Asymmetric synthesis of cyclopropanes with a monofluorinated quaternary stereocenter

Article abstract of DOI:10.1021/ol3024264

New chiral fluorinated reagents (N-(dibromofluoroacetyl)oxazolidinones) were easily synthesized and used in an asymmetric cyclopropanation process. The Michael initiated ring closure reaction provided chiral cyclopropanes bearing a fluorinated quaternary stereocenter. Various electron-deficient alkenes can be used to efficiently obtain chiral polysubtituted fluorinated cyclopropanes in good yields. Moderate to very good cis/trans ratios were obtained with a high level of diastereoselectivity for each isomer.

Full text of DOI:10.1021/ol3024264

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5130–5133
Asymmetric Synthesis of Cyclopropanes
with a Monofluorinated Quaternary
Stereocenter
Pavel Ivashkin, Samuel Couve-Bonnaire, Philippe Jubault,* and Xavier Pannecoucke
ꢀ
INSA de Rouen, UMR 6014 & FR 3038, C.O.B.R.A. Universite de Rouen,
ꢁ
1 rue Tesniere 76131 Mont-Saint-Aignan Cedex, France
philippe.jubault@insa-rouen.fr
Received September 1, 2012
ABSTRACT
New chiral fluorinated reagents (N-(dibromofluoroacetyl)oxazolidinones) were easily synthesized and used in an asymmetric cyclopropanation
process. The Michael initiated ring closure reaction provided chiral cyclopropanes bearing a fluorinated quaternary stereocenter. Various
electron-deficient alkenes can be used to efficiently obtain chiral polysubtituted fluorinated cyclopropanes in good yields. Moderate to very good
cis/trans ratios were obtained with a high level of diastereoselectivity for each isomer.
Presently, the cyclopropylscaffoldand thefluorineatom
are both used for the design and the development of
new bioactive compounds. The fluorinated cyclopropanes
which combine the unique electronic and structural prop-
erties of these two entitieshave already proven tobeof high
interest for the discovery of efficient therapeutic agents.1
Only very few examples of asymmetric synthesis of mono-
fluorinated cyclopropanes have been reported to date.
Haufe et al. have developed the enantioselective cyclopro-
panation of R-fluorostyrenes with ee values up to 99% and
moderate diastereoselectivity.2 Imura et al. reported the
enzymatic resolution3 of 2-fluorocyclopropanecarboxy-
lates. Terashima et al. used a chiral enamine as a substrate
in the SimmonsꢀSmith-like reaction with a fluorinated
zinc carbenoid.4 A good level of facial selectivity was
observed, however with moderate cisꢀtrans selectivity.
Most notably, in a recent work by Hu et al., an efficient
asymmetric cyclopropanation using a chiral fluorinated
sulfoximine was developed.5 Ee values of 93ꢀ98% and
excellent diastereoselectivity were demonstrated for the
cyclopropanes with a tertiary fluorinated carbon from
aromatic and aliphatic R,β-unsaturated Weinreb amides.
These authors also reported the application of sulfoximine
methodology to the synthesis of two cyclopropanes with a
quarternary fluorinated stereocenter (1-fluoro-1-methyl-
cyclopropanes). This time, ee values of 76% and 86% were
observed.
Here we report another approach to the asymmetric
synthesis of quarternary fluorinated cyclopropanes based
on the use of a new chiral N-(dibromofluoroacetyl) oxazo-
lidinone 2. Resulting 1-fluorocyclopropylcarboxylamides 3
can be readily converted into the corresponding acids and
esters thus opening a route to the highly functionalized
monofluorinated cyclopropanes6 in enantiomeric pure
form, which have never been, to our knowledge, described.
(1) (a) Yoshida, S.; Rosen, T. C.; Meyer, O. G. J.; Rosen, T. C.;
Sloan, M. J.; Ye, S.; Haufe, G.; Kirk, K. L. Bioorg. Med. Chem. 2004, 12,
2645. (b) Ye, S.; Yoshida, S.; Frohlich, R.; Haufe, G.; Kirk, K. L. Bioorg.
€
Med. Chem. 2005, 13, 2489. (c) Hruschka, S.; Rosen, T. C.; Yoshida, S.;
€
Kirk, K. L.; Frohlich, R.; Wibbeling, B.; Haufe, G. Bioorg. Med. Chem.
2008, 16, 7148. (d) Nakazato, A.; Kumagai, T.; Sakagami, R.; Yoshi-
kawa, R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi, S.;
Okuyama, S. J. Med. Chem. 2000, 43, 4893. (e) Nakazato, A.; Sakagami,
K.; Yasuhara, A.; Ohta, H.; Yoshikawa, M.; Itoh, M.; Nakamura, M.;
Chaki, S. J. Med. Chem. 2004, 47, 4570. (f) Sakagami, K.; Yasuhara, S.;
Chaki, S.; Yoshikawa, R.; Kawakita, Y.; Saito, A.; Taguchi, A.;
Nakazato, A. Bioorg. Med. Chem. 2008, 16, 4359.
(2) (a) Meyer, O. G. J.; Frohlich, R.; Haufe, G. Synthesis 2000, 1479.
(b) Hruschka, S.; Frohlich, R.; Kirsch, P.; Haufe, G. Eur. J. Org. Chem.
2007, 141.
(4) Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani,
K.; Kamada, M.; Hayakawa, I.; Akiba, T.; Terashima, S. Tetrahedron Lett.
1992, 33, 3487.
(3) Imura, A.; Itoh, M.; Miyadera, A. Tetrahedron: Asymmetry 1998,
9, 3047.
(5) Shen, X.; Zhang, W.; Luo, T.; Wan, X.; Gu, Y.; Hu, J. Angew.
Chem., Int. Ed. 2012, 51, 6966.
r
10.1021/ol3024264
Published on Web 09/27/2012
2012 American Chemical Society

Based on our previous studies on cyclopropanation
using ethyl dibromofluoroacetate,7 we decided to ex-
plore the stereodiscriminating ability of a series of
chiral auxiliaries bound to a common dibromofluoro-
acetyl core. Starting chiral reagents 2aꢀd were pre-
pared in moderate to good yield via the acylation of the
commercially available oxazolidinones1 with CFBr2COCl
(Scheme 1).
lower diastereoselectivity in terms of the absolute config-
uration of the fluorinated stereocenter. To our delight, the
combination of zinc and lithium chloride provided again
the best results (yield and diastereoselection).
Table 2. Cyclopropanation of Benzyl Acrylate with 2c and
Various Metalating Reagents
reagent
tBuLi
yield,a %
cis/transa
dea (trans)
23
64
43
<5
79b
4:96
7:93
5:95
ꢀ
74
18
46
ꢀ
Scheme 1. Preparation of Oxazolidinones 2
iPrMgCl
iPrMgCl/LiCl
Et2Zn
Zn/LiCl
21:79
93
a Determined by 19F NMRwith trifluoroacetophenone as an internal
standard. b Isolated yield.
Thus, with this optimized procedure in hand, the scope
of the cyclopropanation with this new chiral reagent 2c
is given in the Table 3. Reaction takes place with di-
verse monosubstituted Michael acceptors bearing an ester
(entries 1,2), sulfone (entry 3), phosphonate (entry 4), or
nitrile (entry 5) as an electron-withdrawing group leading
to the expected fluorinated cyclopropanes in good to very
Results of the model reaction with benzyl acrylate and
Zn/LiCl8 are given in Table 1. Increasing the size of a side
group clearly leads to better de values for both cis- and
trans-isomers with a concurrent decrease in cisꢀtrans
selectivity. Given the high de values and better stability
demonstrated by 2c, we decided to use this reagent for
further cyclopropanation studies.
Scheme 2. Transformations of Cyclopropanes 3
In addition to an established method of cyclopropa-
nation based on Zn/LiCl, we examined several other
metalating reagents (Table 2). Despite high cisꢀtrans
ratios, all of them demonstrated poorer yields and much
Table 1. Stereochemistry of the Model Reaction of Benzyl
Acrylate with 2aꢀd
a Determined by chiral HPLC. b For determination of ee, the acid 5
was converted to the corresponding methyl ester with 65% yield. See
Supporting Information for details.
2
cis/transa
dea (cis)
dea (trans)
a
b
c
3:97
16:84
21:79
27:73
52
84
84
86
68
86
93
88
d
a Determined by 19F NMR of the crude product.
(6) For several examples of relevant transformations, see: Lemonnier,
G.; Lion, C.; Quirion, J.-C.; Pin, J.-P.; Goudet, C.; Jubault, P.Bioorg. Med.
Chem. 2012, 20, 4716.
(7) Ivashkin, P.; Couve-Bonnaire, S.; Jubault, P.; Pannecoucke, X.
Org. Lett. 2012, 14, 2270.
(8) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Figure 1. X-ray structures of trans-3a and 6.
Angew. Chem., Int. Ed. 2006, 45, 6040.
Org. Lett., Vol. 14, No. 19, 2012
5131

Table 3. Scope of the Cyclopropanation Reaction with a Chiral Oxazolidinone 2c
a Absolute configuration of the cyclopropanes is based on the stereochemical model given in Scheme 3 (for definition of Y see Table 1). b Isolated yield
of both isomers. c Determined by 19F NMR of the crude product. d Single isomer by 19F NMR of the isolated product. e Equimolar mixture of isomers is
formed. f 1.5 equiv of acrylonitrile was used. g Absolute configuration cannot be deduced from our stereochemical model (Scheme 3). h Cisꢀtrans ratio
refers to the stereochemistry of ester groups. i After 1 h at ꢀ20 °C the reaction mixture was stirred at rt overnight.
good overall yields. Di- and trisubstituted alkenes also
react with good overall yields and generally the same level
of diastereoselectivity (entries 6ꢀ9). In most cases the
diastereomerically pure fluorinated cyclopropanes can be
easily separated by column chromatography.
Cleavage of the chiral auxiliary in acrylate-derived
cyclopropanes trans-3a and trans-3b was carried out under
either acidic or basic conditions leading to the ester 4 and
the acid 5, respectively (Scheme 2). In both cases it
proceeded smoothly with no epimerization of the cyclo-
propane and very good recovery of the chiral auxiliary.9
Alternatively, the benzyl ester group, from cis-3a, can be
selectively cleaved by hydrogenolysis. It was then further
transformed into the amide derivative in order to simplify
the analysis procedure.
the two major isomers (cis and trans) of 3a by single-crystal
X-ray analysis (Figure 1). While trans-3a can be easily
crystallized from the crude product, cis-3a had to be
converted into the N-4-bromobenzylamide 6 in order to
obtain crystals of sufficient quality for X-ray analysis.
Both isomers share the same absolute configuration (S)
of the fluorinated stereocenter and differ in the position of
the ester group for trans-3a (amide group for 6).
Formation of a pair of epimeric products during the
MIRC-type cyclopropanation is consistent with highly
stereoselective 1,4-addition followed by a less selective
cyclization leading to a mixture of cis- and trans-isomers
(Scheme 3). Although we do not know the exact structure
of the unstable organozinc intermediate A, it possibly
reacts as a chelated enolate as depicted in Scheme 3. In
such an intermediate the (Z)-configuration of a double
bond should be preferred based on the steric effect of the
voluminous bromine atom. This model can also explain
the observed lowering of cisꢀtrans selectivity with the
increase of bulkiness of the chiral auxiliary (see Table 1).
The cisꢀtrans selectivity of the cyclopropanation of
unsaturated esters may be controlled by chelation in
intermediate B, leading to the preferential formation
Presently, cyclopropanation demonstrates relatively
high diastereoselectivity but, at the same time, highly
variable cisꢀtrans ratios for different types of substrates.
In order to elucidate the origin of this complex stereo-
chemistry we determined the absolute configurations of
(9) See Supporting Information for the synthesis of racemic fluori-
nated cyclopropanes and ee determination.
5132
Org. Lett., Vol. 14, No. 19, 2012

Scheme 3. Stereochemical Model Based on the X-ray Data for trans-3a and 6
of a trans-isomer. This is in contrast with the cis-selective
formation of the sulfone- and phosphonate-derived pro-
ducts 3c,d. The difference may account for a steric effect
of heavy heteroatoms or a change in the mechanism, e.g.
participation of a C-metalated analog of the intermediate B.
Further studies on the structure and reactivity of sul-
fur- and phosphorus-stabilized organozinc compounds
are needed in order to develop a consistent stereochem-
ical model. The stereochemistry of fumarate-derived
cyclopropane 3h is dominated by the 1,2-repulsion of
ester groups which results in the preferential formation
of a pair of isomers in which the two ester groups adopt
a trans relationship.
incorporation of this type of fluorinated scaffolds in
more complex structures are currently under investiga-
tion in our laboratory.
Acknowledgment. This work was supported by MESR
0
ꢁ
ꢀ
(Ministere de l Enseignement Superieur et de la Recherche),
the Region Haute-Normandie (CRUNCH program),
ꢀ
CNRS, University of Rouen, and INSA of Rouen. This
work was also supported by ERDF funding through the IS:
CE-Chem project and Interreg IV A France (Channel) ꢀ
England Program. Both are gratefully thanked for their
financial support (grant to P.I.).
In conclusion, a straightforward two-step procedure for
the asymmetric synthesis of highly functionalized enantio-
merically pure monofluorocyclopropanes was devel-
oped. A stereochemical model of cyclopropanation is
proposed based on the X-ray analysis of major prod-
ucts. Further developments especially devoted to the
Supporting Information Available. Experimental pro-
cedures, spectral data for the new compounds, crystal-
lographic information. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5133