A porphyrin-inspired iron catalyst for asymmetric epoxidation of electron-deficient olefins

Article abstract of DOI:10.1021/acs.orglett.5b00018

An in situ formed porphyrin-inspired iron complex that catalyzes asymmetric epoxidation of di- and trisubstituted enones is described. The reaction provides highly enantioenriched α,β-epoxyketones (up to 99% ee). The practical utility of the new catalyst

Full text of DOI:10.1021/acs.orglett.5b00018

Letter
pubs.acs.org/OrgLett
A Porphyrin-Inspired Iron Catalyst for Asymmetric Epoxidation of
Electron-Deficient Olefins
†
,‡,§
†,‡,§
Bo Chen, Lianyue Wang,†,‡ and Shuang Gao*,†,‡
†,‡
Wen Dai,
Guosong Li,
†
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences, Dalian, 116023, People’s Republic of China
Dalian National Laboratory for Clean Energy, the Chinese Academy of Sciences, Dalian, 116023, People’s Republic of China
‡
*
S Supporting Information
ABSTRACT: An in situ formed porphyrin-inspired iron complex that catalyzes asymmetric epoxidation of di- and trisubstituted
enones is described. The reaction provides highly enantioenriched α,β-epoxyketones (up to 99% ee). The practical utility of the
new catalyst system is demonstrated by the gram-scale synthesis of optically pure epoxide. Hammett analysis suggests that the
transition state of the reaction is electron-demanding and the active oxidant is electrophilic.
he past decades have witnessed rapid progress in the
possessed excellent tolerance for oxidation reactions. With this
background in mind, it was envisioned that we could develop a
highly enantioselective asymmetric epoxidation catalyst for
electron-deficient olefins exploring the iron in combination
with the porphyrin-inspired ligands (Scheme 1). Herein, we
T
asymmetric epoxidation of olefins with chiral organo-
1
2
catalysts and metal-based catalysts. Among existing catalytic
approaches, iron-catalyzed asymmetric epoxidation should offer
many remarkable advantages, as iron is abundant, cheap, and
relatively nontoxic in comparison to other metals and shows
3
variable oxidation states. However, iron-catalyzed asymmetric
Scheme 1. Strategy of Asymmetric Epoxidation of Electron-
epoxidations that can be refined to find application in the
Deficient Olefins
preparation of fine chemicals and pharmaceuticals remain
4
scarce. In view of toughening environmental concerns,
numerous efforts have been dedicated to the development of
iron-based biomimetic or bioinspired systems for asymmetric
epoxidation owing to metalloenzyme-catalyzed reactions
usually exhibiting high reactivity and operating under a green
5
process. Among them, asymmetric epoxidation based on iron
porphyrins, which are the mimics of the cytochrome P450
active site, has been the most extensively studied. Since the
initial success achieved in asymmetric epoxidation using an iron
porphyrin catalyst by Groves in 1983, other catalytic systems
based on iron porphyrins have also been developed and a high
level of enantioselectivity for certain classes of electron-rich
olefins such as styrene derivatives using an environmentally
6
unfriendly oxidant has been achieved. However, asymmetric
epoxidation of the challenging electron-deficient olefins with
iron porphyrins has not been reported until now.
report an efficient and highly enantioselective epoxidation
method of electron-deficient olefins by an in situ formed
porphyrin-inspired chiral iron complex in high yields (up to
We recently developed a new type of porphyrin-inspired N4
ligands bearing chiral oxazoline moieties derived from a chiral
amino alcohol that fulfilled the structural requirements of the
porphyrin ligand in some way. The porphyrin-inspired ligands
have been successfully applied in the manganese-catalyzed
asymmetric epoxidation of electron-rich olefins and asymmetric
9
4%) with excellent enantioselectivities (up to 99% ee), as well
as application of the method to the gram-scale synthesis of
optically pure epoxide.
Received: January 4, 2015
5
d,7
sulfoxidation.
Meanwhile, we demonstrated that the ligands
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00018
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
,b
The development of a general and efficient strategy for
asymmetric epoxidation of trisubstituted cyclic enones is highly
valuable and desirable, as trisubstituted cyclic α,β-epoxyketones,
which possess a chiral quaternary carbon center, are valuable
and versatile ubiquitous structural motifs in organic synthesis
Scheme 2. Substrate Scope of Epoxidation
4c,8
and biologically active compounds. Therefore, we began our
studies with trisubstituted cyclic enones 1a as the model
substrate to assay the best reaction conditions. To evaluate the
ligands, the epoxidation of 1a was initially performed in
acetonitrile at −20 °C with the iron complexes generated in situ
from 5 mol % Fe(OTf) and 5 mol % ligand in the presence of
2
m-CPBA (Table 1, entries 1−8) . To our delight, ligand L2 was
Table 1. Screening the Reaction Conditions
a
b
entry
ligand
oxidant
% yield
% ee
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L2
L2
L2
L2
L2
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
53
54
−
54
78
−
48
54
50
40
54
82
89
90
−
64
65
72
65
64
79
79
82
−
c
9
a
d
Reaction conditions: substrate (0.1 mmol), 30% CH CO H (0.2
1
1
1
1
1
0
1
2
3
4
3
3
e
f
mmol, diluted with 0.1 mL CH CN), Fe(OTf) (10 mol %), L2 (10
3 2
b
mol %), CH CN (1.5 mL), −20 °C, 2 h. Isolated yield. The ee values
3
H O
2
2
c
g
h
were determined by chiral HPLC. m-CPBA (0.2 mmol) was used as
t-BuOOH
−
93
−
85
oxidant.
L2
CH CO H
3
3
a
b
c
Isolated yield. Determined by chiral HPLC analysis. m-CPBA (1.5
d
e
side led to a significant increase in enantioselectivity relative to
the para- and meta-position, probably because of steric
hindrance which is favorable in controlling the enantioselectiv-
ity (Scheme 2, entries 2b−d versus 2g−i, 2k, and 2l).
Presumably as a result of the electron effect, the substrates
containing strong electron-withdrawing substituents such as
nitro or trifluoromethyl groups at the ortho- and para-position
resulted in a deleterious effect on the yield, albeit with good to
excellent enantioselectivity (Scheme 2, entries 2e, 2f, 2m, and
2n). Interestingly, when there was an electron-withdrawing
trifluoromethyl group at the meta-position, excellent enantio-
selectivity and yield were obtained (Scheme 2, entry 2j). A
substrate bearing methyl at the para-position gave the highest
yield (Scheme 2, entry 2o), whereas a substrate with a nitro
group at the para-position led to the lowest one under identical
conditions (Scheme 2, entry 2n), which strongly suggested that
the electronic properties of substrates played a crucial role in
the yields of the asymmetric epoxidation. Encouraged by these
findings, we turned our attention to the cyclic enones
derivatives with two substituents on the phenyl rings.
Gratifyingly, the ee values of the desired epoxides except 2r
were excellent (Scheme 2, entries 2p−v). To extend the
equiv). m-CPBA (2.0 equiv). m-CPBA (2.0 equiv), Fe(OTf) (10
mol %), L2 (10 mol %). H O (2.0 equiv), Fe(OTf) (10 mol %), L2
2
f
2
2
2
g
(
10 mol %). t-BuOOH (2.0 equiv), Fe(OTf) (10 mol %), L2 (10
2
h
mol %). CH CO H (2.0 equiv), Fe(OTf) (10 mol %), L2 (10 mol
3
3
2
%
).
identified as the ligand being the most favorable in view of
enantioselectivity and yield. Subsequently, the oxidant loading
of m-CPBA was examined. We found that the best result was
achieved upon addition of 2 equiv of m-CPBA (Table 1, entries
9
and 10). It is worthy of note that the enantioselectivity
increased when the catalyst loading was raised to 10 mol %
Table 1, entry 11). Finally, the identity of the oxidant was
investigated. When m-CPBA was replaced with H O or t-
(
2
2
BOOH, no desired product was obtained (Table 1, entries 12
and 13). Gratifyingly, using CH CO H as the oxidant led to
further improvement in terms of enantioselectivity and yield
3
3
(
Table 1, entry 14).
With the optimized conditions in hand, we next set out to
explore the substrate scope using a variety of di- and
trisubstituted enones (Scheme 2). Introducing a halogen
substituent at the ortho-position of phenyl groups of the olefin
B
DOI: 10.1021/acs.orglett.5b00018
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrate scope further, we expected that the disubstituted
enone derivative would also be epoxidized. Fortunately, the
present epoxidation could also be successfully applied to a
chalcone derivative, giving the corresponding epoxide in high
yields with moderate enantioselectivity (Scheme 2, entry 2w).
To probe the nature of active oxidant, competitive
asymmetric epoxidations of p-substituted cyclic enones were
conducted under optimized conditions. We found a good linear
In summary, we have successfully developed a highly efficient
and general catalytic asymmetric epoxidation method that
employs an inexpensive and easily available porphyrin-inspired
chiral iron complex, allowing for the epoxidation of a wide
variety of multisubstituted enones in excellent yields with ee
values up to 99%. Hammett analysis confirmed that the active
oxidant was electrophilic, and the practical utility of the catalyst
system was demonstrated by the gram-scale synthesis of the
optically active epoxide. In addition, good results were still
maintained when a low concentration of peracetic acid was
used in our catalyst system. Further studies on the precise
mechanism and extension of the catalyst to other reactions are
underway in our laboratory.
+
+
correlation between the log(k /k ) and σ with negative ρ =
X
H
p
−
0.52 which indicated that the transition state of the reaction
was electron-demanding and the active oxidant was electro-
2n,9
philic (Figure 1).
The above results provided solid evidence
against our catalyst system processing though a nucleophilic
10
Weitz−Scheffer-type epoxidation mechanism.
ASSOCIATED CONTENT
■
*
S
Supporting Information
Experimental procedures, compound characterization data, and
HPLC data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: sgao@dicp.ac.cn.
Author Contributions
§
W.D. and G.L. contributed equally.
Notes
+
p
Figure 1. Hammett plots of log(k /k ) vs σ for the epoxidation of
para-substituted cyclic enones.
The authors declare no competing financial interest.
X
H
ACKNOWLEDGMENTS
This work was gratefully financially supported by the National
Basic Research Program of China (2009CB623505).
■
To further evaluate the practical utility of the catalyst system,
the epoxidation of cyclic enone 1c was carried out on gram
scale under the optimized conditions, and the desired product
2
c was furnished with 82% yield and 91% ee after a prolonged
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