Catalytic Asymmetric Epoxidation of Electron-Deficient Enynes Promoted by Chiral N,N′-Dioxide-Scandium(III) Complex

Article abstract of DOI:10.1002/adsc.201700555

An asymmetric epoxidation of electron-deficient enynes with environmentally benign aqueous hydrogen peroxide as oxidant has been accomplished by developing a chiral N,N′-dioxide-Scandium(III) complex catalytic system. In the presence of 0.5–2 mol% catalys

Full text of DOI:10.1002/adsc.201700555

Title: Catalytic Asymmetric Epoxidation of Electron-Deficient Enynes
Promoted by Chiral N,N'-Dioxide-Scandium(III) Complex
Authors: Hang Zhang, Qian Yao, Lili Lin, Chaoran Xu, Xiaohua Liu,
and Xiaoming Feng
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10.1002/adsc.201700555
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Asymmetric Epoxidation of Electron-Deficient Enynes
Promoted by Chiral N,N'-Dioxide-Scandium(III) Complex
Hang Zhang, Qian Yao, Lili Lin,* Chaoran Xu, Xiaohua Liu and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu, 610064 (China)
Fax : (+86) 28-8541-8249; e-mail: lililin@scu.edu.cn; xmfeng@scu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
be established to furnish a highly chemoselective
enynes with environmentally benign aqueous hydrogen epoxidation of the functionalized enynes.[11]
Abstract. An asymmetric epoxidation of electron-deficient
peroxide as oxidant has been accomplished by developing a
chiral N,N'-dioxide-Scandium(III) complex catalytic
system. In the presence of 0.5-2 mol% catalyst, a variety of
trisubstituted alkynyl oxiranes were obtained in high yields
(up to 97%) with excellent ee values (up to 99%).
Furthermore, control experiments provide a fundamental
insight into the reaction mechanism.
Chiral N,N'-dioxides developed by our group, can
coordinate with various metal salts to form the
complexes, which have been proved to be efficient in
a number of asymmetric transformations.[12] As an
ongoing work in the epoxidation reaction,[13] here we
developed a highly efficient asymmetric epoxidation
of electron-deficient enynes with a low catalyst
loading to 0.5 mol%, giving a variety of trisubstituted
alkynyl oxiranes in high yields (90-97%) and
excellent enantioselectivities (95-99% ee) (Scheme
1c).
Keywords: asymmetric catalysis; epoxidation; electron-
deficient enynes; N,N'-dioxide; Scandium(III)
Chiral epoxide compounds are versatile intermediates
and building blocks in organic synthesis. Since a
milestone achievement was obtained by Sharpless for
the asymmetric epoxidation of allylic alcohols in the
early 1980s,[1] much progress has been made towards
these optically pure compounds.[2, 3, 4, 5] Chiral alkynyl
oxiranes, one type of them, are useful motifs in
numerous biologically active natural and unnatural
compounds.[6] They are also important synthetic
intermediates for a wide range of derivatives.[7] Over
the past few years, many strategies have been devoted
to their synthesis.[8] Among them, enantioselective
epoxidation of enynes provides a direct approach to
chiral alkynyl oxiranes. Shi applied their fructose-
derived ketones as catalysts to efficiently promote the
epoxidation of enynes with oxone as oxidant and give
the products in good yields and ee values (Scheme
1a).[9] On the other hand, aqueous hydrogen peroxide
is probably the most competitive oxidant for its
advantage of cheapness, high atom efficiency and
generating water as the sole by-product. The
epoxidation of unfunctionalized enynes using H2O2 as
oxidant catalyzed by chiral salen-metal catalysts were
efficient (Scheme 1b).[10] However, there was still no
report on the highly enantioselective epoxidation of
trisubstituted enynes with electron-deficient groups.
In this regard, a suitable oxidant and catalyst should
Scheme 1. Direct asymmetric epoxidation of
conjugated enynes.
In the beginning, the enyne 1aa was chosen as the
model substrate and aqueous hydrogen peroxide as
the oxidant to optimize the reaction conditions.
Initially, a series of metal salts complexing with
chiral N,N'-dioxide L-PrPr2 was explored. Many
1
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10.1002/adsc.201700555
Advanced Synthesis & Catalysis
metal complexes, such as the Zn(OTf)2 or Mg(OTf)2
complex, could not promote the reaction (Table 1,
entries 1 and 2). Fortunately, lanthanide metals,
Tb(OTf)3 and Sc(OTf)3 could give high
enantioselectivity though the yield was low. Since
Table 1. Optimization of the reaction conditions.[a]
Entry
Metal salts
Ligand
Yield [%][b]
ee [%][c]
Zn(OTf)2
Mg(OTf)2
n.r. [d]
n.r.
35
-
-
1
2
3
4
5
6
7
8
9
L-PrPr2
L-PrPr2
L-PrPr2
Tb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
92
94
99
98
97
98
99
L-PrPr2
L-PiPr2
L-RaPr2
L-PiMe2
L-PiEt2
L-PiPr3
36
95
61
88
93
90
95
88
10[e]
Sc(OTf)3
Sc(OTf)3
L-PiPr2
L-PiPr2
99
99
11[f]
[a] Unless otherwise noted, all the reactions were carried out with ligand/metal salts (1:1, 10 mol%), 1aa (0.1 mmol), 2
(0.3 mmol) in THF (Tetrahydrofuran, 0.5 mL) at 35 °C for 16 h.
[b] Isolated yield.
[c] Determined by chiral HPLC analysis.
[d] No reaction.
[e] The reactions were carried out with L-PiPr2/metal salts (1:1, 0.5 mol%), 1aa (0.6 mmol), 2 (1.8 mmol) in THF (1.0
mL) at 35 °C for 48 h.
[f] 0.25 mol% catalyst was used and the concentration of 1aa was 0.8 M.
Sc(OTf)3 gave a little higher yield and ee, we next
increased to 0.6 M and prolonging the reaction time
chose Sc(OTf)3 to explore chiral N,N'-dioxide ligands. to 48 h (Table 1, entry 10). When the catayst loading
It was found that the bulky amide subunits of the
ligands have a great influence on the reactivity and
enantioselectivity of the reaction. Both (S)-pipecolic
acid derived L-PiPr2 and (L)-ramipril derived L-
RaPr2 could give the better results. Especially，(S)-
pipecolic acid derived L-PiPr2 improved the activity
sharply, offering the product in 95% yield after 16 h.
Meanwhile, the enantioselectivity was also increased
to 99% ee (Table 1, entries 4-6). The substituent at
the amide moiety of the ligands was also investigated
showing that the yield would decrease gradually as
the steric hindrance was reduced (Table 1, entries 7-
9). To our delight, the catalyst loading could be
reduced to 0.5 mol%, and the same yield and ee value
were maintained when the concentration of 1aa was
was further decreased to 0.25 mol%, the optical
active product could be still obtained albeit in a little
lower yield by increasing the concentration of
substrate to 0.8 M (Table 1, entry 11).
With the optimal conditions established (Table 1,
entry 10), the substrate scope was investigated. As
shown in Table 2, a variety of electron-deficient
enynes were tolerated. The reactivities and
enantioselectivities were influenced little by different
substituents at the aromatic ring (Table 2, entries 1-4).
When the substituent at aromatic ring R2 was varied,
the electronic and steric effect have no significant
effect (Table 2 entries 5-12). When R2 was
trimethylsilyl group, the high yield and ee value were
obtained (Table 2 entrie 13). If it was replaced by the
2
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10.1002/adsc.201700555
Advanced Synthesis & Catalysis
cyclopropyl or propyl groups, lower yields could be
overcomed by increasing the catalyst loading to 2
mol% (90% yields, 99% ee; Table 2, entries 14 and
15). Besides, whether R1, R3 were alkyl or phenyl
Table 2. Substrate scope of electron-deficient enynes of the asymmetric epoxidation.[a]
R2
Ph
Ph
Ph
Entry
1
2
3
4
5
6
7
8
R1
Ph
4-ClC6H4
4-BrC6H4
4-MeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Propyl
R3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
nBu
Me
nBu
4-tBuC6H4
3-ClC6H4
Me
Yield [%][b]
95 (3aa)
96 (3ab)
93 (3ac)
96 (3ad)
97 (3ba)
93 (3bb)
93 (3bc)
95 (3bd)
96 (3be)
97 (3bf)
94 (3bg)
97 (3bh)
96 (3bi)
90 (3bj)
90 (3bk)
93 (3ca)
95 (3cb)
94 (3cc)
95 (3cc)
93 (3da)
97 (3db)
96 (4aa)
ee [%][c]
99
98
99
99
99
99
99
99
99
98
99
99
98
98
99
97
Ph
2-FC6H4
3-FC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
3-MeC6H4
4-tBuC6H4
TMS
Cyclopropyl
Propyl
Ph
Ph
TMS
9
10
11
12
13
14[d]
15[d]
16[d]
17[d]
18[d]
19[d]
20
21
22[d]
96
99
99
99
99
95
TMS
Ph
Ph
Ph
[a] Unless otherwise noted, all the reactions were carried out with L-PiPr2/Sc(OTf)3 (1:1, 0.5 mol%), 1 (0.6 mmol), 2 (1.8
mmol) in THF (Tetrahydrofuran, 1.0 mL) at 35 °C for 48 h.
[b] Isolated yield.
[c] Determined by chiral HPLC analysis.
[d] The reactions were carried out with L-PiPr2/Sc(OTf)3 (1:1, 2 mol%), 1 (0.3 mmol), 2 (0.9 mmol) in THF (0.5 mL) at
35 °C for 48 h.
enantioselectivities (Table 2, entries 16-22). Finally,
The absolute configuration of the 4-bromo-
substituted product 3ac was determined to be (2S, 3R)
by X-ray crystallographic analysis.[14]
To show the synthetic utility of the method, a
gram-scale synthesis of 3bj was performed. As
shown in Scheme 2a, in the presence of 0.5 mol%
catalyst, 5.60 mmol of the enyne substrate 1bj
transformed to the corresponding product 3bj in 96%
yield (1.74 g) with 98% ee. Meanwhile, the
trimethylsilyl group of the product 3bj could be
easily deprotected to transform into 4bj in 93% yield
with 98% ee (Scheme 2b) Moreover, 4bj could
readily undergo a cycloaddition with N-hydroxyl
benzimidoyl chloride to give the product
isoxazolidine 6bj (88% yield, 99% ee, Scheme 2b).
In order to gain an insight into the roles of alkynyl
group in the reaction, control experiments were
performed (Scheme 3). Firstly, the competition
Scheme 2. Gram-scale version and the derivatives.
groups，all the reactions could give the products in
high
yields
(90-97%)
with
excellent
3
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10.1002/adsc.201700555
Advanced Synthesis & Catalysis
reaction of benzylideneacetone 6 and enyne substrate
3c was conducted under standard conditions. The
optical active alkynyl oxirane product 3cc was
obtained in excellent yield and ee value, and trace
amount of the epoxidation product 7 was detected
(Scheme 3a). Subsequently, another competition
experiment between enyne 3c and 1,3-dione substrate
8 was performed. Still, only the epoxidation product
of enyne 3c was obtained (Scheme 3b). It indicated
that alkynyl groups might make the substrates more
reactive, not only featuring an electron-withdrawing
moiety.[15, 16] On the basis of the control experiments,
the X-ray structure of the product 3ac and the
previous work,[16] a possible catalytic model was
proposed to elucidate the origin of the
stereoselectivity. As outlined in Figure 2, the enyne
substrate coordinated to the scandium complex in a
bidentate fashion. The Si face of the enyne 1ac was
shielded by the nearby isopropylphenyl group of the
N,N'-dioxide. So the peroxide attacked the β-carbon
atom of the Michael acceptor enyne 1ac preferably
from the Re face, and the product alkynyl oxirane
was
formed.
Scheme 3. The control experiments.
Figure 1. Possible catalytic model and X-ray structure of the product 3ac.
ºC for 48 h. The reaction mixture was directly purified by
flash column chromatography (ethyl acetate/petroleum
In summary, the asymmetric epoxidation of
electron-deficient enynes was accomplished with
aqueous hydrogen peroxide as oxidant by using a low
catalyst loading of an effective chiral N,N'-dioxide-
ether
= 1/30) to afford the desired product. The
enantiomeric excess was determined by chiral HPLC and
the product propargyl oxirane was determined by NMR
analysis.
scandium(III) complex catalyst.
A
variety of
trisubstituted alkynyl oxiranes were obtained in
excellent yields (90-97%) and ee values (95-99%).
Over the control experiments, the alkynyl groups
might make the substrates more reactive through
coordinating to the scandium complex, not only
featuring an electro-withdrawing moiety.
Acknowledgements
We appreciate the National Natural Science Foundation of China
(Nos. 21432006 and 21572136) for financial support.
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10.1002/adsc.201700555
Advanced Synthesis & Catalysis
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10.1002/adsc.201700555
Advanced Synthesis & Catalysis
UPDATE
Catalytic Asymmetric Epoxidation of Electron-
Deficient Enynes Promoted by Chiral N,N'-
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Adv. Synth. Catal. Year, Volume, Page – Page
Hang Zhang, Qian Yao, Lili Lin,* Chaoran Xu,
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