Catalytic asymmetric epoxidation of 2-cyclopentenones

Article abstract of DOI:10.1002/adsc.201200072

The first highly efficient asymmetric epoxidation of 2-cyclopentenones has been developed. Using a newly designed and readily available Cinchona amine catalyst, 2-cyclopentenones are reacted with hydrogen peroxide to give the corresponding epoxycyclopentanones in high yields and excellent enantioselectivities. Copyright

Full text of DOI:10.1002/adsc.201200072

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DOI: 10.1002/adsc.201200072
Catalytic Asymmetric Epoxidation of 2-Cyclopentenones
Anna Lee,a Corinna M. Reisinger,a and Benjamin Lista,*
a
Max-Planck-Institut fꢀr Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr, Germany
Fax : (+49)-208-306-2999; e-mail: list@mpi-muelheim.mpg.de
Received: January 26, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200072.
Abstract: The first highly efficient asymmetric ep-
oxidation of 2-cyclopentenones has been developed.
Using a newly designed and readily available Cin-
chona amine catalyst, 2-cyclopentenones are react-
ed with hydrogen peroxide to give the correspond-
ing epoxycyclopentanones in high yields and excel-
lent enantioselectivities.
used an enantiomerically pure peroxide reagent in the
epoxidation of 2-cyclopentenone to obtain the prod-
uct in 31% yield and 12% ee.[16] The single published
attempt at asymmetric catalysis of this reaction came
from our own group using a chiral primary amine salt
(DPEN-TRIP) and hydrogen peroxide, giving the ep-
oxide in 33% yield and 78% ee.[15a,17] One problem
connected to cyclopentenone substrates is their con-
siderable “flatness”, rendering them less sensitive to
the steric requirements of a chiral catalyst. In fact,
asymmetric conjugate additions to 2-cyclopentenones
via iminium catalysis are considered to be challenging
in general.[18] The absence of efficient and highly
enantioselective methods for the asymmetric epoxida-
tion of cyclopentenones is particularly poignant in
Keywords: asymmetric catalysis; 2-cyclopente-
nones; epoxidation; organocatalysis; Weitz–Scheffer
epoxidation
The impact of alkene epoxidation catalysis to modern light of the wealth of bioactive natural products pos-
academic and industrial chemistry can hardly be over- sessing a chiral epoxycyclopentanone (for selected ex-
stated. In particular, the catalytic enantioselective ep- amples, see Scheme 1). Here we report a new modi-
oxidation of alkenes has fascinated chemists during fied Cinchona-derived primary amine catalyst that
the past three decades. Originating from Sharplessꢁ provides the first solution to this equally important
seminal discovery of the catalytic asymmetric epoxi- and challenging problem.
dation of allylic alcohols,[1] intensive research to
Recently, we have introduced a new class of quino-
expand the scope of this transformation to other line C-2’-substituted Cinchona-derived primary amine
olefin classes began. Important contributions to this catalysts, which are directly accessible via protecting
endeavour came from Jacobsen,[2] Katsuki,[3] Shi,[4] group-free addition of an organometallic reagent and
Juliꢂ and Colonna,[5] Wynberg,[6] Jackson,[7] Enders,[8] in situ oxidation. One of these amines enabled us to
Shibasaki,[9] and many more.[10] With the advent of develop the first catalytic asymmetric Knoevenagel
aminocatalysis at the beginning of the last decade,[11] condensation.[19] Encouraged by this work and our
new opportunities for the epoxidation of a,b-unsatu- continuing interest in aminocatalytic Weitz–Scheffer
rated carbonyl compounds arose and Jørgensen[12] epoxidations, we wondered how our new catalyst class
and subsequently MacMillan[13] and our group[14] have would perform in the asymmetric epoxidation of cy-
developed secondary amine-based catalysts for the clopentenones. Initial catalyst evaluation studies are
asymmetric epoxidation of a,b-unsaturated aldehydes. shown in Table 1. We first tested the unmodified qui-
Recently, our group has expanded the scope of such nine-derived aminocatalyst in the presence of differ-
aminocatalytic epoxidations by introducing powerful ent standard acid co-catalysts (1a–1c). With hydrogen
Cinchona-derived primary amine-catalyzed epoxida- peroxide, these salts converted 2-cyclopentenone 2a
tions of cyclic and acyclic enones as well as of a- into the corresponding epoxide 3a in moderate yields
branched, a,b-unsaturated aldehydes.[15] Remarkably and enantioselectivities (entries 1–3). After screening
though, one substrate class has remained almost en- various acid additives, we were pleased to find that
tirely unaffected by all previous efforts: 2-cyclopent- (R)-Mosherꢁs acid was beneficial to our reaction
ACHTUNGTRENNUNGenones. To the best of our knowledge, only two at- system. Interestingly, (R)-Mosherꢁs acid indeed im-
tempts for the asymmetric epoxidation of 2-cyclopen- proved both the yield and enantioselectivity (entry 4).
tenones have been reported: The Laschat group has We next evaluated our newly synthesized modified
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Anna Lee et al.
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Scheme 1. Epoxycyclopentanone incorporating natural products and absence of enantioselective 2-cyclopentenone epoxida-
tions.
Table 1. Catalyst evaluation.[a]
Entry
Catalyst
Yield [%][b]
e.r[c]
1
2
3
4
1a
1b
1c
1d
1d
1e
1f
1g
1h
1h
1i
33
50
61
85
88
64
60
60
90
90
60
87.0:13.0
89.0:11.0
89.0:11.0
91.5:8.5
92.5:7.5
93.0:7.0
83.5:16.5
92.5:7.5
95.0:5.0
94.5:5.5
92.5:7.5
5[d]
6[d]
7[d]
8[d]
9[d]
10[d,e]
11[d]
[a]
Reaction conditions: 2a (0.1 mmol), hydrogen peroxide (50% aqueous solution, 0.15 mmol), catalyst 1 (0.01 mmol), acid
co-catalyst (0.02 mmol), 1,4-dioxane (0.4 mL).
Determined by GC-MS.
Determined by GC analysis on a chiral stationary phase.
Reaction was carried out for 168 h at room temperature.
(S)-Mosherꢁs acid was used.
[b]
[c]
[d]
[e]
catalysts 1e–1i in the presence of (R)-Mosherꢁs acid Mosherꢁs acid instead of its (R)-enantiomer did not
(entries 6–11). Excitingly, of these salts, phenyl-modi- diminish catalyst reactivity and only slightly reduced
fied catalyst 1h gave product 3a in 90% yield and the enantiomeric ratio (entry 10).
high enantioselectivity (er=95:5) (entry 9). Using (S)-
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Catalytic Asymmetric Epoxidation of 2-Cyclopentenones
Table 2. Substrate scope.[a]
Entry
1
Substrate
Product
Yield [%][b]
87
er [%][c]
95:5
2
3
89
85
95.5:4.5
96:4
4
5
6
86
65
90
95.5:4.5
96:4
95.5:4.5
7
8
9
90
90
88
96:4
96.5:3.5
95.5:4.5
10
84
97.5:2.5
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Table 2. (Continued)
Entry
Substrate
Product
Yield [%][b]
82
er [%][c]
11
97.5:2.5
12
13
80
80
97.5:2.5
97.5:2.5
14
15
78
97.5:2.5
65
84
98:2
96:4
16
[a]
2 (0.2 mmol), hydrogen peroxide (50% aqueous solution, 0.3 mmol), catalyst 1h (0.02 mmol), (R)-Mosherꢁs acid
(0.04 mmol), 1,4-dioxane (0.8 mL).
Yield of isolated product.
[b]
[c]
Determined by GC analysis on a chiral stationary phase.
It turned out that catalyst 1h is a fairly general cat- and para-substituted arenes can all be used with simi-
alyst that can be used in the epoxidation of various larly high efficiency (entries 13–15).
substituted 2-cyclopentenones under optimized condi-
To illustrate the synthetic utility of our reaction, we
tions (Table 2). For example, methyl (entry 2) and synthesized the highly potent antibacterial epoxide 4
linear alkyl chains at the 3-position are tolerated very (Scheme 2) This compound [(2S,3S)-2-nor-epoxy-
well (entries 3 and 6). But even cyclopentenones that methylenomycin B] has been discovered in the con-
possess branched alkyl groups such as i-Pr, i-Bu, or t- text of structure/activity elucidations of the methy-
Bu at this critical position furnish the corresponding
ACHTUNGTRENlNUGN enomycins and displays particularly strong antibacte-
epoxides in good yields and high enantioselectivities rial activity against E. coli and B. subtilis.[20] The intro-
(entries 4, 5, 7, 9 and 16). The robustness of our reac-
tion to sterical hindrance is further illustrated with
the smooth conversion of substrate 2h containing
a quaternary center within the ring adjacent to the re-
acting carbon atom (entry 8). Excellent enantioselec-
tivities were also obtained with 3-benzyl-substituted
cyclopentenones (entries 10–15). Both electron-defi-
cient (entry 12) and electron-rich (entries 11 and 13)
aromatic substituents gave the desired products in ex-
cellent enantioselectivities. Furthermore, ortho-, meta- (2S,3S)-2-nor-epoxy-methylenomycin B (4).
Scheme 2. First asymmetric synthesis of antibacterial agent
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Catalytic Asymmetric Epoxidation of 2-Cyclopentenones
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Typical Experimental Procedure for the Catalytic
Asymmetric Epoxidation of 2-Cyclopentenones
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Generous support from the Max-Planck-Society and the
Fonds der Chemischen Industrie (Kekulꢀ fellowship to
C.M.R) is gratefully acknowledged.
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