Iron-catalyzed asymmetric epoxidation of β,β-disubstituted enones

Article abstract of DOI:10.1021/ja201873d

The combination of Fe(OTf)₂ and novel phenanthroline ligands enables the catalytic asymmetric epoxidation of acyclic β,β- disubstituted enones, which have been a heretofore inaccessible substrate class. The reaction provides highly enantioenriched α,β-epoxyketones (up to 92% ee) that can be further converted to functionalized β-ketoaldehydes with an all-carbon quaternary center.

Full text of DOI:10.1021/ja201873d

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Iron-Catalyzed Asymmetric Epoxidation of β,β-Disubstituted Enones
Yasuhiro Nishikawa and Hisashi Yamamoto*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S Supporting Information
b
Scheme 1. Epoxidation of Acyclic β,β-Disubstituted
Carbonyl Compounds
ABSTRACT: The combination of Fe(OTf)2 and novel
phenanthroline ligands enables the catalytic asymmetric
epoxidation of acyclic β,β-disubstituted enones, which have
been a heretofore inaccessible substrate class. The reaction
provides highly enantioenriched R,β-epoxyketones (up to
92% ee) that can be further converted to functionalized
β-ketoaldehydes with an all-carbon quaternary center.
he catalytic asymmetric epoxidation of olefins is a powerful
T
strategy for the synthesis of chiral molecules. Thus, numer-
ous efforts have been dedicated to achieving greater efficiency
with less expensive and environmentally benign catalysts and
oxidants as well as applicability to a variety of substrate classes.1
Among various useful methods, the development of an iron-
catalyzed asymmetric epoxidation should provide us with many
advantages, as iron is the most abundant transition metal on the
earth and relatively nontoxic.2ꢀ4 In addition, understanding the
mechanism of iron-catalyzed oxidations, which play important
roles in biological metabolism, may lead to new insights in
biocatalysis and resulting drug design.5 Actually, the biomimetic
asymmetric epoxidation of styrene derivatives with iron porphyrin
complexes was first reported in 1999,6,7 although it has draw-
backs such as the difficult synthesis of the required chiral
porphyrin ligands. After studies pursuing non-heme iron catalysts
that could be easily prepared and modified, Beller and co-workers
reported that the best results were obtained using iron-catalyzed
asymmetric epoxidation of stilbene derivatives with excellent
enantioselectivity.4c,d However, the high selectivity was obtained
for only one specific substrate with 10 mol % catalyst loading.
Therefore, it is apparent that iron has yet to be fully introduced in
asymmetric epoxidations.
catalytic asymmetric epoxidation of acyclic β,β-disubstituted
enones with a newly designed iron complex.
We initially investigated the epoxidation of readily available
(E)-dypnone (1a) as a model substrate using a variety of
complexes consisting of iron metals and phenanthroline ligands
attached to binaphthyl moieties (Table 1). A preliminary screen-
ing of reaction conditions showed that peracetic acid as a
terminal oxidant is crucial in producing epoxides.10 When 1a
was reacted with 5 mol % FeCl2 and monophenanthroline ligand
L1 in the presence of peracetic acid solution in acetonitrile, the
epoxidation resulted in only low conversion of starting material
and low selectivity (entry 1). Replacing FeCl2 with Fe(OTf)2
led to a significant improvement in terms of reactivity and
enantioselectivity (entry 2). Thus, we turned our attention to
the effects of various monophenanthroline ligands. Introduc-
tion of a methyl group at the 20-position in the binaphthyl group
dramatically diminished the reactivity and selectivity (entry 3).
To our delight, we found that the introduction of a phenyl
group at the 3- and 8-positions in the phenanthroline moiety,
which would be expected to restrict the rotation of the bond
between the binaphthyl group and the phenanthroline moiety,
resulted in significantly increased enantioselectivity (entry 4).
After testing various ligands bearing aromatic groups on the
phenanthroline rings (entries 4ꢀ7), we identified L5 as the
ligand providing the best yield and enantioselectivity (entry 6).
A study of the ligand/metal ratio implied that an iron complex
coordinated by two phenanthroline ligands induces high en-
antioselectivity (entries 6, 8, and 9). Furthermore, the catalyst
loading was successfully lowered to 2.5 mol % with only a slight
decrease in the yield and selectivity (entry 10). It should be
noted that only one diastereomer of the epoxide was observed
during the course of this study, while WeitzꢀScheffer-type
epoxidation of trisubstituted R,β-carbonyl compounds often
suffers from low diastereocontrol.9e,g,11 In addition, this
Obviously, the extension of the accessible substrate classes for
catalytic asymmetric epoxidation would be desirable. To the best
of our knowledge, a general method for the catalytic asymmetric
epoxidation of acyclic β,β-disubstituted enones is still lacking,
probably because of stereocongestion at the β-carbon in the
WeitzꢀScheffer-type epoxidation, which is commonly employed
to access R,β-epoxycarbonyl compounds (eq 1 in Scheme 1).1d,8
In the case of acyclic enones, a β-substituent (R3 group) increases
the steric repulsion not only between the β-carbon and the
nucleophile but also between the R3 group and the acyl group,
which causes the substrate to break conjugation to avoid repul-
sion. As a result, the electrophilicity of the double bond in acyclic
β,β-disubstituted enones is thought to be weaker than that in
cyclicor non-β-substitutedenones.9 Incontrast, the deconjugation
described above should increase the reactivity toward electrophilic
epoxidation (eq 2 in Scheme 1).9c,i Herein is a solution to the
Received: March 1, 2011
Published: May 10, 2011
r
2011 American Chemical Society
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|

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Table 1. Screening of Reaction Conditions
2a
entry
metal
FeCl2
ligand (R)
L1 (H)
x
% yielda
% eeb
1
2
10
10
10
10
10
10
10
5
17
3
57
17
83
75
91
86
78
53
86
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
L1 (H)
95
Figure 1. X-ray structure of [Fe(L3)2(CH3CN)(OTf)](OTf) shown
as a CPK model. Thermal ellipsoids correspond to 50% probability. H
atoms and noncoordinating molecules have been omitted for clarity. For
clarity, the triflate group and CH3CN have been replaced by green and
yellow atoms, respectively. See the Supporting Information for details.
C, gray; N, blue; Fe, red.
3
L2 (ꢀ)
L3 (Ph)
<5
4
93
5
L4 (o-Tol)
L5 (m-xylyl)
L6 (m-Et2C6H3)
L5 (m-xylyl)
L5 (m-xylyl)
L5 (m-xylyl)
72
88 (80)c
6
7
64
8
73
9
10 d
15
5
25
had a deleterious effect on the yield of the product, probably
because of the instability of the epoxide obtained under the acidic
conditions, although the high enantioselectivity was still main-
tained (entry 10). On the other hand, the substrate bearing an
alkyl substituent at the β-position turned out to have inferior
reactivity and selectivity relative to aromatic substrates (entry 11).
The substrate with an ethyl group as the R3 substituent kept the
high enantiomeric excess (entry 12). Notably, a single diaster-
eomer was obtained even when (Z)-dypnone was employed,
although the enantioselectivity was poor (entry 13). This fact
could further support the proposal that the reaction proceeds via
a concerted pathway.
Gratifyingly, we realized that this chiral ironꢀphenanthroline
system can be applied not only to R,β-enones but also to a
nonactivated olefin such as trans-R-methylstilbene with good
enantioselectivity (eq 1 in Scheme 2).14 With this result in hand,
we conducted an intermolecular competition reaction to deter-
mine the nature of the active oxidant (eq 2 in Scheme 2).15 The
competition reaction between electron-deficient alkene 1a and
electron-rich alkene 1n showed a 2.4:1 preference for the latter
with comparable enantioselectivities, confirming the electrophilic
nature of the active oxidant.
The utility of chiral R,β-epoxyketones was demonstrated as
shown in Scheme 3. The obtained R,β-epoxyketones 2a and 2l
were converted into the corresponding β-ketoaldehydes 3a and
3l bearing all-carbon quaternary centers via Lewis acid-mediated
rearrangement without significant loss of enantiomeric excess
(eq 1 in Scheme 3).16 Unlike reaction with the substrate having a
phenacyl group, the iron-catalyzed epoxidation of alkyl-substituted
substrate 1o gave the rearranged product 3o as a major com-
pound concomitant with the corresponding epoxide (eq 2
in Scheme 3). Eventually, the pure rearranged product 3o was
successfully obtained in 35% yield over two steps by treatment of
81
a Determined using 1H NMR analysis with 1,1,2,2-tetrachloroethane as
an internal standard. b Determined by chiral HPLC analysis. c The value
in parentheses is the isolated yield. d 2.5 mol % Fe(OTf)2 was used.
diastereospecific epoxide formation in our catalytic system im-
plies a concerted pathway unlike the stepwise mechanism
proposed previously.12n
Next, X-ray crystallographic analysis was carried out on a
single crystal grown in an acetonitrile solution of Fe(OTf)2 and 2
equiv of rac-L3. As illustrated in Figure 1, an octahedral, mono-
nuclear [Fe(L3)2(CH3CN)(OTf)](OTf) complex was identi-
fied in which two homochiral phenanthroline ligands coordinate
the iron center in a cis topology, affording a pseudo-C2-sym-
metric iron complex. Although the bidentate phenanthroline
ligands can in principle adopt many possible diastereomers
on the iron center, including the hetero- or homocombination
of rac-L3, only the diastereomer shown above was selectively
crystallized.13 This selective complexation can be explained
by the πꢀπ interactions between the naphthyl groups and
diphenylphenanthroline. However, the relationship between this
selective formation of an ironꢀligand complex and the enantios-
electivities, as well as the actual structure of the catalyst in the
reaction medium, is still unclear.12
With the optimized conditions in hand, we next examined the
scope of substrates using the Fe(OTf)2ꢀL5 complex (Table 2).
The epoxidations of β,β-disubstituted enones having different
electronic characters on the phenacyl groups proceeded smoothly
in good yields with excellent enantioselectivities (entries 1ꢀ5).
Sterically different types of aromatic substituents were also tolerated
(entries 6ꢀ8). While an electron-deficient aromatic group at the
β-position had no influence on the epoxidation (entry 9), an
electron-rich group such as a naphthyl group at the β-position
the mixture with BF3 OEt2 at room temperature. Furthermore, the
3
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COMMUNICATION
Table 2. Substrate Scope of Epoxidations
Scheme 3. Transformations of Optically Active r,β-
Epoxyketones
entry
1
R1
R2
R3
2
% yielda % eeb
1
2
1a
1b
1c
Ph
Ph
Me 2a
Me 2b
Me 2c
Me 2d
Me 2e
Me 2f
Me 2g
Me 2h
Me 2i
80
78
77
78
70
67
61
88
88
45
20
72
33
91
90
92
92
89
90
92
90
92
92
50
92
6
p-MeOC6H4 Ph
3
p-MeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
4
1d p-FC6H4
5
1e
1f
p-CF3C6H4
m-MeC6H4
o-MeC6H4
6
7
1g
8
1h 2-naphthyl
9
1i
1j
1k
1l
Ph
Ph
Ph
Ph
p-ClC6H4
10
11
12
13
2-naphthyl Me 2j
n-C3H7
Ph
Me 2k
Et 2l
Ph 2m
1m Ph
Me
a Isolated yields. b Determined by chiral HPLC analysis.
’ ASSOCIATED CONTENT
Scheme 2. Asymmetric Epoxidation with a Nonactivated
Olefin and a Competitive Experiment Using Electron-Rich
and Electron-Deficient Olefins
S
Supporting Information. Experimental procedures;
b
characterization of compounds L1ꢀ6, 1aꢀm, 1o, 2aꢀn, 3a,
1
3l, 3o, and 4a, including H NMR and 13C NMR spectra and
HPLC analysis; complete ref 17a; and crystallographic data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yamamoto@uchicago.edu
’ ACKNOWLEDGMENT
This work was partially supported by the National Institutes of
Health (5R01GM068433) and the Uehara Memorial Founda-
tion (Y.N.). We thank Dr. Ian M. Steele for X-ray structure
determination and Antoni Jurkiewicz for his NMR expertise.
chiral R,β-epoxyketones can be transformed to 2-isoxazolidines,17
which are important intermediates in the preparation of a variety of
compounds with 1,3-difunctional groups, such as β-hydroxyketones18
and γ-aminoalcohols.19 Treatment of 2a with hydroxylamine hydro-
chloride in the presence of pyridine furnished highly substituted
2-isoxazoline 4a in optically pure form (eq 3 in Scheme 3).20
In summary, we have developed the first iron-catalyzed
asymmetric epoxidation of acyclic β,β-disubstituted enones. Es-
sential for success was the use of the iron complex consisting of
Fe(OTf)2 and 2 equiv of a carefully designed phenanthroline
ligand. X-ray crystallography revealed a pseudo-C2-symmetric
ironꢀligand complex. Moreover, the construction of chiral all-
carbon quaternary centers was also realized via Lewis acid-mediated
rearrangement of the obtained chiral epoxides. Furthermore, this
work provides a new strategy for designing pseudo-C2-symmetric
orthophenanthroline ligand-based catalysts, which should have a
vast potential for transition-metal-catalyzed organic synthesis in
general.
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