Extremely Efficient Chiral Induction in Conjugate Additions of p-Tolyl α-Lithio-β-(trimethylsilyl)ethyl Sulfoxide and Subsequent Electrophilic Trapping Reactions

Article abstract of DOI:10.1021/jo991635n

Reaction of p-tolyl α-lithio-β-(trimethylsilyl)ethyl sulfoxide with α,β-unsaturated esters gave the conjugate addition products as a single diastereomer. The intermediate enolates were subsequently trapped with various alkyl halides or aldehydes to give the products with extremely high stereoselectivity. The reaction with α,β-unsaturated ketones also proceeded with high diastereoselectivity. Protolysis of the enolates derived from the α-methyl-α,β-unsaturated esters gave the products with high stereoselectivity. The stereo- and regioselective elimination of the sulfinyl group gave chiral homoallylic carboxylates.

Full text of DOI:10.1021/jo991635n

1758
J . Org. Chem. 2000, 65, 1758-1766
Extr em ely Efficien t Ch ir a l In d u ction in Con ju ga te Ad d ition s of
p-Tolyl r-Lith io-â-(tr im eth ylsilyl)eth yl Su lfoxid e a n d Su bsequ en t
Electr op h ilic Tr a p p in g Rea ction s
Shuichi Nakamura, Yoshihiko Watanabe, and Takeshi Toru*
Department of Applied Chemistry, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, J apan
Received October 19, 1999
Reaction of p-tolyl R-lithio-â-(trimethylsilyl)ethyl sulfoxide with R,â-unsaturated esters gave the
conjugate addition products as a single diastereomer. The intermediate enolates were subsequently
trapped with various alkyl halides or aldehydes to give the products with extremely high
stereoselectivity. The reaction with R,â-unsaturated ketones also proceeded with high diastereo-
selectivity. Protolysis of the enolates derived from the R-methyl-R,â-unsaturated esters gave the
products with high stereoselectivity. The stereo- and regioselective elimination of the sulfinyl group
gave chiral homoallylic carboxylates.
In tr od u ction
group often results in formation of complex products.4
Thus, highly stereoselective reactions of readily obtain-
able arylsulfinyl carbanions have long been desired.
In the course of developing a new chiral vinyl anion
equivalent, we found that reactions of the R-carbanion
of p-tolyl 2-(trimethylsilyl)ethyl sulfoxide with aldehydes
and ketones proceeded with extremely high stereoselec-
tion on the face of the R-carbanion, giving the products
with stereochemistry different from that formed in the
nucleophilic reaction of tert-butylsulfinyl carbanions.5 We
have reported in a preliminary communication that the
reaction of the R-sulfinyl carbanion derived from p-tolyl
â-(trimethylsilyl)ethyl sulfoxide with R,â-unsaturated
carbonyl compounds gives the conjugate addition prod-
ucts with complete stereoselectivity.5b We now report in
detail on the stereoselective conjugate additions of p-tolyl
R-lithio-â-(trimethylsilyl)ethyl sulfoxide to R,â-unsatur-
ated carbonyl compounds as well as subsequent stereo-
selective electrophilic reactions to the generated enolates.
We also describe the transformation of the products into
olefins.
The conjugate addition reaction of R-sulfinyl-stabilized
carbanion to R,â-unsaturated carbonyl compounds is a
useful method for the stereoselective formation of a C-C
bond.1,2 However, some limitations have precluded the
general applicability of this method. Casey and co-
workers have disclosed a reaction of tert-butylsulfinyl
carbanions with R,â-unsaturated esters giving conjugate
addition products with high stereoselectivity, whereas
p-tolylsulfinyl carbanions give the adducts with low
stereoselectivity.2 These stereochemical features are
similar to those obtained in the addition of R-sulfinyl
carbanions to carbonyl compounds; e.g., p-tolyl or phe-
nylsulfinyl carbanions generally give the products with
low stereoselectivity and tert-butylsulfinyl carbanions
show high stereoselectivity.3 However, further transfor-
mation of the compounds having a tert-butylsulfinyl
(1) For a recent review, see: (a) Walker, A. J . Tetrahedron: Asym-
metry 1992, 3, 961. R-Sulfinyl carbanions derived from the following
sulfoxides: Allyl sulfoxides: (b) Binns, M. R.; Chai, O. L.; Haynes, R.
K.; Katsifis, A. A.; Schober, P. A.; Vonwiller, S. C. Tetrahedron Lett.
1985, 26, 1569. (c) Nokami, J .; Ono, T.; Wakabayashi, S.; Hazato, A.;
Kurozumi, S. Tetrahedron Lett. 1985, 26, 1985. (d) Hua, D. H.;
Venkataraman, S.; Coulter, M. J .; Sinai-Zingde, C. G. J . Org. Chem.
1987, 52, 719. (e) Hua, D. H.; Venkataraman, S.; Ostrander, R. A.;
Sinai-Zingde, C. G.; MaCann, P. J .; Coulter, M. J .; Xu, M. R. J . Org.
Chem. 1988, 53, 507. (f) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.;
Schober, P. A.; Vonwiller, S. C.; Hambley, T. W. J . Am. Chem. Soc.
1988, 110, 5423. (g) Haynes, R. K.; Katsifis, A. G.; Vonwiller, S. C. J .
Am. Chem. Soc. 1988, 110, 5411. (h) Swindell, C. S.; Blase, F. R.;
Eggleston, D. S.; Krause, J . Tetrahedron Lett. 1990, 31, 5409. R-Sulfinyl
ketimines: (i) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto,
A.; Panangadan, J . A. K.; Hung, M. H.; Brabo, A. A.; Erpelding, A. M.
J . Org. Chem. 1989, 54, 5659. (j) Hua, D. H.; Bharathi, S. N.;
Panangadan, J . A. K.; Tsujimoto, A. J . Org. Chem. 1991, 56, 6998. (k)
Hua, D. H.; Park, J .-G.; Katsuhira, T.; Bharathi, S. N. J . Org. Chem.
1993, 58, 2144. Thioacetal monosulfoxides: (l) Hermann, J . L.;
Richman, J . E.; Schlessinger, R. H. Tetrahedron Lett. 1973, 3271, 3275.
(m) Ogura, K.; Yamashita, M.; Tsuchihashi, G. Tetrahedron Lett. 1978,
1303. (n) Colombo, L.; Gennari, C.; Resnati, G.; Scolastico, C. J . Chem.
Soc., Perkin Trans. 1 1981, 1284. â-keto sulfoxides; (o) Hauser, F. M.;
Rhee, R. P. J . Org. Chem. 1978, 43, 178. (p) Matloubi, F. Solladie, G.
Tetrahedron Lett. 1979, 2141. Other sulfoxide: (q) Ghera, E.; Ben-
David, Y. Tetrahedron Lett. 1979, 4603.
Resu lts
Con ju ga te Ad d ition Rea ction . The conjugate addi-
tion reactions of the R-sulfinyl carbanion, derived from
p-tolyl 2-(trimethylsilyl)ethyl sulfoxide6 1, to R,â-unsatur-
ated esters were examined. The results are summarized
in Table 1.
The sulfoxide 1 was added to a THF solution of lithium
diisopropylamide at -78 °C. After 5 min, methyl acrylate
was added rapidly, and the mixture was stirred for 15
min. The addition product was found to be a single isomer
1
3a by careful analysis of the H NMR spectra and HPLC
(4) (a) Casey, M.; Manage, A. C.; Murphy, P. J . Tetrahedron Lett,
1992, 33, 965. (b) Baker, R. W.; Hockles, D. C. R.; Pocock, G. R.;
Sargent, M. V.; Skelton, B. W.; Sobolev, A. N.; Twiss (ne´e Stanojevic),
E.; White, A. H. J . Chem. Soc., Perkin Trans. 1 1995, 2615.
(5) (a) Kusuda, S.; Ueno, Y.; Toru, T. Tetrahedron 1994, 50, 1045.
(b) Toru, T.; Nakamura, S.; Takemoto, H.; Ueno, Y. Synlett 1997, 5,
449. (c) Nakamura, S.; Takemoto, H.; Ueno, Y.; Toru, T.; Kakumoto,
T.; Hagiwara, T. J . Org. Chem., in press. (d) Nakamura, S.; Watanabe,
Y.; Toru, T. J . Chem. Soc., Prekin Trans. 1 1999, 3403.
(2) (a) Casey, M.; Manage, A. C.; Nezhat, L. Tetrahedron Lett. 1988,
29, 5821. (b) Casey, M.; Manage, A. C.; Gairns, R. S. Tetrahedron Lett.
1989, 30, 6919.
(3) (a) Pyne, S. G.; Boche, G. J . Org. Chem. 1989, 54, 2663. (b) Casey,
M.; Mukherjee, I.; Trabsa, H. Tetrahedron Lett. 1992, 33, 127.
(6) For the preparation of 1, see ref 5a.
10.1021/jo991635n CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/25/2000

Efficient Chiral Induction in Conjugate Additions
J . Org. Chem., Vol. 65, No. 6, 2000 1759
Ta ble 1. Ster eoselective Con ju ga te Ad d ition of p-Tolyl
r-Lith io-â-silyleth yl Su lfoxid e 2 to r,â-Un sa tu r a ted
Ester s
Ta ble 2. Rea ction of p-Tolyl r-Lith io-â-silyleth yl
Su lfoxid e 2 w ith r,â-Un sa tu r a ted Keton es
entry
R
product
yield (%)
diastereomer ratioa
diaster-
diaster-
eomer
ratioa
1
2
3
4
Hb
3a
3b
3c
3d
64
95
97
96
>98:2c
>98:2
>98:2
>98:2c
yield eomer
yield
(%)
Meb
Etb
Ph
entry
R1
R2
4
(%)
ratioa
5
1
2
3
4
H
Me
Ph
Me 4a
Ph 4b 80
Ph 4c
0
5a 38 (54)b
59:41
71:29
55:45
>98:2 5b 20
96:4 5c 22
5d 82
a
1
b
Determined by H NMR. A THF solution of the R,â-unsatur-
ated ester was cooled to -78 °C before addition. c The ration was
also confirmed by HPLC (COSMOSIL, hexane/ethyl acetate )
75:25).
57
0
-(CH2)2-
4d
>98:2
Determined by 1H NMR. A THF solution of 2 was added to
a
b
the enone at -78 °C.
data (Table 1, entry 1). This surprisingly high stereo-
selection was also observed in the reaction of the R-
sulfinyl carbanion 2 with other â-substituted R,â-
unsaturated esters such as methyl crotonate, methyl (E)-
2-pentenoate, and methyl cinnamate. The conjugate
addition products 3b-d were obtained as single stere-
oisomers (Table 1, entries 2-4). In these reactions, the
diastereoselectivity was determined by the 1H NMR
spectra of the crude mixture. The X-ray crystallography
of the adduct 3a established the relative syn configura-
tion between the sulfinyl oxygen and the trimethylsilyl-
methyl group, which was in accord with the stereochem-
istry on the R position of the compounds stereoselectively
formed in the reaction of the R-sulfinyl carbanion 2 and
aldehydes,5a,c but different from the anti configuration
formed in the reaction of tert-butylsulfinyl carbanions
with electrophiles such as aldehydes or R,â-unsaturated
esters.2,3 By the X-ray crystallography, the stereochem-
istry of 3b was assigned to be (RS,3S,4R).
Ta ble 3. Con ju ga te Ad d ition of r-Su lfin yl Ca r ba n ion 2
to r,â-Un sa tu r a ted Ester s a n d Su bsequ en t
Ster eoselective Tr a p p in g Rea ction
diastereomer
entry
R
electrophile
MeI
product yield (%)
ratioa
1
2
3
4
5
6
7
8
9
H
6a
6b
6c
6d
6e
6f
21
59
64
75
70
74
32
90
98
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
Me MeI
Et MeI
Ph MeI
Ph CH2dCHCH2Br
Ph C6H5CH2Br
Ph CH3CH2CHO
Ph iPrCHO
Ph PhCHO
6g
6h
6i
The R-sulfinyl carbanion 2 was reacted with R,â-
unsaturated ketones to give the conjugate and/or
carbonyl addition products 4 and 5, respectively. The
results are summarized in Table 2.
a
Determined by 1H NMR.
Tr a p p in g Rea ction of th e En ola tes. We next ex-
plored trapping reactions of the intermediate enolates
formed after conjugate addition to R,â-unsaturated esters
(Table 3).
The reaction of 2 with R,â-unsaturated ketones was
performed in a manner similar to the reaction with R,â-
unsaturated esters. The reaction with 3-buten-2-one
afforded 38% yield of the carbonyl adduct 5a with low
stereoselectivity together with recovery of a large amount
of the starting sulfoxide 1 due to deprotonation from the
ketone. The product 5a was produced in 54% yield when
a THF solution of the lithium carbanion was added to a
solution of 3-buten-2-one (Table 2, entry 1). Reaction with
1-phenyl-3-buten-1-one and 1,3-diphenyl-2-propen-1-one
gave the conjugate adducts as a major product with high
stereoselectivity (Table 2, entries 2 and 3). The stereo-
chemistry of 4b and 4c was tentatively assigned as
(RS,3S,4R) and (RS,3R,4R), respectively, as in the case
of â-substituted R,â-unsaturated esters. The carbonyl
addition products 5b and 5c were always obtained
without selectivity. It is noteworthy that the reaction
with 2-cyclopentenone yielded the carbonyl addition
product 5d with complete stereoselectivity, although the
stereochemistry has not yet been determined (Table 2,
entry 4).
Reaction of the R-sulfinyl carbanion 2 and methyl
acrylate afforded the intermediate enolate, which was
reacted with methyl iodide. The product 6a was obtained
in 21% yield, because of the inevitable polymerization of
methyl acrylate occurred during the reaction at the
temperature in the region from -78 °C to 0 °C, but the
product was a single diastereomer (Table 3, entry 1).
Reaction of other intermediate enolates with various
alkyl halides showed exclusive formation of the alkylated
products 6a -f composed of a single diastereomer (Table
1
3, entries 2-6). It was confirmed by H NMR spectros-
copy of the crude products that a single isomer was
formed in each reaction. The reaction of the enolate
derived from methyl cinnamate with propionaldehyde
gave the product 6g as a single diastereomer but in low
yield due to the formation of a considerable amount of
3d by the protonation of the enolate during the reaction
(Table 3, entry 7). Reaction of the enolate with iso-
butyraldehyde and benzaldehyde gave the respective

1760 J . Org. Chem., Vol. 65, No. 6, 2000
Nakamura et al.
Ta ble 4. Con ju ga te Ad d ition of r-Su lfin yl Ca r ba n ion 2
to r,â-Un sa tu r a ted Ester s a n d Su bsequ en t
Ster eoselective P r oton a tion
products 6h and 6i in high yield and with complete
stereoselectivity (Table 3, entries 8 and 9). Thus, the
reaction with aldehydes proceeded with complete stereo-
selection not only on the enolate face, but also on the
carbonyl face of the aldehyde. The stereochemistry of the
addition product 6d was proven by chemical transforma-
tion of 6d : desilylsulfenylation of 6d with tetrabutyl-
ammonium fluoride quantitatively yielded the elimina-
tion product 7 as a single diastereomer (Scheme 1).
Sch em e 1
yield
ratio
entry
R
protonation agent
H2O
isopropyl salicylateb
product
(%) syn/antia
The 1H NMR spectrum of 7 showed the methyl protons
at 0.98 ppm and the methoxy protons at 3.69 ppm. On
the other hand, the conjugate addition of a vinyl cuprate
reagent to methyl cinnamate, followed by enolate trap-
ping with methyl iodide, was performed to give an
inseparable 76:24 mixture of two diastereomers of 7, the
minor component of which showed the methyl protons
at 1.22 ppm and the methoxy protons at 3.42 ppm (Figure
1).
1
2
3
4
5
6
7
8
9
H
H
6a
6a
6b
6b
6b
6b
6b
6b
6b
53
63
92
95
93
98
90
90
100
42:58
13:87
31:69
19:81
16:84
10:90
17:83
20:80
66:34
Me H2O
Me ethyl salicylate
Me isopropyl salicylate
Me isopropyl salicylateb
Me ethanolamine
Me 2-aminophenol
Me 2,6-di-tert-butylphenol
Determined by 1H NMR. The protonation reaction was
a
b
carried out at -100 °C.
axial coupling showing the trans configuration in 10.
Hence, the absolute configuration of 6i was assigned to
be (RS,1′S,2R,3R,4R) as shown in Scheme 2.8
We also examined stereoselective protonation of the
enolates formed in the reaction of the R-sulfinyl carbanion
2 with R-methyl-R,â-unsaturated esters, such as methyl
methacrylate and methyl tiglate (Table 4).
F igu r e 1. 1H NMR assignment of 7.
The anisotropy induced by the aromatic group leads
to a specific upfield shift of the R-methyl group in the
syn isomer and the corresponding upfield shift of the
methyl ester in the anti isomer.7 These data suggest the
syn stereochemistry of 7, and accordingly, the adduct 6d
is the (RS,2S,3R,4R) isomer. The stereochemistry of other
alkylated products shown in Table 3 was assumed to be
the same as that of 6d . The stereochemistry of the
product 6i obtained in the reaction of the enolate with
benzaldehyde was proven by transformation of 6i to the
acetonide derivative 10 as shown in Scheme 2: thermal
dehydrosulfenylation of the ester 6i and reduction with
LiAlH4 gave the diol 9, which was then converted to the
acetonide 10.
When the enolates derived from the reaction of 2 with
methyl methacrylate and methyl tiglate were treated
with water, nonstereoselective protonation occurred (Table
4, entry 1). The protonation reaction of the enolate with
isopropyl salicylate at -100 °C gave the 2,3-syn/2,3-anti
products in a ratio of 13:87 (Table 4, entry 2). A similar
result was obtained for the protonation of the enolate
derived from the reaction of 2 with methyl tiglate (Table
4, entry 6). The protonation reaction afforded products
having stereochemistry different from that of products
obtained in the reaction of the enolate with methyl iodide
(Table 3, entries 1 and 2). In contrast, the protonation
reaction with 2,6-di-tert-butylphenol gave a product with
moderately reversed diastereoselectivity in comparison
with products obtained with other protonation agents.
In tr a m olecu la r Cycliza tion . We next studied ste-
reoselective intramolecular cyclization using the â-silyl-
ethyl sulfoxide and ω-halo-R,â-unsaturated esters (Table
5).
Sch em e 2
The reaction of the R-sulfinyl carbanion 2 with ethyl
4-bromo-2-butenoate was performed at -78 °C for 15 min
to give the cyclopropanecarboxylate 11a in 80% yield as
(8) We reasonably assumed that the aldehyde approaches to the
enolate from the endo direction of the bicyclic intermediate, shown in
Figure 5, as in the reaction with alkyl halides. The trapping reactions
of ester enolates with alkyl halides and aldehydes generally occur from
the same direction; see the following. Alkylations: (a) Caine, D. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, pp 1-64. (b) Frater, G. In
Stereoselective Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J .,
Schaumann, E., Eds.; Houben-Weyl: New York, 1996; Vol. 2, pp 723-
791. Aldol reactions: (c) Braun, M. In Stereoselective Synthesis;
Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Ed.;
Houben-Weyl: New York, 1996; Vol. 3, pp 1612-1667.
The stereochemistry of 10 was confirmed on the basis
of the vicinal coupling constant J Râ between C4-H and
C5-H. The observed J value of 10.4 Hz suggests an axial-
(7) (a) Bartlett, P. A.; Barstow, J . F. J . Org. Chem. 1982, 47, 3933.
(b) Daub, G. W.; Shanklin, P. L.; Tata, C. J . Org. Chem. 1986, 51, 3405.
(c) Metz, P.; Mues, C. Tetrahedron 1988, 44, 6841.

Efficient Chiral Induction in Conjugate Additions
J . Org. Chem., Vol. 65, No. 6, 2000 1761
Ta ble 5. Ster eoselective Cycliza tion th r ou gh th e
Con ju ga te Ad d ition of th e r-Su lfin yl Ca r ba n ion 2 to
ω-Ha lo-r,â-u n sa tu r a ted Ester sa
Ta ble 6. Tr ea tm en t of th e Ad d ition P r od u cts w ith TBAF
in to Hom oa llylic Ca r boxyla tes
entry substrate R1
R2
R3 product yield (%)
1
2
3
4
5
6
7
3d
6d
6i
11a
11b
11c
11d
Ph
Ph Me
Ph CH(OH)Ph Me
H
Me
Me
13a
7
quant
quant
85
56
83
13b
13c
13d
13e
13f
-CH2-
-(CH2)2-
-(CH2)3-
-(CH2)4-
Et
Et
Et
Et
92
94
Ta ble 7. Th er m a l Tr ea tm en t of th e Ad d ition P r od u cts
in to Hom oa llylic Ca r boxyla tes
products
T
(°C)
yield
(%)
yield
(%)
entry
n
X
additive 11
12
1
2
3
4
5
6
7
8
9
10
11
12
13
1
2
2
2
2
2
3
3
3
3
4
4
4
Br
Br
Br
I
I
I
-78
-78
11a
11b
80 12a
12b (X ) Br) 87
49 12b (X ) Br) 29
0
0
-78f 0 HMPA 11b
-78
-78f 0
-78f 0 HMPA 11b
-78
11b
11b
28 12b (X ) I)
59
43
22
yield ratio
51
entry substrate R1
R2
R3 product (%)
E/Z
66 12b (X ) I)
1
2
3
4
5
6
7
8
9
3b
3d
6a
6d
6e
6f
6i
11a
11b
11c
11d
Me
Ph
Me Me
Ph Me
H
H
Me
Me
Me
Me
14a
14b
14c
14d
14e
14f
8
14g
14h
14i
14j
86 >98:2
95 >98:2
98 >98:2
90 >98:2
99 >98:2
99 >98:2
94 >98:2
Br
11c
11c
11c
11c
11
72 12c (X ) Br) 18
49 12c (X ) Br) 49
Br -105
Br
Br
Br
Br
I
0
60 12c (X ) Br)
88 12c (X ) Br)
5
4
-78b
-78
0
12d (X ) Br) quant
Ph CH2CHdCH2 Me
-78f 0
-78
11d
11d
93 12d (X ) Br)
80 12d (X ) I)
7
8
Ph CH2Ph
Ph CH(OH)Ph
-CH2-
Me
Me
Et
Et
Et
56
83:17
a
Lithium diisopropylamide (1.25 equiv) was used for lithiation
-(CH2)2-
-(CH2)3-
-(CH2)4-
83 >98:2
92 >98:2
94 >98:2
b
unless otherwise noted. Lithium diisopropylamide (2 equiv) was
10
11
used.
Et
a single diastereomer (Table 5, entry 1). Intramolecular
cyclization to cyclobutanecarboxylate was rather difficult.
The reaction of 2 with ethyl 5-bromo-2-pentenoate at -78
°C for 1 h only gave the conjugate addition product 12b
in 87% yield (Table 5, entry 2). When HMPA was added
to the reaction mixture and warmed to 0 °C, the cyclo-
butanecarboxylate 11b was obtained in 49% yield (Table
5, entry 3). After several attempts to effect cyclization,
the reaction with ethyl 5-iodo-2-pentenoate in the pres-
ence of HMPA at 0 °C led to 66% yield of 11b (Table 5,
entry 6). The reaction with ethyl 6-bromo-2-hexenoate
at -78 °C for 15 min afforded the cyclopentanecarboxy-
late 11c together with a considerable amount of the
uncyclized product 12c, the latter of which was possibly
formed by the protonation from the cyclized product.
Thus, almost selective formation of 11c could be achieved
in 88% yield when 2.0 equiv of LDA was used. The
reaction was also completely diastereoselective (Table 5,
entry 10). The reaction of 2 with ethyl 7-bromo-2-
heptenoate was performed at -78 °C for 1 h to give the
conjugate addition product 12d quantitatively as a single
diastereomer (Table 5, entry 11). The intramolecular
cyclization proceeded smoothly as the reaction temper-
ature was raised to 0 °C, giving the cyclohexanecarboxy-
late 11d in 93% yield (Table 5, entry 12). The stereo-
chemistry of cyclopropane and cyclopentanecarboxylates
11a ,c and the cyclohexanecarboxylic acid derivative
derived from 11d was confirmed to be (RS,1S,1′R,2S) by
their X-ray crystal structure analyses.
the stereoselectivity in the conjugate addition reaction
as well as in the enolate trapping reaction, but also
forming a double bond regioselectively from the products.
The obtained optically active homoallylic carboxylates are
useful in a variety of organic transformations.9 The
conjugate addition products were treated with tetrabu-
tylammonium fluoride or refluxed in benzene in the
presence of pyridine to effect elimination of the sulfinyl
group. Treatment of 3d with tetrabutylammonium fluo-
ride in THF at room temperature afforded the olefin 13a
quantitatively through â-elimination of the trimethylsilyl
and p-tolyl sulfinyl groups starting with an initial attack
of a fluoride ion on the silicon. Other products also yielded
the homoallylic carboxylates in good to excellent yields
as shown in Table 6.
A benzene solution of 3b was heated for 1 h in the
presence of pyridine to give the (E)-vinylsilane 14a in
86% yield (Table 7). All thermal elimination reactions
exclusively formed the E-stereoisomers except for 11a in
which 14g was obtained as an E/Z mixture of 83:17
(Table 7, entry 8). By examination of the vicinal coupling
1
constants of the ring protons in the H NMR spectra, no
epimerization was confirmed to occur during the conver-
sion of the adducts into homoallylic carboxylates.
Discu ssion
Alkylation of the enolates derived from the R,â-
unsaturated esters having a substituent at the â-position
(9) For recent reviews of iodolactonizations, see: Cardillo, G.; Orena,
M. In Stereoselective Synthesis; Helmchen, G., Hoffmann, R. W.,
Mulzer, J ., Schaumann, E., Eds.; Houben-Weyl: New York, 1996; Vol.
8, pp 4698-4750.
Elim in a tion of th e Su lfin yl Gr ou p . The chiral
sulfinyl group together with the â-trimethylsilyl group
functions as a vinyl anion equivalent,5 not only inducing

1762 J . Org. Chem., Vol. 65, No. 6, 2000
Nakamura et al.
F igu r e 2. Plausible transition state in the reaction of R-sulfi-
nyl carbanion 2 and a carbonyl compound.
shows high stereoselectivity and gives products having
the stereochemistry predicted from the Felkin-Anh
model.8,10 The addition of the R-sulfinyl carbanion 2 to
methyl crotonate and the subsequent alkylation gave
products having the same stereochemistry as that pre-
dicted from the Felkin-Anh model. However, the trap-
ping reaction of the enolate, derived from the reaction of
2 with acrylate, with methyl iodide also gave a single
diastereomer of the product. This fact is not in accord
with the results from the Felkin-Anh model, which
usually show low stereoselectivity in alkylation of the
enolates derived from γ-substituted carboxylates.11 Re-
cently, we demonstrated that a silicon-oxygen interac-
tion plays an important role in stabilizing the transition
state for the highly stereoselective reaction of R-lithio-
â-silylethyl sulfoxides with carbonyl compounds.5c Figure
2 shows a plausible transition state that we have
proposed on the basis of the stereochemical outcome as
well as the MO calculation.
F igu r e 3. Transition states for stereoselective conjugate
addition of 1.
In these reactions, the trialkylsilyl group at the posi-
tion â to the sulfinyl is essential to induce high stereo-
selectivity. Obviously, the excellent stereochemical out-
come in the present conjugate addition is also ascribed
to the presence of the â-trimethylsilyl group, since the
reaction of the carbanion derived from 3,3-dimethylbutyl
p-tolyl sulfoxide with methyl crotonate gave a diastere-
omeric mixture in a 69:31 ratio.5b In addition, the
stereochemistry at the carbon R to the sulfinyl group is
the same as that of the products obtained in both
reactions with carbonyl compounds and with R,â-unsat-
urated carbonyl compounds. Therefore, we have assumed
that the conjugate addition reaction proceeds via a
bicyclic transition state that consists of the R-sulfinyl
carbanion and the R,â-unsaturated carbonyl compound
having an s-cis conformation and includes the silicon-
oxygen interaction (Figure 3). There are several discus-
sions about the transition state in the conjugate addition
of R-sulfinyl carbanions derived from allyl sulfoxide1f,g
and ketimine sulfoxide1i,j,k to R,â-unsaturated carbonyl
compounds. In these papers, the reactions proceed via
the 8- or 10-membered cyclic transition state, in which
the R,â-unsaturated carbonyl compound has an s-trans
conformation. However, the reaction of the R-sulfinyl
carbanion 2 with 2-buten-4-olide as an s-trans ester gave
neither a conjugate nor a carbonyl addition product, but
led to recovery of the starting sulfoxide 1. Furthermore,
F igu r e 4. Intra- and intermolecular stereoselective alkylation
of the enolates.
the reaction with 2-cyclopentenone as an s-trans ketone
formed the carbonyl addition product 3d in high yield
without formation of the conjugate addition product
(Table 2, entry 4). These results suggest that the s-cis
conformation of R,â-unsaturated carbonyl compounds
should be important at the transition state for the
conjugate addition in the present reaction.
Figure 3 shows two possible transition states TS-1 and
TS-2 stabilized by the silicon-oxygen interaction as
proposed in the transition state for the reaction of the
R-sulfinyl carbanion with ketones, aldehydes, or tri-
methyl phosphate (see Figure 2).5c Repulsion between the
π-electrons of the R,â-unsaturated ester and the sulfinyl
lone pair of electrons would develop in TS-2, whereas no
such repulsive effect is expected in TS-1. Thus, the
conjugate addition reaction gives the products 3a -d with
high stereoselectivity through the more preferable transi-
tion state TS-1. The high diastereoselectivity observed
in the alkylation of the intermediate enolates with alkyl
halides can also be explained by the intermediate struc-
ture formed through TS-1. The exo face of the bicyclic
intermediate enolate is highly hindered by the trimeth-
ylsilylmethyl group (Figure 4).12 An alkyl halide ap-
proaches only from the less hindered endo direction (the
si face) to the enolate to give the products 6a -f exclu-
sively. Intramolecular cyclization also occurs on the si
face of the enolate in the intermediate from the less
hindered direction to avoid the trimethylsilylmethyl
group, giving a trans compound 11a -d .
(10) (a) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841. (b) Bernhard,
W.; Fleming, I.; Waterson, D. J . Chem. Soc., Chem. Commun. 1984,
28. (c) Yamamoto, Y.; Maruyama, K. J . Chem. Soc., Chem. Commun.
1984, 904. (d) Fleming, I.; Lewis, J . J . J . Chem. Soc., Chem. Commun.
1985, 149. (e) Yamaguchi, M.; Hasebe, K.; Tanaka, S.; Minami, T.
Tetrahedron Lett. 1986, 27, 959. (f) Yamaguchi, M.; Hasebe, M.;
Nakashima, H.; Minami, T. Tetrahedron Lett. 1987, 28, 1785. (g)
Kawasaki, H.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1985, 26, 3031.
(h) McGarvey, G. J .; Williams, J . M. J . Am. Chem. Soc. 1985, 107,
1435. (i) Fleming, I.; Hill, J . H. M.; Parker, D.; Waterson, D. J . Chem.
Soc., Chem. Commun. 1985, 318. (j) Tomioka, K.; Kawasaki, H.; Koga,
K. Tetrahedron Lett. 1985, 26, 3027.
(12) The eight-membered ring chelation of sulfinyl oxygen and ester
enolate has been postulated in the reaction of; Yoshizaki, H.; Tanaka,
T.; Yoshii, E.; Koizumi, T.; Takeda, K. Tetrahedron Lett. 1998, 39, 47.
(11) (a) Kuehne, M. E.; Nelson, J . A. J . Org. Chem. 1970, 35, 161.
(b) Krapcho, A. P.; Dundulis, E. A. J . Org. Chem. 1980, 45, 3236.

Efficient Chiral Induction in Conjugate Additions
J . Org. Chem., Vol. 65, No. 6, 2000 1763
F igu r e 6. Elimination reaction of 11a .
a transition state avoiding the steric interaction between
the trimethylsilyl group and the cycloalkane ring. How-
ever, this is not the case in the elimination reaction of
the cyclopropanecarboxylate 11a , where small interaction
relative to other cycloalkanecarboxylates 11b-d would
occur between the trimethylsilyl and cyclopropyl groups
at the transition state TS-8 to give a mixture of the E-
and Z-olefins (Figure 6).
In summary, p-tolyl 2-(trimethylsilyl)ethyl sulfoxide is
demonstrated to be a powerful chiral vinyl anion equiva-
lent that may be used to construct new chiral centers.
This reaction of p-tolyl 2-(trimethylsilyl)ethyl sulfoxide
with R,â-unsaturated esters provides a convenient method
for the preparation of optically pure homoallylic carboxy-
lates, which have three or four chiral centers, via
subsequent thermal elimination of the sulfinyl group or
concurrent elimination of the sulfinyl and silyl groups.
F igu r e 5. Transition states for the reaction of the enolates
with aldehydes.
The highly stereoselective aldol reaction can be ratio-
nalized by the transition state developed by the addition
of an aldehyde to the intermediate enolate as shown in
Figure 5. If the reaction proceeds through a chairlike
form at the transition state, there would be severe steric
interaction in the concave ring. To avoid this hindrance,
the aldehyde should approach by taking a boatlike form.
Such transition states are depicted as TS-3 or TS-4 in
Figure 5.
A significant steric interaction is anticipated to arise
in TS-4, where the substituent R on the carbaldehyde
such as the ethyl, isopropyl, or phenyl group is located
close to the methine proton. Accordingly, the reaction
proceeds preferentially through TS-3 to give the aldol
product 6g-i.13 The stereochemical outcome in protolysis
of the enolates may be also explained through the bicyclic
intermediate. Protonation with agents capable of forming
a chelating complex with the enolate, shows particularly
high diastereoselectivity in the kinetically controlled
protonation.14 Recently, Krause and co-workers have
reported highly stereoselective protonation of enolates
with ethyl salicylate which are capable of forming a
chelating complex. In our reaction, isopropyl salicylate
gave 2,3-anti-6 with high stereoselectivity. Protonation
with ethanolamine or 2-aminophenol also proceeded to
give the product with high selectivity, whereas protona-
tion with H2O or nonchelating 2,6-di-tert-butylphenol
showed low stereoselectivity.
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for th e Rea ction of p-Tolyl
r-Lit h io-(â-t r im et h ylsilyl)et h yl Su lfoxid es w it h r,â-
Un sa tu r a ted Ester s. Meth yl (RS,3S,4R)-3-Meth yl-4-(p-
tolylsu lfin yl)-5-tr im eth ylsilylp en ta n oa te (3b). To a solu-
tion of diisopropylamine (0.040 mL, 0.285 mmol) in THF (0.40
mL) was added n-butyllithium (1.46 mol L-1, 0.18 mL, 0.263
mmol) at 0 °C, and the mixture was stirred for 10 min. The
reaction mixture was then cooled to -78 °C, and a solution of
p-tolyl (R)-2-(trimethylsilyl)ethyl sulfoxide5a (1) (49.8 mg, 0.207
mmol) in THF (0.40 mL) was added. After being stirred for 5
min, the solution of methyl crotonate (0.030 mL, 0.283 mmol)
in THF (0.4 mL) was added at -78 °C, and the mixture was
stirred for additional 15 min. Saturated aqueous NH4Cl (20
mL) was added, and the mixture was extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure to
leave a residue that was purified by column chromatography
(silica gel 10 g, hexane/ethyl acetate ) 88:12) to give 3b (67.0
Easy elimination of the sulfinyl group and high E
selectivity of the products are apparently due to the effect
of the vicinal silyl group.15 Under thermal conditions, the
silyl group accelerates the elimination, since the silyl
group is a conjugatively electron-withdrawing group.15b
Thus, the elimination proceeded with complete regio-
selectivity. The E-olefins were exclusively formed in most
reactions because the syn elimination proceeds through
mg, 95%): TLC Rf ) 0.36 (hexane/ethyl acetate ) 70/30); [R]26
D
+58.1 (c 0.310, CHCl3); 1H NMR δ -0.15 (s, 9H), 0.68 (dd, 1H,
J ) 2.9, 15.3 Hz), 0.93 (dd, 1H, J ) 11.2, 15.3 Hz), 0.90-1.10
(m, 1H), 1.23 (d, 3H, J ) 7.0 Hz), 2.41 (s, 3H), 2.55-2.75 (m,
2H), 2.87 (dd, 1H, J ) 9.2, 15.2 Hz), 3.73 (s, 3H), 7.30 (d, 2H,
J ) 8.3 Hz), 7.38 (d, 2H, J ) 8.3 Hz); 13C NMR δ -1.4, 7.8,
15.9, 21.3, 33.9, 40.3, 51.7, 67.2, 124.1, 129.6, 140.2, 172.7; IR
(KBr) 2950, 1750, 1060 cm-1; SIMS m/z (rel intensity) 340.2
(M+, 23), 200.2 (100). Anal. Calcd for C17H28O3SSi: C, 59.96;
H, 8.29. Found: C, 59.96; H, 8.29.
(13) It was not successful to obtain the silylated ester enolate by
treatment of the enolate with TMSCl, giving complex products
presumably because of the sila-Pummerer reaction; see: Kita, Y.;
Shibata, N. Synlett 1996, 289.
(14) (a) Awandi, D.; Henin, F.; Muzart, J .; Pete, J .-P. Tetrahedron:
Asymmetry 1991, 2, 1011. (b) Krause, N. Angew. Chem., Int. Ed. Engl.
1994, 33, 1764. (c) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35,
2566. (d) Krause, N.; Ebert, S.; Haubrich, A. Liebigs Ann. 1997, 2409.
(e) Eames, J . Tetrahedron Lett. 1999, 40, 5787.
Tr a p p in g Rea ction of th e En ola te Der ived fr om th e
Rea ction of p-Tolyl r-Lith io-(â-tr im eth ylsilyl)eth yl Su l-
foxide an d r,â-Un satu r ated Ester s. Meth yl (RS,2S,3R,4R)-
2-Meth yl-3-ph en yl-4-(p-tolylsu lfin yl)-5-tr im eth ylsilylpen -
ta n oa te (6d ). To a solution of diisopropylamine (0.090 mL,
0.640 mmol) in THF (0.60 mL) was added n-butyllithium (1.46
(15) (a) Ochiai, M.; Tada, S.; Sumi, K.; Fujita, E. J . Chem. Soc.,
Chem. Commun. 1982, 281. (b) Fleming, I.; Goldhill, J .; Perry, D. A.
J . Chem. Soc., Perkin. Trans. 1 1982, 1563.

1764 J . Org. Chem., Vol. 65, No. 6, 2000
Nakamura et al.
mol L-1, 0.40 mL, 0.584 mmol) at 0 °C, and the mixture was
stirred for 10 min. The reaction mixture was then cooled to
-78 °C. A solution of the sulfoxide 1 (111.2 mg, 0.462 mmol)
in THF (0.50 mL) was added, and the mixture was stirred for
5 min. The solution of methyl cinnamate (97.8 mg, 0.601 mmol)
in THF (0.6 mL) was added, and the mixture was stirred for
an additional 15 min. Methyl iodide (0.06 mL, 0.963 mmol)
was then added. The cooling bath was changed to an ice-water
bath, and the mixture was stirred for 30 min at 0 °C. Usual
workup gave a reduced pressure to leave an oil that was
purified by column chromatography (silica gel 30 g, CH2Cl2/
Et2O ) 99:1) to give 6d (145.2 mg, 75%) and 3d (26.1 mg, 14%).
m/z (rel intensity) 368.1 (M+, 0.6), 262.2 (20), 73.1 (100). Anal.
Calcd for C22H28O3Si: C, 71.70; H, 7.66. Found: C, 71.48; H,
7.88.
(1S,2S)-2-1-P h en yl-[(3S)-3-(3-p h en yl-1-tr im eth ylsilyl-1-
p r op en yl)]-1,3-p r op a n ed iol (9). To a solution of LiAlH4
(110.0 mg, 2.90 mmol) in Et2O (5.0 mL) was added a solution
of 8 (227.9 mg, 0.618 mmol) in Et2O (2.0 mL) at 0 °C. The
reaction mixture was then warmed to room temperature and
stirred for 1 h. Saturated aqueous NH4Cl (20 mL) was added,
and the mixture was extracted with CH2Cl2. The combined
organic extracts were washed with brine and dried over Na2-
SO4. The solvent was removed under reduced pressure to leave
a residue that was purified by column chromatography (silica
gel 15 g, hexane/ethyl acetate ) 90:10) to give 9 (201.5 mg,
6d : TLC Rf ) 0.42 (hexane/ethyl acetate ) 80:20 × 2); [R]26
D
+71.8 (c 0.266, CHCl3); 1H NMR δ -0.20 (s, 9H), 0.49 (dd, 1H,
J ) 10.6, 15.6 Hz), 0.73 (dd, 1H, J ) 1.7, 15.6 Hz), 1.06 (d,
3H, J ) 6.9 Hz), 2.40 (s, 3H), 2.73 (ddd, 1H, J ) 1.7, 3.6, 10.6
Hz), 3.19 (dd, 1H, J ) 3.6, 10.8 Hz), 3.66 (dd, 1H, J ) 6.9,
10.8 Hz), 3.81 (s, 3H), 7.19-7.43 (m, 9H); 13C NMR δ -1.5,
8.4, 16.8, 20.7, 43.5, 51.9, 52.1, 67.1, 124.1, 127.7, 127.9, 128.4,
128.6, 129.6, 130.1, 179.5; IR (KBr) 1730, 1090 cm-1; SIMS
m/z (rel intensity) 416.2 (M+, 7), 276.2 (100). Anal. Calcd for
95%): TLC Rf ) 0.33 (hexane/ethyl acetate ) 80:20); [R]20
D
+56.1 (c 0.746, CHCl3); 1H NMR δ 0.06 (s, 9H), 1.97-2.10 (m,
1H), 2.78 (br, 1H), 3.45 (br, 1H), 3.70-3.92 (m, 3H), 4.57-
4.67 (m, 1H), 5.84 (d, 1H, J ) 18.4 Hz), 6.22 (dd, 1H, J ) 8.8,
18.4 Hz), 7.20-7.42 (m, 10H); 13C NMR δ -1.2, 50.6, 60.6, 75.2,
125.5, 126.4, 127.1, 128.0, 128.3, 128.8, 132.3, 142.8, 143.8,
147.0; IR (neat) 3350, 1250, 880 cm-1; EIMS m/z (rel intensity)
340.2 (M+, 21), 187.2 (82), 73.1(100). Anal. Calcd for C21H28O2-
Si: C, 74.07; H, 8.29. Found: C, 73.80; H, 8.56.
C
23H32O3SSi: C, 66.30; H, 7.74. Found: C, 66.12; H, 7.81.
Met h yl (RS,2R,3R,4R)-3-P h en yl-2-[(S)-p h en ylh yd oxy-
m eth yl]-4-(p-tolylsu lfin yl)-5-(tr im eth ylsilyl)p en ta n oa te
(6i). The reaction was carried out as described above using 1
(140.2 mg, 0.583 mmol), methyl cinnamate (125.0 mg, 0.771
mmol), and benzaldehyde (0.12 mL, 1.18 mmol). Purification
by column chromatography (hexane/ethyl acetate ) 85:15)
(4S,5S)-2,2-Dim e t h yl-4-p h e n yl-5-[(S)-1-p h e n yl-3-t r i-
m eth ylsilyl-2-p r op en yl]-1,3-d ioxa n e (10). A solution of 9
(23.4 mg, 0.068 mmol), 2,2-dimethoxypropane (0.060 mL, 0.488
mmol), and a catalytic amount of p-toluenesulfonic acid in
DMF (5.0 mL) was heated under reflux for 3 h. After the
mixture was cooled, CH2Cl2 was added. The organic solution
was washed with water and brine and dried over Na2SO4. The
solvent was removed under reduced pressure to leave a residue
that was purified by column chromatography (silica gel 3 g,
hexane/ethyl acetate ) 98:2) to give 10 (23.3 mg, 89%): TLC
Rf ) 0.73 (hexane/ethyl acetate ) 80:20); [R]20D +105.2 (c 0.88,
CHCl3); 1H NMR δ 0.07 (s, 9H), 1.36 (s, 3H), 1.46 (s, 3H), 2.31-
2.47 (m, 1H), 3.16 (dd, 1H, J ) 4.1, 9.4 Hz), 3.74 (dd, 1H, J )
5.2, 11.9 Hz), 3.92 (dd, 1H, J ) 11.8, 11.9 Hz), 4.67 (d, 1H, J
) 10.4 Hz), 5.65 (d, 1H, J ) 18.4 Hz), 6.23 (dd, 1H, J ) 9.4,
18.4 Hz), 6.83-7.33 (m, 10H); 13C NMR δ -1.2, 19.7, 29.1, 45.6,
50.7, 60.6, 75.5, 98.8, 126.2, 127.5, 127.8, 128.0, 128.2, 128.3,
128.5, 135.1, 140.0, 141.9, 143.4; IR (neat) 1250, 1230, 1170,
880 cm-1; EIMS m/z (rel intensity) 380.2 (M+, 100), 365.2 (50),
73.1 (100). Anal. Calcd for C24H32O2Si: C, 75.74; H, 8.47.
Found: C, 75.50; H, 8.71.
afforded 6i (290.7 mg, 98%). 6i: TLC Rf ) 0.79 (CH2Cl2/Et2O
1
) 90:10); [R]20 +57.6 (c 0.180, CHCl3); H NMR δ -0.17 (s,
D
9H), 0.58 (dd, 1H, J ) 10.5, 15.7 Hz), 0.73 (dd, 1H, J ) 2.1,
15.7 Hz), 1.70 (br, 1H), 2.38 (s, 3H), 2.56 (ddd, 1H, J ) 2.1,
2.7, 10.5 Hz), 3.57 (s, 3H), 3.75 (dd, 1H, J ) 2.7, 12.1 Hz),
4.00 (dd, 1H, J ) 3.0, 12.1 Hz), 4.60-4.67 (m, 1H), 7.12-7.63
(m, 14H); 13C NMR δ -1.5, 8.4, 21.3, 48.3, 51.7, 56.3, 67.3,
71.5, 124.0, 124.8, 124.9, 125.1, 127.5, 128.1, 128.3, 128.4,
128.8, 129.0, 129.6, 130.0, 185.5; IR (KBr) 3400, 1730, 1090
cm-1; SIMS m/z (rel intensity) 508.2 (M+, 8), 368.2 (45), 184.0
(100). Anal. Calcd for C29H36O4SSi: C, 68.47; H, 7.13. Found:
C, 68.50; H, 7.29.
Rep r esen ta tive P r oced u r e for th e Con ver sion of 6d
in to th e Hom oa llylic Ester s 7 w ith Tetr a bu tyla m m o-
n iu m F lu or id e. Meth yl (2S,3R)-2-Meth yl-3-p h en yl-4-p en -
ten oa te (7). To a solution of 6d (61.0 mg, 0.146 mmol) in THF
(1.0 mL) was added a THF solution of tetrabutylammonium
fluoride (TBAF) (1.0 mol L-1, 0.30 mL, 0.30 mmol) at 0 °C,
and the mixture was stirred for 1 h. THF was then evaporated
under reduced pressure, and the residue was purified by
column chromatography (silica gel 5 g, hexane/CH2Cl2 ) 80:
Rep r esen ta tive P r oced u r e for P r oton a tion of th e
In ter m ediate En olates. Meth yl (RS,2S,3S,4R)- an d (RS,2R,-
3S,4R)-2,3-Dim eth yl-4-(p-tolylsu lfin yl)-5-tr im eth ylsilyl-
p en ta n oa te (6b). To a solution of diisopropylamine (0.040 mL,
0.285 mmol) in THF (0.40 mL) was added n-butyllithium (1.37
mol L-1, 0.17 mL, 0.233 mmol) at 0 °C, and the mixture was
stirred for 10 min. The reaction mixture was then cooled to
-78 °C, and a solution of the sulfoxide 1 (43.2 mg, 0.180 mmol)
in THF (0.40 mL) was added. After the mixture was stirred
for 5 min, a solution of methyl tiglate (26.7 mg, 0.234 mmol)
in THF (0.4 mL) was added, and the mixture was stirred for
an additional 15 min. The reaction mixture was then cooled
to -100 °C. A solution of isopropyl salicylate (116.0 mg, 0.644
mmol) in THF (0.4 mL) was added, and the mixture was
stirred for 15 min. Usual workup gave a residue that was
purified by column chromatography (silica gel 12 g, hexane/
CH2Cl2/Et2O ) 50:35:15) to give syn-6b (6.4 mg, 10%) and anti-
6b (56.1 mg, 88%). The syn/anti ratio was determined to be
10:90 by the 1H NMR analysis of the crude product. syn-6b:
20) to give 7 (30.2 mg, 100%): TLC Rf ) 0.76 (CH2Cl2); [R]26
D
+58.8 (c 0.26, CHCl3); 1H NMR δ 0.98 (d, 3H, J ) 6.9 Hz),
2.84 (dq, 1H, J ) 6.9, 10.4 Hz), 3.45 (dd, 1H, J ) 8.3, 10.4
Hz), 3.69 (s, 3H), 4.97-5.12 (m, 2H), 6.01 (ddd, 1H, J ) 8.3,
10.2, 17.1 Hz), 7.14-7.38 (m, 5H); 13C NMR δ 15.9, 45.2, 51.5,
53.8, 115.4, 126.7, 128.1, 128.7, 139.7, 141.3, 176.1; IR (neat)
1740, 920 cm-1; EIMS m/z (rel intensity) 204.1 (M+, 23), 27.9
(100). Anal. Calcd for C13H16O2: C, 76.44; H, 7.89. Found: C,
76.31; H, 8.02.
Rep r esen ta tive P r oced u r e for th e Con ver sion of 6i
in to th e Hom oa llylic Ester 8 u n d er Th er m a l Con d ition s.
Meth yl (2R,3S)-(E)-2-[(S)-Hyd r oxyp h en ylm eth yl]-3-ph en -
yl-5-tr im eth ylsilyl-4-p en ten oa te (8). A solution of 6i (60.0
mg, 0.118 mmol) and pyridine (0.048 mL, 0.590 mmol) in
benzene (2.0 mL) was heated under reflux for 1 h. After the
mixture was cooled, the solvent was evaporated under reduced
pressure and the residue was purified by column chromatog-
raphy (silica gel 10 g, hexane/CH2Cl2 ) 80:20) to give 8 (41.0
mg, 94%) as a colorless oil: TLC Rf ) 0.43 (hexane/ethyl
TLC Rf ) 0.42 (hexane/ethyl acetate ) 70:30); [R]27 +35.2 (c
D
1
1.05, CHCl3); H NMR δ -0.16 (s, 9H), 0.71 (dd, 1H, J ) 2.7,
15.3 Hz), 0.93 (dd, 1H, J ) 11.3, 15.3 Hz), 1.19 (d, 3H, J ) 6.9
Hz), 1.30 (d, 3H, J ) 7.0 Hz), 2.00-2.20 (m, 1H), 2.41 (s, 3H),
2.73 (ddd, 1H, J ) 2.7, 2.7, 11.3 Hz), 2.92 (dq, 1H, J ) 7.0, 8.6
Hz), 3.73 (s, 3H), 7.30 (d, 2H, J ) 7.5 Hz), 7.38 (d, 2H, J ) 7.5
Hz); 13C NMR δ -1.4, 8.1, 13.4, 15.8, 21.2, 40.1, 44.3, 51.6,
65.0, 123.9, 129.7, 140.3, 140.5, 176.0; IR (KBr) 1740, 1060,
cm-1; SIMS m/z (rel intensity) 354.2 (M+, 10), 214.2 (75), 92.4
(100). Anal. Calcd for C18H30O3SSi: C, 60.97; H, 8.53. Found:
C, 60.99; H, 8.30. anti-6b: TLC Rf ) 0.42 (hexane/ethyl acetate
) 70:30); 1H NMR δ -0.18 (s, 9H), 0.65 (dd, 1H, J ) 2.5, 15.2
acetate ) 80:20); [R]26 +36.5 (c 0.43, CHCl3); 1H NMR δ 0.02
D
(s, 9H), 3.15 (dd, 1H, J ) 3.0, 11.0 Hz), 3.47 (s, 3H), 3.87 (d,
1H, J ) 9.9 Hz), 3.93 (dd, 1H, J ) 8.5, 11.0 Hz), 4.44 (dd, 1H,
J ) 3.0, 9.9 Hz), 5.75 (d, 1H, J ) 18.4 Hz), 6.20 (dd, 1H, J )
8.5, 18.4 Hz), 7.15-7.45 (m, 5H); 13C NMR δ -1.4, 51.3, 53.0,
57.8, 71.8, 125.0, 125.1, 127.0, 127.3, 128.1, 128.3, 129.0, 132.2,
142.5, 145.8, 174.6; IR (neat) 3500, 1720, 1250, 970 cm-1; EIMS

Efficient Chiral Induction in Conjugate Additions
J . Org. Chem., Vol. 65, No. 6, 2000 1765
Hz), 0.93 (dd, 1H, J ) 11.3, 15.2 Hz), 0.90-1.15 (m, 1H), 1.22
(d, 3H, J ) 7.1 Hz), 1.30 (d, 3H, J ) 6.9 Hz), 2.40 (s, 3H), 2.49
(ddd, 1H, J ) 2.4, 2.5, 11.3 Hz), 3.02 (dq, 1H, J ) 6.9, 10.2
Hz), 3.70 (s, 3H), 7.25-7.45 (m, 4H); 13C NMR δ -1.5, 7.9,
12,4, 16.0, 21.3, 40.0, 44.9, 51.6, 67.0, 124.0, 129.5, 140.3, 176.5;
IR (KBr) 1740, 1070, cm-1; SIMS m/z (rel intensity) 354.2 (M+,
11), 214.2 (100), 136.0 (100), 110.3 (100). Anal. Calcd for
C18H30O3SSi: C, 60.97; H, 8.53. Found: C, 61.04; H, 8.46.
St er eoselect ive Cycliza t ion R ea ct ion t h r ou gh t h e
Con ju ga te Ad d ition of th e Su lfin yl Ca r ba n ion 2 to
ω-Ha lo-r,â-u n sa tu r a ted Ester s. Eth yl (RS,1S,2S)-2-[(1R)-
1-(p -Tolylsu lfin yl)-2-(t r im e t h ylsilyl)e t h yl]c yc lop r o-
p a n eca r boxyla te (11a ). To a solution of diisopropylamine
(0.040 mL, 0.285 mmol) in THF (0.28 mL) was added n-
butyllithium (1.44 mol L-1, 0.175 mL, 0.252 mmol) at 0 °C,
and the mixture was stirred for 10 min. The reaction mixture
was then cooled to -78 °C, a solution of sulfoxide 1 (48.3 mg,
0.201 mmol) in THF (0.20 mL) was added, and the mixture
was stirred for 5 min. The solution of ethyl 4-bromo-2-
butenoate (0.040 mL, 0.290 mmol) in THF (0.23 mL) was then
added. After the mixture was stirred for an additional 15 min,
saturated aqueous NH4Cl (20 mL) was added. Usual workup
gave a residue that was purified by column chromatography
(silica gel 15 g, hexane/CH2Cl2 ) 80:20) to give 11a (56.4 mg,
afforded 11b (48.1 mg, 66%) and 12b (X ) I) (22.0 mg, 22%).
12b (X ) I): TLC Rf ) 0.52 (hexane/ethyl acetate ) 70:30);
1H NMR δ 0.17 (s, 9H), 0.73-0.81 (m, 2H), 1.32 (t, 3H, J )
7.1 Hz), 1.92-2.10 (m, 1H), 2.24-2.47 (m, 2H), 2.40 (s, 3H),
2.58 (m, 3H), 3.13 (ddd, 1H, J ) 6.0, 9.9, 10.1 Hz), 3.42 (ddd,
1H, J ) 4.5, 6.7, 10.1 Hz), 4.08-4.32 (m, 2H), 7.28 (d, 2H, J )
8.5 Hz), 7.38 (d, 2H, J ) 8.5 Hz); 13C NMR δ -1.5, 4.5, 7.9,
14.3, 21.3, 32.9, 37.0, 39.5, 60.9, 66.1, 124.1, 129.6, 139.9, 140.7,
172.2; IR (neat) 1730, 1080 cm-1; SIMS m/z (rel intensity) 494.1
(M+, 5), 354.1 (100). Anal. Calcd for C19H31IO3SSi: C,46.15;
H, 6.32. Found: C, 46.23; H, 6.22.
Eth yl (RS,1S,2S)-2-[(1R)-1-(p-Tolylsu lfin yl)-2-(tr im eth -
ylsilyl)eth yl]cyclop en ta n eca r boxyla te (11c). To a solution
of diisopropylamine (0.065 mL, 0.462 mmol) in THF (0.45 mL)
was added n-butyllithium (1.49 mol L-1, 0.290 mL, 0.432
mmol) at 0 °C, and the mixture was stirred for 10 min. The
reaction mixture was then cooled to -78 °C, a solution of
sulfoxide 1 (51.5 mg, 0.214 mmol) in THF (0.22 mL) was added,
and the mixture was stirred for 5 min. The solution of ethyl
6-iodo-2-hexenoate (77.8 mg, 0.352 mmol) in THF (0.23 mL)
was then added. After the mixture was stirred for an additional
15 min, saturated aqueous NH4Cl (20 mL) was added. Usual
workup gave a residue that was purified by column chroma-
tography (silica gel 20 g, hexane/ethyl acetate ) 90:10) to give
11c (71.7 mg, 88%) and 12c (4.2 mg, 4%). 11c: TLC Rf ) 0.49
(hexane/ethyl acetate ) 70:30); [R]20D +108.8 (c 0.332, CHCl3);
1H NMR δ -0.17 (s, 9H), 0.73 (dd, 1H, J ) 3.1, 15.6 Hz), 0.87
(dd, 1H, J ) 11.0, 15.6 Hz), 1.31 (t, 3H, J ) 7.1 Hz), 1.62-
2.18 (m, 6H,), 2.41 (s, 3H), 2.49 (dddd, 1H, J ) 3.1, 8.7, 9.0,
9.0 Hz), 2.82 (ddd, 1H, J ) 3.1, 3.1, 11.0 Hz), 3.19 (ddd, 1H, J
) 8.3, 8.7, 10.1 Hz), 4.19 (q, 2H, J ) 7.1 Hz), 7.28 (d, 2H, J )
8.3 Hz), 7.35 (d, 2H, J ) 8.3 Hz); 13C NMR δ -1.4, 9.2, 14.3,
21.3, 24.4, 27.5, 29.4, 47.8, 48.0, 60.6, 65.8, 123.9, 130.0, 140.3,
175.4; IR (KBr) 1730, 1090 cm-1; SIMS m/z (rel intensity) 380.2
(M+, 21), 240.2 (100). Anal. Calcd for C20H32O3SSi: C, 63.11;
H, 8.47. Found: C, 63.35; H, 8.23. 12c: TLC Rf ) 0.43 (hexane/
ethyl acetate ) 70:30); 1H NMR δ -0.15 (s, 9H), 0.47 (dd, 1H,
J ) 4.0, 14.7 Hz), 0.63 (dd, 1H, J ) 9.8, 14.7 Hz), 1.29 (t, 3H,
J ) 7.2 Hz), 1.60-2.10 (m, 5H), 2.42 (s, 3H), 2.50-2.80 (m,
2H), 3.13 (ddd, 1H, J ) 2.7, 4.0, 9.8 Hz), 3.50-3.65 (m, 2H),
4.16 (q, 2H, J ) 7.2 Hz), 7.29 (d, 2H, J ) 8.2 Hz), 7.59 (d, 2H,
J ) 8.2 Hz); IR (KBr) 2940, 1730, 1480, 1430, 1420, 1390, 1250,
1190, 1100, 1090, 1030, 870, 860, 800 cm-1; SIMS m/z (rel
intensity) 460.1 (M+, 11), 320.1 (9), 241.0 (100), 147.0 (100).
Anal. Calcd for C20H33BrO3SSi: C, 52.05; H, 7.21. Found: C,
52.32; H, 6.94.
80%): TLC Rf ) 0.19 (CH2Cl2/Et2O/hexane ) 35:15:50); [R]20
D
+166.3 (c 0.22, CHCl3); 1H NMR δ 0.00 (s, 9H), 0.80-0.91 (m,
2H), 1.10-1.45 (m, 3H), 1.24 (t, 3H, J ) 7.1 Hz), 1.50-1.65
(m, 1H), 2.19 (ddd, 1H, J ) 7.4, 7.4, 9.1 Hz), 2.43 (s, 3H), 4.11
(q, 2H, J ) 7.1 Hz), 7.32 (d, 2H, J ) 8.1 Hz), 7.48 (d, 2H, J )
8.1 Hz); 13C NMR δ -0.9, 14.0, 14.2, 14.6, 20.6, 21.4, 23.1, 60.7,
66.0, 125.1, 129.6, 139.3, 141.4, 173.1; IR (KBr) 1730, 1090
cm-1; SIMS m/z (rel intensity) 352.2 (M+, 5), 212.2 (41), 93.2
(100). Anal. Calcd for C18H28O3SSi: C, 61.32; H, 8.00. Found:
C, 61.49; H, 8.17.
Eth yl (RS,1S,2S)-2-[(1R)-1-(p-Tolylsu lfin yl)-2-(tr im eth -
ylsilyl)eth yl]cyclobu ta n eca r boxyla te (11b). (1) Rea ction
w ith Eth yl 5-Br om o-2-p en ten oa te. To a solution of diiso-
propylamine (0.045 mL, 0.320 mmol) in THF (0.30 mL) was
added n-butyllithium (1.49 mol L-1, 0.190 mL, 0.283 mmol)
at 0 °C, and the mixture was stirred for 10 min. The reaction
mixture was then cooled to -78 °C, and a solution of the
sulfoxide 1 (54.0 mg, 0.225 mmol) in THF (0.23 mL) was added.
After the mixture was stirred for 5 min, a solution of ethyl
5-bromo-2-pentenoate (81.6 mg, 0.394 mmol) in THF (0.20 mL)
and subsequently HMPA (0.05 mL, 0.297 mmol) were added.
The mixture was warmed to room temperature and stirred for
15 min. Usual workup gave a residue that was purified by
column chromatography (silica gel 12 g, hexane/ethyl acetate
) 85:15) to give 11b (40.3 mg, 49%) and 12b (X ) Br) (29.6
Eth yl (RS,1S,2S)-2-[(1R)-1-(p-Tolylsu lfin yl)-2-(tr im eth -
ylsilyl)eth yl]cycloh exa n eca r boxyla te (11d ). To a solution
of diisopropylamine (0.080 mL, 0.562 mmol) in THF (0.56 mL)
was added n-butyllithium (1.49 mol L-1, 0.36 mL, 0.536 mmol)
at 0 °C, and the mixture was stirred for 10 min. The reaction
mixture was then cooled to -78 °C. A solution of the sulfoxide
1 (103.6 mg, 0.431 mmol) in THF (0.40 mL) was added, and
the mixture was stirred for 5 min. The solution of ethyl
6-bromo-2-hexenoate (144.6 mg, 0.615 mmol) in THF (0.50 mL)
was added, and the mixture was stirred for an additional 15
min. The cooling bath was changed to an ice-water bath, and
the mixture was stirred for 15 min at 0 °C. Usual workup gave
a reduced pressure to leave an oil that was purified by column
chromatography (silica gel 15 g, hexane/ethyl acetate ) 80:
20) to give 11d (158.4 mg, 93%) and 12d (X ) Br) (15.5 mg,
mg, 29%). 11b: TLC Rf ) 0.40 (CH2Cl2/Et2O ) 97:3); [R]20
D
+145.0 (c 0.65, CHCl3); 1H NMR δ -0.18 (s, 9H), 0.62 (dd, 1H,
J ) 9.1, 15.4 Hz), 0.78 (dd, 1H, J ) 3.7, 15.4 Hz), 1.28 (t, 3H,
J ) 7.1 Hz), 1.95-2.28 (m, 4H), 2.41 (s, 3H), 2.61 (ddd, 1H, J
) 3.7, 5.8, 9.1 Hz), 2.80-3.01 (m, 1H), 3.30-3.50 (m, 1H), 4.16
(q, 2H, J ) 7.1 Hz), 7.34 (d, 2H, J ) 7.1 Hz), 7.39 (d, 2H, J )
7.1 Hz); 13C NMR δ -1.4, 8.2, 14.3, 21.3, 21.7, 22.2, 41.8, 41.9,
60.5, 66.0, 124.3, 129.7, 130.2, 139.4, 178.2; IR (neat) 1730,
1090 cm-1; SIMS m/z (rel intensity) 226.2 (69), 185.0 (42), 91.0
(100). Anal. Calcd for C19H30O3SSi: C, 62.24; H, 7.85. Found:
C, 62.46; H, 7.99. 12b (X ) Br): TLC Rf ) 0.25 (CH2Cl2/Et2O
1
) 97:3); H NMR δ -0.17 (s, 9H), 0.68-1.02 (m, 2H), 1.32 (t,
3H, J ) 7.1 Hz), 1.90 (ddd, 1H, J ) 5.8, 10.8, 19.7 Hz), 2.28-
2.45 (m, 2H), 2.40 (s, 3H), 2.47-2.89 (m, 3H), 3.40 (ddd, 1H,
J ) 5.2, 10.8, 11.0 Hz), 3.62 (ddd, 1H, J ) 4.5, 5.8, 11.0 Hz),
4.20 (q, 2H, J ) 7.1 Hz), 7.30 (d, 2H, J ) 7.3 Hz), 7.38 (d, 2H,
J ) 7.3 Hz); 13C NMR δ -1.5, 8.0, 14.3, 21.3, 31.5, 32.3, 37.3,
60.9, 66.2, 124.1, 129.7, 139.9, 140.7, 172.1; IR (neat) 1740,
1090 cm-1; SIMS m/z (rel intensity) 448.1 (M+ + 2, 18), 446.1
(M+, 18), 308.1 (100), 306.1 (100). Anal. Calcd for C19H31BrO3-
SSi: C, 50.99; H, 6.98. Found: C, 51.17; H, 6.70.
7%). 11d : TLC Rf ) 0.49 (hexane/ethyl acetate ) 70:30); [R]20
D
+34.1 (c 0.346, CHCl3); 1H NMR δ -0.14 (s, 9H), 0.56 (dd, 1H,
J ) 2.7, 15.0 Hz), 1.03 (dd, 1H, J ) 11.9, 15.0 Hz), 1.32 (t, 3H,
J ) 7.1 Hz), 1.15-2.10 (m, 9H), 2.40 (s, 3H), 2.51 (ddd, 1H, J
) 2.4, 2.7, 11.9 Hz), 2.99 (ddd, 1H, J ) 3.8, 11.3, 11.3 Hz),
4.19 (q, 2H, J ) 7.1 Hz), 7.29 (d, 2H, J ) 8.3 Hz), 7.37 (d, 2H,
J ) 8.3 Hz); 13C NMR δ -1.4, 6.8, 14.3, 21.3, 25.3, 25.9, 26.2,
30.5, 42.8, 48.4, 60.5, 66.9, 124.0, 129.5, 140.3, 140.4, 175.4;
IR (KBr) 1720, 1050 cm-1; SIMS m/z (rel intensity) 394.2 (M+,
10), 254.2 (100). Anal. Calcd for C21H34O3SSi: C, 63.91; H, 8.68.
Found: C, 64.18; H, 8.51. 12d (X ) Br): TLC Rf ) 0.38
(hexane/ethyl acetate ) 70:30); 1H NMR δ -0.15 (s, 9H), 0.69
(dd, 1H, J ) 3.1, 15.4 Hz), 0.88 (dd, 1H, J ) 11.0, 15.0 Hz),
1.31 (t, 3H, J ) 7.1 Hz), 1.20-1.95 (m, 7H), 2.20-2.40 (m, 1H),
(2) Rea ction w ith Eth yl 5-Iod o-2-p en ten oa te. The reac-
tion was carried out as described above using 1 (48.0 mg, 0.200
mmol), ethyl 5-iodo-2-pentenoate (70.2 mg, 0.272 mmol), and
HMPA (0.045 mg, 0.259 mmol). Purification by column chro-
matography (silica gel 10 g, hexane/ethyl acetate ) 85:15)

1766 J . Org. Chem., Vol. 65, No. 6, 2000
Nakamura et al.
2.41 (s, 3H), 2.66-2.85 (m, 2H), 3.44 (m, 2H), 4.19 (q, 2H, J )
7.1 Hz), 7.30 (d, 2H, J ) 7.4 Hz), 7.38 (d, 2H, J ) 7.4 Hz); IR
(neat) 1730, 1280, 1040 cm-1; SIMS m/z (rel intensity) 476.1
(M+ + 2, 1), 474.1 (M+, 5), 336.1 (32), 334.1 (100). Anal. Calcd
for C21H35BrO3SSi: C, 53.04; H, 7.42. Found: C, 52.82; H, 7.64.
12d (X ) I): TLC Rf ) 0.38 (hexane/ethyl acetate ) 70:30);
1H NMR δ -0.15 (s, 9H), 0.69 (dd, 1H, J ) 3.0, 15.2 Hz), 0.88
(dd, 1H, J ) 11.0, 15.2 Hz), 1.31 (t, 3H, J ) 7.1 Hz), 1.20-
2.50 (m, 8H), 2.20-2.40 (m, 1H), 2.41 (s, 3H), 2.63-2.83 (m,
2H), 3.17-3.28 (m, 2H), 4.19 (q, 2H, J ) 7.1 Hz), 7.28 (d, 2H,
J ) 7.8 Hz), 7.36 (d, 2H, J ) 7.8 Hz); IR (neat) 1730, 1220,
1070 cm-1; SIMS m/z (rel intensity) 522.1 (M+, 2), 382.1 (60),
149.1 (100). Anal. Calcd for C21H35IO3SSi: C, 48.27; H, 6.75.
Found: C, 48.01; H, 6.55.
Ack n ow led gm en t. We thank Dr. Shinya Kusuda,
Ono Pharmaceutical Co., Ltd., for X-ray crystallographic
analysis. This work was partly supported by a Grant-
in Aid for Scientific Research (no. 11650890) from the
Ministry of Education, Science and Culture of J apan.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic char-
acterization for the products 3a ,c,d , 4b,c, 5a -d , 6a -c,e-h ,
13a -f, and 14a -i and X-ray crystallographic data for 11a ,c
and the hydrolyzed 11d . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O991635N