Organocatalytic asymmetric Sulfa-Michael addition of thiols to 4,4,4-trifluorocrotonates

Article abstract of DOI:10.1021/ol201766k

The first asymmetric sulfa-Michael addition of thiols to 4,4,4-trifluorocrotonates for the construction of a stereogenic center bearing a unique trifluoromethyl group and a sulfur atom has been achieved in high yields and excellent enantioselectivities wi

Full text of DOI:10.1021/ol201766k

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4426–4429
Organocatalytic Asymmetric
Sulfa-Michael Addition of Thiols to 4,4,4-
Trifluorocrotonates
Xiu-Qin Dong,† Xin Fang,† and Chun-Jiang Wang*,†,‡
College of Chemistry and Molecular Sciences, Wuhan University, 430072, China, and
State Key Laboratory of Elemento-organic Chemistry, Nankai University, 300071,
China
cjwang@whu.edu.cn
Received July 1, 2011
ABSTRACT
The first asymmetric sulfa-Michael addition of thiols to 4,4,4-trifluorocrotonates for the construction of a stereogenic center bearing a unique
trifluoromethyl group and a sulfur atom has been achieved in high yields and excellent enantioselectivities with a 1 mol % bifunctional
organocatalyst. Subsequent transformation led to the expedient preparation of enantioenriched thiochroman-4-one and the key intermediate of
the potent inhibitor of MMP-3, (R)-γ-trifluoromethyl γ-sulfone hydroxamate.
The chemistry of organofluorine compounds is a rapidly
developing area of research due to their wide range of
applications in a number of important fields such as drug
discovery and materials science.1 Among organofluorine
molecules, chiral trifluoromethylated compounds play a
unique and significant role in agricultural and medicinal
chemistry, as it often imparts enhanced biological activity,
metabolic stability, binding interactions, or other desirable
changes in physical properties to drug molecules.2 One
such example is (R)-γ-trifluoromethyl γ-sulfone hydroxa-
mate (Figure 1), the potent inhibitor of MMP-3 (stro-
melysin-1), and the stereogenic carbon center bearing a
unique CF3 group plays a significant role in the structureÀ
activity relationship.3 Zanda and co-workers reported an
approach to access both of the two enantiomerically pure
γ-trifluoromethyl γ-sulfone hydroxamates by means of a
sulfa-Michael addition of p-methoxythiophenol to chiral
4,4,4-trifluorocrotonamide as the key step, although the
chiral-auxiliary-induced sulfa-Michael addition was not
efficient and delivered the key intermediates as nearly
equimolar mixtures of diastereomers.3 Catalytic asym-
metric sulfa-Michael addition (SMA) constitutes a direct
and versatile approach toward optically active chiral sulfur
† Wuhan University.
‡ Nankai University.
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r
10.1021/ol201766k
Published on Web 07/26/2011
2011 American Chemical Society

a trifluoromethyl group and a sulfur atom at the stereo-
genic carbon center.
Considering the significant role of bifunctional catalysts
played in the asymmetric catalysis,9,10 we envisioned that
an acidÀbase bifunctional catalyst could efficiently en-
hance the nucleophilicity of the thiols and simultaneously
activate the conjugated double bond in 4,4,4-trifluorocro-
tonates through hydrogen bonding interactions with the
ester group and, thereby, realize this challenging sulfa-
Michael addition with high enantioselectivity. Herein, we
report the first catalytic asymmetric sulfa-Michael addi-
tion of thiols to 4,4,4-trifluorocrotonates catalyzed by
bifunctional amine-thiourea in high yields and excellent
enantioselectivities with as low as a 1 mol % catalyst
loading, and further demonstrate that application of the
method allowed for facile access to enantioenriched thio-
chroman-4-one and the key intermediate for the asym-
metric synthesis of the potent MMP-3 inhibitor, (R)-γ-
trifluoromethyl γ-sulfone hydroxamate.
Figure 1. Potent inhibitor of MMP-3 (stromelysin-1): (R)-γ-
trifluoromethyl γ-sulfone hydroxamate.
compounds,4 and much attention has been paid to devel-
oping enantioselective catalytic protocols for this reaction
over the past decades.5À7 However, catalytic asymmetric
sulfa-Michael addition to straightforwardly access the
optically pure intermediates bearing a sulfur atom and a
trifluoromethyl group at the stereogenic center remains a
challenge and has met with little success. To the best of our
knowledge, there was only one example of the asymmetric
sulfa-Michael addition of thiols to4,4,4-trifluorocrotonate
promoted by an enzyme in moderate yield and enantio-
selectivity.8 A catalytic asymmetric version of this trans-
formation may not only diversify the existing asymmetric
sulfa-Michael addition reaction but also be uniquely valu-
able in the efficient construction of building blocks bearing
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J. Am. Chem. Soc. 1997, 119, 12974. (b) Emori, E.; Arai, T.; Sasai, H.;
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Figure 2. Structures of the screened bifunctional organocatalysts.
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To explore the feasibility of the synergistic activation
strategy for the proposed catalytic asymmetric sulfa-
Michael addition process, reaction of thiophenol 1a with
an E isomer of ethyl 4,4,4-trifluorocrotonate 2a11 was
carried out in dichloromethane at room temperature in
the presence of several commonly used acidÀbase bifunc-
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four amine-thioureas were screened since they had been
demonstrated to be efficient for a variety of asymmetric
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Org. Lett., Vol. 13, No. 16, 2011
4427

organocatalytic Michael addition, especially with nitroo-
lefins as the corresponding Michael acceptors (Figure 2).
The results of these reactions, summarized in Table 1,
demonstrate that the SMA reaction proceeded efficiently
in less than 30min, affording the desired Michael adduct as
a single isomer in high yields and with excellent ester-
controlled regioselectivities (Table 1, entries 1À6). How-
ever, the enantioselectivities varied remarkably depending
on the organocatalyst used. For example, naturalcinchona
alkaloids I and II, as the venerable and efficient catalysts
for asymmetric sulfa-Michael addition of unsaturated
enones,12 exhibited good activities but with low enantios-
electivities (Table 1, entries 1 and 2). Among several
commonly used bifunctional amine-thioureas derived
from 1,2-diaminocyclohexane13 or cinchona alkaloids,14
catalyst VI15 developed in this lab recently proved to be the
choice for further investigation (Table 1, entries 3À6). The
change of solvents had a remarkable effect on the enantios-
electivity. Less polar solvents such as dichloromethane,
toluene, and ether were superior to polar and protic sol-
vents (Table 1, entries 6À11). Toluene was the best solvent
of choice and 74% ee was obtained (Table 1, entry 8).
Interestingly, changingthe double-bond geometryof4,4,4-
trifluorocrotonate fromE toZ16 led tothe formation ofthe
opposite enantiomer with remarkably higher enantioselec-
tivity (Table 1, entry 8 vs 13). The observation of the
opposite absolute configuration of 3aa for (E)-2 and (Z)-2
indicated that the ester moiety on the 4,4,4-trifluorobuty-
rates played a key role in the enantioface selection of this
sulfa-Michael addition and the nucleophilic attack oc-
curred from the same face (Si) of C2 irrespective of the
geometry of the double bond. Further examination of the
ester moieties in (E)-4,4,4-trifluorocrotonate revealed that
the bulkier tert-butyl ester afforded better enantioselec-
tivity thanthe corresponding ethyl ester (Table 1, entry 8 vs
12). For 4,4,4-trifluorocrotonate with a Z-geometry, chan-
ging the ester group from ethyl to the bulkier tert-butyl
group had little effect on the reaction and delivered the
same enantioselectivity (95% ee) (Table 1, entry 13 vs 14).
Reducing the reaction temperature from room tempera-
tureto 0 °C did not improvethe enantioselectivity(Table 1,
entry 15). Further optimization displayed that a high yield
and enantioselectivity and fast reaction rate remained
when the reaction was performed with as low as a 1 mol
% catalyst loading (entry 17).
Table 1. Screening Studies of Sulfa-Michael Addition of Thio-
phenol 1a and 4,4,4-Trifluorocrotonates 2 Catalyzed by Bi-
functional Catalystsa
entry
catalyst
2
solvent
3
yieldb (%) eec (%)
1
I (10 mol %)
II (10 mol %)
2a DCM
2a DCM
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
98
93
92
91
95
96
94
94
93
90
97
95
95
90
96
95
95
2 (S)
10 (R)
52 (R)
17 (S)
45 (S)
62 (S)
37 (S)
74 (S)
6 (S)
2
3
III (10 mol %) 2a DCM
IV (10 mol %) 2a DCM
4
5
V (10 mol %)
2a DCM
6
VI (10 mol %) 2a DCM
VI (10 mol %) 2a THF
VI (10 mol %) 2a PhMe
7
8
9
VI (10 mol %) 2a MeCN 3aa
VI (10 mol %) 2a Ether 3aa
VI (10 mol %) 2a MeOH 3aa
10
11
12
13
14
15d
16
17
57 (S)
0
VI (10 mol %) 2b PhMe
VI (10 mol %) 2c PhMe
VI (10 mol %) 2d PhMe
VI (10 mol %) 2c PhMe
3ab
3ac
3ad
3ac
3ac
3ac
86 (S)
95 (R)
95 (R)
95 (R)
95 (R)
95 (R)
VI (5 mol %)
VI (1 mol %)
2c PhMe
2c PhMe
a All reactions were carried out with 0.22 mmol of 1a, 0.20 mmol of 2
in 0.8 mL of solvent. b Isolated yield. c Determined by HPLC analysis.
d Carried out at 0 °C.
Table 2. Asymmetric Sulfa-Michael Addition of Thiols 1 to (Z)-
Ethyl 4,4,4-Trifluorocrotonate 2c with Organocatalyst VIa
entry
R
Prod.
yieldb (%)
eec (%)
1
Ph (1a)
3ac
3bc
3cc
3dc
3ec
3 fc
3gc
3hc
3ic
95
92
89
88
91
90
90
93
90
92
96
83
95
91
93
95
96
93
94
96
90
90
91
57
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2
o-Me-Ph (1b)
m-Me-Ph (1c)
p-Me-Ph (1d)
o-MeO-Ph (1e)
m-MeO-Ph (1f)
p-MeO-Ph (1g)
p-tBu-Ph(1h)
p-F-Ph(1i)
3
4
5
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9
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10
11
12
p-Cl-Ph (1j)
3jc
2-Naphthyl (1k)
Bn (1l)
3kc
3lc
a All reactions were carried out with 0.55 mmol of 1, 0.5 mmol of 2a in
0.2 mL of toulene. b Isolated yield. c Determined by HPLC analysis.
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Trans. 1 1990, 1281. (b) Hamper, B. C. Org. Synth. 1998, 49, 1430.
4428
Org. Lett., Vol. 13, No. 16, 2011

With the optimized reaction conditions in hand, we
turned our attention to the scope of this sulfa-Michael
addition of various thiols to (Z)-ethyl 4,4,4-trifluorocro-
tonate 2c. As summarized in Table 2, a wide array of aryl
thiols reacted smoothly with (Z)-2c to afford the expected
adducts in high yields and excellent enantioselectivities in
the presence of 1 mol % of catalyst VI. Aryl thiols bearing
electron-rich (Table 2, entries 2À8), electron-neutral
(Table 2, entries 1 and 11), and electron-deficient substi-
tuents (Table 2, entries 9 and 10) all worked well, providing
the corresponding products in high yields (88À96%) and
excellent enantioselectivities (90À96% ee). Noticeably, the
substitution pattern of the arene had little effect on the
selectivity of the reaction, and ortho-substituted thiols 1b
and 1e underwent this transformation leading to desired
adduct 3bc and 3ec with 91% ee and 96% ee, respectively
(Table 2, entries 2 and 5). Less reactive alkyl thiol benzyl
mercaptan 1l also worked in this reaction affording a good
yield and moderate enantioselectivity (Table 2, entry 12).
In order to evaluate the significant role of the electron-
withdrawing CF3 group played in this sulfa-Michael addi-
tion reaction, a control experiment was carried out with
thiophenol as the Michael donor and ethyl crotonate as the
Michael acceptor in the presence of 10 mol % VI (Scheme
1). The reaction became very sluggish, and the correspond-
ing product was formed in 50% yield with only 62% ee
even after 40 h. This indicated that the carbonÀcarbon
double bond in ethyl 4,4,4-trifluorocrotonate was greatly
activated by the σ-electron-withdrawing character of the
CF3 group and hence facilitated undergoing this asym-
metric sulfa-Michael addition.17
(R)-5 was easily attained by a one-pot intramolecular
FriedelÀCrafts reaction without loss of enantiomeric ex-
cess. An optical rotation comparison of the obtained acid 4
with the data reported in the literature3a revealed an R
configuration for the generated tertiary stereogenic center
bearing a unique trifluoromethyl group and a sulfur atom
also for the corresponding moiety in 3gc and thiochroman-
4-one 5. Those of other adducts were tentatively proposed
on the basis of these results.
Scheme 2. Synthetic Transformation of the SMA Product (R)-
3gc
In conclusion, we successfully developed the highly
efficient asymmetric sulfa-Michael addition of thiols to
(Z)-ethyl 4,4,4-trifluorocrotonate catalyzed by bifunc-
tional amine-thiourea for the first time. This reaction can
serve as a general method for the direct construction of
chiral building blocks bearing a unique trifluoromethyl
group and a sulfur atom at the stereogenic carbon center,
including the key intermediate of the potent inhibitor of
MMP-3, (R)-γ-trifluoromethyl γ-sulfone hydroxamate.
Further investigations of the scope and synthetic applica-
tion of this methodology are ongoing, and the results will
be reported in due course.
Scheme 1. Control Experiments To Evaluate the Role of the
Electron-Withdrawing CF3 Group Played in the Sulfa-Michael
Addition Reaction
Acknowledgment. This work is supported by the Na-
tional Natural Science Foundation of China (20972117),
the Program for New Century Excellent Talents in
University (NCET-10-0649), the Program for Changjiang
Scholars and Innovative Research Team in University of
the Ministry of Education (IRT1030), 973 Program
(2011CB808600), SRFDP (20090141110042), and the
Fundamental ResearchFundsforthe CentralUniversities.
To demonstrate the utility of this catalytic asymmetric
sulfa-Michael addition, we studied the synthesis of (R)-4, a
key intermediate in the preparation of the potent inhibitor
of MMP-3 (stromelysin-1), (R)-γ-trifluoromethyl γ-sul-
fone hydroxamate3a (Scheme 2). The ester group of (R)-
3gc was efficiently hydrolyzed to give the key intermediate
(R)-carboxylic acid 4 in high yield under mild conditions.18
On the other hand, synthetically useful thiochroman-4-one19
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
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4429