A catalytic michael addition of thiols to α,β-unsaturated carbonyl compounds: Asymmetric michael additions and asymmetric protonafions [15]

Full text of DOI:10.1021/ja980397v

J. Am. Chem. Soc. 1998, 120, 4043-4044
4043
Table 1. Catalytic Asymmetric Michael Additions of Thiols to
Enones Promoted by LSB
A Catalytic Michael Addition of Thiols to
r,â-Unsaturated Carbonyl Compounds: Asymmetric
Michael Additions and Asymmetric Protonations
Eita Emori, Takayoshi Arai,1 Hiroaki Sasai,1 and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo, Hongo, Bunkyo-ku
Tokyo 113-0033, Japan
ReceiVed February 4, 1998
In recent years, the catalytic asymmetric Michael addition
promoted by chiral metal complexes has been recognized as an
efficient method for enantioselective carbon-carbon bond forma-
tions. We2 and others3 have already achieved quite efficient
catalytic asymmetric Michael additions using malonate derivatives
or organometallic reagents. In contrast to these results, a catalytic
asymmetric Michael addition using thiols has not yet been
developed to a synthetically useful level.3c,4 Moreover, the
development of an effective method for the catalytic asymmetric
protonation in Michael additions of thiols to R,â-unsaturated
carbonyl compounds has also not been achieved.5 We have found
that heterobimetallic asymmetric complexes,6 in particular LaNa3-
tris(binaphthoxide) (LSB) and SmNa3tris(binaphthoxide) com-
plexes (SmSB), are very useful catalysts for both above-mentioned
types of asymmetric reactions. In this communication we report
an efficient catalytic asymmetric Michael addition of thiols to
cycloalkenones and an effective catalytic asymmetric protonation
in Michael additions of thiols.
-40 °C for 20 min afforded the Michael adduct 3a in 84% ee
and in 93% yield. The use of THF as the only solvent furnished
3a in 94% yield and only in 2% ee. Although the use of
thiophenol (2b) in the best solvent system gave 3b in 87% yield
and in 68% ee, we were pleased to find that the use of benzyl
mercaptan (2c) afforded 3c in 90% ee and in 86% yield. Having
developed an efficient method for the catalytic asymmetric
Michael addition of a thiol to cyclohexenone (1a), we next
investigated catalytic asymmetric Michael additions using other
cycloalkenones. The results are summarized in Table 1.8,9 To
the best of our knowledge, this is the most efficient catalytic
asymmetric Michael addition of thiols to cycloalkenones.10 In
an attempt to clarify the mechanism for the catalytic asymmetric
Michael addition of thiols, the Michael adduct 4 in 52% ee was
subjected to essentially similar conditions as applied for the
Michael additions to result in the recovery of 4 with 49% ee,
suggesting that the present asymmetric Michael addition is a
kinetically controlled reaction. The proposed catalytic cycle is
shown in Scheme 1. The LaNa3tris(binaphthoxide) complex
(LSB) is a multifunctional asymmetric catalyst. That is, a sodium
naphthoxide moiety should function as a Brønsted base to activate
the thiol, and the center metal (La) should function as a Lewis
acid to control the direction of the cycloalkenone as well as
activate the cycloalkenone, thereby making possible an effective
catalytic asymmetric Michael addition of a thiol to a cycloalk-
enone. Actually, we have obtained several proofs for the above-
mentioned type of mechanism in other reactions.6
First, the catalytic asymmetric Michael addition of 4-tert-butyl-
(thiophenol) (2a) to cyclohexenone (1a) was examined in detail.
Among a variety of heterobimetallic asymmetric complexes,6 it
was found that the use of (R)-LSB gave the best result.7 That is,
treatment of 1a with 2a (1.0 equiv) in the presence of LSB (10
mol %) in toluene containing a small amount of THF (60:1) at
(1) Present address: The Institute of Scientific and Industrial Research,
Osaka University, Ibaraki, Osaka 567, Japan.
(2) (a) Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116,
1571. (b) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 104. (c) Arai, T.; Yamada, Y. M. A.;
Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem. Eur. J. 1996, 2, 1368.
(3) For recent examples using malonate derivatives and other substrates,
see: (a) Sawamura, M.; Hamashima, H.; Shinoto, H.; Ito, Y. Tetrahedron
Lett. 1995, 36, 6479. (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org.
Chem. 1996, 61, 3520. (c) Manickam, G.; Sundararajan, G. Tetrahedron:
Asymmetry 1997, 8, 2271. (d) Keller, E.; Veldman, N.; Spek, A. L.; Feringa,
B. L. Tetrahedron: Asymmetry 1997, 8, 3403. For recent examples using
organometallic reagents, see: (e) Bolm, C.; Ewald, M.; Felder, M. Chem.
Ber. 1992, 125, 1205. (f) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995,
36, 4275. (g) Stangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53, 16503.
(h) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A. H.
M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620. (i) Kno¨bel, A. K. H.; Escher,
I. H.; Pfaltz, A. Synlett 1997, 1429.
Next we paid attention to the intermediate II with an acidic
naphthol moiety. Is it possible to utilize this OH group as an
asymmetric protonation source? This concept led us to the
development of a catalytic asymmetric protonation in Michael
additions of thiols to R,â-unsaturated carbonyl compounds. First
(4) (a) Kobayashi, N.; Iwai, K. J. Am. Chem. Soc. 1978, 100, 7071. (b)
Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417. (c) Yamashita,
H.; Mukaiyama, T. Chem. Lett. 1985, 363. (d) Sera, A.; Takagi, K.; Katayama,
H.; Yamada, H. J. Org. Chem. 1988, 53, 1157. During the preparation of this
manuscript, Tomioka et al. reported an impressive catalytic asymmetric
Michael addition of thiols to, in particular, acyclic R,â-unsaturated esters.
See: Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am. Chem. Soc.
1997, 119, 12974.
(5) For an excellent review, see: (a) Fehr, C. Angew. Chem., Int. Ed. Engl.
1996, 35, 2566. For catalytic asymmetric protonation in Michael additions of
thiols, see: (b) Pracejus, V. H.; Wilcke, F.-W.; Hanemann, K. J. Prakt. Chem.
1977, 319, 219. (c) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y. J.
Chem. Soc., Chem. Commun. 1991, 485. For catalytic asymmetric protonation
of enolates, see: (d) Yanagisawa, A.; Kikuchi, T.; Watanabe, T.; Kuribayashi,
T.; Yamamoto, H. Synlett 1995, 372. (e) Nakamura, Y.; Takeuchi, S.; Ohira,
A.; Ohgo, Y. Tetrahedron Lett. 1996, 37, 2805. (f) Ishihara, K.; Nakamura,
S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854. (g)
Riviere, P.; Koga, K. Tetrahedron Lett. 1997, 38, 7589 and references therein.
(6) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 1236. (b) Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am.
Chem. Soc. 1997, 119, 4783. (c) Yamada, Y. M. A.; Yoshikawa, N.; Sasai,
H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871.
(7) The results using other heterobimetallic asymmetric complexes were
as follows: AlLibis(binaphthoxide), 29% ee; GaNabis(binaphthoxide), 3%
ee; LaLi3tris(binaphthoxide), 10% ee; LaK3tris(binaphthoxide), 39% ee; the
alkali metal free La-BINOL complex, see ref 2a, 22% ee.
(8) The enantiomeric excesses of 3a, 3b, 3c, 4, and 6 were determined by
chiral stationary phase HPLC (DAICEL CHIRALPAK AS, i-PrOH-hexane,
1: 4). The enantiomeric excesses of 5, 8 and 10a were determined by chiral
stationary phase HPLC (DAICEL CHIRALCEL OJ, i-PrOH-hexane, 2:98).
(9) The absolute configurations of 3a and 3b were determined by
comparison with authentic samples.4b The absolute configuration of 3c was
determined by preparing an authentic sample. See: Gawronski, J.; Gawronska,
K.; Wynberg, H. J. Chem. Soc., Chem. Commun. 1981, 307. The absolute
configurations of 4-6 were tentatively determined based on the result of 3c.
(10) The use of ethyl trans-cinnamate gave the adduct in 56% ee and in
41% yield.
S0002-7863(98)00397-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/08/1998

4044 J. Am. Chem. Soc., Vol. 120, No. 16, 1998
Communications to the Editor
Scheme 1. Proposed Catalytic Cycle for the Catalytic
Asymmetric Michael Addition of Thiols to Cycloalkenones
Scheme 2. Proposed Mechanism for the Catalytic Asymmetric
Protonation in Michael Additions of Thiols to R,â-Unsaturated
Thioesters
Table 2. Catalytic Asymmetric Protonations in Michael Additions
of Thiols to R,â-Unsaturated Carbonyl Compoundsa
Table 2.13 To the best of our knowledge, this is the most
satisfactory method for the catalytic asymmetric protonation in
Michael additions of thiols to R,â-unsaturated carbonyl com-
pounds.5 A probable mechanism is shown in Scheme 2. We
believe that the high enantiomeric excesses mentioned above can
be ascribed to the presence of an acidic OH moiety in a well-
organized asymmetric space (see the intermediate IV). This OH
proton stems from the thiol, being transferred during the formation
of III. On the other hand, it is well-known that perfect self-
assembly of heterobimetallic complexes and reactive nucleophiles
such as lithium nitronates and sodium malonates takes place
readily.2c,6a Thus, ready self-assembly of SmSB and the sodium
salt of 2a can be expected by analogy.14 In a catalytic asymmetric
protonation in the presence of a small amount of the sodium salt
of 2a, at least part of the protons would come from thiol 2a
directly, thereby causing a decrease in the resulting ee. Actually,
reaction of 9a with 2a in the presence of (R)-SmSB (10 mol %)
and sodium salt of 2a (9 mol % or 20 mol %) gave 10a with
lower ee (91% yield, 69% ee and 89% yield, 45% ee, respec-
tively), indicating that high ee’s can indeed be ascribed to the
acidic OH BINOL moiety.
In conclusion, we have developed the most efficient catalytic
asymmetric Michael addition of thiols to cycloalkenones and the
most satisfactory catalytic asymmetric protonation in Michael
additions of thiols to R,â-unsaturated thioesters using LnSB.15 In
particular, we believe that the latter catalytic asymmetric synthesis
offers a very efficient methodology for the synthesis of a variety
of biologically significant compounds such as captopril, a
therapeutically useful hypotensive drug.16,17 Moreover, with our
success in developing the latter reaction we could prove a new
capacity of heterobimetallic asymmetric catalysts. Further studies
are currently under investigation.
of all, a catalytic asymmetric reaction using ethyl methacrylate
(7) was examined in detail. As expected, treatment of ethyl
methacrylate (7) with 4-tert-butyl(thiophenol) (2a) (1.0 equiv)
and (R)-LSB (20 mol %) in toluene at -20 °C for 48 h was found
to furnish 8 in 75% ee and in 44% yield. Moreover, the use of
CH2Cl2 as a solvent gave 8 in 82% ee and in 50% yield (Table
2).8,11 We made an effort to optimize the above catalytic
asymmetric reaction. Unfortunately, however, more satisfactory
chemical yields were not obtained. This drawback to the reaction
was finally overcome by the use of a thioester. We were pleased
to find that treatment of the thioester 9a with 4-tert-butyl-
(thiophenol) (2a) and (R)-LSB (20 mol %) in CH2Cl2 at -78 °C
for 2 h furnished 10a in 90% ee and in 93% yield. Even after
reducing the amount of catalyst to 10 mol % (R)-LSB, excellent
results could still be obtained (88% ee, 90% yield). Moreover,
the use of (R)-SmSB as a catalyst gave 10a in 93% ee and in
86% yield.8,12 In a larger scale experiment (1.3 g of starting
material 9a), we could actually decrease the catalyst amount to 2
mol %, affording 10a in 88% ee and 89% yield. These results
together with results using other thioesters are summarized in
Supporting Information Available: Experimental procedures and
characterization data (6 pages, print/PDF). See any current masthead
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JA980397V
(12) The absolute configuration of 10a was unequivocally determined by
converting 10a to 8 on treatment with p-toluenesulfonic acid in ethanol. The
absolute configurations of other adducts were tentatively determined on the
basis of the result of 10a.
(13) Other thiols gave less satisfactory results.
(14) The Michael addition of 2c to 1a using the catalyst derived from (R)-
LSB (10 mol %) and the sodium sodium salt of 2c (9 mol %) gave 3c in 90%
ee, strongly supporting perfect self-assembly of (R)-LSB and the sodium salt
of 2c.
(15) For the synthetic utility of thioesters, see: Fukuyama, T.; Lin, S.-C.;
Li, L. J. Am. Chem. Soc. 1990, 112, 7050.
(16) (a) Shimazaki, M.; Hasegawa, J.; Kan, K.; Nomura, K.; Nose, Y.;
Kondo, H.; Ohashi, T.; Watanabe, K. Chem. Pharm. Bull. 1982, 30, 3139.
(b) Bashiardes, G.; Davies, S. G. Tetrahedron Lett. 1987, 28, 5563.
(17) For a possible conversion of 10 to thiols, see: Mairanovsky, V. G.
Angew. Chem., Int. Ed. Engl. 1976, 15, 281. In addition, Pummerer reaction
or desulfurization should offer another usefulness of 10.
(11) The absolute configuration of 8 was unequivocally determined by
comparison with an authentic sample prepared from methyl (R)-(-)-3-hydroxy-
2-methylpropionate.