Enantioselective cyclopropanation reaction using a conformationally fixed pyridinium ylide through a cation-π interaction

Article abstract of DOI:10.1016/j.tetlet.2006.11.142

Using a chiral pyridinium ylide with a fixed conformation through a cation-π interaction performs enantioselective cyclopropanation of electron-deficient olefins. ¹H NMR, X-ray structural analysis and DFT calculations elucidated the self-comple

Full text of DOI:10.1016/j.tetlet.2006.11.142

Tetrahedron Letters 48 (2007) 855–858
Enantioselective cyclopropanation reaction using a
conformationally fixed pyridinium ylide
through a cation–p interaction
Shinji Yamada,* Jun Yamamoto and Emiko Ohta
Department of Chemistry, Faculty of Science, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan
Received 7 October 2006; revised 18 November 2006; accepted 24 November 2006
Available online 13 December 2006
Abstract—Using a chiral pyridinium ylide with a fixed conformation through a cation–p interaction performs enantioselective cyclo-
propanation of electron-deficient olefins. 1H NMR, X-ray structural analysis and DFT calculations elucidated the self-complexation
and the face-to-face arrangement between the pyridinium and the phenyl rings. The absolute configuration of the product was deter-
mined after conversion into a bicyclic cyclopropane derivative.
Ó 2006 Elsevier Ltd. All rights reserved.
Cyclopropanes constitute various natural products,
biologically active compounds, and synthetic inter-
mediates,1 and, therefore, cyclopropane synthesis has
continued to be an attractive subject.2 There have been
various methods known for the stereoselective cyclo-
propanation of unsaturated compounds such as the
Simmons–Smith reaction,3 addition of carbene com-
plexes,4 biomimetic approach,5 and addition–elimina-
tion reaction of ylides.6–8 Recently, sulfonium6 and
ammonium7 ylide-based enantioselective cyclopropana-
tion has extensively been explored; however, little is
reported on an enantioselective approach using a
pyridinium ylide.8
Letter, we describe a new method for the pyridinium
ylide-based enantioselective cyclopropanation.
Scheme 1 outlined our strategy: (1) An ylide produced
from a pyridinium salt bearing a chiral auxiliary would
form a self-complex with shielding of one of the pyridi-
nium faces. (2) This ylide attacks an electron-deficient
olefin at the unblocked side to form a betaine, which
makes a cyclopropane with recovery of the framework
picolinic amide.
Picolinic amides 1a and 1b were prepared by a coupling
reaction of picolinic acid and 1,3-oxazolidine deriva-
tives. This was converted to pyridinium salts 2a–2e with
the corresponding bromides at 40 °C without a solvent.
The cyclopropanation reaction of benzyliden malono-
nitril 3a with pyridinium salt 2a was carried out in the
presence of Et3N at rt to yield trans-cyclopropane 4a
in good enantiomer ratio with recovery of the chiral
auxiliary 1b (Table 1, entry 1). The enantioselectivity is
determined by HPLC analysis using a chiral stationary
phase. X-ray structural analysis of compound 6 clarified
Continuing our research program on the synthetic
application of pyridine compounds,9 we focused on a
pyridinium ylide-based enantioselective cyclopropana-
tion reaction. In the previous studies, we have reported
a face-selective addition reaction of a nucleophile
toward a pyridinium–p complex to give chiral dihydro-
pyridines,9 where the phenyl ring selectively blocks one
face of the pyridinium ring. This face-selective process
prompted us to use a pyridinium–p complex for cyclo-
propanation reactions using a pyridinium ylide. In this
Keywords: Cyclopropanation; Pyridinium ylide; Cation–p interaction;
Pyridinium–p interaction; Enantioselective reaction.
*
Corresponding author. Tel.: +81 3 5978 5349; fax: +81 3 5978
5715; e-mail: yamada@cc.ocha.ac.jp
Scheme 1. Strategy of enantioselective cyclopropanation.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.142

856
S. Yamada et al. / Tetrahedron Letters 48 (2007) 855–858
Table 1. Enantioselective cyclopropanation by way of pyridinium ylide
Entry
Pyridinium salt
Alkene
Solv
Product
Yielda (%)
erb (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
3a
3a
3a
3a
3b
3c
3d
3e
3e
3f
CH2Cl2
THF
4a
4a
4a
4a
4b
4c
4d
4e
4f
78
87
84
46
82
80
81
49
82
89
90
83:17
62:38
70:30
78:22
81:19
84:16
89:11
96:4
CH3CN
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
91:9
91:9
64:36
10
11
4g
4h
3g
a Isolated yield.
b Enantiomer ratio was determined by HPLC with CHIRALCEL OD.
the trans-selectivity described later, which is in agree-
ment with that reported in the literature of pyridinium
ylide-based cyclopropanation reactions.8
To determine the absolute configuration of the product
cyclopropanes, we attempted to prepare authentic 4c
from reported chiral compound (1R,3S)-58a,c by an ester
exchange reaction (Scheme 2). Treatment of 5 with
sodium ethoxide resulted in a complex mixture and no
ethyl ester 4c was obtained despite exerting much effort.
When the ester exchange reaction was carried out using
28% NaOMe in CH2Cl2 at rt for 5 min, unusual bicyclic
acetal (1R,5R,6S)-6 was obtained instead of correspond-
ing methyl ester in 31% yield, the structure of which
was determined by X-ray crystallographic analysis10 as
shown in Figure 1.11
Compound 6 has a c-lactone framework with an
orthoester moiety. This may be produced via hydrolysis
of an ester with contaminating hydroxide ion, successive
Among the solvents we investigated, CH2Cl2 is the most
effective to give an 83:17 mixture of enantiomers of 4a
(entries 1–4). Cyclopropanation of various alkenes bear-
ing o-methoxyphenyl, pyridyl, and naphthyl substituents
is performed in a good yield with a high selectivity
(entries 5–7). The alkenes having an alkyl substituent
are also available for this reaction. The reaction of 3e
having the bulkiest substituent resulted in the highest
enantioselectivity regardless of the N-substituent of the
pyridinium salt (entries 8 and 9). A cyclohexyl group
is also an effective substituent, however, an ethyl group
is less effective to give lower selectivity, suggesting the
importance in the steric bulkiness to attain a high stereo-
selectivity (entries 10 and 11).
Scheme 2. Unusual formation of bicyclic compound 6 and determi-
nation of absolute configuration.

S. Yamada et al. / Tetrahedron Letters 48 (2007) 855–858
857
Figure 2. ORTEP drawing of 2e at the 30% probability level. Iodo
anion was omitted for clarity.
Figure 1. ORTEP drawing of
6 at the 30% probability level.
Chloroform molecule was omitted for clarity.
cyclization of the resulting carboxylate anion with a
cyano group, and acetalization with MeOH. Similar
transformation of 4c into 6 and comparison of the spe-
cific rotation with that of authentic (1R,5R,6S)-6 clari-
fied that the absolute configuration of 6 is opposite to
that of authentic 6; therefore, the configuration of 4c
is 1S,3R.
Figure 3. Optimized geometries for a model ylide.
The significant high-field shift for one of the CH2CO2Et
protons described above can also be explained by
this geometry.
In order to gain evidence for the self-complexation of 2a
through cation–p interaction, comparison of the 1H
NMR spectra between 2a and 2d was performed. The
spectrum of 2a showed significant broadening of the
pyridinium proton, whereas all protons of 2d clearly
appeared. Remarkable difference was observed in the
chemical shifts of the methylene protons next to the
carbonyl group; while both methylene protons of 2d
appeared as a singlet (d 5.96), each methylene proton
of 2a was separated with higher field shift (d 5.58 and
5.90). In addition, H3 of the pyridinium ring for 2d
was significantly shifted to upper field; the d values of
2a and 2d are 8.08 and 7.15, respectively. These features
DFT calculations of an intermediate pyridinium ylide13
at B3LYP/6-31G* level predicted three stable conform-
ers I–III.14 The pyridinium and the phenyl rings of I
and II arrange in a face-to-face manner and the pyridi-
nium rings are blocked opposite side each other by the
phenyl rings, whereas the two rings of conformer III
having the highest energy are apart from each other.
Conformers I and II are shown in Figure 3. Since
conformer I is much more stable than II, I would be
the major conformer.
1
in the H NMR studies strongly suggest that the phenyl
ring is close to the methylene moiety and prevents the
rotation of the CH2CO2Et moiety.
These studies led to a working model for the stereoselec-
tive formation of cyclopropanes outlined in Scheme 3.
An electron-deficient olefin will approach conformer I
from the less-hindered A-side. Two intermediates A
and B would be produced depending on whether the
ylide attacks Re or Si face of the olefin. The equilibrium
between A and B would shift to A so as to avoid severe
steric repulsion between the CO2Et and the R groups in
B; consequently, (1S,3R)-4 was produced as a major
product.
X-ray structural analysis of pyridinium 2e elucidated the
existence of the pyridinium–p interaction.12 Since 2a–2c
were oily compounds, the corresponding N-methyl
pyridinium salt 2e was used as a model compound. Fig-
ure 2 clearly shows that the pyridinium and the phenyl
rings of 2e are very close to each other with face-to-face
arrangement. The phenyl ring blocks around the N
atom, and the distances between the centroid of the
˚
phenyl group and N and C7 are 3.678 and 3.677 A,
In summary, enantioselective cyclopropanation of elec-
tron-deficient olefins was performed by the reaction with
a pyridinium ylide, the conformation of which is fixed
respectively, suggesting an intramolecular cation–p
interaction between the pyridinium and the phenyl rings.

858
S. Yamada et al. / Tetrahedron Letters 48 (2007) 855–858
Synlett 1994, 575; (d) Stammer, C. H. Tetrahedron 1990,
46, 2231.
3. (a) Andre, A. B.; Andre, B. Org. React. 2001, 58, 1–145;
(b) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am.
Chem. Soc. 2001, 123, 12168.
4. For reviews see: (a) Mass, G. Chem. Soc. Rev. 2004, 33,
183; (b) Doyle, M. P.; Protopopova, M. N. Tetrahedron
1998, 54, 7919; (c) Mass, V. K.; DattaGupta, A.; Sekar, G.
Synthesis 1997, 137; (d) Driess, M.; Gruetzmacher, H.
Angew. Chem., Int. Ed. 1996, 35, 828; (e) Brookhart, M.;
Studabaker, W. B. Chem. Rev. 1987, 87, 411.
5. For a review see: Taylor, R. E.; Engelhardt, F. C.;
Schmitt, M. J. Tetrahedron 2003, 59, 5623.
6. Ye, S.; Huang, Z.-Z.; Xa, C.-A.; Tang, Y.; Dai, L.-X.
J. Am. Chem. Soc. 2002, 124, 2432.
7. (a) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org.
Chem. 2006, 71, 7494; (b) Papageorgiou, C. D.; Cubillo de
Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2004, 43, 4641; (c) Papageorgiou, C. D.; Ley, S. V.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828.
8. Diastereoselective pyridinium ylide-based cyclopropana-
tion: (a) Kojima, S.; Fujitomo, K.; Itoh, Y.; Hiroike, K.;
Murakami, M.; Ohkata, K. Heterocycles 2006, 67, 679; (b)
Kojima, S.; Hiroike, K.; Ohkata, K. Tetrahedron Lett.
2004, 45, 3565; (c) Kojima, S.; Fujitomo, K.; Shinohara,
Y.; Shimizu, M.; Ohkata, K. Tetrahedron Lett. 2000, 41,
9847.
Scheme 3. Plausible mechanism for the selective formation of (1S,3R)-
4.
through a cation–p interaction. The key feature in this
process is that the cation–p interaction allows producing
a chiral environment around the active site, which
enables to distinguish the Re and Si faces of olefins,
although the chiral center is apart from it.
9. (a) Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124,
8184; (b) Yamada, S.; Saitoh, M.; Misono, T. Tetrahedron
Lett. 2002, 43, 647.
10. Racemic 6 was used for X-ray crystallographic analysis.
11. X-ray crystal data for 6: C13H12N2O2ÆCHCl3, M = 379.63,
monoclinic, P21/c, l = 4.945 mmÀ1
,
a = 11.633(3) A,
˚
˚
˚
b = 17.615(4) A, c = 8.7459(15) A, b = 103.342(15)°,
Acknowledgment
V = 1743.8(6) A3, T = 230 K, Z = 4, Dc = 1.446 g cmÀ1
.
A total of 3216 reflections were collected and 3194 are
unique (Rint = 0.051). R1 and wR2 are 0.0835 [I > 2r(I)]
and 0.2661 (all data), respectively. See CCDC 619224.
This work was supported by a Grant-in-Aid for
Scientific Research (B) (No. 17350046) from the Japan
Society for the Promotion of Science.
12. X-ray crystal data for 2e: C18H21N2O2I, M = 424.28,
triclinic,
P-1,
l = 13.946 mmÀ1
,
a = 7.134(3) A,
˚
˚
˚
b = 9.4702(10) A, c = 13.9853(10) A, a = 86.096(16)°,
V = 907.4(4) A3,
References and notes
b = 103.302(15)°,
c = 99.103(10)°,
T = 298 K, Z = 2, Dc = 1.553 g cmÀ1. A total of 4403
reflections were collected and 3170 are unique
(Rint = 0.069). R1 and wR2 are 0.0866 [I > 2r(I)] and
0.2013 (all data), respectively. See CCDC 619223.
13. Instead of ylide of 2a, corresponding methyl ester was
used for the DFT calculations as a model ylide to reduce
conformational freedom.
1. For reviews see: (a) de Meijere, A. Chem. Rev. 2003, 103,
931; (b) The Chemistry of the Cyclopropyl Group; Rappo-
port, Z., Ed.; Wiley: New York, 1987; (c) Wong, H. N. C.;
Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. Rev. 1989, 89,
165; (d) Salaun, J. Chem. Rev. 1989, 89, 1247.
¨
2. For reviews see: (a) Lebel, H.; Marcoux, J.-F.; Molinaro,
C.; Charette, A. B. Chem. Rev. 2003, 103, 977; (b)
Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000,
100, 2789; (c) Burgess, K.; Ho, K.-K.; Moye-Sherman, D.
14. The optimized energies for conformers I–III are
À744019.268, À744017.366, and À744016.064 kcal/mol,
respectively.