Stereoselective formation of activated cyclopropanes with pyridinium ylides bearing a (-)-8-phenylmenthyl group as the chiral auxiliary

Article abstract of DOI:10.1016/S0040-4039(00)01743-3

The reaction of various mono-substituted methylidenemalononitriles with (-)-8-phenylmenthyl α-pyridiniumacetate in the presence of base afforded the corresponding dicyanocyclopropane compounds with exclusive trans-selectivity and good diastereoselectivity

Full text of DOI:10.1016/S0040-4039(00)01743-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9847–9851
Stereoselective formation of activated cyclopropanes with
pyridinium ylides bearing a (−)-8-phenylmenthyl group as
the chiral auxiliary
Satoshi Kojima,* Kouji Fujitomo, Yoshihiro Shinohara, Makoto Shimizu and
Katsuo Ohkata
Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan
Received 16 August 2000; revised 28 September 2000; accepted 29 September 2000
Abstract
The reaction of various mono-substituted methylidenemalononitriles with (−)-8-phenylmenthyl a-pyri-
diniumacetate in the presence of base afforded the corresponding dicyanocyclopropane compounds with
exclusive trans-selectivity and good diastereoselectivity (up to 86:14). The stereochemistry of the major
products were determined to be of 1R configuration by X-ray structural analysis of the crystalline
trans-2,2-dicyano-3-(4-pyridyl)cyclopropanecarboxylate. The geometric and diastereofacial selectivities
were rationalized assuming anti-periplanar approach in the open-chain model, followed by epimerization
and then cyclization to give the cyclopropane compounds. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: pyridinium ylide; activated cyclopropane; 8-phenylmenthyl; diastereoselective.
Cyclopropane derivatives constitute an interesting group of compounds since they are highly
reactive due to their intrinsic ring strain, and have thus been utilized as synthetic intermediates.1
Among the common methods of cyclopropane synthesis, high levels of asymmetric induction
have been reported for catalytic metal–carbenoid reactions.2 However, this approach has not
been extended to reactions with electron-deficient olefins, and for this type of olefin, Michael
addition type reactions have proven to be more appropriate, with rather high selectivities
observed for substrate controlled reactions.3 Highly electron-deficient cyclopropanes, in particu-
lar, have attracted our interest because of their unique reactivity.4 However, asymmetric
synthesis of such compounds by the use of Michael acceptors with two electron withdrawing
groups has essentially been an unexplored area. Pyridine has been utilized as a leaving group in
* Corresponding author. E-mail: skojima@sci.hiroshima-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01743-3

9848
intermolecular reactions,5 and has also been demonstrated to be useful for intramolecular
reactions to furnish cyclopropanes with exclusive trans geometry.6,7 In conjunction with our
recent observations that the (−)-8-phenylmenthyl group is effective in inducing high diastereo-
selectivity in the formation of glycidic esters via the Darzens reaction,8 we have examined the use
of pyridinium ylides bearing this chiral auxiliary for cyclopropane synthesis. Herein we describe
our results (Scheme 1).
NC CN
R2
CO2R*
NC CN
R2
R1
CN
CN
O
R1
base
(S)
+
R*
(R)
N
R1
trans-1R-3
R*=(-)-8-phenylmenthyl
R2
CO2R*
O
CH2Cl2
1
2
trans-1S-3
Scheme 1.
The pyridinium salt utilized in the reactions was prepared by the reaction of (−)-8-phenylmen-
thyl chloroacetate with pyridine. Optimization of reaction conditions for cyclopropanation was
carried out by using phenylmethylidenemalononitrile as substrate. Throughout the whole
investigation, only the trans cyclopropane products could be observed.6,9 A comparison of a
range of solvents (i-PrOH, DMF, DMSO, MeCN, THF, Et2O, toluene, CH2Cl2) with NaH as
the base revealed that the effect of solvent upon selectivity was minimal (68:32 to 83:17) and that
CH2Cl2 was most suitable in terms of both yield (76%) and selectivity (83:17). Along with Et3N
which was used in the originally reported reactions,6,7 NaH, t-BuOK, and KHMDS were
examined as base. Provided that the reaction was carried out in the same solvent (THF, Et2O,
or CH2Cl2), the diastereomeric ratios were essentially the same regardless of which base was
used. It is interesting to note that although the nature of Et3N and metal-containing bases are
different, the selectivity was the same. In the case of Et3N, the ratio was the same whether the
reaction was carried out at 0 or 50°C.
The scope of this asymmetric reaction was examined by carrying it out with several substrates
in CH2Cl2 with either NaH or Et3N, as partially shown in Table 1. Both bases were examined
Table 1
Reaction with various alkylidenemalononitriles in CH2Cl2 with Et3N as base at 0°Ca
Entry
R1
R2
Yield (%)
Diastereomeric ratiob
1
2
3
4
5
6
7
8
9
C6H5
H
H
H
H
H
H
H
H
78
91
91
82
97
96
93
99
82
83:17
83:17
84:16
84:16
70:30
73:27
66:34
86:14
55:45
p-CH3OCOC6H4
p-O2NC6H4
4-Pyridyl
n-Butyl
i-Butyl
i-Propyl
t-Butyl
ꢀ(CH2)5ꢀ
a Typical reaction conditions: a mixture of the pyridinium salt (0.12 mmol), Et3N (0.18 mmol), substrate (0.10
mmol) in CH2Cl2 (2 mL) was stirred for 12 h at 0°C.
1
b The ratio was determined by H NMR of the isolated diastereomeric mixture.

9849
for all the substrates, due to concern that the same selectivity observed for differing bases in the
case of phenylmethylidenemalononitrile could have been coincidental. However, here again the
diastereoselectivity was not affected by the base, regardless of the substrate. While the benzene
ring substituent did not influence the selectivity (entries 1–4), for alkyl substituted substrates, the
bulky t-butylmethylidenemalononitrile gave the best diastereoselectivity (entries 5–8). Whereas
cyclohexanone was a good substrate for diastereoselective glycidic ester synthesis,8 the reaction
of its malononitrile derivative was found to be essentially unselective (entry 9).
The major diastereomer of the cyclopropane derivative bearing a 4-pyridyl group, trans-2,2-
dicyano-3-(4-pyridyl)cyclopropanecarboxylate, turned out to be crystalline and was thus sub-
jected to X-ray structural analysis.10 The absolute stereochemistry upon the cyclopropane ring
was determined to be 1R,3S as shown in Fig. 1. The major diastereomers of the other products
are expected to have analogous stereochemistry. This stereochemistry can be rationalized as
follows, if we assume that the Michael addition of the pyridinium ylide occurs in an anti-peri-
planar fashion, in regards with the alignment of the interacting p bonds, as depicted in Scheme
2. Considering the reaction conditions, the ylide geometry in which the large pyridyl and
8-phenylmenthyloxy ester groups are in a trans relationship is expected to be predominant.
Michael addition should occur from the front-side of this ylide which is not blocked by the
phenyl group, and in a way to minimize gauche interactions to give intermediate cis-A rather
than trans-A. Upon ring closure to give the cyclopropane product, however, this intermediate
cis-A experiences severe steric repulsion between the carboxylate group and the R group, and
thus product formation is an unfavored process. Due to the presence of two carbanion
stabilizing groups, this intermediate should have a relatively long lifetime,4a,d and therefore could
undergo epimerization at the carbon in between the pyridinium and carboxylate groups. This
gives rise to intermediate trans-B, in which steric strain in the cyclization process is alleviated,
and which should thus readily give the observed major diastereomer, trans-1R-3. The loss in
selectivity can be attributed to the long lifetime of the intermediates, which allows for the
competition of retro-Michael reactions that may lead to trans-1S-3 via trans-A. Since ring
closure is expected to be very slow for the reaction of cyclohexylidenemalononitrile, the fact that
diastereoselectivity was low is in good agreement with a fast epimerization process succeeding a
possibly selective Michael addition.
Figure 1. ORTEP drawing of the major 4-pyridyl diastereomer

9850
Scheme 2.
In summary, we have developed a method of preparing optically active highly electron-
deficient cyclopropanes by utilizing the facial discriminating ability of the (−)-8-phenylmenthyl
chiral auxiliary. Effects of substituents upon the pyridine ring are currently under investigation.
Acknowledgements
This work was partially supported by a grant-in-aid (no.11740354) from the Ministry of
Education, Science, Sports, and Culture, Japan. NMR and HRMS spectra data were measured
at the Instrument Center for Chemical Analysis of Hiroshima University.
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9. As an example of characteristic spectroscopic differences between diastereomers, selected 1H NMR signals of
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ring), 5.00 (dt, J=4.5, 11.0 Hz, 1H, CO2CHRR%); minor diastereomer, 1.93 (d, J=8.0 Hz, 1H, ring), 3.36 (d,
J=8.0 Hz, 1H, ring), 4.98 (dt, J=4.5, 11.0 Hz, 1H, CO2CHRR%).
10. Details of the X-ray analysis will be given in a full report.
.