Kinetic resolution of 2,3-epoxy 3-aryl ketones via catalytic asymmetric ring-opening with pyrazole derivatives

Article abstract of DOI:10.1039/c5cc02179k

A highly efficient catalytic kinetic resolution of 2,3-epoxy 3-aryl ketones via asymmetric ring-opening with pyrazole derivatives has been achieved by using a chiral N,N′-dioxide-Sc(III) complex as the catalyst. A wide variety of substrates were readily scoped, and the selectivity factors obtained were excellent (up to >300).

Full text of DOI:10.1039/c5cc02179k

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Kinetic resolution of 2,3-epoxy 3-aryl ketones via
catalytic asymmetric ring-opening with pyrazole
derivatives†
Cite this:DOI: 10.1039/c5cc02179k
Received 14th March 2015,
Accepted 24th April 2015
Tianyu Huang,a Lili Lin,a Xiaolei Hu,a Jianfeng Zheng,a Xiaohua Liua and
Xiaoming Feng*ab
DOI: 10.1039/c5cc02179k
www.rsc.org/chemcomm
A highly efficient catalytic kinetic resolution of 2,3-epoxy 3-aryl can afford both b-pyrazole-substituted alcohols and optically pure
ketones via asymmetric ring-opening with pyrazole derivatives has epoxides8 simultaneously. In addition, b-pyrazole-substituted alcohols
been achieved by using a chiral N,N0-dioxide–Sc(III) complex as the have emerged as potential neuromuscular blocking agents and
catalyst. A wide variety of substrates were readily scoped, and the compounds possessing proneurogenic activity,9 while optically
selectivity factors obtained were excellent (up to 4300).
pure epoxides are among the most versatile compounds in organic
chemistry, because their derivatives have found broad applications
Kinetic resolution (KR) is considered to be one of the most general in synthetic and biological technology.10 Also, encouraged by the
methods to obtain enantiopure molecules. The main types of success of the N,N0-dioxide–Sc(III) complex catalyzed desymmetriza-
functional compounds that have been resolved involve alcohols, tion of meso-epoxides using pyrazole derivatives as nucleophiles,11
epoxides, amines, alkenes and so on.1,2 On the other hand, catalytic herein, we have decided to develop N,N0-dioxide–metal complexes12
asymmetric epoxide ring-opening reactions by nucleophiles3 attract to furnish the first kinetic resolution of racemic 2,3-epoxy 3-aryl
much attention due to the high ring strain of epoxides and ketones via asymmetric ring-opening by employing pyrazole
the convenient synthesis of useful optically enriched 1,2- derivatives as the aza-nucleophiles.
difunctionalized compounds with two adjacent stereocenters.
Our investigation began with the ring-opening of phenyl(3-
Although numerous reports on catalytic asymmetric epoxide phenyloxiran-2-yl)methanone (ꢀ)-1a by 3,5-dimethyl-4-nitro-
ring-opening reactions have been published,4 most of them are 1H-pyrazole 2a as the model reaction to optimize the reaction
desymmetrization of meso-epoxides. Comparatively, the kinetic conditions. A screening of metal salts showed that Sc(OTf)3 was the
resolution of racemic epoxides via the enantioselective catalytic potentially optimal metal salt (see the ESI† for details). Using the
ring-opening method continues to be relatively rare.5,6 Meanwhile, chiral N,N0-dioxide L1–Sc(OTf)3 complex as the catalyst, the desired
only terminal unfunctionalized epoxides can give excellent results product 3a was obtained in 55% yield with 53% ee; meanwhile, the
and the catalysts are focused on Salen based complexes.7 Hence, substrate 1a was recovered in 40% yield with 77% ee (Table 1, entry
the development of new catalytic systems for the ring opening 1). The molar ratio of ligand L1 to Sc(OTf)3 was an important factor
of 1,2-disubstituted epoxides is meaningful and imperative.
in determining the selectivity factor of the reaction. As shown in
Besides, as one of the 1,2-disubstituted epoxides, 2,3-epoxy Table 1, an excess of ligand L1 over Sc(OTf)3 had a positive effect on
3-aryl ketones, to the best of our knowledge, have never been the selectivity factor (Table 1, entries 1–4). When the ratio of ligand
applied in the catalytic asymmetric ring-opening reaction to date, L1 to Sc(OTf)3 was 2 : 1, a better s factor of 50 was obtained. When
due to not only the difficulty in controlling the regioselectivity, but the structure of the chiral ligand was examined, it was found that
also the hardness of KR caused by the high activity of 2,3-epoxy the chiral backbone, the amide moiety and the linker of the ligand
3-aryl ketones. Moreover, the kinetic resolution of racemic 2,3-epoxy all affected the selectivity of the process. As for the chiral backbone,
3-aryl ketones via asymmetric ring-opening by pyrazole derivatives the ligand L1 derived from L-proline exhibited a slight superiority
of the s factor over ligands L2 and L3 (Table 1, entries 4–6).
a Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: xmfeng@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
b Collaborative Innovation Center of Chemical Science and Engineering, Tianjin,
China
In addition, the steric hindrance of the amide subunits had a
crucial influence on both the yield and the stereoselectivity. The
use of ligand L4 with an aromatic substituent on the amine
moiety resulted in an s factor of 51 (Table 1, entry 7). Excitingly,
ligand L5 containing 2,4,6-triisopropyl aniline provided better
results, giving rise to an s factor of 116. When ligand L6 with a
three-carbonic linkage was used, the s factor dropped sharply to
† Electronic supplementary information (ESI) available: Additional experimental
and spectroscopic data. CCDC 1034676. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c5cc02179k
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Table 1 Optimization of the reaction conditions
Table 2 Evaluation of the scope of epoxides
Yieldc (%)
eed (%)
t
(h)
Conv.b
(%)
Entrya
1
3
1
3
1
se
Yieldc (%)
eed (%)
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
26
44
16
48
24
12
12
50
72
72
72
72
27
46
19
48
31
12
48
30
40
12
72
72
50
50
48
48
52
50
52
50
47
37
33
49
51
51
51
52
48
50
51
50
51
50
48
45
47
50
48
48
50
49
50
48
42
32
28
43
50
51
51
48
46
50
49
46
46
48
48
35
49
49
51
52
43
48
46
48
52
63
66
47
49
49
47
42
50
49
47
47
49
49
47
65
95
94
96
93
94
139
120
156
75
111
179
111
72
Entrya
L : M
L
Conv.b (%)
3a
1a
3a
1a
se
2 f,g
3
95
91
85
1
2
3
4
5
6
7
8
1 : 1
1.2 : 1
1.5 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L5
L5
59
56
41
21
14
33
53
51
41
50
39
55
50
39
19
14
18
43
46
39
47
38
40
42
55
70
84
60
52
49
60
49
60
53
66
71
95
89
93
86
93
95
95
96
77
71
50
26
17
47
96
97
67
94
61
7
4 f,g
10
10
50
20
44
51
116
78
139
91
5 j
91 499
95 98
91 499
91
93
97
98
92
95 499
95 499
96 499
82
95
6
7 j
8 f,h
9 f,i
93
83
54
49
88
72
10 f,g
11 f,g
12 f,g
13 f
14 f
15 f
16 f,g
17
113
160
71
206
206
259
31
117
4300
78
57
35
153
25
16
9
10f
11g
a
Unless otherwise noted, the reactions were performed with L-Sc(OTf)3
(10 mol%), 30 mg 3 Å MS and 2a (0.1 mmol) with (ꢀ)-1a (0.1 mmol)
under nitrogen in CH2Cl2 (0.5 mL) at 35 1C for 26 h. All the diastereo-
90
89
1
18 j,k
19 f,h
20 f,g
21 f
22 j,k
23 f,g
24 f,g
97 499
selectivities were up to 419 : 1, determined using H NMR analysis of the
product 3a. b Conv. = ee1a/(ee1a + ee3a). Isolated yield. d Determined using
c
1s
1t
1u
1v
1w
1x
91
90
85
95
83
82
95
89
87
96
79
44
HPLC analysis. e s = ln[(1 ꢁ Conv.)(1 ꢁ ee1a)]/ln[(1 ꢁ Conv.)(1 + ee1a)].
f
5 mol% catalyst loading, 2a (0.2 mmol). g Without 3 Å MS.
78 (Table 1, entries 8 and 9). To our delight, upon reducing the
catalyst loading from 10 mol% to 5 mol% and increasing the
amount of 2a to 2 equiv. (Table 1, entry 10), the product 3a
could be obtained in 47% yield with 95% ee, and substrate 1a
was retrieved in 49% yield with 94% ee simultaneously with
an s factor of 139. Furthermore, when we conducted this trans-
formation without 3 Å molecular sieves (Table 1, entry 11), the
yield of 3a reduced to 38% and the enantiomeric excess of 1a
a
Unless otherwise noted, the reactions were performed with L5-Sc(OTf)3
(5 mol%, 2: 1), 30 mg 3 Å MS and 2a (0.2 mmol) with (ꢀ)-1 (0.1 mmol)
under nitrogen in CH2Cl2 (0.5 mL) at 35 1C. Conv. = ee1/(ee1 + ee3).
b
c
d
e
Isolated yield. Determined using HPLC analysis. s = ln[(1 ꢁ Conv.)-
(1 ꢁ ee1)]/ln[(1 ꢁ Conv.)(1 + ee1)]. 10 mol% catalyst loading. 2a
f
g
h
i
j
k
(0.5 mmol). 2a (0.3 mmol). 2a (0.4 mmol). At 25 1C. 2a (0.1 mmol).
decreased to 61%, which confirmed that the molecular sieves obtained and almost no other byproducts were detected for all
were an indispensable part of the catalytic system. evaluated substrates (see the ESI† for details). To investigate the
With the optimized conditions in hand (Table 1, entry 10), substrates 1 with the alkyl substituent, we tried (3-isobutyloxiran-
the substrate scope of racemic epoxides (ꢀ)-1 was examined 2-yl)(phenyl)methanone under the optimized conditions, but no
firstly. As shown in Table 2, regardless of the electronic nature desired product was detected. The absolute configuration of
or position of the substituents on the aryl rings of R1 and R2, the product 3f (Table 2, entry 6) was determined to be (2S,3S) via
racemic epoxides could undergo the KR process smoothly. Both X-ray crystallography,13 and the others were assigned by comparing
the b-pyrazole-substituted alcohols and the recovered epoxides the Cotton effect of the CD spectra with that of 3f.
were obtained in excellent yields with high to excellent enantio-
Given the remarkable efficiency of the present catalytic system,
selectivities (up to 50% yield, 499 : 1 d.r. and 98% ee), and the various pyrazole derivatives were also examined. As shown in
selectivity factors obtained were also excellent (up to 4300) Table 3, 2b and 2c proceeded the reaction smoothly, providing
(Table 2, entries 1–10, 13–21). Furthermore, fused-ring chalcone the products 3ab, 3gc in 40–49% yields with 88–90% ee, as well
epoxide (ꢀ)-1w as well as heteroaromatic (ꢀ)-1x and multi- as the starting material 1ab, 1gc in 49–50% yields with 90–91% ee.
substituted ones (ꢀ)-1k, (ꢀ)-1l, (ꢀ)-1v were also suitable candi- Significantly, the 3,5-dimethyl substituent on 1H-pyrazole had a
dates for the reaction (s factors of 16–160; Table 2, entries 11 and momentous influence on the conversion of the reaction. When
12, 22–24). In all cases, up to 419: 1 diastereomeric ratios were the standard substrate (ꢀ)-1a was chosen to react with 2d,
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Table 3 Asymmetric ring-opening of epoxides with different pyrazole
derivativesa
Scheme 2 Control experiments.
obtained by reduction, in excellent yield (99%) without any loss
of enantioselectivity (Scheme 1b).
To identify the ‘‘matched/mismatched’’ effect of the epoxide
clearly, we investigated the reaction of 2a with both enantiomeric
forms of the epoxide 1r. The comparative experiments showed very
impressive stereo-differentiation. The matched epoxide (2S,3R)-1r
went through the reaction smoothly, and gave the product (2S,3S)-
3r in 99% yield with 98% ee while the mismatched (2R,3S)-1r gave
only trace amounts of product (Scheme 2).
In conclusion, we have developed an efficient ring-opening and
kinetic resolution of racemic 2,3-epoxy 3-aryl ketones by using
pyrazole derivatives for synthesizing the optically active epoxides,
as well as chiral b-pyrazole-substituted alcohols. The excellent
chemical and optical yields, broad substrate generality, operational
simplicity, and mild reaction conditions highlighted the efficiency
of the chiral N,N0-dioxide–Sc(III) complex system.
a
Unless otherwise noted, the reactions were performed with L5-Sc(OTf)3
(5 mol%, 2 : 1), 30 mg 3 Å MS and 2 (0.2 mmol) with (ꢀ)-1 (0.1 mmol) under
nitrogen in CH2Cl2 (0.5 mL) at 35 1C; isolated yield; s = ln[(1 ꢁ Conv.)-
(1 ꢁ ee1)]/ln[(1 ꢁ Conv.)(1 + ee1)]; Conv. = ee1/(ee1 + ee3); s = starting
material; p = product. b At 25 1C. c 10 mol% catalyst loading.
We appreciate the National Natural Science Foundation of China
(No. 21172151, 21432006, and 21321061) for financial support.
the yield of the product 3ad reduced sharply. With the intention
of speeding up the resolution rate, we changed (ꢀ)-1a to (ꢀ)-1r,
and obtained results with a better s factor of 120. Unfortunately,
1H-pyrazole (2e) did not fit the resolution system, even though
we had explored some other epoxides.
To show the synthetic application of the current system, the
reaction of (ꢀ)-1v was enlarged to a gram scale (1.17 g, 4.0 mmol)
under the optimized reaction conditions, and gave the product
3v in 47% yield with 97% ee, 1v was retrieved in 53% yield
with 89% ee (Scheme 1a). Meanwhile, the products (2S,3S)-3a
could be easily transformed into pinacol (1R,2S,3S)-4a,14 which
is a valuable and versatile intermediate in organic synthesis
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