Enantioselective one-pot synthesis of β-sulfonyl ketones and trisubstituted tetrahydrothiophenes via β-elimination/cycloaddition sequence

Article abstract of DOI:10.1016/j.cclet.2018.01.047

A mild and efficient enantioselective one-pot synthesis of β-sulfonyl ketones and trisubstituted tetrahydrothiophenes via introducing 1,4-dithiane-2,5-diol to the simple kinetic resolution of β-sulfonyl ketones has been described herein. The one-pot reaction sequence including kinetic resolution and cascade sulfa-Michael/Aldol reaction proceeded successively to afford corresponding sulfonyl ketones and tetrahydrothiophenes with high enantioselectivities (85%–98% ee and 84%–95% ee).

Full text of DOI:10.1016/j.cclet.2018.01.047

G Model
CCLET 4437 No. of Pages 4
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Enantioselective one-pot synthesis of
trisubstituted tetrahydrothiophenes via
b
-sulfonyl ketones and
-elimination/cycloaddition
b
sequence
*
Lu Xue, Yidong Liu, Wenling Qin, Hailong Yan
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331,
China
A R T I C L E I N F O
A B S T R A C T
Article history:
A mild and efficient enantioselective one-pot synthesis of
tetrahydrothiophenes via introducing 1,4-dithiane-2,5-diol to the simple kinetic resolution of
b
-sulfonyl ketones and trisubstituted
-sulfonyl
Received 3 December 2017
Received in revised form 4 January 2018
Accepted 24 January 2018
Available online xxx
b
ketones has been described herein. The one-pot reaction sequence including kinetic resolution and
cascade sulfa-Michael/Aldol reaction proceeded successively to afford corresponding sulfonyl ketones
and tetrahydrothiophenes with high enantioselectivities (85%–98% ee and 84%–95% ee).
© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
One-pot synthesis
Enantioselective
b-eliminationd
Asymmetric cycloaddition
Chiral sulfones
Trisubstituted tetrahydrothiophenes
Ion-pairing catalysis
Chiral sulfones are important structure motifs in biologically
active molecules and versatile building blocks in organic synthesis
[1]. Diverse synthetic approaches have been developed for the
formation of chiral sulfones including metal-catalyzed hydrogena-
tion [2], asymmetric substitution [3], cycloaddition [4], carbon–
hydrogen insertion [5], Lewis acid-mediated Diels–Alder reactions
[6], and organocatalytic versions [7]. Recently, our group reported
that adding reactive synthons into the kinetic resolution process
might enhance the enantioselectivities of the products or convert
achiral products into useful enantioenriched molecules. In the
previous report of the asymmetric synthesis of trisubstituted
tetrahydrothiophenes (Scheme 1b) [11], commercially available
1,4-dithiane-2,5-diol [12] showed the impressive ability in direct
construction of trisubstituted tetrahydrothiophenes with enones
in the presence of cation-binding catalyst. By introducing 1,4-
the kinetic resolution of
lective -elimination (Scheme 1a) [8], in which one enantiomer of
racemic -sulfonyl ketones was preferentially eliminated to form
-unsaturated enones and deliver enantioenriched -sulfonyl
b-sulfonyl ketones through enantiose-
b
dithiane-2,5-diol to the simple kinetic resolution of
ketones, two asymmetric reactions including kinetic resolution of
-sulfonyl ketones and cascade sulfa-Michael/Aldol reaction
b-sulfonyl
b
a,
b
b
b
ketones and achiral enones. In a typical kinetic resolution,
unreacted substrates have high enantioselectivities, whereas the
scalemic reaction product is generally discarded. Unless reagents
with a large s value (ꢀ200) are used to produce enantioenriched
products and recover starting materials at 50% conversion [9], it is
difficult to realize such levels of enantioselectivities. Besides, in
classical kinetic resolution via oxidation and elimination [10], the
stereocenters of starting materials are removed to form achiral
products. For these reasons, it is difficult to obtain high
enantioselectivities of both substrates and products in classical
kinetic resolution. To solve the above problems, we hypothesized
proceeded successively to afford chiral sulfonyl ketones and
tetrahydrothiophenes. In this strategy, the stereocontrol of the two
asymmetric reactions in one-pot by means of one ion-pairing
catalyst remains a great challenge.
To verify our hypothesis, we initiated the synthesis with
racemic 3-(4-fluorophenyl)-1-phenyl-3-(phenylsulfonyl)propan-
1-one 2f as a model substrate in the presence of 1,4-dithiane-
2,5-diol and potassium salt as base as well as Song’s oligoEG
catalyst [13]. The effect of potassium salt was firstly examined in
DCM (Table 1, entries 1–5). As expected, the one-pot reaction
sequence including kinetic resolution of
cascade sulfa-Michael/Aldol reaction proceeded smoothly to afford
-sulfonyl ketones (R)-2f and trisubstituted tetrahydrothiophenes
b-sulfonyl ketones and
b
4f in moderate to high enantioselectivities when the potassium
salts were KOCN, phthalimide potassium, KF, and KOAc (Table 1,
* Corresponding author.
E-mail address: yhl198151@cqu.edu.cn (H. Yan).
https://doi.org/10.1016/j.cclet.2018.01.047
1001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: L. Xue, et al., Enantioselective one-pot synthesis of
b-sulfonyl ketones and trisubstituted
tetrahydrothiophenes via -elimination/cycloaddition sequence, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.01.047
b

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CCLET 4437 No. of Pages 4
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L. Xue et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Table 1
Optimization of the reaction conditions.a
Entry
Base
KOCN
Phthalimide potassium DCM
Solvent
Conv. (%)b ee (%)c (2f, 4f) sd
1
2
3
DCM
60
60
60
54
–
74, 73
86, 69
92, 91
72, 81
–
7
10
13
9
Scheme 1. Enantioselective one-pot synthesis of b-sulfonyl ketones and trisubsti-
tuted tetrahydrothiophenes.
KF
DCM
DCM
DCM
THF
4
KOAc
KX
KF
5e
6
–
47
45, 2
47, 2
5
7
7
KF
1,4-dioxane 44
8
9
10
KF
KF
KF
toluene
DCE
CHCl3
58
58
51
24, 86
80, 89
64, 91
2
11
8
entries 1–4). Among them, KF showed the best selectivity (s = 13),
providing both (R)-2f and 4f in high stereoselectivities (92%, 91%)
(Table 1, entry 3). Otherwise, when the bases were KCl, KBr, KI,
KSO2Ph, KPF6, KBF4, K2S2O8, or KSCN, the reaction did not take
place (Table 1, entry 5). In further investigation of solvents,
nonpolar solvents (toluene, DCE and CHCl3) and polar solvents
(THF and 1,4-dioxane) showed the worse selectivity (Table 1,
entries 6–10).
a
Reaction condition: 2f (0.1 mmol), base (0.15 mmol), (R)-A (0.01 mmol), 1,4-
dithiane-2,5-diol (0.05 mmol) in solvent (1.0 mL) at room temperature for 48 h,
unless otherwise specified.
b
Determined by 1H NMR.
The ee value is determined by HPLC analysis (see Supporting information). The
c
absolute configuration of the recovered
tetrahydrothiophenes 4f were assigned by comparison of the measured optical
b-sulfonyl ketones 2f and trisubstituted
Under the optimal reaction conditions (Table 1, entry 3), the
generality of this one-pot protocol was investigated. As summa-
rotation with the reported value.
d
Selectivity values were calculated by the methods of Fiaud: s = ln[(1-Conv.)(1-
rized in Table 2, the reaction with a series of
b
-sulfonyl ketones
ee1)]/ln [(1-Conv.)(1 + ee1)]. All the reported s factors were an average of 3 times
repetition.
e
KX: KCl, KBr, KI, KSO2Ph, KPF6, KBF4, K2S2O8, KSCN.
Table 2
Substrate scope.a
Entry
R1
R2
R3
2
4
ee (%)
Conv. (%)
Yield (%)
s
dr
ee (%)
Yield (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
2-OMe-Ph
4-Me-Ph
4-iPr-Ph
4-tBu-Ph
2-naphthyl
4-F-Ph
2-furyl
3-thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me-Ph
4-iPr-Ph
4-F-Ph
2-furyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
96
90
93
93
86
92
93
95
98
90
90
94
60
59
56
59
59
60
56
59
62
58
59
56
58
56
60
61
38
36
41
38
40
35
42
35
32
41
37
41
37
42
35
36
17
13
21
15
10
13
21
17
17
14
13
23
11
20
15
16
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
89
90
89
90
90
91
84
91
91
88
91
95
92
88
90
87
55
56
52
53
52
57
53
55
57
56
53
54
56
53
57
58
Ph
Ph
Ph
3,4,5-(OMe)3-Ph
4-Me-Ph
Ph
4-Me-Ph
4-Me-Ph
4-Cl-Ph
4-Cl-Ph
85
92
94
96
4-Me-Ph
a
Reaction condition: 2 (0.1 mmol), KF (0.15 mmol), (R)-A (0.01 mmol), 1,4-dithiane-2,5-diol (0.05 mmol) in DCM (1.0 mL) at room temperature for 48 h, unless otherwise
specified.
Please cite this article in press as: L. Xue, et al., Enantioselective one-pot synthesis of
b-sulfonyl ketones and trisubstituted
tetrahydrothiophenes via -elimination/cycloaddition sequence, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.01.047
b

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CCLET 4437 No. of Pages 4
L. Xue et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
1,4-dithiane-2,5-diol (Scheme 2a) to furnish optically pure
-sulfonyl ketones (R)-2f and tetrahydrothiophene 4f. As expected,
b
both products were successfully obtained in the satisfactory
yield and stereoselectivity. Furthermore, in order to further
facilitate this one-pot enantioselective synthetic process, we
decided to start the reaction from
which was used as the raw material to react with sulfinic acid for
the preparation of racemic -sulfonyl ketone. As shown in
Scheme 2b, 5 was quantitatively converted into -sulfonyl ketone
a,b-unsaturated enone 5,
b
b
2f and then transformed into (R)-2f and 4f in untouched yield and
enantioselectivity. This process was worked well even in the
gram-scale.
In order to gain insight into the reaction pathway, we have
carefully studied the reaction process. When the large-scale
reaction was performed with substrate 2f, trace
enone 5 was observed. This observation indicated that the reaction
proceeded with asymmetric -elimination of -sulfonyl ketones
and subsequent cascade sulfa-Michael/Aldol reaction of the in-situ
generated -unsaturated enones. The rate of sulfa-Michael/Aldol
a,b-unsaturated
Scheme 2. Gram-scale experiment.
b
b
a,b
reaction was significantly faster than that of the elimination
reaction (see Supporting information for details). Based on the
experimental observations and previous reports [8,11], we
proposed a plausible pathway of our reaction (Scheme 3).
In summary, we developed a one-pot protocol including kinetic
(rac-2a–2f, 2i–2k) bearing electron-rich or electron-deficient
substitutes on aromatic ring at R1 or R2 position proceeded
smoothly to afford the unreacted sulfones ((R)-2a–2f, 2i–2k) with
high enantioselectivity and satisfactory s factors and trisubstituted
tetrahydrothiophenes (4a–4f, 4i–4k) were formed in high
enantioselectivity and diastereoselectivity. Heteroaryl substrates
(rac-2g, 2h, 2l) were well tolerated under the catalytic system.
Additionally, the substrates with different functional groups on the
sulfone at R3 position (rac-2m–2p) proved to be good substrates for
this reaction.
resolution of
reaction sequence. According to this method, both unreacted
-sulfonyl ketones and trisubstituted tetrahydrothiophenes were
b-sulfonyl ketones and cascade sulfa-Michael/Aldol
b
obtained in high enantioselectivities. This process is characterized
by the simple operation, mild reaction conditions and high
efficiency. Further extension of this protocol is under investigation
in our laboratory.
To evaluate the application prospect of this one-pot process, we
firstly performed a gram-scale reaction between racemic 2f and
Scheme 3. Plausible reaction pathway.
Please cite this article in press as: L. Xue, et al., Enantioselective one-pot synthesis of
b-sulfonyl ketones and trisubstituted
tetrahydrothiophenes via -elimination/cycloaddition sequence, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.01.047
b

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This study was supported by the Fundamental Research Funds
for the Central Universities in China (No. CQDXWL-2014-Z003), the
Scientific Research Foundation of China (No. 21402016), Graduate
Scientific Research and Innovation Foundation of Chongqing, China
(Nos. CYS17044, CYB16032).
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Please cite this article in press as: L. Xue, et al., Enantioselective one-pot synthesis of
b-sulfonyl ketones and trisubstituted
tetrahydrothiophenes via -elimination/cycloaddition sequence, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.01.047
b