Asymmetric cycloaddition of 1,2-dihydropyridine derivatives in the presence of Lewis acids

Article abstract of DOI:10.1246/cl.2008.924

Asymmetric cycloaddition of 1-phenoxycarbonyl- (1) or 1-methoxycarbonyl-1, 2-dihydropyridine (2) with N-acryloyl-(1S)-2,10-camphorsultam (3) produced chiral isoquinuclidine 4a or 5a in good yields with excellent diastereoselectivity in the presence of a Lewis acid such as titanium tetrachloride, zirconium tetrachloride, or hafnium tetrachloride. The absolute stereochemistry assignment of endo-cycloaddition products 4a and 5a has been established to be 1S, 4R, and 7S. Copyright

Full text of DOI:10.1246/cl.2008.924

924
Chemistry Letters Vol.37, No.9 (2008)
Asymmetric Cycloaddition of 1,2-Dihydropyridine Derivatives in the Presence of Lewis Acids
Masafumi Hirama,1 Yuji Kato,1 Chigusa Seki,1 Haruo Matsuyama,ꢀ1 Noriko Oshikiri,2 and Masahiko Iyoda2
1Department of Applied Chemistry, Faculty of Engineering, Muroran Institute of Technology,
Muroran, Hokkaido 050-8585
2Department of Chemistry, Graduate School of Science and Engineering,
Tokyo Metropolitan University, Hachioji, Tokyo 192-0397
(Received June 18, 2008; CL-080613; E-mail: hmatsuya@mmm.muroran-it.ac.jp)
RO2C
Asymmetric cycloaddition of 1-phenoxycarbonyl- (1) or
1-methoxycarbonyl-1,2-dihydropyridine (2) with N-acryloyl-
N
CO2R
O2
S
Lewis acid
(1S)-2,10-camphorsultam (3) produced chiral isoquinuclidine
4a or 5a in good yields with excellent diastereoselectivity in
the presence of a Lewis acid such as titanium tetrachloride,
zirconium tetrachloride, or hafnium tetrachloride. The absolute
stereochemistry assignment of endo-cycloaddition products 4a
and 5a has been established to be 1S, 4R, and 7S.
N
exo-4b
exo-5b
+
+
N
O
O
CH2Cl2, MS-4A
N
S
endo-Adducts
4a: R = C6H5
5a: R = CH3
O2
1: R = C6H5
2: R = CH3
(1S)-3
Scheme 1. Asymmetric cycloaddition of 1,2-dihydropyridine
1 or 2 with (1S)-3.
The isoquinuclidine ring system, azabicyclo[2.2.2]octane,
is common to Iboga-type indole alkaloids of which (+)-cathar-
anthine attracts special interest because of its eminent role as
a biogenetic as well as a synthetic precursor of vinblastine and
related antileukemic bisindole alkaloids (Figure 1).1 Further-
more, isoquinuclidines are valuable intermediates in the synthe-
sis of other alkaloids2 and in medicinal chemistry.3 The Diels–
Alder reaction of 1,2-dihydropyridines with dienophiles is a
well-established route to the synthesis of the azabicyclo-
[2.2.2]octane ring system. For the asymmetric synthesis of
isoquinuclidines, diastereoselective cycloadditions of 1,2-
dihydropyridines with dienophiles having a chiral auxiliary
have been reported.4 Recently, the catalytic enantioselective
synthesis of isoquinuclidines has also been reported.5
We selected 1,2-dihydropyridine derivative 1 or 26 as the
diene and N-acryloyl-(1S)-2,10-camphorsultam (3)7 as the dien-
ophile and investigated their asymmetric Diels–Alder cycloaddi-
tion. The both enantiomers of (1S)- and (1R)-2,10-camphorsul-
tam are easily available and our plan is the stereoselective
synthesis of both enantiomers of isoquinuclidine such as (+)-
catharanthine and (ꢁ)-ibogamine. We report herein an effective
asymmetric cycloaddition of diene 1 or 2 with dienophile 3 in
the presence of a Lewis acid to produce chiral isoquinuclidines
in good yields with high endo-diastereoselectivity.
excess (d.e.) of the endo-cycloaddition product 4a was 38%.
Then, the cycloaddition reaction was carried out in the presence
of a Lewis acid (Scheme 1) and the results are summarized
in Table 1. As a result, the cycloaddition of 1 (2 mmol) with
(1S)-3 (1 mmol) in the presence of titanium tetrachloride
(1.3 mmol) in CH2Cl2 (10 mL) at ꢁ78 ꢂC for 24 h mainly pro-
duced the endo-cycloaddition product 4a (endo/exo = 96/4)
in 99% chemical yield with 94% d.e. (Table 1, Entry 1).8
The reactivity of several Lewis acids for the asymmetric
cycloaddition of 1-phenoxycarbonyl-1,2-dihydropyridine (1)
with (1S)-3 was also investigated.9 In the presence of a Lewis
acid such as zirconium tetrachloride or hafnium tetrachloride,
this cycloaddition produced 4a in good yields, and the diastereo-
selectivity of the endo-cycloaddition product 4a was excellent as
shown in Table 1; for example, TiCl4 (94% d.e.) (Entry 1),
ZrCl4 (96% d.e.) (Entry 2), and HfCl4 (97% d.e.) (Entry 3).
Titanium tetrachloride10 was highly reactive as a Lewis acid,
so it needed low-temperature reaction conditions (Table 1,
Entry 1). When zirconium tetrachloride was used, dropwise
addition of diene 1 gave better result (Table 1, Entry 2).
Hafnium tetrachloride was the most useful Lewis acid and the
cycloaddition reaction proceeded smoothly at room temperature
(Table 1, Entry 3).
The cycloaddition reaction of 1-methoxycarbonyl-1,2-dihy-
dropyridine (2) (3 mmol) and (1S)-3 (1 mmol) was carried out in
refluxing toluene and the corresponding cycloaddition products
endo-5a and exo-5b (endo/exo = 84/16) were obtained in
89% yield (Table 1, Entry 7). However, the d.e. of the endo-
5a was 63%. The cycloaddition of 2 with (1S)-3 in the presence
of titanium tetrachloride at ꢁ78 ꢂC selectively produced the
endo-5a (endo/exo = 100/0) in 63% chemical yield with 95%
d.e. (Table 1, Entry 4). The cycloaddition of 2 (2 mmol) with
(1S)-3 (1 mmol) in the presence of hafnium tetrachloride
(2 mmol) also selectively produced the endo-5a (endo/exo =
100/0) in 87% chemical yield with 96% d.e. (Table 1, Entry 5).
In order to determine the absolute stereochemistry of cyclo-
addition products, the assignment of endo-5a was carried out as
follows (Scheme 2). For the assignment of 5a (Table 1, Entry 4),
5a was converted into the known (1S,4R,7S)-methyl ester 6.11
We first examined the cycloaddition of 1-phenoxycarbonyl-
1,2-dihydropyridine (1) (2 mmol) with N-acryloyl-(1S)-2,10-
camphorsultam (3) (1 mmol). The reaction was carried out in re-
fluxing toluene and the corresponding cycloaddition products
endo-4a and exo-4b (endo/exo = 57/43) were obtained in
82% total yield (Table 1, Entry 6). However, the diastereomeric
N
N
N
H
N
H
CO CH
2
3
(+)-Catharanthine
(–)-Ibogamine
Figure 1. (+)-Catharanthine and (ꢁ)-ibogamine.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.9 (2008)
Table 1. Diastereoselective cycloaddition of 1,2-dihydropyridine 1 or 2 with dienophile (1S)-3
925
Diene
(molar equiv) (molar equiv) (molar equiv)
Dienophile
Lewis acid
Temp
/ꢂC
Time
/h
Yielda
/%
% d.e.c
of endo adduct
Entry
Product
endo/exob
1
2d
3
4
5
6
7
1 (2)
1 (2)
1 (2)
2 (2.2)
2 (2)
1 (2)
2 (3)
(1S)-3 (1)
(1S)-3 (1)
(1S)-3 (1)
(1S)-3 (1)
(1S)-3 (1)
(1S)-3 (1)
(1S)-3 (1)
TiCl4 (1.3)
ZrCl4 (2)
HfCl4 (2)
TiCl4 (1.5)
HfCl4 (2)
—
ꢁ78
rt
rt
24
24
24
24
24
48
24
4a/4b
4a/4b
4a/4b
5a/5b
5a/5b
4a/4b
5a/5b
99
96/4
98/2
98/2
100/0
100/0
57/43
84/16
94
96
97
78 (15)
89 (6)
63 (31)
87 (12)
82
ꢁ78
95e
96e
38
rt
refluxf
refluxf
b
—
89
63e
aIsolated yield. Recovery of (1S)-3 is shown in parentheses. The ratio of endo/exo was determined by HPLC analysis using a
TOSOH TSK-GEL Silica-60. cThe % d.e. of endo isomer was determined by HPLC analysis using a TOSOH TSK-GEL
d
e
Silica-60; 1% EtOH/hexane; flow rate; 1 mL/min, Rt ¼ 45 min (minor), 49 min (major). Dropwise addition of 1. The % d.e.
of endo isomer was determined by HPLC analysis using a TOSOH TSK-GELSilica-60; 1% EtOH/hexane; flow rate; 1 mL/min,
Rt ¼ 60 min (minor), 63 min (major). fReaction in refluxing toluene.
from Catharanthus (L.), ed. by A. Brossi, M. Suffness,
H CO C
3
2
Academic Press, San Diego, 1990, Vol. 37, pp. 77–131.
b) P. Popik, P. Skolnick, Pharmacology of Ibogaine and
Ibogaine-Related Alkaloids. in The Alkaloids. Chemistry
and Biology, ed. by G. A. Cordell, Academic Press, San
Diego, 1999, Vol. 52, pp. 197–231.
H CO C
3
2
N
O
N
4
MeOLi / THF, 1 day
(43%)
O
S
2
7
1
N
CO CH
2
3
6
2
3
S. F. Martin, H. Rueger, S. A. Williamson, S. Grzejszczak,
J. Am. Chem. Soc. 1987, 109, 6124.
(1S, 4R, 7S )
[α] +98° (c 0.95, CHCl )
D
5a
3
G. R. Krow, O. H. Cheung, Z. Hu, Q. Huang, J. Hutchinson,
N. Liu, K. T. Nguyen, S. Ulrich, J. Yuan, Y. Xiao, D. M.
Wypij, F. Zuo, P. J. Carroll, Tetrahedron 1999, 55, 7747.
a) Y. Matsumura, Y. Nakamura, T. Maki, O. Onomura,
Tetrahedron Lett. 2000, 41, 7685. b) D. C. dos Santos,
R. P. de Freitas Gil, L. Gil, C. Marazano, Tetrahedron Lett.
2001, 42, 6109. c) G. Ho, D. J. Mather, J. Org. Chem. 1995,
60, 2271. d) C. Marazano, S. Yannic, Y. Genisson, M.
Mehmandoust, B. C. Das, Tetrahedron Lett. 1990, 31,
1995. e) C. Kouklovsky, A. Pouihes, Y. Langlois, J. Am.
Chem. Soc. 1990, 112, 6672.
11
[α
]
-42.2° (c 1.00, CHCl )
D
3
lit.
[α
]
+109° (CHCl )
D 3
95% d.e.
4
Scheme 2. Absolute configuration of Diels–Alder adduct 5a.
Thus, the reaction of 5a (95% d.e.) with lithium methoxide in
THF afforded (7S)-methyl ester 6 in moderate yield. According
to the stereochemistry of (7S)-6 as shown in Scheme 2, the chiral
isoquinuclidine 4a which was obtained from the reaction of
1-phenoxycarbonyl-1,2-dihydropyridine (1) with N-acryloyl-
(1S)-2,10-camphorsultam (3) (Table 1, Entry 1), has also been
established to be 1S, 4R, and 7S.
The stability and reactivity of 1,2-dihydropyridines are
different in the presence of a Lewis acid. 1-Phenoxycarbonyl-
1,2-dihydropyridine (1) and 1-methoxycarbonyl-1,2-dihydro-
pyridine (2) are stable and its cycloaddition with (1S)-3 proceed-
ed in the presence of a Lewis acid. Though thermal cycloaddi-
tion of 1-tert-butoxycarbonyl-1,2-dihydropyridine with (1S)-3
has been reported, unfortunately attempts to promote an enantio-
selective cycloaddition of 1-tert-butoxycarbonyl-1,2-dihydro-
pyridine with (1S)-3 failed in the presence of a Lewis acid.9
In summary, we have developed a highly diastereoselective
cycloaddition of 1,2-dihydropyridine as diene with dienophile
(1S)-3 that provides an efficient methodology for obtaining
pharmacologically important chiral isoquinuclidines. In the re-
action, the combination of a Lewis acid and dienophile (1S)-3
is effective, affording the corresponding chiral isoquinuclidines
endo-adduct 4a and endo-adduct 5a having 94–97% d.e. with
a very high endo selectivity of 96–100%.
5
a) Pd-POZ catalyst: H. Nakano, N. Tsugawa, K. Takahashi,
Y. Okuyama, R. Fujita, Tetrahedron 2006, 62, 10879.
b) CrIII salen complex catalyst: N. Takenaka, Y. Huang,
V. H. Rawel, Tetrahedron 2002, 58, 8299.
6
7
F. W. Foowler, J. Org. Chem. 1972, 37, 1321.
G.-J. Ho, D. J. Mathre, J. Org. Chem. 1995, 60, 2271; B. H.
Kim, J. Y. Lee, Tetrahedron: Asymmetry 1991, 2, 1359.
General procedure of the cycloaddition of 1 or 2 with (1S)-3,
see: Supporting Information which is available electronically
on the CSJ-journal web site; http://www.csj.jp/journals/
chem-lett/.
Cycloaddition of 1-tert-butoxycarbonyl-1,2-dihydropyridine
with (1S)-3 has been reported: M. M. Campbell, M.
Sainsbury, P. A. Searle, G. M. Davies, Tetrahedron Lett.
1992, 33, 3181.
8
9
10 The X-ray analysis of the TiCl4 complex of N-crotonoyl-
(1S)-2,10-camphorsultam has been reported: W. Oppolzer,
I. Rodriguez, J. Blagg, G. Bernardinelli, Helv. Chim. Acta
1989, 72, 123.
References and Notes
1
11 M. Mehmandoust, C. Marazano, R. Singh, B. Gillet, M.
´
Cesario, J.-L. Fourrey, B. C. Das, Tetrahedron Lett. 1988,
29, 4423.
a) M. E. Kuehne, I. Marko, Syntheses of Vinblastine-Type
Alkaloids. in The Alkaloids. Antitumor Bisindole Alkaloids
Published on the web (Advance View) July 26, 2008; doi:10.1246/cl.2008.924