Organocatalytic asymmetric sulfa-michael addition of thiols to α,β-unsaturated hexafluoroisopropyl esters: Expeditious access to (R)-thiazesim

Article abstract of DOI:10.1021/ol4015305

A highly efficient organocatalytic asymmetric SMA reaction of hexafluoroisopropyl α,β-unsaturated esters has been developed. Introducing electron-withdrawing hexafluoroisopropyl ester is crucial to enhancing the electrophilicity of unsaturated esters as S

Full text of DOI:10.1021/ol4015305

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Organocatalytic Asymmetric
Sulfa-Michael Addition of Thiols to
r,β-Unsaturated Hexafluoroisopropyl
Esters: Expeditious Access to (R)‑Thiazesim
Xin Fang,† Jun Li,† and Chun-Jiang Wang*,†,‡
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072,
China, and State Key Laboratory of Elemento-organic Chemistry, Nankai University,
Tianjin, 300071, China
cjwang@whu.edu.cn
Received May 30, 2013
ABSTRACT
A highly efficient organocatalytic asymmetric SMA reaction of hexafluoroisopropyl R,β-unsaturated esters has been developed. Introducing
electron-withdrawing hexafluoroisopropyl ester is crucial to enhancing the electrophilicity of unsaturated esters as SMA acceptors. The catalytic system
performs well over a broad scope of R,β-unsaturated esters and diversified thiols and provides facile access to (R)-thiazesim in a one-pot protocol.
Optically active chiral sulfur-containing compounds are
the core structural elements prevalent in natural products1
and also have broad applications in many research areas of
biology and chemistry, for example, serving as antibiotics,
chiral ligands or catalysts, and also chiral auxiliaries.2 Among
existing methods, asymmetric sulfa-Michael addition (SMA)
of thiol nucleophiles to electron-deficient alkenes is one of
the most profound and reliable CÀS bond-forming reac-
tions in organic synthesis.3 Due to the simple manipula-
tion and high atom economy, considerable attention has
been paid to developing catalytic asymmetric protocols
for SMA over the past several years.4,5 A variety of
electron-deficient alkenes are now applicable as acceptors
to both metal and organic catalyst-promoted conjugate
additions, such as R,β-unsaturated imides,4aÀf,5aÀd cyclic
and acyclic enone,4gÀj,5eÀh R,β-unsaturated aldehydes,5i
and nitroolefins5j,k (Scheme 1a).
† Wuhan University.
‡ Nankai University.
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r
10.1021/ol4015305
XXXX American Chemical Society

In light of the versatility of the reaction and biological
activity of β-mercapto carboxylic acid derivatives,6 it is
surprising that R,β-unsaturated esters, one of the cost-
efficient Michael acceptors, have seldom been utilized in
therefore improve its reactivity toward nucleophilic attack
of thiols with good stereoselective control contributed by the
H-bonding interactions between the substrates and catalyst
and, hence, fulfill this important yet unsolved sulfa-Michael
addition. Here, we describe a highly efficient organocata-
lyzed asymmetric sulfa-Michael addition of various thiols to
a variety of R,β-unsaturated hexafluoroisopropyl esters.
Furthermore, the current methodology was successfully
applied to the concise synthesis of (R)-thiazesim.
Scheme 1. Reported Catalytic Asymmetric Sulfa-Michael Addition
In order to test our hypothesis, we first examined the
reactivity of different R,β-unsaturated esters toward thio-
phenol (1a) attack to evaluate their electrophilicity in the
presence of the amine-thiourea catalyst I-D developed in
Table 1. Ester Moiety Effect on Catalytic Asymmetric SMA of
Thiophenol 1a with Various R,β-Unsaturated Estersa
catalytic asymmetric SMA probably due to the relatively
low electrophilicity. To our knowledge, there was only one
example of R,β-unsaturated ester-involved asymmetric
SMA catalyzed by a metal complex at low temperature;7a
however, the nucleophile was limited to ortho-substituted
thiophenols and poor results were obtained for the electro-
philic R,β-unsaturated esters with a branched chain or
phenyl group at the β-position. Recently, an organocata-
lytic asymmetric SMA of thiols to cis-ethyl 4,4,4-trifluo-
rocrotonate was reported by this laboratory; however, the
σ-electron-withdrawing CF3 group and synthetically diffi-
cult (Z)-geometry of the specific cis-4,4,4-trifluorocrotonate
are the intrinsic limitations.8 Therefore, the development of
a general synthetic protocol for the asymmetric SMA of
thiols to easily available and diverse R,β-unsaturated esters
is still a highly desirable and challenging goal in synthetic
chemistry.
a All reactions were carried out with 0.2 mmol of R,β-unsaturated
ester and 0.24 mmol of thiophenol 1a in 1 mL of CH2CI2. b Isolated yield.
c Determined by HPLC analysis.
this laboratory recently,11 and the results are shown in
Table 1. Only a trace amount of adduct could be detected
for ethyl cinnamate 3 even after 120 h, while less sterically
hindered ethyl acrylate 2 exhibited high reactivity and the
reaction finished quickly in <10 min in high yield, which
indicates that the β-substituent in unsaturated ester de-
creases its electrophilicity significantly due to unfavored
steric hindrance (Table 1, entries 1 and 2). Replacing the
ester functional group with the 2,2,2-trifluoroethyl group
increases the electrophilicity of cinnamate, and the Michael
adduct was separated in 46% yield with 68% ee although a
long reaction time was still needed (entry 3), which pre-
liminarily verifies our hypothesis on electrophilicity en-
hancement via introducing an electron-withdrawing ester
moiety and enantioselective control via the synergistic
H-bonding activation of both a Michael donor and ac-
ceptor. Subsequently, introducing a bulkier and more
Considering the significant role the hexafluoroisopropyl
ester moiety played in acrylate-involved asymmetric reactions9
and the role an acidÀbase bifunctional organocatalyst played
in catalytic asymmetric synthesis,10 we envisaged that the
electrophilicity of unsaturated esters could be enhanced by
the electron-withdrawing hexafluoroisopropyl ester and
(6) For applications of β-mercapto carboxylic acids in syntheses of
nature products and bioactive peptide inhibitors, see: (a) Lee, A. H. F.;
Chan, A. S. C.; Li, T. Tetrahedron 2003, 59, 833. (b) Beszant, B.; Bird, J.;
Gaster, L. M.; Harper, G. P.; Hughes, I.; Karran, E. H.; Markwell,
R. E.; MilesWilliams, A. J.; Smith, S. A. J. Med. Chem. 1993, 36, 4030.
(7) (a) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 12974. For the example of chiral-auxiliary-
induced SMA of thiols to cinnamates, see: (b) Cousins, G.; Falashaw,
A.; Hoberg, J. O. Org. Biomol. Chem. 2004, 2, 2272. For enzyme-
promoted asymmetric SMA of thiols to (E)-4,4,4-trifluorocrotonate,
see: (c) Kitazume, T.; Murata, K. J. Fluorine Chem. 1988, 39, 75. For
cinchona alkaloids-promoted SMA of thiophenol to maleates, see: (d)
Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 14, 363.
(8) Dong, X.-Q.; Fang, X.; Wang, C.-J. Org. Lett. 2011, 13, 4426. Only
moderate enantioselectivity was observed for (E)-4,4,4-trifluorocrotonate.
(9) (a) Kano, T.; Shirozu, F.; Akakura, M.; Maruoka, K. J. Am.
Chem. Soc. 2012, 134, 16068. (b) Inanaga, K.; Takasu, K.; Ihara, M.
J. Am. Chem. Soc. 2004, 126, 1352. (c) Iwabuchi, Y.; Nakatani, M.;
Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
(10) For reviews on bifunctional organocatalysis, see: (a) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701. (b) Marcelli, T.; van Maarseveen,
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496. (c) Connon,
S. J. Chem.;Eur. J. 2006, 12, 5418.
(11) (a) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem.
Commun. 2008, 1431. (b) Zhang, Z.-H.; Dong, X.-Q.; Chen, D.; Wang,
C.-J. Chem.;Eur. J. 2008, 14, 8780. (c) Wang, C.-J.; Dong, X.-Q.;
Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130,
8606. (d) Dong, X.-Q.; Teng, H.-L.; Wang, C.-J. Org. Lett. 2009, 11,
1265. (e) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Adv.
Synth. Catal. 2012, 354, 1141.
B
Org. Lett., Vol. XX, No. XX, XXXX

electron-withdrawing hexafluoroisopropyl moiety not
only provided a superior level of reactivity but also afforded
much higher enantioselectivity: the reaction finished
smoothly in <12 h leading to the desired adduct in almost
quantitative yield with 82% ee (entry 4).
Encouraged by the promising results, fine-tunable bi-
functional amine-thiourea catalysts I and II were subse-
quently screened, and the representative results are
tabulated in Table 2. It was revealed that both reaction
rate and enantioselectivity were significantly affected by
the configuration matching of the two chiral units in the
amine-thiourea catalysts and the acidity of the third
catalyst (entry 5). Other bifunctional acidÀbase catalysts
were also tested in this transformation, producing the
adduct with slightly lower enantioselectivities (see Sup-
porting Information (SI) for more details). Subsequent
evaluation of solvent effects improved the enantioselec-
tivity to 95% when toluene was used as the solvent (entries
10À13). Upto96% eeand a 95% yield wereachieved when
the reaction was carried out at 0 °C for 18 h (entry 14).
Remarkably, the highyield and excellent enantioselectivity
were maintained even when the SMA reaction was carried
out with a 5 mol % catalyst loading (entry 15). A compar-
able result was still achieved even when the amine-thiourea
catalyst loading was reduced to 1 mol % albeit at the
expense of the reaction time (entry 16).
With the optimal reaction conditions in hand, we then
turned our focus to the substrate scope and generality of
this SMA reaction. In the presence of 5 mol % of catalyst
I-D, the sulfa-Michael addition of different thiols to hexa-
fluoroisopropyl cinnamate 5a was examined, and the
results are tabulated in Table 3. In general, a wide range
of aryl thiols, bearing electron-neutral (entries 1 and 11),
Table 2. Optimization of Catalytic Asymmetric SMA of
Thiophenol 1a with Hexafluoroisopropyl Cinnamate 5aa
entry catal. solvent t (°C) time (h) yield (%)b ee (%)c
1
I-A
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Ether
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
24
12
12
12
72
24
24
24
24
22
9
92
95
96
98
65
92
83
85
94
94
95
88
86
95
96
91
À4
81
77
82
53
15
40
42
69
76
95
14
7
Table 3. Substrate Scope of the Catalytic Asymmetric SMA of
Thiols 1 with Hexafluoroisopropyl Cinnamate 5aa
2
I-B
I-C
I-D
I-E
3
4
5
6
II-A
II-B
II-C
II-D
I-D
I-D
I-D
I-D
I-D
I-D
I-D
7
8
9
10
11
12
13
14
15d
16e
entry
R
product
yield (%)b
ee (%)c
PhMe
1
Ph (1a)
6aa
6ab
6ac
6ad
6ae
6af
96
93
92
97
94
91
92
95
92
93
92
90
82
86
83
88
96
97
95
97
>99
94
98
96
93
98
98
90
93
93
90
91
MeCN
MeOH
PhMe
4
2
o-Me-C6H4 (1b)
m-Me-C6H4 (1c)
p-Me-C6H4 (1d)
p-MeO-C6H4 (1e)
m-F-C6H4 (1f)
4
3
18
24
45
96
96
95
4
PhMe
0
5
PhMe
0
6
a All reactions were carried out with 0.2 mmol of 5a and 0.24 mmol of
1a in 1 mL of solvent. b Isolated yield. c Ee was determined by HPLC
analysis. d Catalyst loading: 5 mol %. e Catalyst loading: 1 mol %.
7
p-F-C6H4 (1g)
6ag
6ah
6ai
8
p-Cl-C6H4 (1h)
p-CF3-C6H4 (1i)
o-NH2-C6H4 (1j)
2-naphthyl (1k)
2-thienyl (1l)
9
10
11
12
13d
14d
15d
16e
6aj
6ak
6al
PhCH2 (1m)
6am
6an
6ao
6ap
p-MeO-C6H4CH2 (1n)
p-Cl-C6H4CH2 (1o)
MeOOCCH2 (1p)
a All reactions were carried out with 0.2 mmol of 5a and 0.24 mmol of
1 in 1 mL of PhMe for 18À30 h. b Isolated yield. c Ee was determined by
HPLC analysis. d For 48 h. e Carried out at À30 °C for 40 h.
H-bonding donor (Table 2, entries 1À9). In general, a
faster reaction rate was observed with organocatalysts I,
which was ascribed to the additional stronger H-bonding
donor contributed by the sulfonamide group, and catalyst
I-D was revealed as the best in terms of enantioselectivity
and reaction rate (entry 4). In contrast, the SMA reaction
became sluggish and the adduct 6aa was separated in only
65% yield even after 72 h when using methylated I-E as the
-rich (entries 2À5 and 10), or -deficient groups (entries 6À9)
on the phenyl ring, reacted smoothly with 5a affording the
(12) (a) Krapcho, J.; Spitzmiller, E. R.; Turk, C. F. J. Med. Chem.
1963, 6, 544. (b) Phippen, C. B. W.; McErlean, C. S. P. Tetrahedron Lett.
2011, 52, 1490. The first asymmetric approach to (R)-thiazesim was
reported through a complicated synthetic route consisting of seven steps
promoted by enzyme; see: (c) Dike, S. Y.; Ner, D. H.; Kumar, A. Bioorg.
Med. Chem. Lett. 1991, 1, 383. For the latest example on the catalytic
asymmetric synthesis of (R)-thiazesim, see ref 4f.
Org. Lett., Vol. XX, No. XX, XXXX
C

To demonstrate the potential utility of this methodology,
this organocatalyzed SMA reaction was applied to the con-
cise synthesis of thiazesim, an antidepressant agent.12
A
Table 4. Substrate Scope of the Catalytic Asymmetric SMA of
Thiophenol 1a with Various R,β-Unsaturated Hexafluoroisopropyl
Esters 5a
concise route was designed to this target molecule that relies
on the highly efficient ent-I-D-catalyzed asymmetric SMA
of 2-aminothiophenol 1j to hexafluoroisopropyl cinnamate
5a (Scheme 2). Treatment of the adduct ent-6aj with TsOH
monohydrate in toluene under reflux gave rise to benzothia-
zepinone 10 in 91% yield. Then, cyclic amide 10 was
N-alkylated with 2-dimethylaminoethyl chloride hydrochloride
leading to (R)-thiazesim in high yield with complete retention
of stereochemistry.4f Furthermore, a one-pot protocol for the
above three-step transformation was also feasible affording
enantiomerically enriched thiazesim in good overall yield
with 98% ee (see SI for more synthetic transformations).
entry
R
product
yield (%)b
ee (%)c
1
Ph (5a)
6aa
6ba
6ca
6da
6ea
6fa
96
95
94
99
93
99
92
94
96
91
90
86
92
96
>99
95
99
96
98
98
98
98
93
96
92
96
2
o-Me-C6H4 (5b)
m-Me-C6H4 (5c)
p-Me-C6H4 (5d)
p-MeO-C6H4 (5e)
p-Cl-C6H4 (5f)
p-Br-C6H4 (5g)
m-Br-C6H4 (5h)
p-CF3-C6H4 (5i)
2-furyl (5j)
3
4
5
6
7
6ga
6ha
6ia
8
9
10
11
12
13
6ja
Scheme 2. Concise Synthesis of (R)-Thiazesim
Me (5k)
6ka
6la
i-Pr (5l)
PhCH2CH2 (5m)
6ma
a All reactions were carried out with 0.2 mmol of 5 and 0.24 mmol of
1a in 1 mL of PhMe. b Isolated yield. c Determined by HPLC analysis.
Michael adducts in high yields (91À97%) with excellent
enantioselectivities (93À 99% ee). The substitution pat-
>
tern of the aromatic ring had almost no effect on the
asymmetric induction. Notably, comparable results were
alsoobservedfor the moresterically hinderedortho-methyl
1b and ortho-amino substituted thiols 1j in terms of
reactivity and enantioselectivity (entries 2 and 10). Hetero-
aromatic thiophene-2-thiol 1l was also tolerated in this
SMA reaction and furnished the corresponding product
6al with 90% ee (entry 12). Less reactive aliphatic thiols
were further evaluated, and good yields and excellent
enantioselectivities (90À93% ee) were achieved for all
tested benzyl thiols albeit with an extended reaction time
(entries 13À15). Noticeably, methyl thioglycolate 1p was
also tolerated in this SMA reaction leading to the product
in 88% yield with 91% ee (entry 16).4j
Next, the potential of this organocatalytic approach
withrespect tothe electrophileisfurtherinvestigatedunder
the optimized reaction conditions. As shown in Table 4, all
tested β-aryl R,β-unsaturated hexafluoroisopropyl esters
have proven to be excellent Michael acceptors affording
the expected adducts (6aaÀ6ia) in high yields and excellent
enantioselectivities (Table 4, entries 1À9). The heteroaro-
matic furyl-substituted unsaturated ester 5j proceeded well
with 1a, delivering the product 6ja in 91% yield and
93% ee (entry 10). β-Alkyl R,β-unsaturated hexafluoroiso-
propyl esters also worked well in this catalytic system
(entries 11À13). The consistently excellent enantioselectiv-
ities obtained with the sterically hindered β-isopropyl (5l) and
β-aryl R,β-unsaturated fluorinated esters (5aÀ5i) are note-
worthy, as the corresponding nonfluorinated esters were
shown to be relatively challenging acceptors in the previous
study employing a metal complex as the catalyst.7a
In summary, we have developed an organocatalyzed
asymmetric sulfa-Michael addition of thiols to a variety of
hexafluoroisopropyl R,β-unsaturated esters for the first
time. Thisorganocatalytic systemexhibitedhigh reactivity,
excellent enantioselectivity, and a broad substrate scope.
Introduction of an electron-withdrawing hexafluoroisopro-
pyl ester moiety was revealed to be the key point in enhanc-
ing the electrophilicity of R,β-unsaturated esters as SMA
acceptors. The ready availability of unsaturated esters and
the great importance of the chiral sulfur-containing com-
pounds make the present methodology particularly interest-
ing in synthetic organic chemistry, as demonstrated by the
expedient synthesis of (R)-thiazesim in a one-pot protocol.
Acknowledgment. This work is supported by the 973
Program (2011CB808600), NSFC (20972117, 21172176),
and NCET-10-0649, IRT1030.
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.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX