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.
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