Stereocontrolled synthesis of [3.1.0]bicyclohexanones by cyclopropanation of enones with benzylidene sulfuranes

Article abstract of DOI:10.1016/S0040-4039(02)01017-1

Bicyclo[3.1.0]hexanones bearing an aryl group on the cyclopropane ring are stereoselectively prepared on reaction of the corresponding benzylidene sulfuranes with cyclopentenones. The synthesis of compounds bearing geminal phenyl and methyl groups on the cyclopropane ring proves to be possible because the corresponding sulfonium salt, inaccessible until now, is now available.

Full text of DOI:10.1016/S0040-4039(02)01017-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5871–5873
Stereocontrolled synthesis of [3.1.0]bicyclohexanones by
cyclopropanation of enones with benzylidene sulfuranes
Alain Krief,a,* Dominique Swinnenb and Denis Billena,c
aLaboratoire de Chimie Organique de Synthe`se, 61 rue de Bruxelles, Namur B-5000, Belgium
bSerono Pharmaceutical Research Institute, 14 chemin des Aulx, Plan-Les-Ouates, Geneva CH-1228, Switzerland
cFond pour la Recherche Scientifique dans l’Industrie et l’Agriculture (F.R.I.A.), 5 rue d’Egmont, Bruxelles B-1000, Belgium
Received 2 April 2002; accepted 29 May 2002
Abstract—Bicyclo[3.1.0]hexanones bearing an aryl group on the cyclopropane ring are stereoselectively prepared on reaction of
the corresponding benzylidene sulfuranes with cyclopentenones. The synthesis of compounds bearing geminal phenyl and methyl
groups on the cyclopropane ring proves to be possible because the corresponding sulfonium salt, inaccessible until now, is now
available. © 2002 Elsevier Science Ltd. All rights reserved.
In the course of a work directed toward the enantiose-
lective synthesis of (1R)-cis-chrysanthemic acid 1, using
tailor-made antibodies,1 we needed stereoisomerically
pure bicyclo[3.1.0]hexane derivatives 2 geminally substi-
tuted on the cyclopropane ring by an aryl group and an
hydrogen or a methyl group (Scheme 1).
DME, −78°C, 0.5 h)4 in the presence of
dichloromethane (DCM, 1.2 equiv.) and (ii) the enones
3 or 4 (4a: P=Ac, 4b: P=TBDMS, 1 equiv., −78°C, 1
h; 20°C, 1 h). The reaction proceeds quite efficiently
and allows the production of the bicyclic derivatives 2
and 5 in good yields (Scheme 2, Table 1).
Although these could be prepared2 by cyclopropanation
of enones 3 and 4 with suitable substituted sulfuranes,
it was known that diphenylsulfonium salts3 could nei-
ther be prepared from diphenyl sulfide and 1-aryl eth-
ane bearing a leaving group at the C1 position nor from
benzyl diphenylsulfonium salts by sequential metala-
tion–methylation reactions.3,4
The syn/anti-ratio of stereoisomer is highly dependant
on the nature of both the enone and the ylide (Table 1),
whereas extremely high stereocontrol leading to the
exo-epimer, is all the time observed. Although this
might result from steric interactions between the 4-sub-
stituent on 4 and the bulky benzylidene diphenylsul-
furanes, we have to recall that ethylidene
diphenylsulfurane provided mainly the endo-stereoiso-
mer from the silyloxy derivative 4b.2a,†
The first experiments have been carried out with
diphenylsulfonium tetrafluoroborate salts (1.2 equiv.)
derived from primary benzyl halides (Ar: Ph, p-NO2-
Ph) on sequential reaction (i) with LDA (1.2 equiv.,
Otherwise it is interesting to note the extremely high
but divergent stereocontrol especially achieved with
Scheme 1.
* Corresponding author. Tel.: +32 81 724539; fax: +32 81 724536; e-mail: alain.krief@fundp.ac.be
† The exo-stereoisomer is nevertheless produced from ethylidenediphenylsulfurane and 4a bearing an acetoxy group.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01017-1

5872
A. Krief et al. / Tetrahedron Letters 43 (2002) 5871–5873
Scheme 2.
p-nitrophenyl derivatives on the enedione 3 and the
g-silyloxy enone 4b (Table 1, entries b and f) and which
contrasts with the poor stereoselectivity provided by the
related g-acetoxy derivative 4a (Table 1, compare entry
d with entries b and f).
Those latter sulfonium salts, unsubstituted at their ben-
zylic site, led to cyclopropane derivatives on reaction
with the enones 3 or 4 under conditions described
above for their diphenyl sulfonium analogs (Scheme 3,
Table 2, entries a–f). This procedure neither works with
the p-nitro-phenyl derivative nor with the homologous
sulfonium salts bearing a methyl substituent at the
benzylic position.
The next objective was the synthesis of geminally aryl-
methyl substituted cyclopropane derivatives and there-
fore the synthesis of the corresponding sulfonium salts.
The latter have finally been successfully prepared, in
almost quantitative yields, from 1-bromo-1-phenyl eth-
ane and its phenyl-substituted analogues (p-Me-, p-
NO2- and p-Cl-Ph) using the more nucleophilic
tetrahydrothiophene (THT)5 rather than diphenyl
sulfide (1.1 equiv. ArCH(Me)X, 2 equiv. THT, 1 equiv.
AgBF4, acetone, 0°C, 4 h). The same procedure also
allows the synthesis of lower homologues from bro-
momethyl benzene and its p-substituted phenyl deriva-
tives (Scheme 3).
Cyclopropanation of enones 3 and 4 was nevertheless
successfully achieved from the sulfonium salt derived
from THT and 1-bromo-1-phenyl ethane at the only
condition that the whole process is carried out at much
Table 2. Reaction of enones 3 and 4 with the benzylidene
sulfuranes derived from THT according to Scheme 2
3 or 4
Ar
R1
Yield (%)
syn
anti
Table 1. Reaction of enones 3 and 4 with benzylidene
a
b
c
d
e
f
g
h
i
3
3
C6H5
p-Me-C6H4
C6H5
H
H
H
H
H
H
Me
Me
Me
72
69a
84
82
88b
87
73
73
73
40
13
50
37
50
50
63
10
05
60
87
50
63
50
50
37
90
95
diphenylsulfuranes according to Scheme 3
4a
4b
4a
4b
3
3 or 4
Ar
R1 2 or 5 (%)
syn
anti
C6H5
p-Me-C6H4
p-Me-C6H4
C6H5
C6H5
C6H5
a
b
c
d
e
f
3
3
4a
4a
4b
4b
C6H5
p-NO2-C6H4
C6H5
p-NO2-C6H4
C6H5
p-NO2-C6H4
H
H
H
H
H
H
86
94
60
45
91
60
88
99.5
50
55
10
0
12
0.5
50
45
90
4a
4b
a Polluted by a small percentage of impurities.
b Traces (1%) of the endo-isomers are observed by 1H NMR.
100
Scheme 3. Synthesis of benzylic sulfonium salts derived from tetrahydrothiophene.
‡ It avoids extensive decomposition of the ylide leading to styrene when the reaction is carried out at −78°C (a yellow color appears once the base
is introduced to the medium but immediately fades). This might result from the rearrangement of the benzylidene sulfurane or from extensive
metalation of the THT moiety followed by an intramolecular b-elimination reaction.6

A. Krief et al. / Tetrahedron Letters 43 (2002) 5871–5873
5873
References
lower temperature (−100°C) with higher amounts of
dichloromethane in which the salt is more soluble
(Table 2, entries g–i).‡ Surprisingly enough, this reac-
tion cannot be extended to aryl substituted derivatives
including the p-methyl substituted one.
1. (a) Krief, A.; Letesson, J.-J.; Swinnen, D.; Billen, D.
Synlett 2001, 931; (b) Krief, A.; Letesson, J.-J.; Billen, D.
Tetrahedron Lett., in press.
2. (a) Krief, A.; Swinnen, D. Tetrahedron Lett. 1996, 37,
7123; (b) Kreiser, W.; Wiggermann, A.; Krief, A.; Swin-
nen, D. Tetrahedron Lett. 1996, 37, 7119; (c) Krief, A.
Pestic. Sci. 1994, 41, 237.
Comparison of the stereochemical results presented in
Table 2, with those described in Table 1 shows that
again the exo-stereoisomers are in all cases produced
from 4 but the reaction involving sulfur ylides derived
from tetrahydrothiophene unsubstituted at the ben-
zylic carbon is generally less syn/anti-stereoselective
(Table 2, entries a–f; compare Table 2, entry a with
Table 1, entry a and Table 2, entry d with Table 1,
entry e).
3. LaRochelle, R. W.; Trost, B. M.; Krepski, L. J. Org.
Chem. 1971, 36, 1126.
4. (a) Corey, E. J.; Jautelat, M.; Oppolzer, W. Tetrahedron
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Chem. 1992, 57, 6265; (c) Zhang, R.; Madaglengoitia, J.
S. J. Org. Chem. 1999, 64, 547.
5. (a) Furstner, A.; Weintritt, H. J. Am. Chem. Soc. 1997,
119, 2944; (b) Hetschko, M.; Gosselck, J. Chem. Ber.
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6. (a) Halazy, S.; Krief, A. Tetrahedron Lett. 1979, 4233; (b)
Halazy, S.; Krief, A. J. Chem. Soc., Chem. Commun.
1979, 1136.
However, very high stereocontrol has been unexpect-
edly observed from enones 4 and sulfonium salts
bearing a methyl group at the benzylic carbon (Table
2, entries h and i, compare Table 2, entry h with
entry c and entry i with entry d).