Asymmetric intramolecular Michael addition of α-sulfinyl vinylic carbanion to enoates

Article abstract of DOI:10.1021/jo0492923

The first example of an asymmetric intramolecular Michael addition reaction with use of α-lithiated vinylic sulfoxide as a Michael donor is reported. Michael addition of the α-lithiated vinylic sulfoxide to (Z)-enoates proceeds with high diastereoselectiv

Full text of DOI:10.1021/jo0492923

Asym m etr ic In tr a m olecu la r Mich a el Ad d ition of r-Su lfin yl Vin ylic
Ca r ba n ion to En oa tes
Naoyoshi Maezaki,† Hiroaki Sawamoto,† Sachiko Yuyama,† Ryoko Yoshigami,†
Tomoko Suzuki,† Mayuko Izumi,† Hirofumi Ohishi,‡ and Tetsuaki Tanaka*,†
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
Suita, Osaka 565-0871, J apan, and Osaka University of Pharmaceutical Sciences,
4-20-1 Nasahara, Takatsuki, Osaka 569-11, J apan
t-tanaka@phs.osaka-u.ac.jp
Received April 28, 2004
The first example of an asymmetric intramolecular Michael addition reaction with use of R-lithiated
vinylic sulfoxide as a Michael donor is reported. Michael addition of the R-lithiated vinylic sulfoxide
to (Z)-enoates proceeds with high diastereoselectivity to give the adducts with (R)-configuration at
the â-position of the ester in the five-membered-ring formation. The selectivity was reversed in
the six-membered-ring formation. The resulting ester enolates were reacted with alkyl halides or
benzaldehyde with high diastereoselectivity.
In tr od u ction
Resu lt a n d Discu ssion
Asym m etr ic In tr a m olecu la r Mich a el Ad d ition of
r-Su lfin yl Vin ylic Ca r ba n ion . We initially examined
the intramolecular Michael addition of four geometric
isomers of the vinylic sulfoxide 1a (Table 1) and found
that the diastereoselectivity of the Michael addition was
significantly affected by the geometry of the enoate but
not the vinylic sulfoxide. That is, upon treatment of the
(E)-enoate (2E,6E)-1a with 1.5 equiv of LDA in THF at
-78 °C, deprotonation of the R-sulfinyl proton and
intramolecular Michael addition of the resulting carban-
ion to the enoate took place rapidly, giving the γ,δ-
unsaturated esters (1′R)- and (1′S)-2a almost without
selectivity (entry 1). In contrast, the intramolecular
Michael addition of the corresponding (Z)-enoate (2Z,6E)-
1a proceeded with very high diastereoselectivity to give
the Michael adduct (1′R)-2a as a single isomer (entry 2).
Products arising from deprotonation at the R-, â-, or
γ-positions of the enoates were not detected at all.
Since R-sulfinyl carbanions generated from (Z)-â-
monosubstituted vinylic sulfoxides are known to isomer-
ize to the thermodynamically more stable (E)-isomer,2,6
we expected that intramolecular Michael addition of (Z)-
vinylic sulfoxides would proceed via (Z)- to (E)-isomer-
ization. However, reaction of the (Z)-vinylic sulfoxides
was sluggish, affording the cyclized products (1′R)- and
(1′S)-2a in poor yield (entries 3 and 4). It should be noted
that the (Z)-enoate (2Z,6Z)-1a showed higher selectivity
than the corresponding (E)-isomer (2E,6Z)-1a even in the
Asymmetric carbon-carbon bond formation is an at-
tractive subject in organic chemistry. Vinylic sulfoxides
have played an important role as a well-known chiral
Michael acceptor.1 In contrast, the application of vinylic
sulfoxide as a “Michael donor” has remained unexplored
for a long time, although generation of R-sulfinyl vinylic
carbanions by R-deprotonation of vinylic sulfoxides was
found more than two decades ago.2 Attempts to employ
the vinyl anion species for asymmetric reaction resulted
in moderate to poor diastereoselectivity,3 except for one
example.4 Recently, we have reported that an intramo-
lecular Michael addition reaction of the R-lithiated vinylic
sulfoxides to enoates proceeds with extremely high di-
astereoselectivity, giving functionalized cyclopentene and
cyclohexene derivatives.5
In this paper, we describe full details of the asymmetric
intramolecular Michael addition, especially the reactivity
and generality of stereochemistry for various substrates.
We also describe two or three asymmetric inductions in
one pot utilizing reactions of the resulting enolates with
electrophiles.
† Osaka University.
‡ Osaka University of Pharmaceutical Sciences.
(1) For review, see: Carren˜o, M. C. Chem. Rev. 1995, 95, 1717-
1760.
(2) Posner, G. H.; Tang, P.-W.; Mallamo, J . P. Tetrahedron Lett.
1978, 42, 3995-3998. Okamura, H.; Mitsuhira, Y.; Miura, M.; Takei,
H. Chem. Lett. 1978, 517-520.
(3) Fawcett, J .; House, S.; J enkins, P. R.; Lawrence, N. J .; Russell,
D. R. J . Chem. Soc., Perkin Trans. 1 1993, 67-73 and references
therein. Haynes, R. K.; Katsifis, A. G. Aust. J . Chem. 1989, 42, 1473-
1483. Haynes, R. K.; Katsifis, A. G. J . Chem. Soc., Chem. Commun.
1987, 340-342.
(6) Maezaki, N.; Izumi, M.; Yuyama, S.; Sawamoto, H.; Iwata, C.;
Tanaka, T. Tetrahedron 2000, 56, 7927-7945. Maezaki, N.; Izumi, M.;
Yuyama, S.; Iwata, C.; Tanaka, T. Chem. Commun. 1999, 1825-1826.
Posner, G. H. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic
Press: New York, 1983; Vol. 2A, pp 225-241. Schmidt, R. R.; Speer,
H.; Schmid, B. Tetrahedron Lett. 1979, 4277-7280.
(4) Solladie´, G.; Moine, G. J . Am. Chem. Soc. 1984, 106, 6097-6098.
(5) Maezaki, N.; Yuyama, S.; Sawamoto, H.; Suzuki, T.; Izumi, M.;
Tanaka, T. Org. Lett. 2001, 3, 29-31.
10.1021/jo0492923 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/20/2004
J . Org. Chem. 2004, 69, 6335-6340
6335

Maezaki et al.
TABLE 1. Effects of Olefin Geom etr y on In tr a m olecu la r Mich a el Ad d ition a
yield (%)b
vinylic
entry
substrate
enoate
sulfoxide
solvent
(1′R)-2
(1′S)-2
dr (1′R:1′S)
1
2
3
4
5
6
7
8
9
(2E,6E)-1a
(2Z,6E)-1a
(2E,6Z)-1a
(2Z,6Z)-1a
(2Z,6E)-1a
(2Z,6E)-1a
(2Z,6E)-1a
(2Z,6E)-1a
(2Z,6E)-1a
E
Z
E
Z
Z
Z
Z
Z
Z
E
E
Z
Z
E
E
E
E
E
THF
THF
THF
THF
toluene
ether
DMEc
THFc
THFd
44
71
12
19
33
20
37
30
0
40
0
10
0
8
4
8
4
0
52:48
100:0
55:45
100: 0
80:20
83:17
82:18
88:12
a
b
All reactions were carried out with LDA (1.5 equiv) at -78 °C unless otherwise cited. Isolated yield. c Reaction was carried out at
d
-40 °C. Reaction was carried out at 0 °C.
TABLE 2. F ive-Mem ber ed Rin g F or m a tion by
In tr a m olecu la r Mich a el Ad d ition a
reaction of (Z)-vinylic sulfoxides. The reaction was con-
siderably affected by the solvent. The best solvent was
THF. Other solvents such as toluene, ether, and DME
significantly reduced the yield (entries 5-7). The reaction
should be carried out at low temperature, since the
reaction at higher temperature (-40 °C) was sluggish,
giving (1′R)- and (1′S)-2a in 30% and 4% yields, respec-
tively (entry 8). At 0 °C, the reaction afforded a complex
mixture (entry 9).
To examine the generality of this reaction, intramo-
lecular Michael addition of several vinylic sulfoxides was
investigated. The results are summarized in Table 2. The
size of the ester moiety showed significant effects on the
yield, but not the selectivity (entries 1-4), wherein the
reactions proceeded with excellent diastereoselectivity,
yielding five-membered-ring adducts with predominance
of the (R)-isomer. However, the yield was decreased
depending on the bulkiness of the ester moiety, in the
order Me > Et > i-Pr . t-Bu. Introduction of geminal
methyl groups on the alkyl chain improved the yield
presumably due to a geminal substituent effect.7 Thus,
the (Z)-enoate (2Z)-1e afforded (1′R)-2e in 89% yield with
high diastereoselectivty (entry 5), but the corresponding
(E)-enoate (2E)-1e provided (1′R)-2e in 49% yield with
poor diastereoselectivity (entry 6). The selectivity was
reduced in the reaction of â,â-disubstituted vinylic sul-
foxide 1f (entry 7). Asymmetric Michael addition was
conducted on γ-oxygenated vinylic sulfoxide 1g, which
could undergo elimination of the oxygen. The cyclized
product (1′R)-2g was obtained in 71% yield with excellent
diastereoselectivity (entry 8).
a
All reactions were carried out with LDA (1.5 equiv) in THF
at -78 °C. Isolated yield unless otherwise stated. c Combined
b
yield of (1′R)- and (1′S)-2. Determined by 1H NMR spectroscopic
d
data on the basis of the signals due to the olefinc proton of vinylic
sulfoxide.
In a six-membered ring formation, the stereochemistry
of the enoate moiety affected the diastereoselectivity
(Table 3). In contrast to the fact that the reaction with
(Z)-enoate (2Z)-1h proceeded with very high selectivity
(entry 1), the selectivity for the corresponding (E)-enoate
(2E)-1h was very poor (entry 2). Interestingly, structural
determination of the product revealed that the selectivity
was completely reversed, giving the (1′S)-isomer pre-
dominately. Functionalized substrates 1i-k also fur-
nished the cyclized products with an (S)-carbon stereo-
center with high diastereoselectivity (entries 3-5). An
attempt for seven-membered ring formation failed, giving
a complex mixture (entry 6).
The absolute configuration of the major products (1′R)-
2a and (1′S)-2h was determined by the PGME (phenyl-
glycine methyl ester) method8 after conversion into the
corresponding (R)- and (S)-PGME amides 3a -d by hy-
(8) (a) Yabuuchi, T.; Kusumi, T. J . Org. Chem. 2000, 65, 397-404.
(b) For recent review, see: Seco, J . M.; Quin˜oa´, E.; Riguera, R. Chem.
Rev. 2004, 104, 17-117.
(7) Review: J ung, M. E. Synlett 1999, 843-846.
6336 J . Org. Chem., Vol. 69, No. 19, 2004

Asymmetric Intramolecular Michael Addition
TABLE 3. Six-m em ber ed Rin g F or m a tion by th e
In tr a m olecu la r Mich a el Ad d ition Rea ction a
SCHEME 1
TABLE 4. Effects of Ad d itives on In tr a m olecu la r
Mich a el Ad d ition of (2Z,6E)-1a a
yield (%)b
entry
additive (equiv)
(1′R)-2
(1′S)-2
dr (1′R:1′S)
1
2
3
4
5
6
none
71
52
33
21
51
45
0
8
7
11
7
16
100: 0
87:13
83:17
66:34
88:12
74:26
HMPA (0.2)
HMPA (1)
HMPA (5)
TMEDA (1)
LiI (2)
a
All reactions were carried out with LDA (1.5 equiv) in THF
b
at -78 °C. Isolated yield.
known to solvate the metal cation and disrupt the weak
chelation, caused a dose-dependent decrease of both yield
and diastereoselectivity (Table 4, entries 1-4). Addition
of TMEDA and LiI showed effects similar to those of
HMPA on the yield and selectivity (entries 5 and 6).
These results indicate that reagents disrupting the
chelation cause remarkable decrease of the yield and
selectivity. Although details of the reaction mechanism
are not clear, chelation seems to play some important
role for diastereoselectivity as well as reactivity.
On e-P ot Tw o or Th r ee Asym m etic In d u ction s by
In tr am olecu lar Mich ael Addition Followed by Tr ap-
p in g w ith Electr op h iles. The intramolecular Michael
addition of R-sulfinyl vinyl carbanion generates a new
anion species, which is expected to react with electro-
philes diastereoselectively, providing two stereocenters
in a one-pot operation reaction.
After cyclization of vinylic sulfoxide (2Z,6E)-1a , the
resulting enolate was trapped with MeI. Methylation
proceeded in a stereoselective fashion, giving 5a with
(1′R,2R)-configuration predominantly along with a trace
of its C2-epimer 6a (Table 5, entry 1). In contrast to
intramolecular Michael addition, the reaction was not
influenced by the addition of a chelating agent (entry 2).
The chelation seems not to play an important role in the
alkylation, which proceeds at higher temperature than
the intramolecular Michael addition. The same diaste-
reoselectivity was observed with other alkyl halides
(entries 3-5). However, secondary alkyl iodide did not
react with the enolate (entry 6).
a
All reactions were carried out with LDA (2.5 equiv) in THF
at -78 °C. Isolated yield. c 1.5 equiv of LDA was used.
b
drolysis of the esters (LiOH in aqueous MeOH) followed
by condensation with (R)- or (S)-PGME (PyBOP, HOBT,
and N-methylmorpholine). The 1H NMR spectroscopic
data revealed that the amides 3a -d are enantiomerically
pure and no loss of optical purity was observed during
the cyclization. The assignment was also confirmed by
transformation of (1′S)-2a and (1′S)-2h into known acids
4a and 4b (Scheme 1).9 The configuration of products 2e,
2j, and 2k was assigned by the PGME method. Those of
other products were assumed by comparison of 1H NMR
spectral data.
To clarify the reaction mechanism, the cyclized prod-
ucts (1′R)- and (1′S)-2a were treated with 1.5 equiv of
LDA at -78 °C for 30 min, and then the reaction was
quenched by regular workup. This operation resulted in
complete recovery of the starting materials, wherein
neither the retro-Michael reaction nor C2-epimerization
via recyclization was observed. The results suggest that
the intramolecular Michael addition is irreversible and
kinetically controlled. We examined the effect of reagents
affecting coordination of the sulfoxide on the intramo-
lecular Michael addition. Addition of HMPA, which is
The absolute configuration of methylated product 5a
was unambiguously confirmed by X-ray single-crystal
analysis. The assignment was consistent with the results
of the PGME method.8 The absolute configuration of the
other products 5b-d was determined by the PGME
method.
(9) (a) Mislow, K.; Steinberg, I. V. J . Am. Chem. Soc. 1955, 77, 3807-
3810. (b) Takano, S.; Yamada, O.; Iida, H.; Ogasawara, K. Synthesis
1994, 592-596. In the case of compound 4a , considerable loss of optical
purity during derivatization was observed presumably as a result of
26
strong alkaline conditions in the desulfurization reaction [4a : [R]D
+78.0 (lit.10b [R]D +107.4); 4b: [R]D +81.9 (lit.10b [R]D +84.4)].
30
26
30
J . Org. Chem, Vol. 69, No. 19, 2004 6337

Maezaki et al.
TABLE 5. In tr a m olecu la r Mich a el Ad d ition F ollow ed
by Alk yla tion a
entry
RX
product
yield of 5 (%)b
dr (5:6)c
F IGURE 1. Plausible reaction mechanism for diastereose-
1
2
3
4
5
6
MeI
MeI, HMPA
BnBr
AllylBr
MOMCl
i-PrI
5a /6a
5a /6a
5b/6b
5c/6c
5d /6d
62
48
54
50
45
trace
96:4
95:5
97:3
98:2
95:5
lective alkylation of enolate.
SCHEME 2
a
All reactions were carried out with LDA (1.5 equiv) and RX
(5 equiv) in THF at -78 °C. Isolated yield. c Determined by 1H
NMR spectroscopic data on the basis of the signals due to the
olefinc proton of vinylic sulfoxide.
b
TABLE 6. In tr a m olecu la r Mich a el Ad d ition F ollow ed
by Ald ol Rea ction a
configuration of the C3 position was determined by the
modified Mosher method,11 and that of the C1′ position
was assumed from the results of protonation and alkyl-
ation.
PhCHO
(equiv)
yield (%)b
7a + 7b
entry
temp (°C)
dr (7a :7b)
It was found that both products, 7a and 7b, have
(1′R,2S) configuration. The ratio of C3-epimers was
variable depending on the reaction temperature.
Diastereoselectivity of the alkylation can be explained
as follows. The sterically less demanding enolate inter-
mediate I would be more stable than intermediate II
(Figure 1). The alkylation proceeded from the opposite
side of the sulfinyl group in intermediate I, giving 5a -d
preferentially. Taking into account the fact that the
chelating reagent had no effect on the selectivity, chela-
tion would not always be necessary to rigidify the
conformation at 0 °C.
Benzaldehyde also approaches from the same side of
the enolate intermediate II to afford the aldols with
(1′R,2S) configuration. High selectivity at high temper-
ature presumably is attributed to isomerization from 7b
to the stable product 7a via retro-aldol reaction.
1
2
3
4
-78
5
5
63
60
58
29
1:1.3c
13:1d
0
0
0
2
25:1d
5e
3.4:1c
a
All reactions were carried out with LDA (1.5 equiv) in THF
at -78 °C. Combined yield of 7a and 7b . c Determined by 1H
b
NMR spectroscopic data on the basis of the signals due to the
olefinc proton of vinylic sulfoxide. Determined by HPLC. e 5 equiv
d
of HMPA was added.
Then, we examined intramolecular Michael reaction
followed by aldol reaction with benzaldehyde, wherein
three stereocenters were constructed in a one-pot reac-
tion.
Vinylic sulfoxide (2Z,6E)-1a was treated with LDA (1.5
equiv) and then the reaction was quenched with benzal-
dehyde at -78 °C (5 equiv) to give the adducts 7a and
7b as shown in Table 6. Interestingly, diastereoselectivity
of the aldol reaction was remarkably improved at high
temperature.
Con clu sion
We have found that the intramolecular Michael addi-
tion of the R-sulfinyl vinylic carbanion proceeds with
excellent selectivity. (Z)-Configuration of the enoate was
essential to achieve the high diastereoselectity. While
five-membered ring formation afforded (1′R)-adducts, the
reversed selectivity was observed in the six-membered
The relative stereochemistry at the C2 and C3 posi-
tions was confirmed as shown in Scheme 2. Since
separation of the adducts 7a and 7b was difficult, a
mixture of them was reduced to sulfides 8a and 8b.
Reduction to diol followed by acetalization converted 8a
and 8b into acetonides 9a and 9b, respectively. Com-
parison of coupling constants between C4 and C5 protons
1
(10) The relation of the diastereomers 7a ,b and 8a ,b were confirmed
by reduction of almost pure 7a into 8a .
(11) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096. For a recent review, see ref 8b.
in the H NMR spectral data for 9a (J ) 3.1 Hz) and 9b
(J ) 11.6 Hz) revealed that the adducts, 7a and 7b, were
assigned as anti and syn, respectively.10 The absolute
6338 J . Org. Chem., Vol. 69, No. 19, 2004

Asymmetric Intramolecular Michael Addition
143.5, 146.8, 172.4. IR 3334, 1732, 1010. MS (FAB) m/z 385
(MH+). HRMS (FAB) calcd for C22H25O4S 385.1474, found
385.1472.
ring formation. The resulting enolates were trapped
diastereoselectivly with alkyl halide and benzaldehyde,
giving two or three contiguous stereocenters in a one-
pot reaction.
Meth yl (2S,3S)-3-P h en yl-2-[(1R)-2-(p-tolylth io)-2-cyclo-
p en ten yl]-3-(2,2,2-tr iflu or oa cetoxy)p r op a n oa te (8a ) a n d
Meth yl (2S,3R)-3-P h en yl-2-[(1R)-2-(p-tolylth io)-2-cyclo-
p en ten yl]-3-(2,2,2-tr iflu or oa cetoxy)p r op a n oa te (8b). (CF3-
CO)2O (0.160 mL, 1.14 mmol) was added to a mixture of the
sulfoxides 7a and 7b (112 mg, 0.292 mmol, 7a :7b ) 1:1.3) and
NaI (127 mg, 1.02 mmol) in acetone (2 mL) with stirring at 0
°C and the stirring was continued at the same temperature
for 5 min. The reaction was quenched with saturated NaHCO3
and the mixture was extracted with Et2O. The extract was
washed with saturated Na2S2O3, saturated NaHCO3, and brine
prior to drying and solvent evaporation. The residue was
chromatographed on silica gel with hexanes-EtOAc (40:1) to
give 8a (57.1 mg, 42%) as a colorless powder and 8b (64.3 mg,
Exp er im en ta l Section
Melting points are uncorrected. NMR spectra were recorded
in CDCl3 solution at 500 MHz (1H) and 125, 75, or 67.8 MHz
(13C). IR absorption spectra (FT: diffuse reflectance spectro-
scopy) were recorded with KBr powder, and only noteworthy
absorptions (cm-1) are listed. Column chromatography was
carried out with Merck silica gel 60 (70-230 mesh) or Kanto
Chemical silica gel 60N (spherical, neutral, 63-210 µm). All
air- or moisture-sensitive reactions were carried out in flame-
dried glassware under an atmosphere of Ar or N2. All solvents
were dried and distilled according to standard procedures. All
organic extracts were dried over anhydrous MgSO4, filtered,
and concentrated with a rotary evaporator under reduced
pressure. The general procedure of intramolecular Michael
addition and characterization data of the vinyl sulfoxides (1′R)-
and (1′S)-2a 12-c, 2h , and the PGME amides 3a -d were given
in the Supporting Information of ref 5.
48%) as a yellow oil. 8a : Mp 79.3-81.0 °C (MeOH). [R]26
D
-73.0 (c 1.82, CHCl3). 1H NMR δ 2.14-2.22 (m, 1H), 2.15-
2.39 (m, 3H), 2.32 (s, 3H), 3.26-3.32 (m, 1H), 3.42 (s, 3H), 3.49
(dd, J ) 11.0, 3.1 Hz, 1H), 5.74-5.78 (m, 1H), 6.47 (d, J )
11.0 Hz, 1H), 7.12 (d, J ) 7.9 Hz, 2H), 7.26 (d, J ) 7.9 Hz,
2H), 7.29-7.36 (m, 3H), 7.40 (dd, J ) 7.9, 1.8 Hz, 2H). 13C
NMR δ 21.0, 28.1, 31.2, 46.1, 51.7, 54.0, 78.6, 114.2 (q, J C,F
)
284 Hz), 127.5, 128.6, 129.2, 129.9, 129.9, 131.1, 134.8, 136.8,
137.2, 137.3, 156.0 (q, J C,F ) 42 Hz), 170.8. IR 1786, 1149. MS
(EI) m/z (%) 464 (M+, 71.8), 167 (100). HRMS (EI) calcd for
Gen er a l P r ocu d u r e of In tr a m olecu la r Mich a el Ad d i-
tion F ollow ed by Alk yla tion : Meth yl (2R)-2-[(1R)-2-[(R)-
(p-Tolylsu lfin yl)]-2-cyclop en ten yl]p r op a n oa te (5a ). A so-
lution of LDA (2.0 M in heptane/THF/ethylbenzene) (0.195 mL,
0.390 mmol) was added to a solution of the enoate (2Z,6E)-1a
(72.4 mg, 0.260 mmol) in THF (4 mL). After 20 min, MeI (83
µL, 1.30 mmol) was added to the mixture and the whole was
stirred at 0 °C for 30 min. The reaction was quenched with
saturated NH4Cl and the solvent was evaporated. The residue
was dissolved with EtOAc and washed with brine prior to
drying and solvent evaporation. The residue was chromato-
graphed on silica gel with hexanes-EtOAc (2:1) to give 5a
(47.4 mg, 62%) as a colorless powder. Mp 67.0-68.5 °C
(hexanes-EtOAc). [R]25D +63.1 (c 1.43, CHCl3). 1H NMR δ 1.09
(d, J ) 7.3 Hz, 3H), 1.82 (dddd, J ) 16.5, 8.5, 4.9, 3.7 Hz, 1H),
1.95 (ddt, J ) 16.5, 9.8, 7.3 Hz, 1H), 2.35-2.56 (m, 2H), 2.42
(s, 3H), 3.22 (qd, J ) 7.3, 3.1 Hz, 1H), 3.24-3.31 (m, 1H), 3.62
(s, 3H), 6.55 (m, 1H), 7.32 (d, J ) 7.9 Hz, 2H), 7.49 (d, J ) 7.9
Hz, 2H). 13C NMR δ 10.2, 21.4, 25.7, 32.3, 41.0, 45.6, 51.6,
124.4, 129.8, 139.0, 141.0, 142.4, 147.2, 175.5. IR 1732, 1043.
MS (EI) m/z (%) 292 (M+, 1.1), 153 (100). HRMS (EI) calcd for
C
24H23F3O4S (M+) 464.1269, found 464.1268. 8b: [R]26D -36.4
1
(c 1.43, CHCl3). H NMR δ 2.04 (dddd, J ) 13.4, 8.5, 3.7, 3.1
Hz, 1H), 2.12 (dtd, J ) 13.4, 9.2, 8.9 Hz, 1H), 2.18-2.32 (m,
2H), 2.34 (s, 3H), 2.79-2.85 (m, 1H), 3.69 (s, 3H), 3.37 (dd, J
) 9.8, 3.1 Hz, 1H), 5.53-5.56 (m, 1H), 6.57 (d, J ) 9.8 Hz,
1H), 7.12 (d, J ) 7.9 Hz, 2H), 7.23 (d, J ) 7.9 Hz, 2H), 7.27-
7.36 (m, 5H). 13C NMR δ 21.1, 29.5, 31.2, 45.7, 51.9, 54.6, 78.9,
114.4 (q, J C,F ) 284 Hz), 127.9, 128.6, 129.2, 130.0, 130.1, 131.4,
134.6, 135.7, 136.6, 137.4, 155.9 (q, J C,F ) 41 Hz), 171.3. IR
1790, 1740. MS (EI) m/z (%) 464 (M+, 71.8), 464 (100). HRMS
(EI) calcd for C24H23F3O4S (M+) 464.1269, found 464.1261.
(4S,5R)-2,2-Dim eth yl-4-p h en yl-5-[(1R)-2-(p-tolylth io)-2-
cyclop en ten yl]-1,3-d ioxa n e (9a ). The sulfide 8a (33.7 mg,
0.0726 mmol) was added to a suspension of LiAlH4 (13.8 mg,
0.36 mmol) in THF (0.5 mL) with stirring at 0 °C and the
stirring was continued at the same temperature for 5 min. The
reaction was quenched with saturated NH4Cl and the mixture
was extracted with EtOAc. The extract was washed with water
and brine prior to drying and solvent evaporation. The residue
(27.7 mg) was dissolved with EtOAc (2 mL) and PPTS (0.4
mg, 2 µmol) and 2-methoxypropene (9 µL, 0.09 mmol) and the
whole was stirred at room temperature for 2 h. The reaction
was quenched with saturated NaHCO3 and the mixture was
extracted with EtOAc. The extract was washed with water and
brine prior to drying and solvent evaporation. The residue was
chromatographed on silica gel with hexanes-EtOAc (40:1) to
C
C
16H20O3S (M+) 292.1133, found 292.1129. Anal. Calcd for
16H20O3S: C, 65.72; H, 6.89; S, 10.97. Found: C, 65.70; H,
6.90; S, 10.90.
Meth yl (2S,3S)-3-Hyd r oxy-3-p h en yl-2-[(1R)-2-[(R)-(p-
tolylsu lfin yl)]-2-cyclop en ten yl]p r op a n oa te (7a ). A solu-
tion of LDA (2.0 M in heptane/THF/ethylbenzene) (54 µL, 0.11
mmol) was added to a solution of the enoate (2Z,6E)-1a (20.1
mg, 0.072 mmol) in THF (1 mL). After 20 min, PhCHO (37
µL, 0.36 mmol) was added to the mixture and the whole was
stirred at 0 °C for 30 min. The reaction was quenched with
saturated NH4Cl and the solvent was evaporated. The residue
was dissolved with EtOAc and washed with brine prior to
drying and solvent evaporation. The residue was chromato-
graphed on silica gel with hexanes-EtOAc (3:1) to give 7a
give 9a (15.1 mg, 55% in two steps) as a colorless oil. [R]27
D
1
-85.5 (c 0.72, CHCl3). H NMR δ 1.53 (s, 6H), 1.41-1.49 (m,
1H), 1.65-1.74 (m, 1H), 1.89-1.96 (m, 2H), 2.02 (dtd, J ) 5.5,
3.1, 1.8 Hz, 1H), 2.32 (s, 3H), 2.96-3.02 (m, 1H), 4.02 (dd, J )
12.2, 1.8 Hz, 1H), 4.19 (dd, J ) 12.2, 3.1 Hz, 1H), 5.15-5.18
(m, 1H), 5.26 (d, J ) 3.1 Hz, 1H), 7.09 (d, J ) 7.9 Hz, 2H),
7.15-7.31 (m, 5H), 7.38 (d, J ) 7.9 Hz, 2H). 13C NMR δ 19.2,
21.1, 29.5, 30.2, 30.6, 40.8, 45.9, 65.4, 73.5, 99.2, 125.9, 126.9,
127.8, 129.7, 130.5, 130.8, 132.4, 137.2, 140.7, 140.8. IR 1724.
MS (EI) m/z (%) 380 (M+, 65.8), 216 (100). HRMS (EI) calcd
for C24H28O2S (M+) 380.1810, found 380.1810.
(16.7 mg, 60%, 7a :7b ) 13:1) as a yellow oil. [R]27 -107.5 (c
D
0.26, CHCl3). 1H NMR δ 2.06-2.13 (m, 1H), 2.37-2.48 (m, 2H),
2.41 (s, 3H), 2.59-2.70 (m, 1H), 3.11 (dddd, J ) 11.0, 7.9, 4.9,
3.1 Hz, 1H), 3.29 (s, 3H), 3.51 (dd, J ) 10.4, 3.1 Hz, 1H), 5.00
(t, J ) 10.4 Hz, 1H), 5.06 (d, J ) 10.4 Hz, 1H), 6.64 (dd, J )
5.2, 2.4 Hz, 1H), 7.24 (t, J ) 7.3 Hz, 1H), 7.33 (t, J ) 7.3 Hz,
2H), 7.35 (d, J ) 8.5 Hz, 2H), 7.40 (d, J ) 7.3 Hz, 2H), 7.53 (d,
J ) 8.5 Hz, 2H). 13C NMR δ 21.2, 26.3, 31.7, 44.8, 51.2, 53.7,
72.2, 124.3, 126.5, 127.3, 128.1, 130.0, 137.0, 141.1, 143.4,
X-r a y An a lysis. Crystal data for 5a :
C16H20O3S, M )
292.38, monoclinic, space group P21, a ) 7.941(4) Å, b ) 7.367-
(4) Å, c ) 13.372(6) Å, R ) 90.0°, â ) 97.40°(4), γ ) 90.0°,
volume ) 775.8(7) Å3, Z ) 2, Dc ) 1.252 Mg m-3, µ ) 1.891
mm-1, crystal dimensions 0.4 × 0.1 × 0.02 mm3, F(000) ) 312,
T ) 293(2) K, θ ) 3.33-67.54°. 1868 reflections measured,
unique reflections 1485 [Rint ) 0.1380], min and max. Absorp-
tion correction factor 0.615 and 1.000, R1 ) 0.0734, wR2 )
(12) The HRMS of 3a reported in the Supporting Information of ref
5 is incorrect, and should be revised as follows: HRMS (FAB) calcd
for C23H26NO4S (MH+) 412.1583, found 412.1577.
J . Org. Chem, Vol. 69, No. 19, 2004 6339

Maezaki et al.
0.2116 for 1479 reflections with I > 2σ(I) and R1 ) 0.1187,
wR2 ) 0.2501 for all reflections and 84 refined parameters.
Final electron density 0.489 and -0.491 eÅ-3, S ) 1.490,
absolute Flack structure parameter -0.02(8).
The data set was collected on a Rigaku AFC5R diffracto-
meter with Cu‚KR radiation (λ ) 1.5418 Å). The structure was
solved by direct methods with SHELX-9713 and refined by full-
matrix least squares on F2 by SHELXL-97.14 Non-hydrogen
atoms were refined by the anisotropic temperature factor and
hydrogens were isotropic. The hydrogens were placed by the
riding method. The molecular views were realized by ORTEP-
III.15
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and characterization data for compounds 1a -1l,
2e-2g, 2i-2k , 4a , 4b, 5b-5d , and 9b. General procedure for
preparation of PGME amide. ORTEP drawing and CIF file for
5a . 1H NMR spectral data of compounds (1′R)-2e-2g, (4′S)-
2i, (1′S)-2j-k , 5a -5d , and 7a . This material is available free
of charge via the Internet at http://pubs.acs.org. Crystal and
data collection parameters have been deposited with the
Cambridge Crystallographic Data Center (CCDC-231930,
email: deposit@ccdc.cam.ac.uk).
(13) Sheldrick, G. M. SHELX97, Program for the Direct method for
Crystal Structures; University of Goettingen: Goettingen, Germany,
1997.
(14) Sheldrick, G. M. SHELXL97, Program for the Refinement of
Crystal Structures; University of Goettingen: Goettingen, Germany,
1997.
J O0492923
(15) Burnett, M. N.; J ohnson, C. K. ORTEP-III; Oak Ridge National
Laboratory: Oak Ridge, TN, 1996; Report ORNL-6895.
6340 J . Org. Chem., Vol. 69, No. 19, 2004