Steric Tuning of Reactivity and Enantioselectivity in Addition of Thiophenol to Enoates Catalyzed by an External Chiral Ligand

Full text of DOI:10.1021/ja9729950

12974
J. Am. Chem. Soc. 1997, 119, 12974-12975
Communications to the Editor
of thiophenol with enoates to give the addition products in high
enantioselectivity, overcoming the above drawbacks.7
We have been involved in the asymmetric reactions of
organolithiums or lithium ester enolates with imines or enoates
under control of chiral ether or amino ether ligands, giving the
chiral products.8 On the basis of these studies on asymmetric
reactions of lithiated carbonucleophiles, lithium thiophenolate,
and chiral compounds 1-3 were chosen as the nucleophile and
representative chiral ligands, respectively.
Steric Tuning of Reactivity and Enantioselectivity in
Addition of Thiophenol to Enoates Catalyzed by an
External Chiral Ligand
Katsumi Nishimura, Masashi Ono, Yasuo Nagaoka, and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences
Kyoto UniVersity, Yoshida, Sakyo-ku, Kyoto 606-01, Japan
ReceiVed August 26, 1997
The addition of a thiol to an electron-deficient olefin to form
a sulfur-carbon bond constitutes a key reaction in biosynthesis
as well as in chemical synthesis of biologically potent com-
pounds.1 The asymmetric additions of thiols to conjugated
unsaturated carbonyl compounds bonded covalently by chiral
auxiliary have been well-documented to give the adducts with
high level of diastereoselectivity.2 The enantioselective reac-
tions have also been developed with the use of chiral amine
catalysts.3 Especially, cinchona alkaloids4 and proline-derived
chiral amines5 were shown to be good catalysts that form
stereochemically ordered complexes with substrates and thiols.
In spite of impressive progress, catalytic asymmetric addition
of a thiol to a prochiral olefin has not yet reached at the
satisfactory level. The asymmetric synthesis with use of chiral
olefins has the drawback, from a chemical economic viewpoint,
of requiring at least an equal amount of chiral auxiliary.6 The
chiral amine-catalyzed reactions require reactive olefins and
relatively high temperature to promote the reaction because of
poor reactivity of thiol activated by an amine. We describe
herein that a combination of lithium thiophenolate and an
external chiral ligand catalyzes asymmetric addition reaction
It is reasonable to draw a scenario that lithium thiophenolate
has a nucleophilic reactivity higher than amine-activated thiol,
and the lithium cation coordinates with the two or three
heteroatoms of 1-3 to form a chiral chelate,9 allowing asym-
metric addition of thiophenol. Indeed, the reaction of thiophenol
(5a, 3 equiv) with methyl crotonate (4) proceeded smoothly in
the presence of 0.08 equiv of lithium thiophenolate and 0.1 equiv
of 18,9 in toluene at -20 °C for 2 h to afford (S)-methyl
3-phenylthiobutanoate (6a)10 in 92% yield. The ee was
determined by chiral stationary phase HPLC (Daicel Chiralcel-
OD) to be 6%. The reaction mediated by (-)-sparteine (2)11
gave (S)-6a in 15% ee and 85% yield after 3 h at -20 °C.
Fortunately, we found that the chiral amino ether 312 gave (S)-
6a in a reasonably good ee of 71% and 99% yield after 3 h at
-20 °C. In the absence of lithium thiophenolate the reaction
mediated by 3 is sluggish, giving 6a in 0.5% yield after 6 days
at room temperature. Although the enantioselectivity is unsat-
isfactory, these reactions indicate the higher reactivity of lithium
thiophenolate than that of amine-activated thiophenol.
To improve the enantioselectivity, the reaction with 3 was
allowed to cool at -60 °C for 47 h to give (S)-6a in 74% ee,
but in 55% yield. The reaction did not proceed at -78 °C.
These unsatisfactory results clearly indicate that lithium thiophe-
nolate itself requires much more activation. Thus, the size of
2-substituent of thiophenol (5) was found to exert profound
effects on the reactivity as well as enantioselectivity (Table 1).
It is interesting that both reactivity and enantioselectivity
increased along with the increase of the size of 2-substituent.
The most bulky compound 2-tert-butylthiophenol (5d) reacted
with 4 within 1 h at -20 °C, giving 6d in 90% ee and 99%
yield. These favorable and size-dependent effects of 2-substit-
(1) Review: Mikolajczyk, M.; Drabowicz, J.; Kielbasinski, P. Stereo-
selective Synthesis. In Methods of Organic Chemistry; Georg Thime
Verlag: Stuttgart, 1995; Vol. E21e, Chapter 5. (a) Schmidt, U.; O¨ hler, E.
Angew. Chem., Int. Ed. Engl. 1976, 15, 42. (b) Trost, B. M.; Keeley, D. E.
J. Org. Chem. 1975, 40, 2013. (c) Evans, D. A.; Truesdale, L. K.; Grimm,
K. G.; Nesbitt, S. L. J. Am. Chem. Soc. 1977, 99, 5009-5017. (d) Shono,
T.; Matsumura, Y.; Kashimura, S.; Hatanaka, K. J. Am. Chem. Soc. 1979,
101, 4752-4753. (e) Shibasaki, M.; Nishida, A.; Ikegami, S. J. Chem. Soc.,
Chem. Commun. 1982, 1324-1325. (f) Suzuki, K.; Ikegawa, A.; Mu-
kaiyama, T. Chem. Lett. 1982, 899-902. (g) Miyata, O.; Shinada, T.;
Ninomiya, I.; Naito, T.; Date, T.; Okamura, K.; Inagaki, S. J. Org. Chem.
1991, 56, 6556-6564. (h) Kita, Y.; Shibata, N.; Miki, T.; Takemura, Y.;
Tamura, O. Chem. Pharm. Bull. 1992, 40, 12-20. (i) Miyata, O.;
Yamaguchi, S.; Ninomiya, I.; Naito, T.; Okamura, K. Chem. Pharm. Bull.
1996, 44, 636-638.
(2) (a) Nagao, Y.; Kumagai, T.; Yamada, S.; Fujita, E. J. Chem. Soc.,
Perkin Trans. 1 1985, 2361-2367. (b) Wu, M. J.; Wu, C. C.; Tseng, T. C.
J. Org. Chem. 1994, 59, 7188-7189. (c) Tomioka, K.; Muraoka, A.; Kanai,
M. J. Org. Chem. 1995, 60, 6188-6190. (d) Miyata, O.; Shinada, T.;
Ninomiya, I.; Naito, T. Tetrahedron 1997, 53, 2421-2438.
(3) (a) Bosnich, B. Asymmetric Catalysis; Martinus Nijhoff Publishers:
Boston, 1986. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1994.
(7) Tomioka, K. Synthesis 1990, 541-549.
(8) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 2060-2061 and references cited therein.
(9) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111,
8266-8268.
(10) Puzicha, G.; Le´vai, A.; Szila´gyi, L. Monatsch. Chem. 1988, 119,
933-944.
(4) (a) Wynberg, H.; Greijdanus, B. J. Chem. Soc., Chem. Commun. 1978,
427-428. (b) Kobayashi, N.; Iwai, K. J. Am. Chem. Soc. 1978, 100, 7071-
7072. (c) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417-
430. (d) Kobayashi, N. Polym. J. 1981, 16, 205-211. (e) Keniya, J.; Natu,
A. A.; Gogte, V. N. Chem. Ind. 1986, 243. (e) Kumar, A.; Salunkhe, R.
V.; Rane, R. A.; Dike, S. Y. J. Chem. Soc., Chem. Commun. 1991, 485-
486.
(5) (a) Suzuki, K.; Ikegawa, A.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1982, 55, 3277-3282. (b) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985,
363-366.
(6) An inclusion complex of chiral host with cycloalkenone has been
used in enantioselective asymmetric reaction of thiol, which needs an
equivalent amount of chiral host. Toda, F.; Tanaka, K.; Sato, J. Tetrahe-
dron: Asymmetry 1993, 4, 1771-1774.
(11) The external chiral diamine ligand, (-)-sparteine 2, for the conjugate
addition of carbonucleophile was first reported by Kretchmer. Kretchmer,
R. A. J. Org. Chem. 1972, 37, 2744-2747. For the recent use of
organolithium-2 complex, see: (a) Tsukazaki, M.; Tinkl, M.; Roglans,
A.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. J. Am. Chem. Soc. 1996,
118, 685-686. (b) Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1996,
118, 12218-12219. (c) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552-560.
(12) Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4585-4586.
Synthesis of 3 was improved to 88% yield by treating sodium 2-(N,N-
dimethylamino)-1,2-diphenylethy alcoholate with fluoroanisole chromium
tricarbonyl in DMF and following iodine oxidation, according to the reported
procedure (Davies, S. D.; Hume, W. E. Tetrahedron Lett. 1995, 36, 2673-
2674).
S0002-7863(97)02995-8 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 52, 1997 12975
Table 1. 2-Substituent Effects of 5 on Reactivity and
Enantioselectivity
Table 2. Asymmetric Addition of 2-TMSC6H4SH 5e to Methyl
Enoates 7
5
R
time (h)
yield (%)
ee (%)a
a
b
c
d
e
H
Me
i-Pr
t-Bu
TMS
3
2
2
1
1
99
93
99
99
97
71
79
85
90
88
a The absolute configuration was determined to be S for 6a,10 b,15
and e10 by specific rotation and tentatively assigned by analogy for
6c,d.
uents are attributable to both inhibition of solvation of the
thiolate anion13 and formation of the sterically defined mono-
meric chelated structure where the lithium cation is coordinated
by the three heteroatoms of the tridentate ligand 3 as shown in
9. This situation is supported by the crystal structure of
2-substituted thiophenolates.14 Lithium thiophenolate forms a
polymer containing an infinite Li-S chain, and the lithium is
coordinated by two external pyridine molecules. On the other
hand, lithium 2-methylthiophenolate forms a monomeric crystal
containing a lithium coordinated by three external pyridine
ligands.
a Ee was determined by chiral stationary phase HPLC. b -78 °C.
f
c Reference 10. d -40 °C. e Reference 18. Reference 19. g -20 °C.h 5a
was used instead of 5e at -70 °C in toluene. i Reference 20.
We then turned our attention to 2-(trimethylsilyl)thiophenol
(5e)16 as a nucleophile, equivalent to an activated thiophenol
5a. The reaction of 5e (3 equiv) with 4 (7: R ) Me) in the
presence of 0.08 equiv of lithiated 5e and 0.1 equiv of 3 in
toluene proceeded at -20 °C for 1 h, affording (S)-6e in 88%
ee and 97% yield. The reaction at -78 °C for 120 h in toluene-
hexane (1:1) gave (S)-6e (8: R ) Me) in 97% ee and 99%
yield (Table 2). The chiral ligand 3 was recovered quantitatively
for reuse. Treatment of (S)-6e with triflic acid17 at room
temperature for 10 min gave the protodesilylated ester (S)-6a
of 97% ee in 99% yield.
chain (7, R ) i-Pr) or phenyl group (R ) Ph) at the 3-position,
giving relatively lower ee’s.
Cyclopentenecarboxylate was converted to the corresponding
cis adduct1g in high ee, whereas 6-membered enoates gave cis
products in relatively lower ee’s.
The absolute configuration of 8 was determined in four of
the 11 different cases among shown in Table 2, and the sense
of asymmetric induction is the same. The attack of thiol takes
place from the top face of 7.
The stereochemistry is determined at the addition step of
lithium thiophenolate to enoate. Treatment of racemic 8 (R )
Me) under the asymmetric reaction conditions, 3 equiv of 5e,
0.08 equiv of lithium thiolate, and 0.1 equiv of 3 in toluene-
hexane (1:1) at -20 °C for 3 h, recovered racemic 8. On the
other hand, 8 (R ) Me), with 90% ee, was treated with 3 equiv
of 5e and 0.08 equiv of thiolate with recovery of 8 of unchanged
ee of 90%. These results indicate that kinetic control is
operative in the asymmetric addition reaction.
Some of the results obtained using 5e in toluene-hexane (1:
1) are summarized in Table 2. The reaction of acyclic trans-
enoates 7 (R ) Me, Et, Pr, Bu, i-Bu, PhCH2) generally affords
8 in high ee. Exception is the enoates bearing a branched side
(13) For kinetic studies on the effect of 2-substituted thiophenol on
reaction rate: S-Garwood, D. J. Org. Chem. 1972, 37, 3797-3803.
(14) For X-ray crystallography of lithium 2-substituted thiophenolate:
(a) Banister, A. J.; Clegg, W.; Gill, W. R. J. Chem. Soc., Chem. Commun.
1987, 850-852. (b) Sigel, G. A.; Power, P. P. Inorg. Chem. 1987, 26, 2819-
2822.
Acknowledgment. We gratefully acknowledge financial support
from Japan Society for Promotion of Science (RFTF-96P00302), the
Ministry of Education, Science, Sports and Culture, and the Science
and Technology Agency, Japan.
(15) Breitschuh, R.; Seebach, D. Synthesis 1992, 83-89.
(16) Smith, K.; Lindsay, C. M.; Pritchard, G. J. J. Am. Chem. Soc. 1989,
111, 665-669.
(17) Ha¨bich, D.; Effenberger, F. Synthesis 1978, 755-756.
(18) Dike, S. Y.; Ner, D. H.; Kumar, A. Bioorg. Med. Chem. Lett. 1991,
1, 383-386.
Supporting Information Available: Details of the experimental
procedure, characterization data and determination of the absolute
configuration (20 pages). See any current masthead page for ordering
information and Internet access instructions.
(19) The absolute configuration was determined by converting to
(cyclopent-2-enyl)methanol: Maeda, K.; Inoue, Y. Bull. Chem. Soc. Jpn.
1994, 67, 2880-2882.
(20) The absolute configuration was determined by converting to
tetrahydronaphthalene-1-carboxylic acid: Haller, J.; Hense, T.; Hoppe, D.
Synlett 1993, 726-728.
JA9729950