Asymmetric epoxidation of α,β-unsaturated ketones via an amine-thiourea dual activation catalysis

Article abstract of DOI:10.1016/j.tetlet.2021.152941

A simple asymmetric epoxidation method is developed to effectively synthesize chiral α-carbonyl epoxides through an amine-thiourea dual activation catalysis. In this method, TBHP, as an oxidant, determined the reaction rate, and the chiral amine-thiourea catalyst effectively controlled the stereoselectivity of the reaction, and KOH promoted deprotonation. 22 examples of α,β-unsaturated ketones with various substituent groups are smoothly converted into α-carbonyl epoxides with moderate to excellent enantiomeric excess.

Full text of DOI:10.1016/j.tetlet.2021.152941

Tetrahedron Letters 68 (2021) 152941
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric epoxidation of
a,b-unsaturated ketones via an
amine-thiourea dual activation catalysis
Lu-Wen Zhang a,1, Li Wang b, ,1, Nan Ji a, Si-Yang Dai b, Wei He a,
⇑
⇑
a Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, PR China
b School of Pharmacy, Xi’an Medical University, Xi’an 710021, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple asymmetric epoxidation method is developed to effectively synthesize chiral a-carbonyl epox-
ides through an amine-thiourea dual activation catalysis. In this method, TBHP, as an oxidant, determined
the reaction rate, and the chiral amine-thiourea catalyst effectively controlled the stereoselectivity of the
reaction, and KOH promoted deprotonation. 22 examples of a,b-unsaturated ketones with various sub-
Received 28 December 2020
Revised 10 February 2021
Accepted 12 February 2021
Available online 24 February 2021
stituent groups are smoothly converted into
a
-carbonyl epoxides with moderate to excellent enan-
tiomeric excess.
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Asymmetric epoxidation
Chalcone
Chiral amine-thiourea
Organocatalyst
Chiral epoxides are very effective intermediates in organic syn-
thesis [1]. Due to the special tension of the hetero-tricyclic ring, it
is easy to achieve selective ring opening and functional group con-
version reactions, so that many valuable optically active materials
and drugs can be synthesized [2]. Since 1980s, Sharpless’s group
[3] has successfully achieved the asymmetric epoxidation reaction
of allylic alcohol through Ti-tartaric acid catalysis, which made a
major breakthrough in this field. Subsequently, various catalytic
strategies [4] continued to emerge, among which organocatalysts
have green economy and sustainability, and always received
extensive attention [5].
Cinchona alkaloids have natural chiral environmental structure
and strong ability to be modified later. Since 1853, cinchona alka-
loids were first reported [6] to be used as chiral additives in asym-
metric synthesis, and they have attracted much attention as
organocatalysts or chiral ligands in asymmetric synthesis [7]. Cin-
chona alkaloids can also be used to catalyze epoxidation reactions,
for example, Deng’s group [8] initially realized the asymmetric
epoxidation of chalcone with high enantiomeric excess (Fig. 1a).
Saha-Möller’s group [9] and Jurczak’s group [10] developed an
enantioselective
obtain epoxides (Fig. 1d). In addition, our group have used
c
-elimination [11] process can also be applied to
-man-
D
nitol-derived novel chiral amine-thioureas [12] (Fig. 1e) to success-
fully achieve an asymmetric Henry reaction. In the amine-thiourea
bifunctional catalysts [13] derived from cinchona alkaloids, the
double hydrogen bond donor of the thiourea unit and the tertiary
amine of quinine form a dual activation mode, thereby efficiently
realizing asymmetric conversion.
Chiral a-carbonyl epoxides are important synthetic molecules
for the synthesis of natural products and drugs [14], due to one
or several stereogenic centers are either preserved or modified.
Therefore, the development of asymmetric epoxidation reactions
of a,b-unsaturated ketones are of great significance. Based on the
application of amine-thiourea bifunctional catalysts of our previ-
ous works [12,13c–d], we envisaged the use of a large sterically
hindered multi-chiral thiourea unit combined with quinine to form
a bifunctional catalyst may realize the asymmetric epoxidation of
chalcone compounds. Herein, we report an efficient method for
asymmetric epoxidation of chalcone compounds, using cheap and
easily available TBHP as an oxidant, and realizing chirality induc-
enantioselective epoxidation of
cally active phase-transfer catalysts derived from cinchona alka-
loids (Fig. 1b-c). Very recently, a chiral amine-thiourea catalyzed
a
,b-unsaturated ketones with opti-
tion via a
tiomeric excess was up to 96%.
In order to obtain chiral -carbonyl epoxides with high enan-
tioselectivities, we firstly screened the reaction conditions. With
chalcone 2a as the reaction template substrate and -mannitol-
derived chiral amine-thioureas 1e as the catalyst, the reaction con-
ditions including additives, solvents, oxidants and reaction tem-
peratures were screened (Table 1). First, solvent had a great
D-mannitol-derived chiral thioureas, and the enan-
a
D
⇑
Corresponding authors.
E-mail addresses: wangli1@xiyi.edu.cn (L. Wang), weihechem@fmmu.edu.
cn (W. He).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2021.152941
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Lu-Wen Zhang, L. Wang, N. Ji et al.
Tetrahedron Letters 68 (2021) 152941
enantiomeric excess of 2a gradually increased (Table 1, entries
11–14). 3a with an enantiomeric excess of 65% was obtained
when 0.2 equivalent of TBHP was used (Table 1, entry 14).
Therefore, we adopted the method of adding oxidant in batches
to reduce the reaction rate to obtain high conversion and
enantioselectivity (Table 2, entry 15). Temperature was also very
important for the chiral induction process (Table 1, entries 16–
18). By reducing the reaction temperature to À20 °C, 3a can be
obtained with a yield of 75% and an enantioselectivity of 94%
(Table 1, entry 17).
With the optimal reaction conditions in hand, we investigated
the range of
a,b-unsaturated ketones. When the 4-position sub-
stituents of phenyl were electron-withdrawing groups of F, Cl, Br,
I, NO2, 3b-3f were obtained in moderated yields (58–90%) and high
enantiomeric excesses (84–96%). Specifically, when the substituent
was CF3, 2g was transformed to 3g with a 40% yield and a 44%
enantiomeric excess. Substrates with electron-donating sub-
stituents at the 4-position of phenyl, including Me and tBu to
achieve good performance asymmetric epoxidation with 83–89%
enantiomeric excesses (3h-3i). 3j was synthesized with high con-
version rate, but the enantiomeric excess was only 42%. The above
results demonstrated that the 4-position substituted substrates
with electron donating or withdrawing group both can efficiently
realize the asymmetric epoxidation reaction, except individual
groups, such as CF3 and OMe. Subsequently, we considered the
3-position substitution chalcones. Unexpectedly, the 3-OMe sub-
stituted substrate 2n got the product 3n with an 81% enantiomeric
excess, while the 3-Cl substituted substrate 2k only got 66% enan-
tiomeric excess, and these results were inconsistent with the prod-
ucts of 4-position substituent. 2l and 2m could give the products
with 83% and 80% enantiomeric excesses. Above this, substrates
with substituted groups at the 3-position have a certain weakening
effect on the asymmetric epoxidation transformation. In contrast,
modification of the 2-position on the phenyl group greatly affected
the asymmetric transformation. When Cl and Br were used to mod-
ify the 2-position of the phenyl group, the products 3o and 3p with
Fig. 1. Quinine and its derivatives are used to synthesize a,b-epoxy ketones.
influence on the asymmetric epoxidation reaction (Table 1, entries
1–7). When the reaction was proceeded in DMF, ether, ethanol, and
THF, 2a was transformed to 3a with the opposite configuration
(Table 1, entries 1–4). In comparison, xylene and acetone showed
high conversion activities but low enantioselectivities (Table 1,
entries 5–6). Toluene can be used as the best solvent to gain 3a
with high yield and moderate enantiomeric excess (Table 1, entry
7). Later, we adjusted the amount of KOH with toluene as the sol-
vent (Table 1, entries 8–10). Surprisingly, we chose 0.2 equivalents
of KOH as the matching additive, and found that the enantioselec-
tivity of 3a was slightly improved, while the reaction yield had a
bit reduction (Table 1, entry 9). However, when less than 0.2 equiv-
alents of KOH was used, the reaction yield and enantioselectivity
were reduced (Table 1, entry 10).
In this transformation, the amount of oxidant [4a,5a,8–10,15]
and the method of addition were very critical. Initially, we made
detailed adjustments to the amount of oxidant. When 1.7, 1.2,
0.6, and 0.2 equivalents of TBHP were used, the yields of 2a were
greatly reduced as the amount of TBHP decreased, but the
(aR, bS) configuration were obtained. However, the products 3q
and 3r were generated with electron-donating Me and OMe have
Table 1
Reaction Optimization.
Entrya
Additive (X eq.)
Oxidant (Y eq.)
Solvent
Tem.(°C)
Yield(%)b
ee. (%)c
1
2
3
4
5
6
7
8
KOH (5)
KOH (5)
KOH (5)
KOH (5)
KOH (5)
KOH (5)
KOH (5)
KOH (1)
KOH (0.2)
KOH (0.1)
KOH (0.2)
KOH (0.2)
KOH (0.2)
KOH (0.2)
KOH (0.2)
KOH (0.2)
KOH (0.2)
KOH (0.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.7)
TBHP (1.2)
TBHP (0.6)
TBHP (0.2)
TBHP (1.2)d
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
DMF
Et2O
EtOH
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t
30
40
35
65
70
60
85
80
80
67
86
80
50
20
80
78
75
50
À51
À32
À7
À20
24
34
49
49
52
43
39
52
56
65
69
75
94
xylene
acetone
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
16
17
18
r.t.
0
À20
À45
92
a
c
General conditions: 2 (0.1- mmol), 1e (10-mol%), KOH (0.2 equiv.), TBHP (1.2 equiv.), toluene (2 mL), À20- °C), 5–72 h. bIsolated yield.
Enantiomeric excess was determined by chiral HPLC analysis using Chiralpak OD-H column, and absolute configuration was established by comparing with the literature
data [4a]
d
Adding TBHP in portions, 0.02 mmol each time.
2

Lu-Wen Zhang, L. Wang, N. Ji et al.
Tetrahedron Letters 68 (2021) 152941
Table 2
Substartes scope of
a,b-unsaturated ketones in the asymmetric epoxidation.
.
Entrya,b
Substrate
Yield (%)c
ee (%)d
Product
1
2
3
4
5
6
7
8
R = Ph
R = 4-F-Ph
R = 4-Cl-Ph
R = 4-Br-Ph
R = 4-I-Ph
75
61
62
81
63
90
40
71
52
80
60
61
76
81
40
51
48
67
78
60
94
86
88
96
89
84
44
89
83
42
66
83
80
81
À51
À67
45
81
91
55
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
R = 4-NO2-Ph
R = 4-CF3-Ph
R = 4-Me-Ph
R = 4-tBu-Ph
R = 4-OMe-Ph
R = 3-Cl-Ph
R = 3-Br-Ph
R = 3-NO2-Ph
R = 3-OMe-Ph
R = 2-Cl-Ph
R = 2-Br-Ph
R = 2-Me-Ph
R = 2-OMe-Ph
R = 3,4-di-Me-Ph
9
10
11
12
13
14
15
16
17
18
19
20
3s
3t
21
22
25
19
79
3u
3v
À31
a
b
c
General conditions: 2 (0.1 mmol), 1e (10 mol%), KOH (0.2 equiv.), TBHP (1.2 equiv.), toluene (2 mL), À20 °C, 5–72 h.
Adding TBHP in portions, 0.02 mmol each time.
Isolated yield.
d
Enantiomeric excess determined by chiral HPLC analysis, absolute configurations were established by comparing with the literature data [4a].
normally (
a
S, bR) configuration. In addition, 3s had 3,4-dimethyl
In conclusion, an asymmetric epoxidation reaction of
urated ketones based on a TBHP-promoted amine-thiourea dual
activation model was developed. A series of -carbonyl epoxides
a,b-unsat-
modification, which also achieved high conversion, with an 82%
yield and a 91% enantiomeric excess.
a
In addition, we also expanded the substrates of other skeleton
structures, but the results were not particularly desired. Substrate
2t with naphthyl skeleton, in this catalytic system, a moderated
yield and an enantiomeric excess were obtained. In addition, dif-
ferent aliphatic substrates have also been investigated. For exam-
ple, when R was cyclohexyl, the yield of 3u was only 25%, but
the enantioselectivity was 79%. However, the product 3v with a
tert-butyl substitution, which had only a poor yield and a low
enantiomeric excess. Besides, we also investigated that when the
R group was methyl or cyclopropyl, the asymmetric epoxidation
reaction could not proceed.
with high optical activities were synthesized, and enantiomeric
excess was up to 96%. In addition, a reasonable analysis of the reac-
tion mechanism is carried out, and two possible reaction transition
states are proposed. Here, we exhibited a successful asymmetric
epoxidation reaction of a,b-unsaturated ketones, which was a good
example to expand the synthetic application range of the novel
amine-thiourea catalyst. Further research on the application of
the cinchona based amine-thiourea catalysts is still going on.
Based on the current results, plausible transition state (TS)
models for this base-promoted epoxidation reaction of
rated ketones 2a with TBHP catalyzed by chiral thioureas 1e are
proposed (Fig. 2). In transition state A, the carbonyl group of ,b-
a,b-unsatu-
a
unsaturated ketones 2a is activated by the double hydrogen bonds
donor of the thiourea unit 1e and TBHP is deprotonated by the ter-
tiary amine of quinine in cinchona alkaloid moiety, which formed a
dual activation mode. Under the advantageous chiral environment
and the large steric hindrance of
the activated chalcone from Si-face, thereby providing a (
D
-mannitol, [tBuOOÀ] can attack
S, bR)
a
configuration product 3a, which is consistent with experiments
[4a]. On the contrary, in the transition state B, it is preferable to
perform
a Re-face attack to obtain a product of (aR, bS)
configuration.
Fig. 2. Proposed reaction transition state models.
3

Lu-Wen Zhang, L. Wang, N. Ji et al.
Tetrahedron Letters 68 (2021) 152941
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Declaration of Competing Interest
We declare that no conflict of interest exits in the submission of
this manuscript and manuscript is approved by all authors for pub-
lication. The work described was original research that has not been
published previously and not under consideration for publication
elsewhere, in whole or in part. All the authors listed have approved
the manuscript that is enclosed.
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Acknowledgments
This work was supported by the Shaanxi Province Key Research
and Development Program (grant no. 2019ZDLSF03-03) and the
National Science and Technology Major Project of China Key New
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