A non-heme iron(III) complex with porphyrin-like properties that catalyzes asymmetric epoxidation

Article abstract of DOI:10.1021/ja304219s

In this report, we describe an iron(III) complex containing a carbazole-based tridentate ligand that catalyzes highly enantioselective asymmetric epoxidation of (E)-alkenes at room temperature. The non-heme iron(III) complex has a five-coordinated trigonal-bipyramidal structure, and its two-electron oxidized state has the similar electronic structure as that of iron porphyrins.

Full text of DOI:10.1021/ja304219s

Communication
pubs.acs.org/JACS
A Non-Heme Iron(III) Complex with Porphyrin-like Properties That
Catalyzes Asymmetric Epoxidation
Takashi Niwa* and Masahisa Nakada*
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo, 169-8555, Japan
S
* Supporting Information
structural requirements that can also accommodate the
ABSTRACT: In this report, we describe an iron(III)
complex containing a carbazole-based tridentate ligand
that catalyzes highly enantioselective asymmetric epox-
idation of (E)-alkenes at room temperature. The non-
heme iron(III) complex has a five-coordinated trigonal-
bipyramidal structure, and its two-electron oxidized state
has the similar electronic structure as that of iron
porphyrins.
introduction of a chiral environment near the iron center. We
envisioned that a 1,8-(bisoxazolyl)carbazole ligand developed in
our laboratory could serve this purpose even though it is a
tridentate and not tetradentate ligand (Figure 1). The
etalloporphyrins exist as catalytic centers in various
Menzymes, realizing surprising chemical transformations
with high efficiency.1 Interest in these systems has focused on
not only their biological and medical importance but also their
potential utility as efficient catalysts in organic synthesis.2
Hence, numerous studies of metalloporphyrins to elucidate the
reaction mechanisms of enzymes that contain them have been
reported thus far.3−8 Cytochrome P450 oxidases are well-
understood enzymes that contain iron porphyrins as catalytic
centers.9,10 These enzymes catalyze the oxidation of nonpolar
compounds including drugs, steroids, and pollutants using
dioxygen as a terminal oxidant with excellent efficiency.11
Because of their efficient catalysis, the reaction mechanism of
cytochrome P450 oxidases in metabolic reactions12−15 as well
as asymmetric catalysis has been extensively explored in order
to better understand the reaction mechanism of iron porphyrin
derivatives.16,17 However, the number of highly efficient and
practical metalloporphyrin-type catalysts that enable enantio-
selective transformations has been limited. This unfortunate
situation is attributable to the limited variations within
porphyrin ligands, which possess a highly planar structure
that prohibits flexibility in design as well as the introduction of
chirality near the metal center. Moreover, the preparation of a
porphyrin ligand bearing a variety of functional groups requires
many steps, rendering the screening and optimization of a
desired catalyst difficult.
Figure 1. Carbazole-based tridentate ligand as a surrogate porphrin
ligand.
carbazole-based tridentate ligand has planarity, relatively long
π-conjugation, and an acidic N−H that can become anionic and
exhibit strong σ-donation. Moreover, since the chiral oxazolines
that coordinate to the iron center are easily prepared from α-
amino acids, the chiral environment is easily introduced and
effectively tunable. 1,8-(Bisoxazolyl)carbazole ligands were
developed for asymmetric catalysis in Nozaki-Hiyama-Kishi
reactions in our laboratory,21 and we have demonstrated that
these ligands induce high enantioselectivity and have excellent
tolerance for redox reactions.
Herein, we report the development of a non-heme iron(III)
complex bearing a carbazole-based tridentate ligand that
displays iron porphyrin-like properties and catalyzes the
asymmetric epoxidation of (E)-alkenes with excellent enantio-
selectivity.22−24 The two-electron oxidized state of the complex
confers upon it a similar electronic state as those found in iron
porphyrins,25 even though the tridentate carbazole ligand and
porphyrins have different numbers of binding sites. We
demonstrate that the unique catalysis of iron porphyrins can
be mimicked by this iron complex bearing a carbazole-based
tridentate ligand, which features simple and straightforward
preparation as well as plenty extensive capacity for fine-tuning.
We found that the cationic iron(III) complex of 1a, which
was prepared from FeCl2·4H2O, the tridentate carbazole ligand,
and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl] borate
(NaBARF), catalyzed the asymmetric epoxidation of trans-
stilbene (2a) to afford the desired chiral epoxide 3a with
In 1983, Groves and co-workers reported the first
asymmetric epoxidation catalyzed by a chiral iron porphyrin
complex.18 However, despite considerable efforts to develop
asymmetric catalysis with chiral metalloporphyrins,17,19,20 an
easily available and practical iron porphyrin catalyst has not
been reported until now.
The unique properties of iron porphyrins are attributed to
the structure of the porphyrin ligand, which has a highly
conjugated planar structure with strong donor moiety. The
challenge lies in finding a new surrogate ligand that fulfills these
Received: May 2, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja304219s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
moderate yield and high enantioselectivity (Table 1, entry 1).26
The yield was diminished owing to the competitive formation
Table 1. Asymmetric Epoxidations of 2a with Catalytic Iron
Complexes of 1a and 1b
a
b
entry
1
complex
additive
time (min)
yield (%)
ee (%)
83
1a
1a
1a
1b
None
30
60
60
60
35
c
d
2
None
trace
55
NA
3
4
SIPrAgCl
SIPrAgCl
88
d
trace
NA
a
b
Isolated yields. Ee determined by HPLC. For HPLC conditions, see
c
d
Supporting Information. Reaction in the absence of NaBARF. Not
Figure 2. Proposed reaction mechanism of the asymmetric
epoxidation and spectra of the intermediates. (a) X-ray crystal
structure of the iron complex 1c. Hydrogen atoms have been omitted
for clarity. Black: carbon, red: oxygen, blue: nitrogen, green: chlorine,
purple: iron. (b) Proposed reaction mechanism of the asymmetric
epoxidation. The g values and shapes written below each compound
were obtained by EPR spectroscopy. (c) UV−vis spectra of a solution
containing A (green line, measured at 20 °C) and B (red line,
measured at −10 °C). The inset shows enlargement of the area
between 600 and 725 nm.
available.
of diphenylacetaldehyde. No epoxidation was observed in the
absence of NaBARF (entry 2). The yield and enantioselectivity
were improved when SIPrAgCl (SIPrN,N′-bis(2,6-diisopro-
pylphenyl)-4,5-dihydroimidazol-2-ylidene), a silver salt which
has been commonly used as a SIPr donor to various transition
metals, was used in the reaction (entry 3). Interestingly, no
epoxidation occurred in the presence of iron complex 1b that
features a tridentate bis(oxazolinylphenyl)amine (BOPA)
ligand,27 which lacks the C−C bond between the two phenyl
rings that is present in the carbazole-based tridentate ligand
(entry 4). These results indicate that the π-conjugation system
of the carbazole-based tridentate ligand is required for the
catalytic activity of the iron complex in the epoxidation
reaction.
To explore the epoxidation mechanism and the similarity
between the cationic complex of 1a and iron porphyrins, iron
complexes including the intermediates in the epoxidation were
analyzed using several techniques (Figure 2). The structure of
the iron complex 1a was estimated to be the same as that of 1c
based on the X-ray crystal structure of 1c (Figure 2a),28 which
has a five-coordinated trigonal-bipyramidal structure. We next
turned our attention to iron intermediates in the epoxidation
and analyzed the mixture of iron complex 1a, NaBARF, and
SIPrAgCl (Figure 2b) using several different techniques. The
mixture containing intermediate A, which was prepared by
stirring 1a, NaBARF, and SIPrAgCl in dichloromethane at
room temperature for 10 min, was obtained as a yellow-green
solution. The UV−vis spectrum of this solution exhibited
strong absorbance at 347 nm (ε = 2.0 × 104 M−1 cm−1) and a
very weak, broad signal centered at 710 nm (ε = 2.7 × 103 M−1
cm−1, Figure 2c). Electron paramagnetic resonance (EPR)
spectroscopy analysis of a frozen solution of A showed multiple
strong signals around g = 4.1 with hyperfine splitting and a
weak signal around g = 2.0 at −196 °C (Figure S1-a). Because
the observed spectrum was similar to those of typical iron
porphyrins that possess an intermediate-spin state (S = 3/2),29
this result indicates that the intermediate A has S = 3/2 spin
state as well.
Studies focused on the oxidation mechanism of P450
oxidases and iron porphyrins with iodosobenzene have
proposed several candidates for the intermediate: (i) an
iron(V)−oxo complex, (ii) an iron(IV)−oxo complex bearing
a π-cation radical, and (iii) an iodosobenzene activated by an
iron(III) complex, which acts as a Lewis acid without any redox
change.5,30 To the best of our knowledge, the consensus
reached through a great number of analyses using several
techniques as well as theoretical studies is that candidate (ii) is
the intermediate.
In this context, analyses of intermediates in the epoxidation
were conducted. A green solution including oxidized
intermediate B was prepared by combining the solution
containing A with iodosobenzene at −23 °C and stirring for
10 min. The color of the solution changed to yellow at room
temperature within several minutes, which indicated low
stability of the intermediate B. A UV−vis spectrum of the
resulting solution was recorded at −10 °C, which showed that a
new signal appeared at 660 nm (ε = 1.4 × 104 M−1 cm−1). This
absorption band has typically been observed in the UV−vis
spectrum of iron(IV)−oxo species,31 and therefore is suggestive
that oxidation of the iron complex A proceeds in a similar
manner to that of iron porphyrins. EPR analysis of a mixture
containing B at −196 °C revealed a sharp and symmetrical
signal centered at g = 2.0 (Figure S1-b).32 This result suggests
that B has the low spin state S = 1/2, and the observed
unpaired electron is attributable to a π-radical in the ligand.
B
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Journal of the American Chemical Society
Communication
Notably, a nearly identical change was observed in both the
EPR spectra (Figure S2) and the UV−vis spectra (Figure S3)
even in the absence of SIPr ligand. Furthermore, the EPR
spectrum of iron(V)-oxo complex has been reported, which
shows multiple asymmetrical signals owing to anisotropy of the
d-orbital of the iron and differs from ours.33 This fact could rule
out the possibility that B is the (i) iron(V)−oxo complex.
On the basis of the above results and discussion, although
further studies are still required, we propose that the key
intermediate in the epoxidation is the (ii) iron(IV)−oxo
complex bearing a π-cation radical, and the iron complex
bearing the carbazole ligand has similar properties to those of
iron porphyrins, at least as they concern the oxidation reaction.
Next, the scope of the asymmetric epoxidation of alkenes
using cationic complex of 1a was investigated (Figure 3).34
1,2-dihydronaphthalene (3o) afforded the product with low
enantioselectivity (Figure 3d). To the best of our knowledge,
the catalytic asymmetric epoxidation of (E)-alkenes with the
cationic complex of 1a and SIPrAgCl shows the highest
enantioselectivity and yield compared with the previously
reported asymmetric epoxidations using other chiral iron
porphyrins. Although the Shi epoxidation affords the product
with excellent enantioselectivity and yield,36 the iron complex
developed in our laboratory has advantages in low catalyst
loading (1 mol %), short reaction time (<1 h), and availability
of both enantiomers of the ligand, which allows us to prepare
the chiral epoxide with the desired stereochemistry.
In summary, we have reported the first non-heme iron(III)
complex displaying porphyrin-like properties that catalyzes
highly enantioselective asymmetric epoxidation. It was
discovered that the two-electron oxidation of the cationic
iron(III) complex of 1a generates an iron(IV) cation radical
species, which has the same electronic structure as that of iron
porphyrins in spite of their different numbers of binding sites.
The carbazole-based tridentate ligand has been shown to be a
good surrogate for traditional porphyrins, allowing for flexibility
in design as well as simple and straightforward preparation. The
non-heme iron(III) complex we have developed opens up new
avenues for utilizing metalloporphyrin chemistry to accelerate
the development of ideal and practical new artificial catalysts for
other useful transformations. The highly enantioselective
catalytic asymmetric epoxidation of (E)-alkenes shown here is
a model for these kinds of investigations. Further studies on
characterization of the intermediate, mechanism of chiral
induction, as well as substrate scope, are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
EPR and UV−vis spectra, HPLC data, experimental proce-
dures, and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*niw@aoni.waseda.jp; mnakada@waseda.jp
■
Notes
The authors declare no competing financial interest.
Figure 3. Scope of the asymmetric epoxidation with the cationic iron
complex of 1a. Various (E)-alkenes were transformed to the
corresponding chiral epoxides under the optimized conditions.
Substrate scope includes (a) stilbene derivatives and (b) cinnamyl
alcohol derivatives. (c) Direct benzylic oxidation is observed in the
reaction of 2n. (d) Epoxidation of (Z)-alkene 2o afforded the desired
epoxide with reduced enantioselectivity. The isolated yield and
enantiomeric excess are given below each product. Ee’s were
determined by HPLC. See Supporting Information for experimental
details.
ACKNOWLEDGMENTS
■
This work was financially supported in part by The Grant-in-
Aid for Scientific Research on Innovative Areas “Organic
Synthesis based on Reaction Integration. Development of New
Methods and Creation of New Substances” (No. 2105), The
Grant-in-Aid for Young Scientists (B) (24750096), and the
Global COE program “Center for Practical Chemical Wisdom”
by MEXT, and a Waseda University Grant for Special Research
Projects. We are grateful to Mr. K. Yoshiya, Profs. T.
Yamaguchi and K. Ishihara (Waseda University) for performing
UV−vis spectrometer, and also to Prof. Tsunehiko Higuchi
(Nagoya City University) for helpful discussion.
Epoxidation of trans-stilbene derivatives (Figure 3a) as well as
cinnamyl alcohol derivatives (Figure 3b) smoothly afforded
chiral (S, S)-epoxides with excellent enantioselectivity, whereas
moderate selectivity was observed in the epoxidation of
substrates bearing an electron-rich aromatic group. The
epoxidation of alkene 2n under the optimized conditions
afforded the desired epoxide 3n along with aldehyde 4 as a
byproduct (Figure 3c). Formation of 4 suggests that the
catalytic epoxidation proceeds via an iron oxo complex, which is
known to promote benzylic oxidation.35 The epoxidation of
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