Asymmetric conjugate addition reactions of polymer-supported highly enantioenriched β-(trimethylsilyl)ethyl sulfoxides

Article abstract of DOI:10.1016/S0040-4039(02)00213-7

Optically active β-(trimethylsilyl)ethyl sulfoxides supported on Merrifield resin were treated with LDA and subsequently with methyl cinnamate at -78°C. Thermal treatment or reaction with TBAF liberated the optically active methyl 3-phenyl-5-trimethylsilylpent-4-enoate or methyl 3-phenylpent-4-enoate, respectively, in good yields with high enantioselectivity.

Full text of DOI:10.1016/S0040-4039(02)00213-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2381–2383
Asymmetric conjugate addition reactions of polymer-supported
highly enantioenriched b-(trimethylsilyl)ethyl sulfoxides
Shuichi Nakamura, Youhei Uchiyama, Satoshi Ishikawa, Ryuta Fukinbara, Yoshihiko Watanabe†
and Takeshi Toru*
Department of Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
Received 26 December 2001; revised 21 January 2002; accepted 25 January 2002
Abstract—Optically active b-(trimethylsilyl)ethyl sulfoxides supported on Merrifield resin were treated with LDA and subse-
quently with methyl cinnamate at −78°C. Thermal treatment or reaction with TBAF liberated the optically active methyl
3-phenyl-5-trimethylsilylpent-4-enoate or methyl 3-phenylpent-4-enoate, respectively, in good yields with high enantioselectivity.
© 2002 Elsevier Science Ltd. All rights reserved.
Solid-phase organic reactions have been extensively
studied as a tool for the synthesis of chemical libraries.1
Among them, solid-phase asymmetric reactions are of
great importance in the pharmaceutical industry.
Recently, we reported highly efficient asymmetric con-
jugate addition reaction of the a-sulfinyl carbanion,
derived from p-tolyl b-(trimethylsilyl)ethyl sulfoxide, to
a,b-unsaturated carbonyl compounds.2 We have exam-
ined its application to the solid-phase reaction. More
recently, Solladie´ and co-workers have reported the
stereoselective reduction of b-ketosulfoxides on Wang
resin3 and the electrophilic reaction of their enolates.4
These reports prompted us to communicate our reac-
tions of polymer-supported sulfoxides. We now report
a convenient synthesis of optically active pentenoates
by conjugate addition of resin-bound chiral b-
(trimethylsilyl)ethyl sulfoxides including a new method
for cleavage of the products from the resin. Our strat-
egy is shown in Scheme 1.
We focused on the spacer as a crucial key fragment in
the solid-phase synthesis. Scheme 2 summarizes the
synthetic routes for the preparation of chiral 4-hydroxy-
phenyl 2-(trimethylsilylethyl) sulfoxide 4a and 4%-
hydroxybiphenyl 2-(trimethylsilyl)ethyl sulfoxide 4b.
The optically active sulfoxides 2a,b were prepared from
(S)-diacetone-
-glucosyl methanesulfinate 15 with 4-
D
(tert-butyldimethylsiloxy)phenyl- and 4%-(tert-butyl-
dimethylsiloxy)biphenylmagnesium bromide in good
yields. The reaction of the DAG methanesulfinate
Scheme 1.
Keywords: solid-phase synthesis; sulfoxides; Michael reactions; asymmetric reactions; desulfurization.
* Corresponding author. Tel.: 81-52-735-5217; fax: 81-52-735-5217; e-mail: toru@ach.nitech.ac.jp
† Deceased, June 23, 2001.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00213-7

2382
S. Nakamura et al. / Tetrahedron Letters 43 (2002) 2381–2383
Scheme 2.
1 with Grignard reagents in THF gave the sulfoxides
with low optical purity. The racemization was mini-
mized when the reaction was performed in toluene, and
both sulfoxides 2a,b were obtained with 95% ee. Treat-
ment of 2a,b with LDA and (iodomethyl)-
trimethylsilane gave the siloxyaryl b-silylethyl sulfox-
ides 3a,b,6 which were then selectively deprotected with
tetrabutylammonium fluoride (TBAF) to afford chiral
4-hydroxyphenyl- and 4%-hydroxybiphenyl b-silylethyl
sulfoxides 4a,b (Scheme 2).
solution reaction. We found that the stereoselectivity of
the conjugate addition depended on the spacer. The
4%-hydroxybiphenyl b-silylethyl sulfoxide 4b with 95%
ee, prepared as shown in Scheme 2, was reacted with
the resin 5a to give 6b. The conjugate addition to
methyl cinnamate and subsequent heating in benzene
gave the ester (R)-8 in 51% yield with 90% ee.10
On the other hand, the b-silylethyl sulfoxide bound to
the modified Merrifield resin 5b,11 was subjected to the
conjugate addition, and subsequent elimination
afforded (R)-8 in 67% yield with 52% ee (Scheme 4).
These results show that stereoselectivity depends on the
linker, and the linear spacer may give high stereoselec-
tivity as obtained in the reaction of the biphenylsulfinyl
carbanion.
The polymer-supported b-silylethyl sulfoxide 6a was
prepared by treatment of Merrifield resin 5a (0.9 mmol/
g) with hydroxyphenyl b-silylethyl sulfoxide 4a in the
presence of NaH in DMF at room temperature
(Scheme 3). Incorporation of the b-silylethyl sulfoxide
in the resin 6a was confirmed by the absorption at 1045
cm−1(wSꢀO) and the disappearance of the absorption at
1267 cm−1 (wCꢀCl) in the FT-IR spectrum. The resin 6a
was treated with 2 equiv. of LDA in THF at −78°C.
After 30 min, 2 equiv. of methyl cinnamate was added.
After stirring for 15 min, the reaction was quenched
with aqueous NH4Cl solution. The resin 7a was filtered,
washed with cold ether and subsequently with ethyl
acetate. The conjugate reaction was confirmed to occur
by the absorption at 1737 cm−1 (wCꢁO).7 Then the resin
7a was heated in benzene for 1 h to undergo successful
cleavage of methyl 3-phenyl-5-trimethylsilylpent-4-
enoate (R)-8 in 48% yield on the basis of 5a. The
thermal syn elimination of the sulfoxides often encoun-
ters non-regioselectivity.8 It should be noted that the
b-silyl group not only accelerated the PhSOH elimina-
tion but also controlled the regioselective formation of
the double bond even in the polymer-supported reac-
tion as in the solution reaction reported before.2,9 By
the 1H NMR spectral and HPLC (Chiralcel OD-H)
analyses, the stereochemistry of the major enantiomer
of 8 was determined to be the (R,E)-isomer. The optical
purity of (R)-8 was 75% ee in contrast to the exclusive
formation of a single diastereomer of the product in the
Scheme 3.

S. Nakamura et al. / Tetrahedron Letters 43 (2002) 2381–2383
2383
Scheme 4.
Scheme 5.
Cleavage of the vinyl analogue was also achieved by the
desilylsulfinylation. Thus, treatment of 7b with tetra-
butylammonium fluoride in THF at 0°C gave (R)-9 in
56% yield with 90% ee (Scheme 5).
dez, I.; Alcudia, F. Tetrahedron Lett. 1994, 35, 5719–
5722. We reported an efficient method for the
preparation of sulfinates, see: Watanabe, Y.; Mase, N.;
Tateyama, M.; Toru, T. Tetrahedron: Asymmetry 1999,
10, 737–745.
In summary, we have shown a highly efficient asymmet-
ric conjugate addition of the polymer-supported b-
silylethyl sulfoxides as an extremely useful linker for the
solid synthesis. The products were efficiently obtained
with high stereoselectivity by cleavage of the products
from the resin together with the formation of a double
bond.
6. (a) Kusuda, S.; Ueno, Y.; Toru, T. Tetrahedron 1994, 50,
1045–1062; (b) Nakamura, S.; Takemoto, H.; Ueno, Y.;
Toru, T.; Kakumoto, T.; Hagiwara, T. J. Org. Chem.
2000, 65, 469–474, see also Ref. 2.
7. Solladie´ and co-workers have observed the unsuccessful
methylation of the a-sulfinyl carbanion derived from the
methyl sulfoxide on Wang resin, see Ref. 4.
8. (a) Paulmier, C. Selenium Reagents and Intermediates in
Organic Synthesis; Selenoxides and Selenones. Pergamon:
Oxford, 1986; Chapter V, pp. 125–161; (b) Emerson, D.
W.; Craig, A. P.; Potts, I. W., Jr. J. Org. Chem. 1967, 32,
102–105.
9. Cleavage by the selenoxide elimination from resin has
been reported, see: (a) Michels, R.; Kato, M.; Heitz, W.
Makromol. Chem. 1976, 177, 2311–2320; (b) Nicolaou, K.
C.; Pastor, J.; Barluenga, S.; Winssinger, N. Chem. Com-
mun. 1998, 18, 1947–1948; (c) Nicolaou, K. C.; Cho, S.
Y.; Hughes, R.; Winssinger, N.; Smethurst, C.;
Labischinski, H.; Endermann, R. Chem. Eur. J. 2001, 7,
3798–3823; (d) Horikawa, E.; Kodaka, M.; Nakahara,
Y.; Okuno, H.; Nakamura, K. Tetrahedron Lett. 2001,
42, 8337–8339.
References
1. For reviews, see: (a) Balkenhohl, F.; von dem Bussche-
Hu¨nnefeld, C.; Lasky, A.; Zechel, C. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2288–2337; (b) Do¨rwald, F. Z.
Organic Synthesis on Solid Phase; Wiley-VCH: Wein-
heim, 2000; (c) Seneci, P. Solid-Phase Synthesis and Com-
binatorial Technologies; John Wiley: New York, 2000.
2. (a) Toru, T.; Nakamura, S.; Takemoto, H.; Ueno, Y.
Synlett 1997, 5, 449–450; (b) Nakamura, S.; Watanabe,
Y.; Toru, T. J. Chem. Soc., Perkin Trans. 1 1999, 3403–
3404; (c) Nakamura, S.; Watanabe, Y.; Toru, T. J. Org.
Chem. 2000, 1758–1766.
10. We have demonstrated an important role of the b-silyl
group in high stereoselectivity in the electrophilic reaction
of the a-sulfinyl carbanion, see Refs. 2 and 6.
11. Nicolaou, K. C.; Winssinger, N.; Vourloumis, D.;
Oshima, T.; Kim, S.; Pfefferkorn, J.; Xu, J.-Y.; Li, T. J.
Am. Chem. Soc. 1998, 120, 10814–10826.
3. Rolland, C.; Hanquet, G.; Ducep, J.; Solladie´, G. Tetra-
hedron Lett. 2001, 42, 7563–7566.
4. Rolland, C.; Hanquet, G.; Ducep, J.; Solladie´, G. Tetra-
hedron Lett. 2001, 42, 9077–9080.
5. (a) Fernandez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J.
Org. Chem. 1992, 57, 6789–6979; (b) Khiar, N.; Fernan-