Iron(II)-catalyzed asymmetric epoxidation of trisubstituted α,β-unsaturated esters

Article abstract of DOI:10.1002/ejoc.201403220

The asymmetric epoxidation of trisubstituted α,β-unsaturated esters was developed. The oxidation utilizes a pseudo-C₂-symmetric iron(II) catalyst [Fe(L)₂(CH₃CN)(OTf)](OTf) (Tf = trifluoromethylsulfonyl) and pera

Full text of DOI:10.1002/ejoc.201403220

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403220
Iron(II)-Catalyzed Asymmetric Epoxidation of Trisubstituted α,β-Unsaturated
Esters
[a]
[a,b]
Lan Luo and Hisashi Yamamoto*
Keywords: Synthetic methods / Asymmetric synthesis / Epoxidation / Enantioselectivity / Iron
The asymmetric epoxidation of trisubstituted α,β-unsaturated
esters was developed. The oxidation utilizes a pseudo-C
symmetric iron(II) catalyst [Fe(L*) (CH CN)(OTf)](OTf) (Tf =
2 3
trifluoromethylsulfonyl) and peracetic acid as oxidant and
yields α,β-epoxy esters with high enantiomeric purity (up to
99%ee).
2
-
Introduction
Nevertheless, the utilization of enantioenriched epoxy
ketones is relatively narrow compared to epoxy esters,
which can be readily converted into other functional groups
such as epoxy carboxylic acid, amides, and alcohols. Given
such exciting results as those obtained with β,β-disubsti-
tuted enones, we turned our attention to α,β-unsaturated
esters, from which derivations are expected to be fruitful.
Examples of other systems that target α,β-unsaturated
The oxidation reaction is one of the most powerful and
fundamental transformations in organic chemistry. Among
oxidation reactions, epoxidation of alkenes has been exten-
sively studied, as subsequent ring opening of epoxides af-
fords versatile building blocks for the synthesis of more
complex molecules. Pioneering contributions to asymmetric
epoxidation, such as Katsuki–Sharpless epoxidation and
Jacobsen epoxidation,[ have involved the use of chiral
metal complexes.
Since then, methods for epoxidation have flourished, in-
cluding those towards electron-deficient olefins, which are
less reactive to electrophilic oxidants. Approaches to these
targets are typically nucleophilic and generally execute
through a Weitz–Scheffer-type mechanism. Examples of
[
1]
[9]
[10]
esters are yttrium-chiral biphenyldiol, chiral dioxirane,
2]
[11]
and chiral Mn–salen complexes.
More recently, Cussó
[12]
et al. reported a chiral Fe–bipyrrolidine catalyst that was
used to access a wide range of carbonyl-adjacent olefins,
including α,β-unsaturated esters.
Results and Discussion
[
3]
such systems include chiral ligand--metal peroxides,
phase-transfer catalysts,[ and polyamino acid catalysts.
4]
[5]
Unlike the majority of epoxidations of α,β-unsaturated
However, no single method can serve as the ultimate solu- esters, which generally employ disubstituted trans-alkenes,
[
6]
tion for the epoxidation of electron-deficient systems.
Bioinspired iron complexes, in particular, caught our at- An initial trial with the –C(CH ) (iPr) ester (Table 1) by
we started with the less reported trisubstituted (E)-alkene.
3
2
tention, owing to their low cost, abundance, and environ- using conditions similar to those reported in preceding
[
7]
mentally benign nature. In fact, many iron catalysts have work gave valuable results. Upon brief optimization of the
been developed in the past, including heme and non-heme reaction conditions, we found performing the reaction at
biomimetic systems.[ Our interest in β,β-disubstituted en- –20 °C significantly deteriorated the yield and enantio-
ones and α,β-unsaturated esters prompted our development selectivity (Table 1, entry 4), whereas raising the tempera-
of a non-heme phenanthroline-based ligand for the epoxid- ture to 20 °C produced a lower yield but similar selectivity.
ation of unsaturated carbonyl compounds. This catalyst has Two equivalents of peracetic acid were also observed to be
been proven to be effective in the asymmetric epoxidation the most desirable conditions (Table 1, entry 2). In addition,
of β,β-disubstituted enones, which are sterically congested stirring the complex formation and epoxidation reactions at
7]
[
8]
at the β carbon and thus have been hitherto inaccessible.
1200 rpm was important to provide ideal results in terms of
yields and enantioselectivities. Prompt addition of the oxi-
dant was also desirable, presumably owing to the short life-
time of the iron–oxo species.
[
[
a] Department of Chemistry, The University of Chicago,
5
735 South Ellis Avenue, Chicago, Illinois 60637, USA
Realizing that the –C(CH ) (iPr) ester generated better
3
2
E-mail: yamamoto@uchicago.edu
http://yamamotogroup.uchicago.edu/main.html
b] Molecular Catalyst Research Center, Chubu University,
results than the tert-butyl ester (Table 2, entries 1 and 2),
we further screened a variety of alkoxy moieties on the ester
that could serve as an auxiliary group for improving stereo-
chemical induction. Subsequent screening of different esters
1
200 Matsumoto, Kasugai, Aichi 487-8501, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403220.
Eur. J. Org. Chem. 2014, 7803–7805
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7803

L. Luo, H. Yamamoto
SHORT COMMUNICATION
Table 1. Optimizing reaction conditions for the epoxidation of α,β-
unsaturated esters.
Table 2. Asymmetric epoxidation of α,β-unsaturated esters cata-
lyzed by chiral Fe–phenanthroline catalyst.
[
a]
[a]
Entry[a]
R1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
tBu
49
58
69
30
43
26
18
90
94
95
70
90
76
63
C(CH
C(CH
iPr
C(Et)
CH(tBu)
3
3
)
)
2
2
(iPr)
(tBu)
3
2
cyclododecanyl
Entry
AcOOH
Temperature
[°C]
Yield[b]
[%]
ee[c]
[%]
[a] All reactions were performed on a 0.15 mmol scale by using
[equiv.]
Fe(OTf) (5 mol-%), ligand (10 mol-%), peracetic acid (32 wt.-% in
2
3
dilute acetic acid, 2 equiv.) in CH CN (0.6 mL) at 0 °C and
quenched after 2 h. [b] Yield of isolated product. [c] Determined by
HPLC on a chiral stationary phase.
1
2
3
4
5
6
7
8
1.8
2
2.2
2
2
2
0
0
0
–20
20
0
42
58
51
32
38
43
57
54
92
94
86
66
92
78
86
95
Conclusions
[
[
[
d]
e]
f]
2
2
0
0
In summary, we developed a highly enantioselective
epoxidation of trisubstituted α,β-unsaturated esters cata-
CN lyzed by a chiral iron–phenanthroline complex by using per-
[
(
[
a] Unless otherwise stated, reactions were performed in CH
0.6 mL) and stirred at 1200 rpm. [b] Yield of isolated product.
c] Determined by HPLC on a chiral stationary phase. [d] Reaction
3
acetic acid as the oxidant. This oxidation enantioselectively
targets trans-α-methylcinnamic acid esters, of which the
was performed in 0.3 mL of CH
in 1.2 mL of CH CN. [f] Fe(OTf)
3
CN. [e] Reaction was performed
(10 mol-%. Tf = trifluoromethyl-
–
C(CH ) (tBu) and –C(CH ) (iPr) esters gave ideal results.
2 2 2 2
3
2
sulfonyl) and L* (20 mol-%) were used.
The enantioselectivity was remarkably high for substrates
bearing a large group at the β position and was maintained
even in cases of lower yields.
revealed the importance of the alkoxy group on the enantio-
selectivity of the reaction. As a general trend, tertiary
alcohol based esters (Table 2, entries 1–3 and 5) performed
better than secondary alcohol based esters (Table 2, en-
tries 4, 6, and 7), owing to higher steric hindrance. Among
Experimental Section
General Procedure for the Asymmetric Epoxidation of Unsaturated
Esters: A solution of Fe(OTf)
2
(0.32 mL, 0.008 mmol, 0.025 m in
CH CN) and CH CN (0.32 mL) were sequentially added to a
3
3
flame-dried test tube charged with ligand L* (10.3 mg, 0.016 mmol)
and a stir bar under a nitrogen atmosphere, which resulted in a
light yellow solution. The complex was stirred vigorously
(1200 rpm) for 2–3 h at room temperature. Another dry test tube
them, –C(CH ) (tBu) ester (Table 2, entry 3) provided an
2
2
optimum result with respect to both yield and enantio-
selectivity.
Our exploration into the substrate scope revealed that was charged with the substrate (0.15 mmol) and was flushed with
CN from
either the –C(CH ) (tBu) or –C(CH ) (iPr) ester could be nitrogen. The iron complex (0.6 mL, 0.0075 mmol) in CH
used to induce high enantioselectivity. Whereas in some
3
2
2
2 2
the first test tube was added by syringe, and the vessel was cooled
to 0 °C for 10 min with vigorous stirring (1200 rpm). Peracetic acid
cases the –C(CH ) (tBu) ester gave a higher yield and ee
2
2
(
63 μL, 32 wt.-% in dilute acetic acid, 0.3 mmol) was added to the
(Table 3, 4a and 2c), it provided a lower yield than its
mixture by microsyringe at once, which yielded a near-black solu-
tion. The mixture was stirred at this temperature for 2 h and was
–
C(CH ) (iPr) analogue (see compounds 4b and 4e) if the
2
2
starting ester had lower solubility in acetonitrile. Neverthe-
less, high ee values were still maintained even in such cases.
Enantioselectivities were remarkably high for substrates
then quenched with 10% Na
3 mL). The mixture was extracted with CH
Na SO , and concentrated in vacuo. The residue was purified by
2
S
2
O
3
in 1:1 saturated NaHCO
3 2
/H O
(
2
2
Cl , dried with
2
4
with a large naphthyl group at the β position (see com- flash chromatography (hexane/CH Cl = 1:1) to furnish the epox-
2
2
pounds 4e, 4g, and 4j). In terms of reactivity, the epoxid- ide. The column was flushed with ethyl acetate (100%) to elute the
ation of para-substituted phenyl olefins gave a higher yield ligand.
of the epoxide product than meta- and ortho-substituted
ones. Although this catalytic system works well for phenyl
and naphthyl systems, it is not applicable to substrates bear-
Acknowledgments
ing an alkyl, furyl, or thienyl group at the β position of the This work was supported by the US National Institutes of Health
ester.
(NIH) (2R01GM068433). The authors thank Dr. Yasuhiro Nishi-
7804
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7803–7805

Iron(II)-Catalyzed Asymmetric Epoxidation
Table 3. Substrate scope of epoxidation.[a,b,c]
[
a] All reactions were performed on a 0.15 mmol scale by using Fe(OTf)
peracetic acid (32 wt.-% in dilute acetic acid, 2 equiv.) in CH CN (0.6 mL) at 0 °C and quenched after 2 h. [b] Yields of the isolated
products are given. [c] The ee values were determined by HPLC on a chiral stationary phase.
2
(5 mol-%), ligand (10 mol-%), substrate (0.15 mmol), and
3
kawa for his preliminary experimental results. Dr. Antoni Jurkiew-
icz and Dr. Jin Qin are thanked for their assistance in NMR spec-
troscopy and mass spectrometry, respectively.
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N. M. Garrido, I. S. Marcos, P. Basabe, J. G. Urones, Curr. Org.
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7
[
1
Published Online: November 6, 2014
Eur. J. Org. Chem. 2014, 7803–7805
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7805