Highly efficient asymmetric epoxidation of electron-deficient α,β-enones and related applications to organic synthesis

Article abstract of DOI:10.1002/adsc.200900041

The asymmetric epoxidation of electrondeficient olefins has been achieved using inexpensive and readily available prolinols as catalysts with good to excellent yields and enantioselectivities. The utility of the resulting chiral epoxides was illustrated b

Full text of DOI:10.1002/adsc.200900041

FULL PAPERS
DOI: 10.1002/adsc.200900041
Highly Efficient Asymmetric Epoxidation of Electron-Deficient
a,b-Enones and Related Applications to Organic Synthesis
Changwu Zheng,a Yawen Li,a Yingquan Yang,a Haifeng Wang,a Haifeng Cui,a
Junkang Zhang,a and Gang Zhaoa,*
a
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 lingling Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: zhaog@mail.sioc.ac.cn
Received: January 20, 2009; Published online: June 16, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900041.
Abstract: The asymmetric epoxidation of electron- pounds featuring a concise synthesis of (À)-(5R,6S)-
deficient olefins has been achieved using inexpensive balasubramide.
and readily available prolinols as catalysts with good
to excellent yields and enantioselectivities. The utili-
ty of the resulting chiral epoxides was illustrated by Keywords: asymmetric catalysis; enones; epoxida-
elaboration to several synthetically useful com- tion; stereoselectivity; synthesis
Introduction
desirable to delve into this reaction to address these
problems.
The catalytic enantioselective epoxidation of olefins is
In our previous studies,[7] we have observed a mod-
one of the most widely studied reactions in asymmet- erate rate-accelerating effect arising from the pres-
ric catalysis due to the extensive presence of the re- ence of electron-withdrawing groups on the phenyl
sulting chiral epoxide structures in biologically active ring of R2 (R2 =substituted phenyl groups) (Figure 1).
compounds as well as their great utility in organic We envisioned that when the R2 groups were more
synthesis.[1] As an important type of functionalized electron-withdrawing groups such as CF3, CCl3 and
olefins, acyclic a,b-unsaturated ketones have been CO2R rather than the previously used aryl groups or
among the most investigated targets in this field and alkyl groups, the reactivity of the double bond in the
numerous catalysts such as metal complexes,[2] phase- Michael-type addition step in the transition state may
transfer catalysts (PTC),[3] chiral N-oxides[4] and poly- be further increased and, more importantly, the use of
peptides[5] have been applied to the asymmetric epox- these groups would give rise to products allowing
idation of these compounds with varied degrees of facile further conversions to various synthetically
success. Recently, the asymmetric organocatalytic ep- useful structures. Herein, we report the details of this
oxidation of a,b-unsaturated aldehydes or ketones research.
has emerged as a promising area,[6] which is highlight-
ed with several advantages such as mild reaction con-
ditions, simple experimental manipulations, inexpen-
sive and readily available catalysts. Our group has
also developed several new catalysts for this transfor-
mation.[7] Despite these advances, the present system
principally suffers from a narrow substrate scope re-
stricted mostly to chalcones, which are not easily con-
vertible to other useful structures for practical uses in
organic synthesis.[6,7] In addition, the reaction general-
ly requires long reaction times (4–6 days) due to the
low reactivity of these substrates. Therefore, it is still
Figure 1. Proposed transition state for the prolinol-catalyzed
epoxidation of a,b-unsaturated ketones.
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Results and Discussion
action conditions,[6,7] the reaction times were signifi-
cantly reduced for the epoxidation of 1a with moder-
To begin with, a series of 4-substituted prolinols was ate to excellent yields in the presence of 15 mol% of
synthesized as catalysts for evaluation in this research the catalysts 7a–7g and 7i using n-hexane as the sol-
(Figure 2).[7b,8] Firstly, the epoxidation of a-keto esters vent at room temperature (Table 1, entries 1–11). Par-
1 was investigated and methyl 2-oxo-4-phenylbut-(E)- ticularly, with the optimal catalyst 7f, the reaction
3-enoate 1a was selected as the probe substrate for could proceed to completion within 4 h affording the
catalyst evaluation (Table 1). As expected, in compar- desired product 2a in 94% yield and 90% ee (Table 1,
ison with the reactions of chalcones under similar re- entry 6). Furthermore, high enantioselectivity (91%
ee) could still be achieved when the loading of 7f was
lowered from 15 mol% to 10 mol%, albeit with a
drop in the yield (Table 1, entry 12). Finally, the high-
est enantioselctivity was obtained (96% ee) with 83%
yield when the reaction was conducted with 10 mol%
of 7f at À108C (Table 1, entry 14) and this condition
was adopted for our subsequent study of the substrate
scope.
The results of the epoxidation of a selected spec-
trum of a-keto esters under the above optimized reac-
tion conditions are shown in Table 2. In general, most
of the examined substrates with different substituents
in both the ester moiety and phenyl ring could afford
the desired products in good yields and with excellent
enantioselectivities in 9–15 h, irrespective of the elec-
tronic nature or the steric hindrance of the substitu-
Figure 2. Catalysts evaluated in this study.
ents. It seemed that both the reaction rate and yield
were greatly influenced by the solubility of the sub-
strate a-keto esters in n-hexane. For instance, the ep-
Table 1. Screening of catalysts and solvents for the enantio-
selective epoxidation of a-keto ester 1a.[a]
Table 2. Asymmetric epoxidation of b,g-unsaturated a-keto
esters catalyzed by 7f.[a]
Entry Catalyst Solvent Temp.
Time Yield
[h]
ee
[8C]
[%][b]
[%][c]
Entry R1, R2
Time Prod- Yield ee
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7i
hexane 20
hexane 20
hexane 20
hexane 20
hexane 20
hexane 20
hexane 20
hexane 20
30
30
30
18
30
4
30
14
30
30
30
5
53
74
79
95
89
94
75
53
73
47
trace
79
94
83
À80
À85
À75
À85
À83
90
46
47
88
[h]
uct
[%][b] [%][c]
1
Ph, Me (1a)
11
11
11
11
9
14
9
15
15
15
10
2a
2b
2c
2d
2e
2f
2g
2h
2i
83
90
91
91
92
96
90
87
89
88
87
60
52
96
95
94
94
96
94
96
98
98
94
97
94
92
2
Ph, Et (1b)
3
Ph, Allyl (1c)
4
Ph, i-Pr (1d)
5
Ph, t-Bu (1e)
6
Ph, Bn (1f)
9
10
11
7f
7f
7f
CCl4
toluene 20
THF 20
hexane 20
hexane
hexane À10
20
7
8
9
10
11
12[d]
13[d]
p-F-C6H4, Me (1g)
p-Cl-C6H4, Me (1h)
p-Br-C6H4, Me (1i)
o-Br-C6H4, Me (1j)
m-Cl-C6H4, Me (1k)
p-NO2-C6H4, Me (1l) 12
p-Me-C6H4, Me (1m) 24
88
[d]
–
12[e] 7f
13[e] 7f
14[e] 7f
91
95
96
2j
2k
2l
0
7
11
2m
[a]
Unless otherwise specified, the reaction was carried out
with 2.0 equiv of TBHP in the presence of 15 mol% of 7
at 208C.
Isolated yields after flash column chromatography.
Enantiomeric excess was determined by HPLC analysis
using a chiral column.
[a]
Unless otherwise specified, the reaction was carried out
with 2.0 equiv of TBHP in the presence of 10 mol% of
7f at À108C.
[b]
[c]
[b]
[c]
Isolated yield after flash column chromatography.
Determined by HPLC analysis using chiral columns. The
absolute configuration of 2 was determined to be 2S,3R.
The reaction was carried out at room temperature.
[d]
[e]
Not determined.
10 mol% of 7f was employed.
[d]
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Highly Efficient Asymmetric Epoxidation of Electron-Deficient a,b-Enones
FULL PAPERS
Table 3. Screening of catalysts and solvents for the enantio-
selective epoxidation of a, b-unsaturated trichloromethyl
ketones 3.[a]
Table 4. Asymmetric epoxidation of a,b-unsaturated tri-
chloromethyl ketones.[a]
Entry
R
Time Prod- Yield
ee
[h]
uct
[%][b] [%][c]
Entry Catalyst Solvent Temp. Time Yield
ee
[8]
[h]
[%][b]
[%][c]
1
2
3
4
5
6
7
8
9
Ph (3a)
15
10
10
7
10
24
4a
4b
4c
4d
4e
4f
4g
4h
4i
77
82
93
81
83
36
84
50
43
86
81
86
86
84
56
76
99
75
[d]
p-F-C6H4 (3b)
p-Cl-C6H4 (3c)
p-Br-C6H4 (3d)
m-Cl-C6H4 (3e)
o-Cl-C6H4 (3f)
p-NO2-C6H4 (3g) 15
PhCH=CH (3h)
Me (3i)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7f
7h
7i
7f
7f
7f
hexane 20
hexane 20
hexane 20
hexane 20
hexane 20
hexane 20
hexane 20
48
15
48
15
15
20
48
48
48
48
48
trace
62
trace
35
77
54
trace
trace
trace
62
–
–61
[d]
–
–67
86
81
[d]
36
36
–
–
–
[d]
CCl4
20
[d]
toluene 20
[a]
Unless otherwise specified, the reaction was carried out
with 2.0 equiv. of TBHP in the presence of 20 mol% of
7f at 208C.
Isolated yield by flash column chromatography.
Converting 4 to corresponding a-epoxy esters followed
by HPLC analysis. The absolute configuration of 4 was
determined to be 2R, 3S.
10
hexane
hexane
0
0
85
85
11[e] 7f
57
[b]
[c]
[a]
Unless otherwise specified, the reaction was carried out
with 2.0 equiv. of TBHP in the presence of 20 mol% of 7
at 208C.
Isolated yields after flash column chromatography.
Enantiomeric excess was determined by HPLC analysis
using a chiral column.
[b]
[c]
[d]
[e]
Not determined.
15 mol% of 7f was employed.
er the desired product with moderate enantioselectivi-
ty and acceptable yield (Table 4, entry 9).
The efficient catalyst system was also extended to
oxidation of substrates 1l and 1m, which are poorly the epoxidation of a,b-unsaturated trifluoromethyl
soluble in n-hexane, only provided the desired prod- ketones (Table 5). Preliminary investigations showed
ucts in moderate yields after 12 and 24 h, respectively, that the reaction was best performed with catalyst 7d
even at elevated temperatures (Table 2, entries 12 and at 08C in n-hexane (Table 5, entries 1–8). We specu-
13).
lated that a less effective catalyst for the epoxidation
Subsequently, the epoxidations of another useful of 1 and 3 was nevertheless advantageous for the ep-
type of a,b-enones, namely the a,b-unsaturated tri- oxidation of the a,b-unsaturated trifluoromethyl
chloromethyl ketones 3 were investigated (Table 3 ketone with respect to its more electron-withdrawing
and Table 4). It seemed that the sterically more de- nature than trichloromethyl or ester group. The same
manding trichloromethyl group was inferior to the ad- effect was also observed in the catalyst loadings. In-
jacent ester group in a-keto esters 1 for the present creasing the catalyst loading promoted the reaction
transformation: under the similar reaction conditions rate, however, the observed enantioselectivities were
as above, the desired epoxides were generally ob- compromised (Table 5, entries 4 and 5). Using 7d as
tained with diminished yields and enantioselectivities the catalyst, the products were generally obtained in
even with a slightly larger amount of the catalyst 7f good yields within 12–28 h. para-Substituted sub-
(Table 3, entries 1–7). However, accelerations in the strates gave rise to the epoxides with high enantiose-
reaction rates were still observed as expected and the lectivities except for the ethyl group-substituted 5f,
reactions could go to completion within 7–36 h which was probably due to its enhanced electron-do-
(Table 4). When the reaction was conducted at a nating nature (Table 5, entries 9–13). Substrates 5g
lower temperature, no improvement in the enantiose- and 5i with substituents at the 2-position were found
lectivity was observed (Table 3, entries 10 and 11). to be less reactive, affording the corresponding prod-
Moreover, steric factors seemed to play a large role in ucts in lower yields and enantioselectivities, which
this system since substrate 3f bearing a substituent at was similar to the observations in the epoxidation of
the 2-position of the phenyl ring gave rise to the de- a, b-unsaturated trichloromethyl ketones (Table 5, en-
sired epoxide with both apparently lower yield and tries 14 and 16). Notably, the resulting epoxides were
enantioselectivity (Table 4, entry 6). Notably, aliphatic quickly transformed to their hydrated forms in the
ketone 3i could also undergo the epoxidation to deliv- process of work-up.[9]
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Table 5. Epoxidation of a,b-unsaturated trifluoromethyl ketones catalyzed by 7.[a]
Entry
Catalyst
Solvent
R
Temp. [8C]
Time [h]
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
7d
7e
7f
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
CCl4
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
p-F-C6H4 (5b)
p-Cl-C6H4 (5c)
p-Br-C6H4 (5d)
p-CH3-C6H4 (5e)
p-Et-C6H4 (5f)
o-Cl-C6H4 (5g)
m-Cl-C6H4 (5h)
o,p-di-Cl-C6H3 (5i)
20
20
20
20
20
0
20
20
0
0
0
0
0
10
18
8
8
8
18
8
8
12
12
12
18
18
28
18
28
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
6f
6g
6h
6i
78
72
80
76
82
76
85
52
88
84
82
80
81
65
79
70
72
51
-52
64
60
96
66
21
90
90
95
95
78
52
89
53
7d[d]
7d[e]
7d
7d
7d
7d
7d
7d
7d
7d
7d
7d
7d
toluene
9
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
10
11
12
13
14
15
16
0
0
0
[a]
Unless otherwise specified, the reaction was carried out with 2.0 equiv. of TBHP in the presence of 10 mol% of catalyst
7.
[b]
[c]
Isolated yields by flash column chromatography.
Determined by HPLC analysis using the chiral column Daicel Chiralcel AS-H. Configuration (2S,3R) for 6a obtained by
7d, 7e and (2R,3S) by 7f.
20 mol% of 7d was used as the catalyst.
[d]
[e]
30 mol% of 7d was used as the catalyst.
In an effort to realize our goal of generating syn-
Reduction of the b-epoxy-a-keto esters 2 with
thetically useful structures, efficient further transfor- sodium borohydride in the presence of anhydrous cal-
mations of the a-epoxy ketones obtained above were cium chloride furnished the chiral diol 9 in excellent
then investigated (Scheme 1). First, hydrazinolysis of yield.[12] This compound could then be easily trans-
the trifluoromethyl epoxide 6d with phenylhydrazine formed to dihydroxytetrahydrofuran 10, a structure
afforded the heterocyclic compound
trifluoroACHTUNGTRENNUNG
8
with
a
that can be seen in many natural products,[13] by re-
methyl-substituted quaternary carbon centre fluxing in water for three hours.[14] Alternatively, com-
in 85% yield.[10] These types of heterocyclic com- pound 9 could also be converted to another useful
pounds are useful intermediates in the preparation of synthon, the epoxy aldehyde 11.
biologically interesting compouds.[11]
Scheme 1. Synthetic transformations of the chiral epoxides 2i and 6d: a) NaBH4, CaCl2, MeOH, 08C, dr=2:1, 1.5 h; b)
Water, reflux, 3 h; c) NaIO4, CH2Cl2, room temperature, 1 h; d) PhNHNH2, EtOH, À158C, 3 h.
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Highly Efficient Asymmetric Epoxidation of Electron-Deficient a,b-Enones
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.
Scheme 2. Synthetic transformations of the chiral epoxide 4a: a) NH3 H2O, CH3CN, room temperature, 1 h; b) ethanolamine,
CH3CN, room temperature, 10 h; c) CH3CN, room temperature, 10 h; d) YbACTHNUGTRNEUNG(OTf)3, CH3CN, room temperature, 10 h; e)
NaHCO3, MeOH, 308C, 0.5 h.
Conversions of the a,b-epoxy trichloromethyl ke- thetic context. In addition, we have demonstrated the
tones were more facile due to the good reactivity of synthetic utility of our epoxide substrates, leading to
the trichloromethyl group as
a
leaving group the efficient synthesis of (À)-(5R,6S)-norbalasubra-
(Scheme 2). The amides 12–14 could be easily ob- mide and (À)-(5R,6S)-balasubramide in good yields
tained in high yields by the reactions of 4a with the over three steps. Studies on the further applications
corresponding amines in acetonitrile without any cat- of these epoxidations in organic synthesis are in prog-
alyst.[15] The products 12 and 13 thus obtained are im- ress.
portant intermediates in organic synthesis.[16] Further-
more, using an YbACTHNUTRGNEUNG(OTf)3-catalyzed intramolecular
ring-opening reaction of the epoxide structure, a
straightforward synthesis of chiral (À)-(5R,6S)-balasu-
bramide 15b was achieved with good yield in two
steps from 4a. This may be the most efficient method
for the synthesis of this compound up to date.[16b,17] By
heating in methanol in basic conditions for 0.5 hour,
the product 4a could be easily transformed to a-
epoxy ester 16. The absolute configuration of the ep-
oxide 4a was determined to be 2R,3S by comparison
Experimental Section
General Procedure for the Asymmetric Epoxidation
of a,b-Unsaturated Ketones
To a solution of ketone 1a (0.1 mmol) and catalyst 7 (0.005–
0.02 mmol) in hexane (1.0 mL) was added TBHP (0.2 mmol,
6.35M in toluene, 30 mL) at the appropriate temperature,
and the resulting mixture was stirred for the specified time
(Table 1, Table 2, Table 3, and Table 4). After completion as
of the optical rotation value of the product 16 with indicated by TLC, the crude mixture was concentrated on a
that reported.[18]
rotary evaporator. The residue was directly purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate
10:1) to give the pure epoxide 2a as a white solid; yield:
80%; mp 708C; [a]D27:3: À139.9 (c 0.55, CHCl3); 1H NMR
Conclusions
(300 MHz, CDCl3): d=7.39 (m, 3H), 7.33 (m, 2H), 4.20 (dd,
J=1.5 Hz, 13.5 Hz, 2H), 3.93 (s, 3H); 13C NMR (75 MHz,
In conclusion, we have achieved the highly efficient
and enantioselective epoxidation of three types of
electron-deficient a,b-unsaturated ketones in syntheti-
cally useful yields. This reaction largely expands the
CDCl3): d=187.94, 160.75, 134.50, 129.37, 128.77, 125.88,
60.72, 60.11, 53.23; IR (film): n=3222, 1755, 1693, 1364,
1288, 1133, 1023, 701 cmÀ1; EI-MS: m/z (abundance)=206
(M+, 3.10), 91 (100), 121 (67.25), 90 (22.85), 65 (22.19), 89
method for the synthesis of epoxides useful in a syn- (19.09), 77 (17.69), 51 (15.29), 119 (13.82); anal. calcd. for
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Changwu Zheng et al.
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C11H10O4: C 64.07, H 4.89; found: C 64.34, H 5.10; HPLC
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hexane/i-PrOH, 1.00 mLminÀ1):
tmajor =19.1 min, tminor =
13.9 min.
2,2,2-Trichloro-1-[(2R,3S)-3-phenyloxiran-2-yl]ethanone
(4a): Jelly; yield: 77%; [a]2D6: À127.1 (c 1.00, CHCl3); IR
(neat): n=2925, 1756, 1599, 1454, 1069 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=7.35–7.42 (m, 5H), 4.29 (d, J=
0.9 Hz, 1H), 4.15 (d, J=0.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=184.16, 134.12, 129.51, 128.87, 125.79, 96.89,
61.33, 57.19; EI-MS: m/z (abundance)=229 (M+ÀCl, 6.95),
91 (100.00), 105 (37.03), 131 (34.48), 77 (22.87), 103 (20.52),
89 (14.67), 51 (13.69) 65 (10.37); HR-MS: m/z=228.9820,
calcd. for C10H7Cl3O2: 228.9823; HPLC (separation condi-
tions: Chiralcel OD-H, 208C, 220 nm, 90:10 hexane/i-PrOH,
1.00 mLminÀ1): tmajor =18.9 min, tminor =25.2 min.
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Mol. Catal. A: Chem. 2007, 273, 1; f) S.-P. Kee, A. Gav-
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2,2,2-Trifluoro-1-[(2S,3R)-3-phenyloxiran-2-yl]ethane-1,1-
diol (6a): White solid; yield: 76%; mp 139–1408C; [a]D22:9
:
51.5 (c 0.75, CHCl3); IR (film): n=3422, 1465, 1189,
721 cmÀ1
;
19F NMR (282 MHz, CDCl3): d=À84.3 (s, 3 F);
1H NMR (300 MHz, CDCl3): d=3.40 (s, 1H), 3.95 (s, 1H),
7.18–7.31 (m, 5H); MS (EI): m/z=216 (M+ÀH2O); HPLC
(separation conditions: Chiralcel AS-H, 208C, 254 nm, 90:10
hexane/i-PrOH, 1.00 mLminÀ1):
tmajor =18.6 min, tminor =
22.6 min.
Acknowledgements
Research support from the National Natural Science Founda-
tion of China (No. 20172064, 203900502, 20532040Y), QT
Program, Shanghai Natural Science Council, and Excellent
Young Scholars Foundation of National Natural Science
Foundation of China (20525208)
˙
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