 was good to high, however, the
diastereoselectivity of endo-(40S)-3 was moderate (from 43% de to
63% de). Next, the reaction of 1,2-dihydropyridine 1 and (4R)-2,
Entry
Ti-TADDOLate 4b
(mol equiv)
Solvent
Yielda/% 6
% ee of
endo-6b
1
2
3
4
5
4b (0.3)
4b (0.3)
4b (0.3)
4b (0.3)
4b (0.3)
CH2Cl2
Toluene
Mesitylene
Hexylbenzene
Toluene/hexane (2:1)
97
78
85
94
98
10 (7S)
70 (7S)
67 (7S)
68 (7S)
73 (7S)
a
Isolated yield.
b
Enantiomeric excess (% ee) was determined by HPLC analysis using a Daicel
CHRALPAK AD column; 25% 2-propanol/n-hexane, flow rate 0.5 mL/min, 254 nm,
tR¼34.7 min (minor), 55.9 min (major).

1776
C. Seki et al. / Tetrahedron 68 (2012) 1774e1781
Table 4
entry 1). The preferable solvents for this cycloaddition were alkyl-
benzene, such as toluene. The DeA reaction of 1 (2 equiv) with 5
(1 equiv) using catalyst 4b (0.3 equiv) in toluene was carried out at
Solvent effect on diastereoselectivity of endo-3 in the DeA reaction of 1 and (4S)-2
Entry
Ti-TADDOLate
4b (mol equiv)
Solvent
Yielda/% 3
% de of
endo-3b
0
ꢀC for 24 h to give the cycloaddition product endo-(7S)-6 in 78%
1
2
3
4
5
4b (0.3)
4b (0.3)
4b (0.3)
4b (0.3)
4b (0.3)
CH2Cl2
Toluene
Mesitylene
Toluene/hexane (1:1)
Toluene/hexane (2:1)
99
99
97
99
98
66 (40S)
92 (40S)
93 (40S)
84 (40S)
89 (40S)
yield with 70% ee (Table 2, entry 2).
We examined the above DielseAlder reaction in several different
solvents in order to see how the coordinating properties of the sol-
vent would affect yield and enantioselectivity of endo-(7S)-6 (Table
2). The DielseAlder reaction was highly influenced by solvent as
shown in Table 2; the chemical yield and enantioselectivity of endo-
(7S)-6 were as follows: in CH2Cl2 (97% yield,10% ee) (Table 2, entry 1),
in toluene (78% yield, 70% ee) (entry 2). The best result was obtained
in the solvent of toluene/hexane (2:1) (98% yield, 73% ee) (entry 5).
The absolute stereochemistry of the endo-6 was established as
(1S,4R,7S) by comparing the sign of the optical rotation with the lit-
a
Isolated yield.
b
Diastereomeric excess (% de) was determined by HPLC analysis using a TOSOH
TSK-GEL Silica-60; 5% 2-propanol/n-hexane, flow rate 0.8 mL/min, 254 nm,
tR¼18 min (minor), 28 min (major).
of 1 (2 equiv) with (4S)-2 (1 equiv) using 0.3 equiv of Ti-(2R,3R)-
TADDOLate 4b was carried out in a solvent at 0 ꢀC for 24 h to give the
cycloaddition product endo-(40S)-3. The reactivity of the DeA re-
action was highly influenced by solvent as shown in Table 4; the
chemical yields of endo-(4S0)-3 were high (97e99%), however, there
was a large difference in the diastereoselectivity of endo-(40S)-3 be-
tween dichloromethane (66% de) and toluene (92% de) (Table 4,
entries 1 and 2). The best solvent was found in the Table 2 (toluene/
hexane) and Table 4 (toluene and mesitylene), nevertheless, CH2Cl2
was used in Table 1. This solvent effect as shown in Table 4 is similar
to the results as shown in Table 2. It was reported by Narasaka et al.
that the enantioselectivity of cycloaddition product changes with
solvent when the DeA reaction of N-acryloyl-1,3-oxazolidin-2-one
derivatives and butadiene was investigated in the presence of Ti-
(2R,3R)-TADDOLate 4b as a catalyst.11 As the reason of this solvent
effect, it was estimated that the diastereoselectivity of this reaction is
dependent on the donor and acceptor ability of the solvent.12 In
solvent having large acceptor number, such as dichloromethane, the
diastereomeric excess of endo-(40S)-3 is lower (66% de) than that in
toluene (92% de). That is, to attain high chemical yield and diaster-
eoselectivity, it is necessary to carry out the reaction in a solvent
having small donor and acceptor numbers, which means that the
molecular interaction between the solvent and the titanium complex
with a dienophile should be minimized. When the reaction of 1 and
(4S)-2 was investigated in mesitylene in the presence of Ti-(2R,3R)-
TADDOLate 4b, the diastereoselectivity of endo-(40S)-3 (93% de) was
similar value as that of the reaction in toluene (92% de). For the aim of
decreasing acceptor number of solvent, the reaction in mixed solvent,
such as toluene and hexane was attempted, however, the diaster-
eoselectivity of endo-(40S)-3 was 84% de or 89% de (entries 4 and 5).
erature value of (7R)-benzyl ester 7 {lit.,2a
½
a 2D4
ꢂ
ꢁ59.92 (c 2.52, CHCl3),
97% ee} as follows: the reaction of the endo-6 (½a D24
þ76.7 (c 1.42,
ꢂ
CHCl3); 67% ee) with benzyl alcohol using n-BuLi as a base (PhCH2OLi)
in THF at 0 ꢀC afforded the corresponding (7S)-benzyl ester 7 {½a 2D4
ꢂ
þ63.9 (c 1.07, CHCl3)} in good yield (83%) (see Experimental section).
2.4. DielseAlder reaction of 1-(phenoxycarbonyl)-1,2-
dihydropyridine 1 with chiral dienophile 2 using Ti-(2R,3R)-
TADDOLate catalyst 4
As shown in Scheme 3, the DeA reaction of 1 (2 equiv) with (4S)-
2 (1 equiv) using 0.5 equiv of Ti-(2R,3R)-TADDOLate 4b in toluene
was carried out at 0 ꢀC for 24 h to give the cycloaddition product
endo-(40S)-3 in 99% yield with 90% de (Table 3, entry 3). Using of
0.3 equiv of 4b, the yield of endo-(40S)-3 was 99% and the di-
astereomeric excess was 92% de {½a D24
ꢁ58.3 (c 0.50, CHCl3)} (entry
ꢂ
2). Since the DeA reaction of 1 with (4S)-2 using 0.1 equiv of 4b
proceeded slowly, the reaction time was extended to 48 h to give
the product endo-(40S)-3 in 83% yield with 87% de and the recovery
of (4S)-2 was 14% yield (entry 1). In the case of using 0.1 equiv of 4b
the yield and the diastereoselectivity of (40S)-3 were decreased.
Therefore, the best quantity of catalyst was 0.3 equiv.
2.5. Determination of absolute stereochemistry of
cycloaddition product 3
Scheme 3. The DeA reaction of 1 and (4S)-2 using Ti-(R,R)-TADDOLate catalyst 4b.
The absolute stereochemistry of the endo-(40S)-3 was estab-
lished as (1R,4S,7R) by comparing the sign of the optical rotation
Table 3
Effect of catalyst quantity in the DeA reaction of 1 and (4S)-2
Yielda/% 3
% de of endo-3b
with the literature value of (7R)-benzyl ester 7 {lit.,2a
[
a
]
D ꢁ59.92 (c
Entry
Ti-TADDOLate
4b (mol equiv)
Time/h
2.52, CHCl3), 97% ee} as follows: the reaction of the endo-(40S)-3
ꢂ
(½a 2D4
ꢁ65.6 (c 1.00, CHCl3); 97% de) with benzyl alcohol using n-
1
2
3
4b (0.1)
4b (0.3)
4b (0.5)
48
24
24
83 (14)
99
99
87 (40S)
92 (40S)
90 (40S)
BuLi as a base (PhCH2OLi) in THF at 0 ꢀC afforded the corresponding
(7R)-benzyl ester 7 {½a D24
ꢁ81.4 (c 0.57, CHCl3)} in moderate yield
ꢂ
a
Isolated yield. Recovery of (4S)-2 is shown in parentheses.
Diastereomeric excess (% de) was determined by HPLC analysis using a TOSOH
(65%) (Scheme 4).
b
TSK-GEL Silica-60; 5% 2-propanol/n-hexane, flow rate 0.8 mL/min, 254 nm,
tR¼18 min (minor), 28 min (major).
Then, we investigated the solvent effect of the DeA reaction of
1,2-dihydropyridine 1 (2 equiv) and (4S)-2 (1 equiv) using 0.3 equiv
of Ti-(2R,3R)-TADDOLate 4b at 0 ꢀC for 24 h (Table 4).
In order to improve the diastereoselectivity of the cycloaddition
product endo-(40S)-3, the DeA reaction of 1 with (4S)-2 was
examined in various solvents in the presence of 0.3 equiv of
Scheme 4. Determination of absolute configuration of (40S)-3.
ꢀ
Ti-(2R,3R)-TADDOLate 4b and molecular sieves 4 A. The DeA reaction

C. Seki et al. / Tetrahedron 68 (2012) 1774e1781
1777
On the other hand, the absolute configuration of isoquinuclidine
derivative endo-(40R)-3, which was obtained from the reaction of 1
and (4R)-2 in the presence of Ti-TADDOLate 4, has been established
to be (1S,4R,7S).
give (7R)-3 in high yield with 92% de (Table 2, entries 1e3), while
the combination of Ti-(2R,3R)-TADDOLate 4 and (4R)-2 was a mis-
matched pair to afford (7S)-3 in moderate to good yield with 70% de
(entries 4e6).
Based on the X-ray structure of complex of Ti-(2R,3R)-TAD-
DOLate 4a (R1¼R2¼CH3) with N-[(E)-cinnamoyl]-1,3-oxazolidin-2-
2.6. Matchemismatch effect on diastereoselectivity of 3 in
the DeA reaction of 1 and (4S)-2 {or (4R)-2} using Ti-(2R,3R)-
TADDOLate catalyst 4 {or Cu(OTf)2/(4S,40S)-bisoxazoline
catalyst 8}
one reported by Jf
rgensen et al.,13 we considered the reaction
mechanism of the asymmetric DeA reaction of 1,2-
dihydropyridine 1 and (4S)-2 using Ti-(2R,3R)-TADDOLate 4b
(R1¼Ph, R2¼CH3) (Fig. 2). As shown in Fig. 2, in the complex of
matched pair {4b and (4S)-2} 1,2-dihydropyridine 1 can approach
predominantly from the si face to give (7R)-3 (up to 92% de) since
the re face of the acryloyl group on the dienophile is shielded by
the benzyl group of dienophile (4S)-2 and the phenyl group at
pseudoequatorial position of Ti-(2R,3R)-TADDOLate 4b. On the
other hand, in the complex of mismatched pair {4b and (4R)-2}
1,2-dihydropyridine 1 can approach from the re face to give (7S)-3
(up to 70% de) since the si face of the acryloyl group on the
dienophile is shielded by the benzyl group of dienophile (4R)-2 in
the complex of Ti-(2R,3R)-TADDOLate 4b. In the complex of mis-
matched pair {4b and (4R)-2}, the re face of the acryloyl group on
the dienophile is also shielded by phenyl group at pseudoequa-
torial position of Ti-(2R,3R)-TADDOLate 4b. Consequently, it is
assumed that both the chemical yield and the diastereoselectivity
of (7S)-3 are lower than those of (7R)-3 produced from the
matched pair {4b and (4S)-2}.
As shown in Scheme 5, in order to test the possibility of
matchemismatch effect on the diastereoselectivity of DeA cyclo-
addition product endo-3, the reaction of 1,2-dihydropyridine 1 and
(4S)-2 {or (4R)-2} in the presence of Ti-(2R,3R)-TADDOLate 4 was
carried out in toluene at 0 ꢀC for 24 h and the results are summa-
rized in Table 5.
On the other hand, Cu(OTf)2/(4S,40S)-bis(oxazoline) catalysts 8
were chosen because of the abundance of literature data for their
catalysis of DielseAlder reactions involving oxazolidinones and
related substrates.14 Ready availability of various bis(oxazoline) li-
gands with differing steric volumes allowed for the possibility to
assess the importance of the chiral ligand size relative to the
dienophile (4R)-2 in controlling diastereoselection. The DeA re-
action of 1 (2 equiv) and (4R)-2 (1 equiv) using 30 mol % of
Cu(OTf)2/(4S,40S)-bisoxazoline catalyst (CH3-box ligand) 8a as
a chiral Lewis acid catalyst afforded endo-(7S)-3 in 89% yield with
Scheme 5. Asymmetric DeA reaction of 1,2-dihydropyridine 1 with (4S)-2 {or (4R)-2}
using Ti-(2R,3R)-TADDOLate 4.
Table 5
Matchemismatch effect on diastereoselectivity of 3 in the DeA reaction of 1 and
(4S)-2 {or (4R)-2} using Ti-TADDOLate 4
Entry Diene
(mol equiv) (mol equiv) (mol equiv)
Dienophile Ti-TADDOLate 4 Product Yielda/% % de of
endo-3 endo-3b
1
2
3
4
5
6
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
(4S)-2 (1)
(4S)-2 (1)
(4S)-2 (1)
(4R)-2 (1)
(4R)-2 (1)
(4R)-2 (1)
4a (0.3)
4b (0.3)
4c (0.3)
4a (0.3)
4b (0.3)
4c (0.3)
(7R)-3
(7R)-3
(7R)-3
(7S)-3
(7S)-3
(7S)-3
96
99
99
87
92
88
55 (22) 70
73 (15) 68
51 (36) 68
a
Isolated yield. Recovery of (4R)-2 is shown in parentheses.
Diastereomeric excess (% de) was determined by HPLC analysis using a TOSOH
b
TSK-GEL Silica-60; 5% 2-propanol/n-hexane, flow rate 0.8 mL/min, 254 nm,
tR¼18 min (minor), 28 min (major).
In the DeA reaction of 1 (2 equiv) and (4S)-2 (1 equiv) using
0.3 equiv of Ti-(R,R)-TADDOLate 4a (R1¼R2¼CH3), only endo-(7R)-3
was obtained in 96% yield with 87% de (Table 5, entry 1). In the DeA
reaction of 1 and (4S)-2 using 0.3 equiv of 4b (R1¼Ph, R2¼CH3),
endo-(7R)-3 was obtained in 99% yield with 92% de {½a D24
ꢁ58.3 (c
ꢂ
0.50, CHCl3)} (entry 2). The DeA reaction of 1 and (4S)-2 using
0.3 equiv of 4c (R1¼R2¼Ph) afforded endo-(7R)-3 in 99% yield with
88% de (entry 3). However, in the DeA reactions of 1 (2 equiv) and
(4R)-2 (1 equiv) using 0.3 equiv of 4aec, both the chemical yield
and the diastereoselectivity [70% de {½a D24
þ40.9 (c 0.85, CHCl3)}] of
ꢂ
endo-(7S)-3 are lower than those of endo-(7R)-3 produced from the
matched pair {(4S)-2 and 4} (entries 4e6). As a result, the combi-
nation of Ti-(2R,3R)-TADDOLate 4 and (4S)-2 was a matched pair to
Fig. 2. Plausible complex formation of Ti-(2R,3R)-TADDOLate catalyst 4b and (4S)-2
{or (4R)-2}.

1778
C. Seki et al. / Tetrahedron 68 (2012) 1774e1781
95% de in dichloromethane at 0 ꢀC for 24 h (Fig. 3). The endo-(7S)-3
was obtained in 87% yield with 97% de by DielseAlder reaction of 1
(2 equiv) with (4R)-2 (1 equiv) using 30 mol % of Cu(OTf)2/(4S,40S)-
bis(oxazoline) catalyst (i-C3H7-box ligand) 8b as a chiral catalyst.
trifluoromethanesulfonate, indium chloride, phenyl chloroformate,
toluene, and mesitylene were purchased from Wako Pure Chemical
Ind. Pyridine, tetrahydrofuran, dichloromethane, hexane, ethanol,
2-propanol, diethyl ether, triethylamine, and sodium borohydride
were purchased from Kanto Kagaku Reagent Division. Zirconium
ꢀ
tetrachloride and molecular sieves 4 A were purchased from Merck
Co. Chiral (S,S)-bis(oxazoline) ligands 8a (CH3-box) and 8b (i-C3H7-
box) were prepared according to method described by Ishihara
et al.16 1H NMR spectra and 13C NMR spectra were recorded at
270 MHz and 67.8 MHz on a JEOL JNM-EX 270 FT NMR SYSTEM and
500 MHz and 125 MHz on a JEOL JNM-ECA in CDCl3 using tetra-
methylsilane as an internal standard. Specific rotations were
recorded at the sodium D line with a polarimeter at room tem-
perature. The enantiomeric excess (ee) or diastereomeric excess
(de) of the cycloaddition products was determined by high per-
formance liquid chromatography (HPLC) using the CHIRALPAK AD-
H (25 cm) or TOSOH TSK-GEL Silica-60 (25 cm).
4.2. General procedure for asymmetric cycloaddition of
1-(phenoxycarbonyl)-1,2-dihydropyridine 1 with dienophile 2
in the presence of Lewis acid (Table 1)
An oven-dried round-bottom flask containing a stir bar were
charged dichloromethane (3 mL) solution of (4S)-2 (116 mg,
0.50 mmol), molecular sieves 4 A (200 mg) and Ti(i-PrO)2Cl2
ꢀ
Fig. 3. Plausible complex formation of Cu(II)/(4S,40S)-bis(oxazoline) catalyst 8b and
(4R)-2: matched pair.
(237 mg, 1.0 mmol) at room temperature and the solution was
stirred for 30 min under nitrogen. Then the solution was cooled to
0
ꢀC, and the dichloromethane (3 mL) solution of 1-(phenox-
The results with the copper Lewis acid catalyst 8 suggested that
amplification of diastereoselectivity of (7S)-3 was excellent for
Lewis acid with square planar geometry. It is well established that
Cu(II)/(4S,40S)-bis(oxazoline) catalysts 8 react via distorted square
planar geometries upon complexation to bidentate substrates.15 In
the reaction, the choice of the combination of Cu(II)/(4S,40S)-
bis(oxazoline) 8 and dienophile (4S)-2 {or (4R)-2} is also important.
ycarbonyl)-1,2-dihydropyridine 1 (201 mg, 1.0 mmol) was added
and the solution was stirred at 0 ꢀC for 24 h. The reaction was
stopped by addition of saturated NaHCO3 solution and water and
the product was extracted with chloroform. The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (20%
ethyl acetate in hexane), and endo-(40S)-3 was obtained in 99% yield
(214 mg, 0.49 mmol) with 63% de Diastereomeric excess (% de) of
endo-(40S)-3 was determined by HPLC analysis using a TOSOH TSK-
GEL Silica-60; eluent, 5% 2-propanol/n-hexane; flow rate, 0.8 mL/
min: 254 nm, retention time, tR (minor)¼18 min, tR (major)¼
28 min. The reaction conditions, chemical yields, and optical yields
are shown in Table 1.
In the complex of
a matched pair {8b and (4R)-2} 1,2-
dihydropyridine 1 can approach from the re face to give (7S)-3
(up to 97% de) since the si face of the acryloyl group on the dien-
ophile is shielded by the benzyl group of dienophile (4R)-2 and C-4
iso-propyl substituents of bisoxazoline in the complex of Cu(II)/
(4S,40S)-bis(oxazoline) 8b (Fig. 3).
4.2.1. Chiral isoquinuclidine derivative endo-(40S)-3 (63% de). Yield
3. Conclusion
214 mg, 99%; ½a 2D4
ꢂ
ꢁ42.6 (c 0.50, CHCl3). 1H NMR [ppm] (500 MHz,
CDCl3, 20 ꢀC):
d 1.54e1.59 (0.5H, m), 1.72e1.77 (0.5H, m), 2.14e2.19
In conclusion, we have accomplished the synthesis of chiral
isoquinuclidine derivative endo-(7R)-3 (up to 92% de) {or endo-
(7S)-3 (up to 97% de)} by DielseAlder reaction of 1,2-
dihydropyridine 1 with chiral oxazolidinone dienophile (4S)-2 {or
(4R)-2} using Ti-(2R,3R)-TADDOLate 4 {or Cu(II)/(4S,40S)-bis(ox-
azoline) 8} as a chiral Lewis acid catalyst, respectively. In the DeA
reaction, the combination of Ti-(2R,3R)-TADDOLate 4 {or Cu(II)/
(4S,40S)-bis(oxazoline) 8} and chiral dienophile (4S)-2 {or (4R)-2}
affected the chemical yield and the diastereoselectivity of the chiral
isoquinuclidine derivative endo-(7R)-3 {or endo-(7S)-3}.
(0.5H, m), 2.31e2.36 (0.5H, m), 2.71 (1H, dd, J¼13.3, 9.8 Hz), 2.89e2.93
(1H, m), 3.09 (0.5H, td, J¼10.63, 2.6 Hz), 3.22 (0.5H, td, J¼10.4, 2.5 Hz),
3.29 (1H, d, J¼13.3 Hz), 3.40 (1H, dd, J¼10.6, 1.9 Hz), 3.56 (1H, dd,
J¼10.3, 1.9 Hz), 4.13e4.16 (2H, m), 4.21e4.29 (1H, m), 4.52e4.60 (1H,
m), 5.17e5.19 (0.5H, m), 5.24e5.26 (0.5H, m), 6.48e6.51 (1H, m),
6.54e6.62 (1H, m), 7.12e7.14 (1H, m), 7.16e7.21 (4H, m), 7.24e7.28
(1H, m), 7.30e7.37 (4H, m); 13C NMR [ppm] (125 MHz, CDCl3, 20 ꢀC):
d
28.58, 30.84, 37.79, 45.17, 46.66, 47.75, 55.60, 66.32, 121.81, 125.22,
127.42, 129.04, 129.23, 129.26, 129.38, 129.42, 130.73, 132.45, 133.57,
134.86, 135.20, 151.32, 152.65, 153.44, 173.01.
4. Experimental section
4.2.2. Chiral isoquinuclidine derivative endo-(40R)-3 (58% de). Yield
4.1. General information
214 mg, 99%; ½a 2D4
ꢂ
þ30.6 (c 0.57, CHCl3). 1H NMR [ppm] (500 MHz,
CDCl3, 20 ꢀC):
d 1.54e1.59 (0.5H, m), 1.72e1.77 (0.5H, m), 2.14e2.19
(4S)-4-Benzyl-2-oxazolidin-2-one, (4R)-4-benzyl-2-oxazolidin-
(0.5H, m), 2.31e2.36 (0.5H, m), 2.71 (1H, dd, J¼13.3, 9.8 Hz),
2.89e2.93 (1H, m), 3.09 (0.5H, td, J¼10.63, 2.6 Hz), 3.22 (0.5H, td,
J¼10.4, 2.5 Hz), 3.29 (1H, d, J¼13.3 Hz), 340 (1H, dd, J¼10.6, 1.9 Hz),
3.56 (1H, dd, J¼10.3, 1.9 Hz), 4.13e4.16 (2H, m), 4.21e4.29 (1H, m),
4.52e4.60 (1H, m), 5.17e5.19 (0.5H, m), 5.24e5.26 (0.5H, m),
6.48e6.51 (1H, m), 6.54e6.62 (1H, m), 7.12e7.14 (1H, m), 7.16e7.21
(4H, m), 7.24e7.28 (1H, m), 7.30e7.37 (4H, m); 13C NMR [ppm]
2-one,
(2R,3R)-2,3-O-isopropylidene-1,1,4,4-tetraphenyl-1,2,3,4-
butanetetrol, (2R,3R)-2,3-O-(1-phenylethylidene)-1,1,4,4-tetraphenyl-
1,2,3,4-butanetetrol, dichlorotitanium diisopropoxide, acrylic acid,
acryloyl chloride, dimethyl
and copper(II) trifluoromethanesulfonate were purchased from
L
-(þ)-tartrate, trimethyl ortho-formate,
Tokyo Chemical Ind. Co. Hafnium tetrachloride, scandium

C. Seki et al. / Tetrahedron 68 (2012) 1774e1781
1779
(125 MHz, CDCl3, 20 ꢀC):
d 28.58, 30.84, 37.79, 45.17, 46.66, 47.75,
55.60, 66.32, 121.81, 125.22, 127.42, 129.04, 129.23, 129.26, 129.38,
129.42, 130.73, 132.45, 133.57, 134.86, 135.20, 151.32, 152.65, 153.44,
173.01.
4.3. General procedure for asymmetric cycloaddition of
1-(phenoxycarbonyl)-1,2-dihydropyridine 1 with N-acryloy-
loxazolidin-2-one 5 using chiral titanium complex Ti-(2R,3R)-
TADDOLate 4b (Table 2)
An oven-dried round-bottom flask containing a stir bar were
charged toluene/hexane (2:1) (6 mL) solution, powdered molecular
4.4.1. Benzyl ester endo-(7S)-7. Yield 162.2 mg, 83%; ½a D24
ꢂ
þ63.9 (c
sieves 4 A (230 mg), Ti(i-PrO)2Cl2 (35.5 mg, 0.15 mmol), and
1.07, CHCl3; 67% ee); lit.2a benzyl ester endo-(7R)-7: ½a 2D4
ꢂ
ꢁ59.92 (c
ꢀ
(2R,3R)-TADDOL (R1¼Ph, R2¼CH3) (79.3 mg, 0.15 mmol) at room
temperature and the solution was stirred for 30 min under nitro-
gen. When to the solution was added dienophile 5 (116 mg,
0.50 mmol) the color of the solution changed into yellow and
2.52, CHCl3; 97% ee). 1H NMR [ppm] (500 MHz, CDCl3, 20 ꢀC):
d
1.92e1.99 (2H, m), 2.91 (1H, br s), 3.04 (0.5H, td, J¼10.6, 2.4 Hz),
3.16 (0.5H, d, J¼10.2 Hz), 3.22e3.26 (1H, m), 3.35 (0.5H, dd, J¼10.6,
2.1 Hz), 3.49 (0.5H, dd, J¼10.2, 2.1 Hz), 5.06e5.16 (2H, m), 5.23e5.28
(1H, m), 6.33e6.38 (1H, m), 6.47e6.52 (1H, m), 7.09e7.17 (2H, m),
7.18e7.21 (1H, m), 7.29e7.37 (7H, m); 13C NMR [ppm] (125 MHz,
the solution cooled to
0
ꢀC. Then 1-(phenoxycarbonyl)-1,2-
dihydropyridine 1 (201 mg, 1.00 mmol) was added and the solu-
tion was stirred at 0 ꢀC for 24 h. The reaction was stopped by ad-
dition of saturated NaHCO3 solution and the product was extracted
with chloroform. The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (20% ethyl acetate in hexane),
and endo-6 was obtained in 98% yield (173 mg, 0.49 mmol) with
73% ee. Enantiomeric excess (% ee) was determined by HPLC anal-
ysis using a Daicel CHIRALPAK AD-H column; eluent, 25% 2-
propanol/n-hexane; flow rate, 0.8 mL/min; 254 nm; retention
time, tR (minor)¼34.7 min, tR (major)¼55.9 min. The reaction
conditions, chemical yields, and optical yields are shown in Table 2.
CDCl3, 20 ꢀC):
d 25.93, 30.60, 43.81, 46.91, 47.52, 66.56, 121.65,
121.72, 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.
4.5. General procedure for cycloaddition of
1-(phenoxycarbonyl)-1,2-dihydropyridine 1 with chiral
dienophile 2 in the presence of Ti-(2R,3R)-TADDOLate 4 (Tables
3e5)
An oven-dried round-bottom flask containing a stir bar was
charged with toluene (3 mL) solution of (2R,3R)-TADDOL (R1¼Ph,
2
ꢀ
R ¼Me) (79 mg, 0.15 mmol), dry powdered molecular sieves 4 A
(200 mg), and Ti(i-PrO)2Cl2 (36 mg, 0.15 mmol) at room temperature
and the solution was stirred for 1 h under nitrogen. Then (4S)-2
(116 mg, 0.50 mmol) was added and the solutionwas stirred at room
temperature for 30 min, and the solution was cooled to 0 ꢀC. To this
solution was added the toluene (2 mL) solution of 1-(phenox-
ycarbonyl)-1,2-dihydropyridine 1 (201 mg, 1.0 mmol) and the so-
lution was stirred at 0 ꢀC for 24 h. Then saturated NaHCO3 solution
and water were added and the product was extracted with chlo-
roform. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was purified
by column chromatography on silica gel (20% ethyl acetate in hex-
ane), and endo-(40S)-3 was obtained in 99% yield (214 mg,
0.49 mmol) with 92% de Diastereomeric excess (% de) of endo-(40S)-
3 was determined by HPLC analysis using a TOSOH TSK-GEL Silica-
60; 5% 2-propanol/hexane; flow rate, 0.8 mL/min, 254 nm; retention
time, tR (minor)¼18 min, tR (major)¼28 min. The reaction condi-
tions, chemical yields, and optical yields are shown in Tables 3e5.
4.3.1. Chiral isoquinuclidine derivative endo-(7S)-6 (73% ee). Yield
173 mg, 98%; ½a 2D4
ꢂ
þ86.2 (c 1.00, CHCl3). 1H NMR [ppm] (500 MHz,
CDCl3, 20 ꢀC):
d
1.56 (0.5H, ttd, J¼13.0, 5.6, 2.8 Hz), 1.71 (0.5H, ttd,
J¼13.0, 5.3, 2.8 Hz), 2.23 (0.5H, ddd, J¼12.9, 10.1, 2.7 Hz), 2.39 (0.5H,
ddd, J¼13.0, 10.3, 2.6 Hz), 2.89e2.92 (1H, m), 3.09 (0.5H, td, J¼10.7,
2.6 Hz), 3.22 (0.5H, td, J¼10.4, 2.6 Hz), 3.41 (0.5H, dd, J¼10.6,
2.0 Hz), 3.56 (0.5H, dd, J¼10.3, 1.9 Hz), 3.90e4.03 (2H, m), 4.15e4.19
(0.5H, m), 4.23e4.27 (0.5H, m), 4.37e4.46 (2H, m), 5.10e5.12 (0.5H,
m), 5.18e5.20 (0.5H, m), 6.46e6.50 (1H, m), 6.52e6.60 (1H, m),
7.11e7.13 (1H, m), 7.15e7.20 (2H, m), 7.33e7.37 (2H, m); 13C NMR
[ppm] (125 MHz, CDCl3, 20 ꢀC):
d 27.66, 28.60, 30.47, 30.75, 42.55,
42.69, 44.60, 44.78, 46.54, 47.09, 47.15, 62.12, 62.19, 121.75, 121.84,
125.16, 125.20, 129.18, 129.21, 130.89, 132.45, 133.43, 134.61, 151.24,
151.25, 152.85, 152.87, 152.89, 153.37, 154.85, 166.19, 172.87, 173.01.
4.4. Conversion of endo-(40S)-6 to benzyl ester (7S)-7
An oven-dried round-bottom flask containing a stir bar was
charged THF (4 mL) solution of benzyl alcohol (0.10 mL, 1.00 mmol)
and to the solution was added n-BuLi (1.57 M in hexane, 0.50 mL,
0.78 mmol) at ꢁ78 ꢀC under nitrogen and the solution was stirred
for 5 min. Then to this solution was added the solution of endo-6
4.5.1. Chiral isoquinuclidine derivative endo-(40S)-3 (92% de). Yield
214 mg, 99%; ½a 2D4
ꢂ
ꢁ58.3 (c 0.50, CHCl3). 1H NMR [ppm] (500 MHz,
CDCl3, 20 ꢀC):
d 1.54e1.59 (0.5H, m), 1.72e1.77 (0.5H, m), 2.14e2.19
(0.5H, m), 2.31e2.36 (0.5H, m), 2.71 (1H, dd, J¼13.3, 9.8 Hz), 2.89e2.93
(1H, m), 3.09 (0.5H, td, J¼10.63, 2.6 Hz), 3.22 (0.5H, td, J¼10.4, 2.5 Hz),
3.29 (1H, d, J¼13.3 Hz), 3.40 (1H, dd, J¼10.6, 1.9 Hz), 3.56 (1H, dd,
J¼10.3, 1.9 Hz), 4.13e4.16 (2H, m), 4.21e4.29 (1H, m), 4.52e4.60 (1H,
m), 5.17e5.19 (0.5H, m), 5.24e5.26 (0.5H, m), 6.48e6.51 (1H, m),
6.54e6.62 (1H, m), 7.12e7.14 (1H, m), 7.16e7.21 (4H, m), 7.24e7.28
(1H, m), 7.30e7.37 (4H, m); 13C NMR [ppm] (125 MHz, CDCl3, 20 ꢀC):
{½a 2D4
þ76.7 (c 1.42, CHCl3), 67% ee; 178 mg, 0.52 mmol} in THF
ꢂ
(2 mL), and the solution was warmed to 0 ꢀC and stirred for 3 h. The
reaction was quenched with 5 mL of saturated NH4Cl solution and
the product was extracted with chloroform. The combined organic
layers were dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (25% ethyl acetate in hexane), and benzyl
ester endo-(7S)-7 was obtained in 83% yield (162.2 mg, 0.43 mmol).
d
28.58, 30.84, 37.79, 45.17, 46.66, 47.75, 55.60, 66.32, 121.81, 125.22,
127.42, 129.04, 129.23, 129.26, 129.38, 129.42, 130.73, 132.45, 133.57,
134.86, 135.20, 151.32, 152.65, 153.44, 173.01.
The enantiomeric excess (67% ee) of (7S)-benzyl ester 7 {½a D24
þ63.9
ꢂ
(c 1.07, CHCl3)} as shown in the following Scheme was determined
by HPLC analysis using a DAICEL CHIRALPAK AD-H column; eluent,
5% 2-propanol/hexane; flow rate, 0.8 mL/min; 254 nm; retention
time, tR (minor)¼21.1 min, tR (major)¼23.8 min.
4.5.2. Chiral isoquinuclidine derivative endo-(40R)-3 (70% de). Yield
119 mg, 55%; ½a 2D4
ꢂ
þ40.9 (c 0.85, CHCl3). 1H NMR [ppm] (500 MHz,
CDCl3, 20 ꢀC):
d 1.54e1.59 (0.5H, m), 1.72e1.77 (0.5H, m), 2.14e2.19

1780
C. Seki et al. / Tetrahedron 68 (2012) 1774e1781
(0.5H, m), 2.31e2.36 (0.5H, m), 2.71 (1H, dd, J¼13.3, 9.8 Hz), 2.89e2.93
(1H, m), 3.09 (0.5H, td, J¼10.63, 2.6 Hz), 3.22 (0.5H, td, J¼10.4, 2.5 Hz),
3.29 (1H, d, J¼13.3 Hz), 3.40 (1H, dd, J¼10.6, 1.9 Hz), 3.56 (1H, dd,
J¼10.3, 1.9 Hz), 4.13e4.16 (2H, m), 4.21e4.29 (1H, m), 4.52e4.60 (1H,
m), 5.17e5.19 (0.5H, m), 5.24e5.26 (0.5H, m), 6.48e6.51 (1H, m),
6.54e6.62 (1H, m), 7.12e7.14 (1H, m), 7.16e7.21 (4H, m), 7.24e7.28
(1H, m), 7.30e7.37 (4H, m); 13C NMR [ppm] (125 MHz, CDCl3, 20 ꢀC):
obtained in 87% yield (188 mg, 0.435 mmol) with 97% de Di-
astereomeric excess (% de) of endo-(7S)-3 was determined by HPLC
analysis using a TOSOH TSK-GEL Silica-60; 5% 2-propanol/n-hex-
ane; flow rate, 0.8 mL/min, 254 nm; retention time, tR (minor)¼
20 min, tR (major)¼30 min.
4.7.1. Chiral isoquinuclidine derivative endo-(7S)-3 (97% de). Yield
d
28.58, 30.84, 37.79, 45.17, 46.66, 47.75, 55.60, 66.32, 121.81, 125.22,
188 mg, 87%; ½a 2D4
ꢂ
ꢁ65.6 (c 1.00, CHCl3). 1H NMR [ppm] (500 MHz,
127.42, 129.04, 129.23, 129.26, 129.38, 129.42, 130.73, 132.45, 133.57,
134.86, 135.20, 151.32, 152.65, 153.44, 173.01.
CDCl3, 20 ꢀC):
d 1.54e1.59 (0.5H, m), 1.72e1.77 (0.5H, m), 2.14e2.19
(0.5H, m), 2.31e2.36 (0.5H, m), 2.71 (1H, dd, J¼13.3, 9.8 Hz),
2.89e2.93 (1H, m), 3.09 (0.5H, td, J¼10.63, 2.6 Hz), 3.22 (0.5H, td,
J¼10.4, 2.5 Hz), 3.29 (1H, d, J¼13.3 Hz), 3.40 (1H, dd, J¼10.6, 1.9 Hz),
3.56 (1H, dd, J¼10.3, 1.9 Hz), 4.13e4.16 (2H, m), 4.21e4.29 (1H, m),
4.52e4.60 (1H, m), 5.17e5.19 (0.5H, m), 5.24e5.26 (0.5H, m),
6.48e6.51 (1H, m), 6.54e6.62 (1H, m), 7.12e7.14 (1H, m), 7.16e7.21
(4H, m), 7.24e7.28 (1H, m), 7.30e7.37 (4H, m); 13C NMR [ppm]
4.6. Conversion of endo-(40S)-3 to benzyl ester (7R)-7
An oven-dried round-bottom flask containing a stir bar was
charged with THF (2 mL) solution of benzyl alcohol (0.08 mL,
0.8 mmol) and to this solution was added n-BuLi (1.57 M in hexane,
0.4 mL, 0.63 mmol) at ꢁ78 ꢀC under nitrogen and the solution was
stirred for 5 min. Then to this solution was added the solution of
(125 MHz, CDCl3, 20 ꢀC):
d 28.58, 30.84, 37.79, 45.17, 46.66, 47.75,
55.60, 66.32, 121.81, 125.22, 127.42, 129.04, 129.23, 129.26,
129.38, 129.42, 130.73, 132.45, 133.57, 134.86, 135.20, 151.32, 152.65,
153.44, 173.01.
endo-(40S)-3 {½a 2D4
ꢁ65.6 (c 1.00, CHCl3), 97% de; 121 mg,
ꢂ
0.28 mmol} in THF (4 mL), and the solution was warmed to 0 ꢀC and
stirred for 3 h. The reaction was quenched with 10 mL of saturated
NH4Cl solution and the product was extracted with chloroform. The
organic layer was dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (25% ethyl acetate in hexane), and endo-
(7R)-7 was obtained in 78% yield (78.6 mg, 0.22 mmol). The en-
4.8. Preparationof1-(phenoxycarbonyl)-1,2-dihydropyridine18
An oven-dried three necked round-bottom flask containing a stir
bar was charged with pyridine (24.0 g, 303 mmol), ethanol (180 mL),
and NaBH4 (6.0 g,159 mmol) and the mixture were stirred together
at ꢁ78 ꢀC, and then phenyl chloroformate (32.0 g, 204 mmol) was
added slowly to the solution by a dropping funnel for 1 h. The
mixture was stirred at ꢁ78 ꢀC for 24 h. The solution was poured into
ice-water, and the mixture was stirred until the H2 bubble stopped.
The mixture was extracted with diethyl ether (100 mLꢃ3) and the
ether solution was dried over anhydrous sodium sulfate. The or-
ganic layer was filtered and the diethyl ether was removed in vacuo.
The residue was recrystallized from ethanol to give the product 1 as
a white solid in 67% yield (27.50 g, 136.7 mmol). The ratio of 1,2-
dihydropyridine and 1,4-dihydropyridine (97:3) was measured by
antiomeric excess (97% ee) of (7R)-benzyl ester 7 {½a D24
ꢁ81.4 (c
ꢂ
0.57, CHCl3)} as shown in Scheme 4 was determined by HPLC
analysis using a DAICEL CHIRALPAK AD-H column; eluent, 5% 2-
propanol/hexane; flow rate, 0.8 mL/min, 254 nm; retention time,
tR (minor)¼28.7 min, tR (major)¼32.0 min.
4.6.1. Benzyl ester endo-(7R)-7. ½a D24
ꢁ81.4 (c 0.57, CHCl3; 97% ee);
ꢂ
Yield 78.6 mg, 78%; lit.2a
½
a 2D4
ꢂ
ꢁ59.92 (c 2.52, CHCl3; 97% ee). 1H
NMR [ppm] (500 MHz, CDCl3, 20 ꢀC):
d 1.92e1.99 (2H, m), 2.91 (1H,
br s), 3.04 (0.5H, td, J¼10.6, 2.4 Hz), 3.16 (0.5H, d, J¼10.2 Hz),
3.22e3.26 (1H, m), 3.35 (0.5H, dd, J¼10.6, 2.1 Hz), 3.49 (0.5H, dd,
J¼10.2, 2.1 Hz), 5.06e5.16 (2H, m), 5.23e5.28 (1H, m), 6.33e6.38
(1H, m), 6.47e6.52 (1H, m), 7.09e7.17 (2H, m), 7.18e7.21 (1H, m),
1H NMR (
d 4.44e4.59 and 2.89 ppm).
4.8.1. 1-(Phenoxycarbonyl)-1,2-dihydropyridine 1. Yield 27.50 g,
67%; white solid (ethanol), mp 64e66 ꢀC; 1H NMR [ppm]
7.29e7.37 (7H, m); 13C NMR [ppm] (125 MHz, CDCl3, 20 ꢀC):
d 25.93,
(270 MHz, CDCl3, 25 ꢀC):
d
4.45 (1H, q, J¼3.8, 2.0 Hz), 4.59 (1H, br
30.60, 43.81, 46.91, 47.52, 66.56, 121.65, 121.72, 125.25, 128.07,
128.16, 128.21, 128.51, 128.55, 129.17, 129.21, 130.54, 135.69, 151.22,
s), 5.22e5.31 (1H, m), 5.59e5.62 (1H, m), 5.88e5.93 (1H, m), 6.84
(1H, dd, J¼20.0, 7.7 Hz), 7.13 (2H, d, J¼7.6 Hz), 7.22 (1H, t,
J¼8.2 Hz), 7.38 (2H, t, J¼7.8 Hz); 13C NMR (CDCl3, 67.8 MHz, 25 ꢀC):
153.58, 153.61, 172.33. (7S)-benzyl ester 7 (99% ee): ½a D24
þ90.4 (c
ꢂ
0.71, CHCl3); ½a D24
þ74.46 (c 0.39, DMSO); (7R)-benzyl ester 7 (97%
ꢂ
d
43.78, 105.82, 119.47, 121.54 (2C), 121.82, 125.35, 125.67, 126.06,
ee): lit.2b
[a
]
D ꢁ59.92 (c 2.52, DMSO).
129.36 (2C), 150.81.
4.7. General procedure for cycloaddition of 1-(phenoxy-
carbonyl)-1,2-dihydropyridine 1 with chiral dienophile 2 in
the presence of Cu(OTf)2/(4S,40S)-bis(oxazoline) 8 (Fig. 3)
4.9. Preparation of N-acryloyl-4-benzyloxazolidin-2-one 29
An oven-dried three necked round-bottom flask containing
a stir bar was charged with solution of acrylic acid (1.88 g,
26 mmol), triethylamine (5.06 g, 50 mmol), and THF (100 mL) and
to this solution was added acryloyl chloride (2.17 g, 24 mmol) at
ꢁ20 ꢀC. A white solid was formed instantaneously. The mixture was
stirred at ꢁ20 ꢀC for 1 h. Lithium chloride (1.06 g, 25 mmol) was
added, followed by 4-benzyloxazolidin-2-one (3.540 g, 20 mmol).
The mixture was allowed to warm to room temperature and stirred
for 24 h. The reaction was quenched by addition of 0.2 M HCl
(240 mL), and THF was removed in vacuo. The residue was parti-
tioned between ethyl acetate and 0.2 M HCl (60 mL). The organic
layer was washed subsequently with 0.2 M HCl (60 mL), brine
(60 mL), 1 M sodium bicarbonate (60 mL, two times), and brine
(60 mL). The organic solution was then dried over sodium sulfate
and filtered. Ethyl acetate was removed in vacuo, and the white
solid was dissolved in toluene. The toluene solution was filtered
through a silica gel bed, and the white solid was washed with
An oven-dried round-bottom flask containing a stir bar was
charged with dichloromethane (3 mL) solution of (4S,40S)-bis(ox-
azoline) (i-C3H7-box ligand) 8b (40 mg, 0.15 mmol), dry activated
ꢀ
molecular sieves 4 A (230 mg), and Cu(OTf)2 (54 mg, 0.15 mmol) at
room temperature and the solution was stirred for 1 h under ni-
trogen. Then (4R)-2 (116 mg, 0.50 mmol) was added and the solution
was stirred at room temperature for 30 min, and the solution was
cooled to 0 ꢀC. To this solution was added the dichloromethane
(2 mL) solution of 1-(phenoxycarbonyl)-1,2-dihydropyridine 1
(201 mg,1.0 mmol) and the solutionwas stirred at 0 ꢀC for 24 h. Then
saturated NaHCO3 solution and water were added and the product
was extracted with chloroform. The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated under vac-
uum. The residue was purified by flash column chromatography on
silica gel (20% ethyl acetate in hexane), and endo-(7S)-3 was

C. Seki et al. / Tetrahedron 68 (2012) 1774e1781
1781
Alkaloids. Chemistry and Biology; Cordell, G. A., Ed.; Academic: San Diego, 1999;
Vol. 52, pp 197e231; (c) Khana, M. O. F.; Levid, M. S.; Clarkc, C. R.; Ablordep-
peya, S. Y.; Lawd, S.-J.; Wilsone, N. H.; Bornef, R. F. Stud. Nat. Prod. Chem. 2008,
34, 753e787 Total syntheses of Iboga alkaloids via DielseAlder reaction of
a dihydropyridine with a dienophile. (þ)-Ibogamine: (d) Buchi, G.; Coffen, D. L.;
Kocsis, K.; Sonnet, P. E.; Ziegler, F. E. J. Am. Chem. Soc. 1965, 87, 2073e2075; (e)
Buchi, G.; Coffen, D. L.; Kocsis, K.; Sonnet, P. E.; Ziegler, F. E. J. Am. Chem. Soc.
1966, 88, 3099e3109; (f) Ikezaki, M.; Wakamatsu, T.; Ban, Y. J. Chem. Soc., Chem.
Commun. 1969, 88e89 (þ)-Catharanthine; (g) Buchi, G.; Kulsa, P.; Ogasawara,
K.; Rosati, R. L. J. Am. Chem. Soc. 1970, 92, 999e1005; (h) Marazano, C.; LeGoff,
M.; Fourrey, J.; Das, B. C. J. Chem. Soc., Chem. Commun. 1981, 389e391; (i)
Raucher, S.; Bray, B. L. J. Org. Chem. 1985, 50, 3236e3237; (j) Kuehne, M. E.;
Bornmann, W. G.; Earley, W. G.; Maqrko, I. J. Org. Chem. 1986, 51, 2913e2917; (k)
Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc. 1987, 109, 442e446; (l)
Reding, M. T.; Fukuyama, T. Org. Lett. 1999, 1, 973e976 Synthesis of (þ)-ca-
tharanthine via resolution: (m) Stzantay, C.; Bolcskei, H.; Gacs-Baitz, E. Tetra-
hedron 1990, 46, 1711e1732 and references cited therein.
2. Enantioselective DielseAlder reaction of dihydropyridines: Pd-POZ catalyst: (a)
Nakano, H.; Tsugawa, N.; Takahashi, K.; Okuyama, Y.; Fujita, R. Tetrahedron
2006, 62, 10879e10887; (b) Nakano, H.; Tsugawa, N.; Fujita, R. Tetrahedron Lett.
2005, 46, 5677e5681 Cr(III) salen complex catalyst: (c) Takenaka, N.; Huang, Y.;
Rawal, V. H. Tetrahedron 2002, 58, 8299e8305 (ꢁ)-Ibogaine: (d) He, D. Y.;
McGough, N. N.; Ravindranathan, A.; Jeanblanc, J.; Logrip, M. L.; Phamluong, K.;
Janak, P. H.; Ron, D. J. Neurosci. 2005, 25, 619e628 Chiral organocatalysts: (e)
Nakano, H.; Osone, K.; Takeshita, M.; Kwon, E.; Seki, C.; Matsuyama, H.; Takano,
N.; Kohari, Y. Chem. Commun. 2010, 4827e4829; (f) Suttibut, C.; Kohari, Y.;
Igarashi, K.; Nakano, H.; Hirama, M.; Seki, C.; Matsuyama, H.; Uwai, K.; Takano,
N.; Okuyama, Y.; Osone, K.; Takeshita, M.; Kwon, E. Tetrahedron Lett. 2011, 52,
4745e4748.
toluene. Concentration of toluene solution to dryness afforded the
N-acryloyl-4-oxazolidin-2-one 2, which was recrystallized from
hexane as a white crystalline solid (2.914 g, 63% yield).
4.9.1. N-Acryloyl (4S)-4-benzyloxazolidin-2-one (4S)-2. Yield 2.914 g,
63%; white solid (recrystallized from hexane), mp 72e73 ꢀC; lit.9a mp
72e73 ꢀC; ½a 2D4
ꢂ
þ85.0 (c 1.00, CHCl3); lit.9b
½
a 2D4
ꢂ
þ80.1 (c 2.41, CHCl3).
1H NMR [ppm] (500 MHz, CDCl3, 20 ꢀC):
d
2.82 (1H, dd, J¼13.5,
9.6 Hz), 3.36 (1H, dd, J¼13.5, 3.3 Hz), 4.19e4.26 (2H, m), 4.72e4.77
(1H, m), 5.95 (1H, dd, J¼10.5, 1.8 Hz), 6.62 (1H, dd, J¼17.0, 1.8 Hz), 7.23
(2H, d, J¼6.8 Hz), 7.29 (1H, t, J¼7.3 Hz), 7.35 (2H, t, J¼7.0 Hz), 7.52 (1H,
dd, J¼17.0, 10.5 Hz); 13C NMR [ppm] (125 MHz, CDCl3, 20 ꢀC):
d 37.80,
55.32, 66.28, 127.38, 127.41, 129.01 (2C), 129.46 (2C), 132.00, 135.22,
153.35, 164.92.
4.9.2. N-Acryloyl
(4R)-4-benzyloxazolidin-2-one
(4R)-2. Yield
2.035 g, 44%; white solid (recrystallized from hexane), mp
71e72 ꢀC; lit.9a mp 72e73 ꢀC; ½a 2D4
ꢂ
ꢁ83.4 (c 1.0, CHCl3); lit.9a
½
a 2D4
2.82
ꢂ
ꢁ74.2 (c 0.84, CHCl3). 1H NMR [ppm] (500 MHz, CDCl3, 20 ꢀC):
d
(1H, dd, J¼13.5, 9.6 Hz), 3.36 (1H, dd, J¼13.5, 3.3 Hz), 4.19e4.26 (2H,
m), 4.72e4.77 (1H, m), 5.95 (1H, dd, J¼10.5, 1.8 Hz), 6.62 (1H, dd,
J¼17.0, 1.8 Hz), 7.23 (2H, d, J¼6.8 Hz), 7.29 (1H, t, J¼7.3 Hz), 7.35 (2H,
t, J¼7.0 Hz), 7.52 (1H, dd, J¼17.0,10.5 Hz); 13C NMR [ppm] (125 MHz,
3. Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987,
109, 6124e6134.
4. Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Tetrahedron 2009, 65,
3239e3245.
CDCl3, 20 ꢀC):
d 37.80, 55.32, 66.28, 127.38, 127.41, 129.01 (2C),
129.46 (2C), 132.00, 135.22, 153.35, 164.92.
5. Krow, G. R.; Cheung, O. H.; Hu, Z.; Huang, Q.; Hutchinson, J.; Liu, N.; Nguyen, K.
T.; Ulrich, S.; Yuan, J.; Xiao, Y.; Wypij, D. M.; Zuo, F.; Carroll, P. J. Tetrahedron
1999, 55, 7747e7756.
6. For 1,2-dihydropyridine possessing a chiral center: (a) Matsumura, Y.; Naka-
mura, Y.; Maki, T.; Onomura, O. Tetrahedron Lett. 2000, 41, 7685e7689 Dihy-
4.10. Preparation of (4R,5R)-a,a, ,a
a0 0-2,2-hexaphenyl-4,5-
dimethanol-1,3-dioxalone (TADDOL 4c, R1[Ph, R2[Ph)11,17,18
dropyridine having
Mehmandoust, M.; Marazano, C.; Singh, R.; Gillet, B.; Cesario, M.; Fourrey, J.-L.;
4423e4426; (c) dos Santos, D. C.; de Freitas
a chiral auxiliary attached to the nitrogen; (b)
An oven-dried round-bottom flask containing a stir bar and
reflux condenser was charged with a mixture of benzophenone
Das, B. C. Tetrahedron Lett. 1988, 29,
Gil, R. P.; Gil, L.; Marazano, C. Tetrahedron Lett. 2001, 42, 6109e6111; (d) Mar-
azano, C.; Yannic, Y.; Mehmandoust, M.; Das, B. C. Tetrahedron Lett. 1990, 31,
1995e1998 DielseAlder reaction in which the dienophile has a chiral auxiliary:
(e) Kouklovsky, C.; Pouihes, A.; Langlois, Y. J. Am. Chem. Soc. 1990, 112,
6672e6679; (f) Campbell, M. M.; Sainsbury, M.; Searle, P. A.; Davis, G. M. Tet-
rahedron Lett. 1992, 33, 3181e3184; (g) Hirama, M.; Kato, Y.; Seki, C.; Mat-
suyama, H.; Oshikiri, N.; Iyoda, M. Chem. Lett. 2008, 37, 924e925; (h) Hirama,
M.; Kato, Y.; Seki, C.; Nakano, H.; Takeshita, M.; Oshikiri, N.; Iyoda, M.; Mat-
suyama, H. Tetrahedron 2010, 66, 7618e7624; (i) Hirama, M.; Suttibut, C.; Hu-
tabarat, N. D. M. R.; Seki, C.; Sakuta, N.; Tsuchiya, T.; Kohari, Y.; Nakano, H.;
Uwai, K.; Takano, M.; Yasui, M.; Okuyama, Y.; Osone, M.; Takeshita, M.; Mat-
suyama, H. Heterocycles 2012, 84, 377e384 Selected leading references on the
racemic DielseAlder reaction of dihydropyridines: (j) Craig, D.; Kuder, A. K.;
Efroymson, J. J. Am. Chem. Soc. 1950, 72, 5236e5238; (k) Sliwa, H.; Bot, Y. L.
Tetrahedron Lett. 1977, 18, 4129e4132; (l) Campbell, M. M.; Mahon, M. F.;
Sainsbury, M.; Searle, P. A.; Davis, G. M. Tetrahedron Lett. 1991, 32, 951e954.
7. For general reviews, see: (a) Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S., J
frgensen, K. A., Eds.; Wiley-VCH: New York, NY, 2002; (b)
Comprehensive Asymmetric Catalyst; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: New York, NY, 1999; Vols. IeIII.
8. (a) Fowler, F. W. J. Org. Chem. 1972, 37, 1321e1323; (b) Sundberg, R. J.;
Bloom, J. D. J. Org. Chem. 1981, 46, 4836e4842.
9. (a) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271e2273; (b) Evans, D. A.;
Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238e1256.
10. Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92e138.
11. (a) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimoto,
J. J. Am. Chem. Soc. 1989, 111, 5340e5345; (b) Mikami, K.; Motoyama, Y.; Terada,
M. J. Am. Chem. Soc. 1994, 116, 2812e2820; (c) Pellissier, H. In Privileged Chiral
Ligands and Catalysts. TADDOLate Ligand; Zhou, Qi-Lin, Ed.; Wiley-VCH: 2011;
pp 333e359.
12. Gutmann, V. The DonoreAcceptor Approach to Molecular Interactions; Plenum:
New York NY, 1978.
13. The X-ray analysis of the complex of Ti-(2R,3R)-TADDOLate 4a with N-[(E)-
cinnamoyl]-1,3-oxazolidin-2-one has been reported: Gothelf, K. V.; Hazell,
(3.64 g, 20 mmol), dimethyl
L
-(þ)-tartrate (7.13 g, 40 mmol), and
trimethyl orthoformate (4.25 g, 40 mmol), acetonitrile (20 mL), and
indium trichloride (0.22 g, 1 mmol) and the solution was refluxed
for 7 days. The solution was cooled to room temperature, and the
solution was concentrated under reduced pressure. Then the resi-
due was purified by silica gel column chromatography (20% ethyl
acetate in hexane) to give the acetal in 23% yield. An oven-dried
three necked round-bottom flask containing
a stir bar was
charged with THF (4 mL) solution of 2 M PhMgBr/THF (12 mL,
24 mmol) and to this solution was added the THF (8 mL) solution of
the acetal (1.37 g, 4.0 mmol) under nitrogen at 0 ꢀC, and the solu-
tion was stirred at room temperature for 1 day. The reaction was
quenched with saturated NH4Cl solution (15 mL). The product was
extracted with ethyl acetate and the organic layer was washed with
brine and dried over anhydrous Na2SO4. After the removal of ethyl
acetate, the residue was purified by silica gel column chromatog-
raphy (10% ethyl acetate in hexane) to give the TADDOL 4c (R1¼Ph,
R2¼Ph) in 77% yield.
4.10.1. TADDOL 4c. White solid, mp 77e80 ꢀC; ½a D24
þ150.6 (c 1.00,
ꢂ
CHCl3), lit.18
½
a 2D0
d
ꢂ
þ187.7 (c 0.505, CHCl3). 1H NMR [ppm] (270 MHz,
CDCl3, 25 ꢀC):
2.08 (2H, s), 5.53 (2H, s), 6.75e7.73 (30H, m); 13C
NMR [ppm] (97.8 MHz, CDCl3, 25 ꢀC):
d 79.49 (2C), 83.64 (2C),
112.06, 115.26, 124.94, 125.68, 126.18, 126.43, 126.57, 126.75, 127.08,
127.75, 127.94. 128.02, 128.20, 128.52, 129.16, 129.57, 142.32, 144.56,
145.69.
R. G.; J
frgensen, K. A. J. Am. Chem. Soc. 1995, 117, 4435e4436.
14. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325e335.
15. Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121,
7559e7573.
References and notes
16. Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett. 2005, 7, 1971e1974.
17. Smith, B. M.; Graham, A. E. Tetrahedron Lett. 2006, 47, 9317e9319.
18. Irurre, J.; Alonso-Alija, C.; Piniella, J. F.; Alvarez-larena, A. Tetrahedron: Asym-
metry 1992, 3, 1591e1596.
1. (a) Kuehne, M. E.; Marko, I. In Syntheses of Vinblastine-type Alkaloids. The Al-
kaloids. Antitumor Bisindole Alkaloids from Catharanthus roseus (L.); Brossi, A.,
Suffness, M., Eds.; Academic: San Diego, 1990; Vol. 37, pp 77e131; (b) Popik, P.;
Skolnick, P. In Pharmacology of Ibogaine and Ibogaine-related Alkaloids. The