The highly enantioselective Diels-Alder reaction of 1,2-dihydropyridine using chiral cationic palladium-phosphinooxazolidine catalyst for the synthesis of chiral isoquinuclidines

Article abstract of DOI:10.1016/j.tetlet.2005.06.089

The enantioselective Diels-Alder reactions of 1-phenoxycarbonyl-1,2- dihydropyridine with 1-alkylated acryloyl-pyrazolidin-3-ones using chiral cationic palladium-phosphinooxazolidine (Pd-POZ) catalyst afforded chiral isoquinuclidines with excellent enanti

Full text of DOI:10.1016/j.tetlet.2005.06.089

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5677–5681
The highly enantioselective Diels–Alder reaction of
1,2-dihydropyridine using chiral cationic palladium–
phosphinooxazolidine catalyst for the synthesis
of chiral isoquinuclidines
Hiroto Nakano,* Natsumi Tsugawa and Reiko Fujita
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 14 May 2005; revised 13 June 2005; accepted 17 June 2005
Available online 5 July 2005
Abstract—The enantioselective Diels–Alder reactions of 1-phenoxycarbonyl-1,2-dihydropyridine with 1-alkylated acryloyl-pyrazol-
idin-3-ones using chiral cationic palladium–phosphinooxazolidine (Pd–POZ) catalyst afforded chiral isoquinuclidines with excellent
enantioselectivity (up to 97% ee).
Ó 2005 Elsevier Ltd. All rights reserved.
The 2-azabicyclo[2.2.2]octanes (isoquinuclidines) are
found widely in natural products, particularly among
the iboga-type indole alkaloids, members of which have
varied and interesting biological properties.1 In particu-
lar, there are pharmacologically important vinca alka-
loids such as vinblastine and vincristine, which are
created through the coupling of catharanthine 1, which
possesses isoquinuclidines, with the aspidosperma por-
tion (Fig. 1).2 Most recently, it was also indicated that
ibogaine 2 reduces cravings for alcohol and other drugs
of abuse by its ability to boost levels of a growth factor
known as glial cell line-derived neurotrophic factor
(GDNF) (Fig. 1).3 Furthermore, isoquinuclidines are
also valuable intermediates in the synthesis of other
alkaloids4 and in medicinal chemistry.5 Therefore, it is
meaningful to establish an effective asymmetric synthetic
methodology of chiral isoquinuclidines. A well-estab-
lished route to this ring system is through the Diels–Al-
der (DA) reaction of 1,2-dihydropyridines with
dienophiles. However, there has been little work to date
on the asymmetric version of this reaction and almost all
examples of asymmetric DA reactions of 1,2-dihydro-
pyridines are a diastereoselective version in which a
diene or dienophile has a chiral auxiliary.6 Despite its
obvious advantages, to the best of our knowledge,
only one example employing a Cr–BINAM catalyst
has been reported to date by Rawal et al. for the cata-
lytic enantioselective version of the DA reaction, but
nevertheless, this afforded only modest asymmetric
induction (up to 85% ee).7 Recently, we reported that
the cationic Pd–POZ complex A is an effective catalyst
in the DA reaction of cyclic or acyclic dienes with oxaz-
olidone dienophiles.8 Therefore, we applied cationic
Pd–POZ catalysts to the enantioselective DA reactions
of 1,2-dihydropyridines with imide dienophiles such
as acryloyl-1,3-oxazolidin-2-one and 1-substituted acry-
loyl-pyrazolidin-3-ones (Fig. 1).
MeO
N
N
N
H
N
H
O
OMe
1
2
2+
+2X-
Ph
O
Ph
N
Pd
Keywords: Enantioselective Diels–Alder reaction; 1,2-Dihydropyr-
idine; Chiral cationic palladium–phosphinooxazolidine catalyst; Chiral
isoquinuclidines.
P
Ph
Ph
A
*
Corresponding author. Tel.: +81 22 234 4181; fax: +81 22 275
2013; e-mail: hnakano@tohoku-pharm.ac.jp
Figure 1. Cationic Pd–POZ catalyst.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.089

5678
H. Nakano et al. / Tetrahedron Letters 46 (2005) 5677–5681
Herein, we wish to report the successful enantioselective
DA reaction of 1,2-dihydropyridine as a diene, giving
chiral isoquinuclidines at synthetically useful levels of
enantiomeric excess (ee). Thus, the DA reaction of 1-
phenoxycarbonyl-1,2-dihydropyridine 5 with 1-benzyl-
2-acryloyl-pyrazolidin-3-one 8a using chiral cationic
Pd–POZ catalyst 4a afforded chiral isoquinuclidines
with a good chemical yield (80%) and excellent enantio-
selectivity (97% ee).
lent isolated yield (98%) and with moderate enantio-
selectivity (76% ee, entry 1). Cooling to ꢀ25 °C led to
a slight increase in enantioselectivity (82% ee), but the
chemical yield decreased to 84% (entry 2). The use of
perchlorate complex 4b brought about a slight decrease
in chemical yield (90%), but DA adduct 7 was obtained
at 84% ee (entry 3). Unfortunately, the reaction at
ꢀ25 °C did not show an increase in enantioselectivity
(entry 4). On the other hand, tetrafluoroborate complex
4c afforded the highest enantioselectivity (88% ee), but
chemical yield was poor (46%, entry 5). Triflate complex
4d did not show satisfactory catalytic activity (37%, 74%
ee, entry 6).
For the catalytic enantioselective version of the DA
reaction, we first tested the reaction of common acry-
loyl-1,3-oxazolidine-2-one 6 with 1-phenoxycarbonyl-
1,2-dihydropyridine 5. The cationic Pd–POZ catalysts
4a–d were prepared by the reactions of PdCl2–POZ 3
and the corresponding AgX (X = SF6, ClO4, BF4,
OTf) in dry CH2Cl2 using our previously reported pro-
cedure (Scheme 1).8 The DA reaction of diene 5 with
dienophile 6 was carried out at 0 °C in CH2Cl2 in the
presence of 10 mol % of the prepared cationic Pd–POZ
catalysts 4a–d to give DA adduct 7. The results are sum-
marized in Table 1. The obtained DA adduct 7 was
exclusively the endo-form.7 The reaction catalyzed by
the antimonate complex 4a gave DA adduct 7 in excel-
In order to improve enantioselectivity in the reaction, we
explored the possibilities presented in a report by Sibi
et al.,9 who examined a novel 1-substituted 2-crotonyl-
pyrazolidin-3-one as a dienophile based on the concept
of Ôchiral relayÕ, and reported that the combination of
this dienophile and nonoptimized Cu-bis-oxazoline cat-
alyst can bring about an excellent asymmetric induction
in the DA reaction with cyclopentadiene as a diene. We
applied the 1-substituted 2-crotonyl-pyrazolidin-3-one
dienophile to the DA reaction of 1,2-dihydropyridine 5
using cationic Pd–POZ catalysts 4a–d. New 1-substi-
tuted 2-crotonyl-pyrazolidin-3-ones 8a–c were prepared
following the procedure reported by Sibi et al.9
2+
Ph
O
Ph
O
First, we examined the effectiveness of dienophiles 8a–c
using superior antimonate catalyst 4a. The reactions of
diene 5 with dienophiles 8a–c were carried out at 0 °C
in the presence of 10 mol % of the prepared Pd–POZ
catalysts 4a–d to give the corresponding endo-DA ad-
ducts 9a–c.10 The results are summarized in Table 2. A
significant difference was observed in chemical yield
and enantioselectivity corresponding to the different
substituent groups on the nitrogen at the 1-position.
When 1-benzyl substituted derivative 8a was used, a dra-
matic increase in enantioselectivity to 97% ee was ob-
served with good chemical yield (80%, entry 1).
Despite our expectations, the reaction with the bulkier
1-naphthylmethyl derivative 8b was slow and brought
about a decrease in both chemical yield and enantio-
selectivity (entry 2). Similarly, the reaction with 1-ethyl
substituted derivative 8c was also sluggish and did not
give satisfactory results, although the reasons for this
remain unclear (entry 3).
Ph
Ph
+2X-
N
N
1) PdCl2
Cl
Cl
Ph
Ph
Pd
Pd
2) AgX
CH2Cl2
rt
P
P
Ph
Ph
a: X=SbF6
b: X=ClO4
c: X=BF4
d: X=OTf
4a-d
3
Scheme 1.
Table 1. Enantioselective DA reaction of 5 with 6
PhO2C
N
O
catalysts
O
O
(10 mol%)
7
+
N
O
CH2Cl2
N
O
Next, we examined the effects of other counterions in the
reaction with superior dienophile 8a. Cationic perchlo-
rate catalyst 4b gave DA adduct 9a in good chemical
yield (87%) and with fairly good enantioselectivity
(94%, entry 4). Tetrafluoroborate catalyst 4c afforded
the best enantioselectivity (97% ee) with good chemical
yield (76%, entry 5) in results almost identical to those
achieved with antimonate catalyst 4a. However, triflate
catalyst 4d did not give satisfactory reactivity or enantio-
selectivity (60%, 89% ee, entry 6). The reactions with
superior cationic catalysts 4a and 4c at ꢀ25 °C did not
afford better results for chemical yields and enantioselec-
tivities than the results at 0 °C (entries 7 and 8). Further-
more, the effect of reducing the molar ratio of catalyst 4a
was examined. At low catalytic loading to 5 mol % of
N
CO2Ph
O
[7R ]-7
Yielda
(%)
6
5
Entry
Catalyst
Temperature
(°C)
Time
(h)
eeb
(%)
1
2
3
4
5
6
4a
4a
4b
4b
4c
4d
0
ꢀ25
0
24
48
24
48
24
24
98
84
90
73
46
37
76
82
84
82
88
74
ꢀ25
0
0
a Isolated yields.
b ee of endo isomer was Determined by HPLC analysis using a Daicel
Chiralcel AD column.7

H. Nakano et al. / Tetrahedron Letters 46 (2005) 5677–5681
Table 2. Enantioselective DA reaction of diene 5 with 8a–ca
5679
PhO2C
N
O
O
7
catalysts
CH2Cl2
+
O
N
O
N
N
N
R
CO2Ph
N
R
[7R ]-9a-ca
5
8a-c
a: R=Ph
a: R=Ph
b: R=1-Naph
c: R=Me
b: R=1-Naph
c: R=Me
Entry
Dienophile
Catalyst
Ligand (mol %)
Temperature (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
8a
8b
8c
4a
4a
4a
10
10
10
0
0
0
24
72
72
80
47
42
97
33
43
4
5
6
8a
8a
8a
4b
4c
4d
10
10
10
0
0
0
24
24
24
87
76
60
94
97
89
7
8
8a
8a
4a
4c
10
10
ꢀ25
ꢀ25
48
48
76
76
95
89
9
10
8a
8a
4a
4a
5
2.5
0
0
24
24
78
59
95
84
a After conversion to benzyl ester [7R]-10, the absolute configuration were determined.
b Isolated yields.
c ee of endo isomer was determined by HPLC analysis using a Daicel Chiralcel AD column.
4a, equally satisfactory results (78%, 95% ee) were ob-
tained, 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 4a and 1-benzyl-
pyrazolidin-3-one dienophile 8a were most effective in
obtaining chiral isoquinuclidines 9a with excellent
enantioselectivity.
Finally, we also examined the effectiveness of four kinds
of chiral catalysts (Cu–bis-oxazoline–11,9 Pd–BINAP–
12,12 Pd–POZ–1313 and 2-azanorbornane-based Pd–
POZ–148 complexes) in the DA reaction of 1-phenoxy-
carbonyl-1,2-dihydropyridine 5 with 1-benzyl-2-pyraz-
olidin-3-one dienophile 8a. The reactions were carried
out at 0 °C in the presence of 10 mol % of catalysts
11–14 to give the corresponding DA adduct 9a. The re-
sults are shown in Table 3. The effective complex 11 in
SibiÕs experiment9 did not show catalytic activity (entry
1). Complex 11, acting as superior catalyst in many reac-
tions, had low reactivity and afforded only moderate
chemical yield (57%) even at 72 h of reaction time,
although it gave excellent enantioselectivity (96% ee,
entry 2). Furthermore, catalyst 13 gave DA adduct 9a
in low chemical yield (35%), but with 85% ee (entry 3).
Unfortunately, our developed norbornane-based POZ
catalyst 14 did not work well in this reaction (entry 4).
For the absolute stereochemistry assignments of the new
DA adducts, both the obtained 9a–c and the known
(7R)-7 were converted to benzyl ester 10 (Scheme 2).
Thus, the reactions of 9a–c or (7R)-7 with BnOH using
n-BuLi as a base in THF afforded (7R)-benzyl ester 1011
in moderate yields (9a: 60%; 9b: 64%; 9c: 64%; 7: 38%).
The obtained 10 is expected to serve as an effective chiral
synthetic intermediate.
In conclusion, we have developed the high enantioselec-
tive Diels–Alder reaction of 1,2-dihydropyridine that
provides an efficient methodology for obtaining phar-
macologically important chiral isoquinuclidines. In the
reaction, the combination of cationic Pd–POZ catalyst
4a with SbF6 counterion and 1-benzyl-2-acryloyl-pyraz-
olidin-3-one dienophile 8a as a dienophile is most effec-
tive, affording the corresponding DA adduct 9a at 97%
ee. These results indicate that the combination of Pd–
POZ catalyst 4 with 1-substituted pyrazolidin-3-one
dienophile 8 is useful not only in the DA reaction of
1,2-dihydropyridine but also in other DA reactions with
PhO2C
PhO2C
PhO2C
O
N
N
N
n-BuLi
BnOH
n-BuLi
BnOH
7
THF
0 °C, 4h
38%
THF
0 °C
O
O
O
O
N
OBn
N
a: R=Ph
O
N
R
7h, 60%
b: R=1-Naph
24h, 64%
c: R= Me
9h, 64%
(7R)-10
(7R)-9a-c
Scheme 2.
(7R)-7

5680
H. Nakano et al. / Tetrahedron Letters 46 (2005) 5677–5681
Table 3. Catalyst screen
5 þ 8a catalysts ð10 mol%Þ 9a
ƒƒƒƒƒƒƒƒƒ!
CH2Cl2 0ꢁC
Entry
Catalyst
Time (h)
Yielda (%)
eeb (%)
Config.c
1
2
3
4
11
12
13
14
72
72
24
24
No reaction
—
96
85
10
—
57
31
54
7R
7S
7S
a Isolated yields.
b ee of endo isomer was determined by HPLC analysis using a Daicel Chiralcel AD column.
c After conversion to benzyl ester [7R]-10, the absolute configuration were determined.
2+
Ph
2+
Ph
P
O
O
+2OTf2
+2SbF6
Pd
N
N
Cu
P
Ph
Ph
11
12
2+
2+
Ph
Ph
N
O
O
+2SbF6
N
+2SbF6
Pd
Pd
P
P
Ph
Ph
Ph
Ph
13
14
4. Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak,
S. J. Am. Chem. Soc. 1987, 109, 6124–6134.
other dienes and in other asymmetric processes. Further
studies to examine the scope and limitations of this com-
bination system for the catalytic asymmetric version of
the DA reactions of 1,2-dihydropyridines are now in
progress.
5. (a) Mitch, C. H. U.S. Patent 5,834,458, 1998; Chem. Abstr.
1999, 129, 343498; (b) Mitch, C. H. U.S. Patent 5,889,019,
1999; Chem. Abstr. 1999, 130, 252363; (c) 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, 5, 7747–
7756.
References and notes
6. (a) dos Santos, D. C.; de Freitas Gil, R. P.; Gil, L.;
Marazano, C. Tetrahedron Lett. 2001, 42, 6109–6111; (b)
Matsumura, Y.; Nakamura, Y.; Maki, T.; Onomura, O.
Tetrahedron Lett. 2000, 41, 7685–7689; (c) Ho, G.;
Mather, D. J. J. Org. Chem. 1995, 60, 2271–2273; (d)
Marazano, C.; Yannic, Y.; Mehmandoust, M.; Das, B. C.
Tetrahedron Lett. 1990, 31, 1995–1998; (e) Kouklovsky,
C.; Pouilhes, A.; Langlois, Y. J. Am. Chem. Soc. 1990,
112, 6672–6679; (f) Campbell, M. M.; Mahon, M. F.;
Sainsbury, M.; Searle, P. A.; Davies, G. M. Tetrahedron
Lett. 1991, 32, 951–954; (g) Sundberg, R. J.; Bloom, J. D.
J. Org. Chem. 1981, 46, 4836–4842.
1. (a) Kuehne, M. E.; Marko, I. In Syntheses of Vinblastine-
type Alkaloids. The Alkaloids. Antitumor Bisindole Alka-
loids from Catharanthus roseus (L.); Brossi, A., Suffness,
M., Eds.; Academic Press: San Diego, 1990; Vol. 37, pp
77–131; (b) Popik, P.; Skolnick, P. In Pharmacology of
Ibogaine and Ibogaine-related Alkaloids. The Alkaloids.
Chemistry and Biology; Cordell, G. A., Ed.; Academic
Press: San Diego, 1999; Vol. 52, pp 197–231; (c) Glick, S.
D.; Maisonneuve, I. M.; Szumlinski, K. K. In Mechanisms
of Action of Ibogaine: Relevance to Putative Therapeutic
Effects and Development of a Safer Iboga Alkaloid Conge-
ner. The Alkaloids; Alper, K. R., Glick, S. D., Cordell, G.
A., Eds.; Academic Press: San Diego, 2001; Vol. 56, pp
39–53.
2. (a) Buchi, G.; Coffen, D. L.; Kocsis, K.; Sonnet, P. E.;
Ziegler, F. E. J. Am. Chem. Soc. 1966, 88, 3099–3109; (b)
Marazano, C.; LeGoff, M.; Fourrey, J.; Das, B. C.
J. Chem. Soc., Chem. Commun. 1981, 389–391; (c)
Redding, M. T.; Fukuyama, T. Org. Lett. 1999, 1, 973–
976.
7. Takenaka, N.; Huang, Y.; Rawal, V. H. Tetrahedron 2002,
58, 8299–8305.
8. (a) Nakano, H.; Okuyama, Y.; Suzuki, Y.; Fujita, R.;
Kabuto, C. Chem. Commun. 2002, 1146–1147; (b) Nak-
ano, H.; Takahashi, K.; Okuyama, Y.; Senoo, C.; Tsug-
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Org. Chem. 2004, 69, 7092–7100.
9. Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J.
Am. Chem. Soc. 2001, 123, 8444–8445.
10. A representative procedure for the DA reaction of 1-
phenoxycarbonyl-1,2-dihydropyridine 5 with 1-substituted
2-acryloyl-5,5-dimethyl-pyrazolidin-3-ones 8 using cat-
ionic Pd–POZ complex 4a: a suspension of PdCl2–POZ
3. He, D. Y.; McGough, N. N.; Ravindranathan, A.;
Jeanblanc, J.; Logrip, M. L.; Phamluong, K.; Janak,
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H. Nakano et al. / Tetrahedron Letters 46 (2005) 5677–5681
5681
complex 3 (28.1 mg, 0.07 mmol) and AgSbF6 (27.4 mg,
0.2 mmol) in CH2Cl2 (1 mL) was stirred at room temper-
ature for 1 h under Ar. The suspension was cooled at 0 °C
and diene 5 (402.0 mg, 2 mmol) and 1-benzyl-2-acryloyl-
5,5-dimethyl-pyrazolidin-3-one 8a (103.3 mg, 0.4 mmol)
were added. The reaction mixture was stirred under Ar at
0 °C for 24 h. The mixture was then quenched with
saturated NaHCO3 solution and extracted with CHCl3.
The combined organic layers were washed with brine,
dried with anhydrous MgSO4 and concentrated. The
residue was chromatographed on a column of silica gel
with hexane–AcOEt = 1:1 to afford 9a (147 mg, 80%).
cooled (ꢀ78 °C) solution of benzylalcohol (0.1 mL,
1.0 mmol) in 6 mL of THF. The resulting solution was
stirred for 5 min and a solution of DA adduct 9a (97% ee,
240 mg, 0.52 mmol) in THF was added. The solution was
warmed to 0 °C and stirred for 3 h. The mixture was then
quenched with saturated NH4Cl solution and the solvent
was evaporated under reduced pressure. H2O was added
to the residue and extracted with CHCl3. The combined
organic layers were dried with anhydrous MgSO4 and
concentrated. The residue was chromatographed on a
column of silica gel with AcOEt–CHCl3 = 1:3 to afford
20
[7R]-benzyl ester 10 (113 mg, 60%). Colourless oil. ½aꢂD
¼
20
Colourless prism. Mp 165–168 °C. ½aꢂD ¼ ꢀ52.95 (c 0.68,
ꢀ59.92 (c 2.52, DMSO). 1H NMR (CDCl3): d 1.91–
2.07 (m, 2H), 2.91 (br s, 1H), 3.05 (d, 1/2H, J = 10.6), 3.16
(d, 1/2H, J = 10.3), 3.22–3.26 (m, 1H), 3.35 (d, 1/2H,
J = 10.6), 3.49 (d, 1/2H, J = 10.3), 5.07–5.16 (m, 2H),
5.24–5.27 (m, 1H), 6.34–6.38 (m, 1H), 6.48–6.54 (m, 1H),
7.04–7.13 (m, 2H), 7.17–7.20 (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. HRMS (EI) m/z calcd for
C22H21NO4 (M+) 363.1471. Found 363.1471.
1
CHCl3). H NMR (CDCl3) d : 1.12–1.24 (m, 6H), 1.53–
1.64 (m, 3H), 1.94–2.18 (m, 1H), 2.56–2.59 (m, 1H), 2.64–
2.69 (m, 1H), 2.84 (br s, 1H), 3.06 (d, 1/2H, J = 10.6), 3.18
(d, 1/2H, J = 10.3), 3.35 (d, 1/2H, J = 10.6), 3.50 (d, 1/2H,
J = 10.3), 4.00 (br s, 1H), 4.03 (br s, 2H), 5.07 (br s, 1H),
6.39–6.44 (m, 2H), 7.12–7.13 (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. HRMS (EI) m/z calcd for
C27H29N3O4 (M+) 459.2158. Found 459.2176.
12. Ghosh, A. K.; Matsuda, H. Org. Lett. 1999, 1, 2157–
2159.
11. Conversion from DA adduct 9a to benzyl ester 10: n-BuLi
(0.73 mL, 1.0 M in hexane, 0.78 mmol) was added to a
13. Hiroi, K.; Watanabe, K. Tetrahedron: Asymmetry 2002,
13, 1841–1843.