Face-selective addition to a cation-π complex of a pyridinium salt: Synthesis of chiral 1,4-dihydropyridines

Article abstract of DOI:10.1021/ja0203317

Selective shielding of one side of the pyridinium face by way of intramolecular cation-π complex formation enabled nucleophiles to attack only from the non-shielded side, and consequently, chiral 1,4-dihydropyridines were produced stereoselectively with u

Full text of DOI:10.1021/ja0203317

Published on Web 06/19/2002
Face-Selective Addition to a Cation-π Complex of a Pyridinium Salt:
Synthesis of Chiral 1,4-Dihydropyridines
Shinji Yamada* and Chisako Morita
Department of Chemistry, Faculty of Science, Ochanomizu UniVersity, Bunkyo-ku, Tokyo 112-8610, Japan
Received March 4, 2002
Table 1. 1H NMR Chemical Shifts (ppm)a for 1a, 1b, 2a and 2b,
An intramolecular π-π interaction is recognized as a powerful
and ∆δ Valuesb
conformation-controlling tool in various face-selective addition
δ1a
δ1b
∆δ1b
δ2a
δ2b
∆δ2b
reactions such as aldol reactions, conjugate additions, Diels-Alder
reactions, and [3 + 2] and [2 + 2] cycloadditions.1 In contrast,
although a cation-π interaction2 has a stronger interactive force,
little is known about its application to synthetic reactions except
for stereoselective â-galactosylation in the presence of calixarene,3
selective photoisomerization of diphenylcyclopropane,4 and chemose-
lective hydroperoxidation of alkenylarenes in zeolite.5
2H
4H
5H
6H
8.76
7.82
7.36
8.67
8.66
7.67
7.36
8.70
-0.10
-0.15
0.00
9.17
8.47
8.11
9.15
9.10
7.73
7.67
8.93
-0.07
-0.74
-0.44
-0.22
0.03
a Measured at 270 MHz in 2.5 mM solution of CDCl3. b The ∆δ values
were calculated using the equations, ∆δ1b ) δ1b - δ1a, ∆δ2b ) δ2b -
δ2a.
As part of our research program on the development of a new
synthetic method of chiral 1,4-dihydropyridines by face-selective
nucleophilic addition to pyridinium salts,6 we focused on a cation-π
interaction between a pyridinium and a phenyl ring7 as a conforma-
tion-controlling tool. Since chiral 1,4-dihydropyridines continue to
be of great interest in relation with calcium agonists,8 NADH
models,9 and intermediates for alkaloid syntheses,10 the stereose-
lective synthesis of these compounds has attracted the attention of
researchers.6,11 Here we report a new synthetic method of chiral
1,4-dihydropyridines by way of a face-selective addition to a
cation-π complex.
Our strategy for the stereoselective synthesis of 1,4-dihydropy-
ridines is outlined in Scheme 1: (a) conversion of compound A
containing both a pyridine and a phenyl moiety into a pyridinium
salt gives rise to an attractive force between the two entities to
form a cation-π complex B; (b) the selective shielding of one side
of the pyridinium face by the phenyl ring enables nucleophiles to
attack the complex only from the nonshielded side, which will result
in 1,4-dihydropyridine C stereoselectively.
obvious that the ∆δ2b values are negatively larger than the ∆δ1b
values, suggesting a considerable conformational difference between
1b and 2b; the pyridine and the phenyl ring of 1b would be apart
from each other, whereas the phenyl ring of 2b would be so close
to shield the pyridinium protons. On the other hand, the differences
between ∆δ1c and ∆δ2c were very small.
X-ray analyses clarified significant geometrical differences
between 1b and 2b (Figure 1). The most striking structural feature
in 2b is that the pyridinium and the phenyl rings lie parallel to
each other and the two rings are arranged face-to-face, the distance
between which is about 3.4 Å. On the other hand, the pyridine and
the phenyl moieties of 1b are apart from each other. These
geometrical difference can reasonably explain the small ∆δ1b and
Scheme 1
1
negatively larger ∆δ2b in the H NMR studies described above.
The fact that the geometry largely depends on whether the pyridine
nucleus has a cationic charge unambiguously evidences that a
cation-π interaction governs the conformation of 2b. Similar
intramolecular Py+-π interactions have been postulated in some
reaction intermediates.15 Although charge transfer is considered to
be a major attractive force in several Py+-π complexes,16 no
charge-transfer absorption was observed in the present complex.
The cation-π complex formation in 2b prompted us to study
the face-selective addition of nucleophiles to 1b and 1c. For
nucleophiles, we employed ketene silyl acetals 3a and 3b. Since
most face-selective nucleophilic 1,4-addition to pyridinium salts
has been performed under chelation-controlling conditions,11 ketene
silyl acetals have scarcely been employed for the face-selective
addition reactions except for our previous report.6c Addition of
ketene silyl acetals 3a to 1b and 1c in the presence of methyl
chloroformate in CH2Cl2 gave 1,4-adducts 4b and 4c as a major
product with a small amount of 1,6-adducts, respectively, as shown
We prepared nicotinic amide derivatives 1b and 1c having chiral
2,2-dimethyloxazolidines12,13 and their N-methyl salts 2b and 2c
for the geometrical studies. Achiral 1a and 2a were used as the
standard compounds. Although intramolecular π-π interactions are
postulated in some benzyloxazolidinone derivatives during asym-
metric addition reactions,14 our previous studies indicated that the
oxazolidinones are a less effective chiral auxiliary for the present
purpose.6c
Table 1 lists the chemical shifts for the pyridine and pyridinium
protons of 1 and 2, and the ∆δ value that is the changes in the
chemical shifts compared to those for standards 1a and 2a. It is
* Corresponding author. E-mail: yamada@cc.ocha.ac.jp, Fax: 81-3-5978-5715.
9
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J. AM. CHEM. SOC. 2002, 124, 8184-8185
10.1021/ja0203317 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Figure 2. Working model for nucleophilic addition to a cation-π complex.
supported by structural optimization of the intermediary pyridinium
cation by ab initio calculations at the RHF/3-21G* level,17 where
conformer II is 2.1 kcal/mol more stable than conformer I. There-
fore, the equilibrium between conformers I and II favors II; as a
result, a nucleophile will attack the conformer II from the non-
shielded side to give a chiral dihydropyridine in good stereoselec-
tivity.
In summary, we have shown the first evidence for the existence
of an intramolecular cation-π interaction between a pyridinium
cation and a benzyl moiety. Moreover, the utility of the intramo-
lecular cation-π interaction was demonstrated by the synthesis of
chiral 1,4-dihydropyridines with excellent stereoselectivity. Since
the cation-π interaction generally has a stronger interactive force
than the π-π interaction, it will be a promising conformation-
controlling tool for a variety of synthetic reactions.
Figure 1. X-ray structures for 1b (a) and 2b (b). The thermal ellipsoids
are set at the 30% probability level for each. The hydrogen atoms and a
counterion are omitted for clarity. Selected interatomic distances for 2b
(Å): C3‚‚‚C8 3.323, C3‚‚‚C13 3.491, C4‚‚‚C8 3.551, C4‚‚‚C9 3.557, C4‚
‚‚C10 3.530, C4‚‚‚C11 3.511, C4‚‚‚C12 3.441, C4‚‚‚C13 3.454, C5‚‚‚C12
3.354.
Table 2. Addition of Ketene Silyl Acetals to 1
Acknowledgment. This work was financially supported by a
Grant-in-Aid for Scientific Research (C) (No. 13650901) from the
Japan Society for the Promotion of Science.
de/% of
4 or 5b
a
entry
compd
acetal
solv
yield/%
(1,4-: 1,6-)b
1
2
3
4
5
6
7
1b
1c
3a
3a
3a
3a
3a
3bc
3b
CH2Cl2
CH2Cl2
CHCl3
THF
toluene
CH3CN
CH2Cl2
94
60(94)
90
56(99)
70(99)
80
86:14
78:22
93:7
87:13
97:3
>99
Supporting Information Available: Crystallographic data for 1b,
2b and 4b, synthetic procedures and spectral data for 1a-1c, 2a, 2b,
4b and 5b, and optimized structures for two isomers of 5b with their
stereochemical assignment (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
12
1b
1b
1b
1b
1b
>99
>99
>99
>99:1
93:7
>99(93:7)d
61(99)
>99(94:6)d
References
a Isolated yields. Conversion yield is indicated in parentheses. b Deter-
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diastereomer ratio.
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to 1b gave excellent selectivity (entry 1), whereas the selectivity
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effect of the dihydropyridine moiety (4.9 Hz and δ 4.41 for the
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The absolute configuration of the stereogenic center for 4b was
clarified to be S by X-ray analysis. Analogously, the two chiral
centers for the major isomer of 5b are assigned to be (4R,1′S). This
indicates that the cation-π interaction will occur with the re face
of the pyridinium ring, and the nucleophiles attack from the si face
of the complex II as shown in Figure 2. This working model was
JA0203317
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J. AM. CHEM. SOC. VOL. 124, NO. 28, 2002 8185