Stereocontrolled one-pot synthesis of cycloalkane derivatives possessing a quaternary carbon using allyl phenyl sulfone

Article abstract of DOI:10.1016/j.tet.2009.08.058

Stereocontrolled one-pot synthesis of cyclopentane derivatives possessing quaternary carbon using allyl phenyl sulfone and epoxyiodide was presented. Furthermore, application of this protocol to the synthesis of cycloalkane derivatives with different ring

Full text of DOI:10.1016/j.tet.2009.08.058

Tetrahedron 65 (2009) 8668–8676
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereocontrolled one-pot synthesis of cycloalkane derivatives possessing
a quaternary carbon using allyl phenyl sulfone
*
Koichiro Ota, Takao Kurokawa, Etsuko Kawashima, Hiroaki Miyaoka
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2009
Received in revised form 22 August 2009
Accepted 25 August 2009
Available online 28 August 2009
Stereocontrolled one-pot synthesis of cyclopentane derivatives possessing quaternary carbon using allyl
phenyl sulfone and epoxyiodide was presented. Furthermore, application of this protocol to the synthesis
of cycloalkane derivatives with different ring sizes was successful.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Allyl phenyl sulfone
One-pot synthesis
Cyclopentane
Cyclopropane
1. Introduction
stereocenters. In our laboratory, we have achieved the total syn-
thesis of marine eicosanoides bacillariolides3,4 and constanolactone
To date, a variety of carbon–carbon bond formation reactions
have been developed for the construction of carbon frameworks. In
particular, the use of alkylsulfones has frequently been employed to
synthesize medicinal and natural organic compounds since the
sulfonylcarbanion generated by an appropriate base readily facili-
tated carbon–carbon bond formation following reaction with alkyl
halide, epoxide, ester, acyl halide or aldehyde.1 We previously
reported on the one-pot synthesis of cycloalkane derivatives IVa
using allyl phenyl sulfone and disubstituted epoxide Ia having
a leaving group (X) via alkyl sulfone IIa and anion IIIa (Fig. 1).2 The
protocol we developed comprises a sequence of coupling and cy-
clization reactions. The sulfonylcarbanion generated from allyl
phenyl sulfone reacted with disubstituted epoxymesylate Ia
(X¼OMs) to afford epoxysulfone IIa, and was followed bycyclization
of regenerated sulfonylcarbanion IIIa by excess base in situ. Here, by
selecting an appropriate stereochemistry of the epoxide, it was
possible to control the stereochemistry of the hydroxy group at the
neighboring positionof the cycloalkane. Additionally, converting the
vinyl group to a formyl group in cycloalkane IVa facilitated control of
E
5,6 using this one-pot protocol synthesis of cycloalkane derivatives.
SO2Ph
Base
R
O
R
O
Base
R'
R'
X
R'
SO2Ph
Ia R = H
Ib R = Me
IIa R = H
IIb R = Me
SO2Ph
R
R''
R
O
*
R'
R'
*
*
SO2Ph
R
HO
HO
IIIa R = H
IIIb R = Me
IVa R = H
IVb R = Me
Va R = H
Vb R = Me
Figure 1. One-pot synthesis of cyclopentane derivatives from epoxide possessing
a leaving group and allyl phenyl sulfone via epoxysulfone.
Marine-derived natural products often have the common partial
structure Vb, which possesses a chiral quaternary carbon. Reiswigin
A (a potent anti-herpes virus marine terpenoid),7 cyanthiwigin E (a
potent anti-tumor marine terpenoid),8 and aragusterol A (a potent
anti-tumor marine steroid)9 are just some examples that have been
reported (Fig. 2). We supposed that the common partial structure
Vb could be successfully constructed using the aforementioned
one-pot reaction. With this view in mind, trisubstituted epoxide Ib
(R¼Me) was employed in the one-pot protocol. The carbanion of
the stereochemistry at the a-position of the aldehyde. Moreover,
a new carbon–carbon bond could readily be constructed from the
aldehyde, and so this one-pot protocol enabled us to synthesize
cycloalkane derivatives Va, which possess three contiguous
* Corresponding author.
E-mail address: miyaokah@ps.toyaku.ac.jp (H. Miyaoka).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.058

K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
8669
sulfone (1.2 equiv) and nBuLi (1.1 equiv) to generate epoxysulfone 3
in 57% yield and epoxyiodide 5 (43% recovered) (entry 4). Epoxy-
sulfone 3 was successfully obtained in 99% yield using allyl phenyl
sulfone (1.2 equiv) and nBuLi (2.3 equiv) (entry 6).
H
H
H
H
O
O
O
Table 1
OH
Coupling reaction of epoxide possessing a leaving group and allyl phenyl sulfone to
reiswigin A
cyanthiwigin E
epoxysulfone 3
SO2Ph
OH
O
n
BuLi
OH
H
H
R"
R'
Ph
X
Ph
SO2Ph
O
THF,
O
-78 °C to -20 °C
OH
1 X = OMs
4 X = OTs
5 X = I
3
H
H
O
common partial
structure Vb
H
aragusterol A
Entry
SM
X
Allyl phenyl
sulfone (equiv)
nBuLi (equiv)
Yield (%)
Figure 2. Marine natural products possessing a common partial structure.
1
2
3
4
5
6
1
4
5
5
5
5
OMs
OMs
l
l
l
l
2.4
2.4
2.4
1.2
1.7
1.2
2.3
2.3
2.3
1.1
1.6
2.3
35
43
Quant.
57
82
allyl phenyl sulfone reacted with trisubstituted epoxide Ib to gen-
erate epoxysulfone IIb, and deprotonation of epoxysulfone IIb
afforded carbanion IIIb. The cyclization of carbanion IIIb generated
cyclopentane IVb, which possesses a quaternary chiral center.
Cyclopentane IVb could then readily be converted to the common
partial structure Vb (Fig. 1). In this paper, we wish to report on the
stereocontrolled one-pot synthesis of cycloalkane derivatives pos-
sessing a quaternary carbon using allyl phenyl sulfone and tri-
substituted epoxyiodide.
99
Next, we investigated conditions for the 5-exo cyclization pro-
cess of epoxysulfone 3 (Table 2). In order to confirm the regiose-
lectivity of the cyclization reaction, epoxysulfone 3 was treated
with nBuLi or LDA to generate a mixture of 5-exo cyclization product
2 (16 or 21%) and 6-endo cyclization product 7 (35 or 42%) (entries 1
and 2). Generally, the intramolecular cyclization reaction of an
epoxide with base generates a 5-exo cyclization product. The 5-exo
cyclization reaction was inhibited as a result of steric hindrance by
the methyl group, thereby resulting in the generation of cyclo-
hexane 7. We supposed that undesired cyclization was due to low
reactivity of the epoxide group. Consequently, we investigated the
addition of Lewis acid to elevate the reactivity of the epoxide group
(entries 3–7). Initially, the activating ability of Lewis acids
(1.1 equiv) such as EtAlCl2, Et2AlCl, Me3Al, BF3$OEt2, and TiCl(OiPr)3
for epoxide was investigated to promote cyclization of the sulfonyl-
carbanion, which was generated from epoxysulfone 3 and nBuLi
(1.1 equiv). When Lewis acid was added, cyclopentane 2 and its
diastereomer 6 were also obtained. Of the Lewis acids investigated,
2. Results and discussion
One-pot synthesis of the cycloalkane was initially performed
according to a previously reported method.2 Epoxymesylate 1,
which was synthesized from 3-phenylpropanal, was reacted with
the sulfonylcarbanion generated by deprotonation of allyl phenyl
sulfone (2.4 equiv) with nBuLi (2.3 equiv) to afford a small amount
of cyclopentane 2 (4–19% yield) and a large amount of complex
mixtures comprising undesired compounds (Scheme 1). This one-
pot reaction consisted of a coupling process (the coupling of allyl
phenyl sulfone and epoxymesylate) and a cyclization process (the
cyclization of epoxysulfone). Since epoxymesylate 1 essentially
decomposed under these reaction conditions, we decided to opti-
mize the reaction conditions in each process.
SO2Ph
SO2Ph
Table 2
(2.4 eq.)
Ph
Cyclization of epoxysulfone 3 to cyclopentane derivatives
n
SO2Ph
BuLi (2.3 eq.)
OH
Ph
OMs
4-19%
base
2
O
THF, -78 °C to r.t.
Ph
Ph
+
SO2Ph
Lewis acid
THF
1
+
O
OH
complex mixture of
2
undesired compounds
3
SO2Ph
SO2Ph
Scheme 1. One-pot synthesis of cyclopentane derivative 2 under previously reported
+
reaction conditions.
Ph
Ph
H
At first, the coupling process involving trisubstituted epoxide
and allyl phenyl sulfone was optimized (Table 1). We have syn-
thesized epoxytosylate 4 and epoxyiodide 5 from 3-phenyl-
propanal to select the leaving group (entries 1–3). The
sulfonylcarbanion, which was generated from allyl phenyl sulfone
(2.4 equiv) and nBuLi (2.3 equiv) was then reacted separately with
epoxymesylate 1, epoxytosylate 4, and epoxyiodide 5. Epoxyiodide
5, which possesses iodine as the leaving group was reacted with the
carbanion of allyl phenyl sulfone to generate epoxysulfone 3 in
quantitative yield (entry 3). The amount of these reagents was then
optimized using epoxyiodide 5 (entries 4–6). Epoxyiodide 5 was
reacted with the sulfonylcarbanion generated from allyl phenyl
OH
OH
6
7
Entry
Base
Lewis acid
(1.1 equiv)
Temp
Yield (%)
(1.1 equiv)
2
6
7
1
2
3
4
5
6
7
nBuLi
LDA
d
ꢀ78 ꢁC to 0 ꢁ
ꢀ78 ꢁC to 0 ꢁ
ꢀ78 ꢁC to 0 ꢁ
ꢀ78 ꢁC to rt
ꢀ78 ꢁC to rt
ꢀ78 ꢁC to 0 ꢁ
ꢀ78 ꢁC to rt
C
C
C
16
21
52
64
66
31
26
d
35
42
d
d
d
d
d
d
d
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
EtAlCl2
Et2AlCl
Me3Al
BF3$OEt2
TiCl(OiPr)3
32
16
12
28
11
C

8670
K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
Me3Al was found to be the most effective in terms of chemical yield
and selectivity (entry 5).
Finally, we optimized conditions of the one-pot protocol to
synthesize cyclopentane derivatives by combining the best con-
ditions determined for each step (Table 3). The sulfonylcarbanion,
prepared from allyl phenyl sulfone (1.2 equiv) and nBuLi
(2.3 equiv), was reacted with epoxyiodide 5 at ꢀ78 ꢁC. Following
confirmation of the disappearance of epoxyiodide 5 by TLC, Me3Al
(1.1 equiv) was added to the reaction mixture to generate epox-
The relative configuration of cyclopentanes 2 and 6 was de-
termined by NOESY spectrum analysis and chemical conversions.
Firstly, configuration of the vinyl and 1-hydroxy-3-phenylpropyl
groups was determined from the NOESY spectrum (Fig. 3). trans-
Configuration of the vinyl and 1-hydroxy-3-phenylpropyl groups in
2 was determined by NOE correlation between vinyl and methyl
protons. cis-Configuration of the vinyl and 1-hydroxy-3-phenyl-
propyl groups in 6 was determined by NOE correlation between the
vinyl proton and methine proton of the hydroxy group. Next, the
relative configuration of the methyl and hydroxy groups was de-
termined by chemical conversions and NOESY spectrum analysis
ysulfone 3 (50%), a-sulfone 2 (8%), and b-sulfone 6 (4%) (entry 1).
Since epoxysulfone 3 was obtained as a major product, these
conditions were insufficient for the 5-exo cyclization reaction.
nBuLi was then added after completing a coupling reaction (en-
tries 2–5). Following confirmation of the generation of epoxy-
sulfone 3, nBuLi (2.1 equiv) and Me3Al (2.2 equiv) were added to
(Scheme 2). Cyclopentane 6 was converted to
nolysis and oxidation of the hemiacetal. The NOE correlation be-
tween methyl and methine protons of -lactone in 8 suggested that
the methyl group and methine proton of -lactone were oriented
on the same face of the lactone ring. Therefore, the stereochemistry
of the hydroxygroup in 6 was found to be in the -configuration. The
stereochemistry of the hydroxy group in 2 was elucidated following
chemical conversions. Cyclopentane 6 was converted to (E)-alkene 9
by rearrangement of the phenylsulfonyl group with BPO. Cyclo-
pentane 2 was also converted to (E)-alkene 9 by rearrangement of
the phenylsulfonyl group with BPO. Therefore, the stereochemistry
g
-lactone 8 by ozo-
generate a-sulfone 2 (66%) and b-sulfone 6 (18%) (entry 5).
However, the chemical yield of cyclopentane derivatives 2 and 6
was not very high when excess nBuLi was used from the begin-
ning (entry 6).
g
g
b
Table 3
One-pot synthesis of cyclopentane derivatives from epoxyiodide 5 and allyl phenyl
sulfone
Ph
SO2Ph
SO2Ph
O
3
of the hydroxygroupin 2 was also found to be in the
b
-configuration.
n
+
BuLi, THF,
SO2Ph
-78 °C to -20 °C
then
Ph
I
H
PhO2S
H2C
CH3
OH
H2C
O
Ph
Ph
CH3
n
BuLi, Me3Al,
5
-78 °C
OH
Ph
H
2
Ph
PhO2S
H
H
+
SO2Ph
NOE
OH
2
6
Figure 3. Selected NOE correlations of 2 and 6.
OH
6
1)O3, NaHCO3
O
MeOH/CH2Cl2, -78 °C,
then Me2S, r.t., 52%
Entry nBuLi (first) Allyl phenyl
nBuLi (second) Me3Al
Yield (%)
SO2Ph
CH3
(equiv)
sulfone (equiv) (equiv) (equiv)
6
O
3
2
6
2) TPAP, NMO, 4A MS
CH2Cl2, r.t., quant.
H
1
2
3
4
5
6
2.3
2.3
2.3
2.3
2.3
4.4
1.2
1.2
1.2
1.2
2.4
1.2
d
1.1
1.1
2.2
2.2
2.2
2.2
50
9
d
d
d
d
8
4
Ph
1.1
1.1
2.1
2.1
d
38 14
54 12
59 18
66 18
55 14
NOE
8
PhO2S
BPO
BPO
6
2
CCl4, reflux,
55%
CCl4, reflux,
54%
Ph
Next, generated cyclopentane 2 was easily converted to the
OH
9
common partial structure Vb by removal of the phenylsulfonyl
group (Scheme 3). The hydroxy group in cyclopentane 2 was
protected as a MOM ether and the phenylsulfonyl group was
Scheme 2. Chemical conversion of
b-sulfone 6 to lactone 8 and chemical conversions
of -sulfone 6 and -sulfone 2 to sulfone 9.
b
a
The relative configuration of cyclohexane 7 was determined by
examination of the NOESY spectrum (Fig. 4). The NOE correlation
between methyl and vinyl protons and between the vinyl proton
and one of methylene protons suggested that the methyl, vinyl, and
2-phenylethyl groups were oriented on the same face of the cyclo-
hexane ring. The relative configuration of 7 was therefore de-
termined to be that shown in Figure 4.
1) MOMCl, DIPEA,
SO2Ph
DMAP, ClCH2CH2Cl,
60 °C, 99%
H
H
Ph
Ph
2) Na(Hg), Na2HPO4,
MeOH/THF, r.t., 99%
OH
OMOM
NOE
2
10
CH3
OH
BH3·THF,
H2C
H
H
THF, 45 °C
H
OH
Ph
Ph
then NaOH, H2O2,
r.t., 87%
CH3
PhO2S
H
H
OMOM
NOE
11
NOE
7
Figure 4. Selected NOE correlations of 7.
Scheme 3. Conversion of cyclopentane derivative 2 to a common partial structure.

K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
8671
eliminated using Na(Hg) and Na2HPO4 to generate trisub-
SO2Ph
(2.2 eq.),
H
stituted (E)-olefin 10. The stereochemistry of the olefin in 10
was elucidated by examination of the NOESY spectrum.
Trisubstituted olefin 10 was converted to alcohol 11, which
corresponds to partial structure Vb, via stereoselective hydro-
boration using BH3/THF. The stereochemistry of alcohol 11 was
elucidated by examination of the NOESY spectrum. It therefore
became possible to introduce various functional groups using
alcohol 11. The one-pot protocol to synthesize cyclopentane
derivatives was successfully extended to the use of trisub-
stituted epoxide.
Next, the synthesis of cyclopentane derivatives possessing
ethyl or phenyl groups in lieu of methyl groups was examined
(Scheme 4). The sulfonylcarbanion that was generated using
nBuLi (3.0 equiv) and allyl phenyl sulfone (3.1 equiv) was reacted
with epoxyiodide 12 possessing an ethyl group. Following
completion of the coupling reaction, nBuLi (2.7 equiv) and Me3Al
(2.9 equiv) were added to give cyclopentane 13 as a single di-
astereomer in moderate yield (38%). The relative configuration of
13 was determined by examination of the NOESY spectrum. The
one-pot synthesis of epoxyiodide 14 possessing a phenyl group
with the sulfonylcarbanion under similar reaction conditions did
not generate cyclopentane 15, but a degradation product. Fur-
ther examination of the reaction conditions is necessary for
a one-pot synthesis of the cyclopentane possessing ethyl or
phenyl groups.
n
SO2Ph
BuLi (2.1 eq.),
THF, -78 °C to -20 °C
Ph
Ph
I
CH3
n
then BuLi (1.1 eq.),
-78 °C to -20 °C, 91%
O
OH
17
16
NOE
SO2Ph
(2.1 eq.),
n
BuLi (2.05 eq.),
THF, -78 °C to -20 °C
SO2Ph
Ph
I
Ph
n
then BuLi (1.5 eq.),
Me3Al (1.1 eq.), -78 °C,
95%
O
18
OH
19
H
SO2Ph
Ph
CH3
OH
H
H
H
NOE
20
Scheme 5. One-pot synthesis of cyclopropane and cyclopentane derivatives.
3. Conclusion
In summary, we have successfully expanded an efficient pro-
tocol for the synthesis of cyclopentane derivatives using tri-
substituted epoxide. Furthermore, application of this protocol to
the synthesis of cycloalkane derivatives possessing different ring
sizes was successful. Optically active cycloalkane derivative is
produced by this one-pot synthesis using optically active epoxy-
iodide, which is prepared by asymmetric epoxidation. The syn-
thesis of natural products by application of the present one-pot
reaction is now being undertaken.
SO2Ph
(3.1 eq.),
n
H
BuLi (3.0 eq.),
THF, -78 °C to -20 °C
SO2Ph
Et
Ph
I
Ph
n
then BuLi (2.7 eq.),
Me3Al (2.9 eq.),
-78 °C to r.t., 38%
O
CH3
OH
13
12
NOE
4. Experimental
4.1. General
SO2Ph
(2.4 eq.),
n
BuLi (2.3 eq.),
THF, -78 °C to -20 °C
SO2Ph
Ph
Ph
Melting points (mps) were measured using a Yazawa melting
point apparatus BY-2 and are uncorrected. IR spectra were recorded
using a Jasco FT-IR/620 spectrometer. 1H and 13C NMR spectra were
recorded on a Bruker DRX-400 spectrometer. Chemical shifts are
Ph
I
Ph
n
then BuLi (2.1 eq.),
Me3Al (2.2 eq.),
-78 °C to r.t.,
O
OH
15
14
given on the
d (ppm) scale using tetramethylsilane (TMS) as the
Scheme 4. One-pot synthesis of cyclopentane derivatives from epoxyiodides 12 and 14
with allyl phenyl sulfone.
internal standard (s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet; br, broad). High resolution ESIMS (HRESIMS)
spectra were obtained using a Micromass LCT spectrometer. Ele-
mental analysis data were obtained using an Elemental Vavio EL.
Furthermore, the developed protocol was applied to the syn-
thesis of cycloalkane derivatives possessing different ring sizes
(Scheme 5). The sulfonylcarbanion that was generated by nBuLi
(2.1 equiv) and allyl phenyl sulfone (2.2 equiv) was reacted with
epoxyiodide 16. Following completion of the coupling reaction,
nBuLi (1.1 equiv) was added to the reaction mixture. As a result,
the 3-exo cyclization reaction was carried out without addition of
a Lewis acid, to generate cyclopropane 17 as a single diastereomer
in good yield (91%). The relative configuration of 17 was de-
termined by examination of the NOESY spectrum. Under the re-
action conditions developed, a one-pot reaction of epoxyiodide 18
with the sulfonylcarbanion did not generate the 4-exo product
cyclobutane 19, but generated the 5-endo product cyclopentane
20 as a single diastereomer in good yield (95%). The relative
configuration of 20 was determined by examination of the NOESY
spectrum. We supposed that the regioselectivity of the cyclization
reaction resulted from steric strain derived from the generated
cyclobutane and steric hindrance of the substituted group of ep-
oxide 18.
4.2. (2S
*
,3S )-2-(3-Iodopropyl)-2,3-dimethyl-3-
*
phenethyloxirane (5)
To a solution of (E)-4-methyl-7-phenylhept-4-en-1-ol10 (4.79 g,
23.5 mmol) in CH2Cl2 (59.0 mL) were added DMAP (4.30 g,
53.2 mmol) and p-toluenesulfonyl chloride (5.14 g, 27.0 mmol) at
0 ꢁC. The mixture was stirred for 30 min at rt. The reaction mixture
was diluted with Et2O, washed with H2O and brine, dried, and then
concentrated to afford the crude tosylate. To a solution of the crude
tosylate in CH2Cl2 (120 mL) were added Na2HPO4 (10.0 g,
70.4 mmol) and m-CPBA (7.50 g, 28.2 mmol) at 0 ꢁC. The mixture
was stirred for 1 h at rt. The reaction mixture was diluted with Et2O,
washed with saturated aqueous NaHCO3 solution, H2O and brine,
and then dried. Removal of the solvent gave a residue, which was
purified by silica gel column chromatography (hexane/AcOEt¼3:1)
to generate epoxytosylate 4 (7.43 g, 85% yield) as a colorless oil. IR

8672
K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
(neat) 2925, 1356, 1173 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
ppm:
(1H, m), 6.31 (1H, dd, J¼17.4, 10.9 Hz), 5.12 (1H, d, J¼10.9 Hz), 4.72
(1H, d, J¼17.4 Hz), 4.48 (1H, m), 3.39 (1H, m), 3.01 (1H, ddd, J¼13.5,
11.2, 4.9 Hz), 2.72 (1H, ddd, J¼13.5, 11.2, 5.5 Hz), 2.44 (1H, ddd,
J¼14.1, 10.8, 5.1 Hz), 2.29 (1H, ddd, J¼13.0, 10.2, 4.4 Hz), 2.06 (2H,
m),1.93 (1H, m), 1.75 (1H, m), 1.61 (1H, m),1.48 (1H, m), 1.02 (3H, s);
7.77 (2H, m), 7.35–7.26 (5H, m), 7.19 (3H, m), 4.01 (2H, m), 2.81 (1H,
m), 2.69 (2H, m), 2.44 (3H, s), 1.90–1.64 (4H, m), 1.49 (2H, m), 1.09
(3H, s); 13C NMR (100 MHz, CDCl3)
d ppm: 144.7, 141.2, 133.1, 129.8,
128.4, 128.4, 127.9, 126.1, 70.3, 62.7, 60.2, 34.3, 32.6, 30.4, 24.5, 21.6,
16.4; HRESIMS (m/z) calcd for C21H27O4S (MþH)þ 375.1611, found
375.1630. Anal. Calcd for C21H26O4S: C, 67.35; H, 7.00. Found: C,
67.45; H, 7.24.
To a solution of epoxytosylate 4 (49.5 mg, 132
(1.30 mL) were added NaHCO3 (12.2 mg, 145
13C NMR (100 MHz, CDCl3)
d ppm: 143.0, 137.8, 135.9, 133.4, 130.1,
128.6, 128.3, 128.1, 125.6, 119.1, 80.4, 75.1, 57.5, 35.3, 34.5, 33.6, 31.0,
21.0, 20.7; HRESIMS (m/z) calcd for C23H28O3S (MþH)þ 385.1837,
found 385.1834. Anal. Calcd for C23H28O3S: C, 71.84; H, 7.34. Found:
C, 71.91; H, 7.20. Compound 6: mp 148–150 ꢁC. IR (neat) 3491, 2948,
mmol) in acetone
mmol) and NaI
(198 mg, 1.32 mmol) at rt. The mixture was stirred for 2 h at the
same temperature. The reaction mixture was diluted with Et2O and
then filtered through a silica gel pad. Removal of the solvent gave
a residue, which was purified by silica gel column chromatography
(hexane/AcOEt¼9:1) to generate epoxyiodide 5 (38.8 mg, 89%
1278, 1128 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d ppm: 7.76 (2H, m),
7.57 (1H, m), 7.45 (2H, m), 7.25 (5H, m), 6.39 (1H, dd, J¼17.5,
10.8 Hz), 5.23 (1H, d, J¼10.8 Hz), 4.83 (1H, d, J¼17.5 Hz), 3.72 (1H,
ddd, J¼16.7, 10.1, 6.0 Hz), 2.90 (1H, ddd, J¼14.1, 10.1, 4.9 Hz), 2.61
(1H, ddd, J¼13.7, 9.6, 6.9 Hz), 2.22 (2H, m), 2.03 (3H, m), 1.85 (1H,
m), 1.71 (2H, m), 1.63 (1H, m), 1.52 (3H, s); 13C NMR (100 MHz,
yield) as a colorless oil. IR (neat) 2925 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d
ppm: 7.37–7.24 (5H, m), 3.21 (2H, m), 2.95–2.72 (3H, m),
CDCl3) d ppm: 142.1, 137.6, 135.2, 133.2, 130.5, 128.5, 128.4, 127.9,
2.04–1.83 (4H, m), 1.64 (2H, m), 1.19 (3H, s); 13C NMR (100 MHz,
125.8, 119.4, 81.0, 75.8, 56.3, 34.5, 34.1, 33.1, 31.4, 20.7, 20.2; HRE-
SIMS (m/z) calcd for C23H28O3S (MþH)þ 385.1837, found 385.1834.
Anal. Calcd for C23H28O3S: C, 71.84; H, 7.34. Found: C, 71.61; H, 7.15.
CDCl3)
d ppm: 141.2, 128.4, 128.4, 126.1, 62.8, 60.2, 39.3, 32.7, 30.4,
29.2, 16.5, 6.2; HRESIMS (m/z) calcd for C14H20OI (MþH)þ 331.0559,
found 331.0545. Anal. Calcd for C14H19OI: C, 50.92; H, 5.80. Found:
C, 51.00; H, 5.92.
4.5. (3S
*
,3aR
*
,6aS )-6a-Benzenesulfonyl-3a-methyl-3-
*
phenethylhexahydrocyclopenta[c]furan-1-one (8)
4.3. (2S
*
,3S )-2-(4-Benzenesulfonylhex-5-enyl)-2-methyl-
*
3-phenethyloxirane (3)
A cold (ꢀ78 ꢁC) solution of
b-sulfone 6 (50.0 mg, 0.130 mmol) in
CH2Cl2 (1.30 mL) and MeOH (1.30 mL) was treated with ozone until
a blue color persisted for more than 10 h. Excess ozone was removed
using an argon flow. The reaction mixture was treated with excess
Me2S (0.095 mL, 1.30 mmol), allowed to warm slowly to rt for over
1 h, and then stirred for 12 h at the same temperature. The mixture
was diluted with Et2O, washed with H2O and brine, and then dried.
Removal of the solvent gave a residue, which was purified by silica
gel column chromatography (CHCl3/AcOEt¼15:1) to generate the
hemiacetal (26.3 mg, 52%) as a colorless solid. Mp 171–179 ꢁC. IR
To a solution of allyl phenyl sulfone (129 mg, 0.710 mmol) in THF
(4.50 mL) was added nBuLi (0.680 mmol, hexane solution) at
ꢀ78 ꢁC and the mixture was warmed to 0 ꢁC. The mixture was
stirred for 30 min at the same temperature. After cooling to ꢀ78 ꢁC,
a solution of epoxyiodide 5 (99.0 mg, 0.300 mmol) in THF (1.50 mL)
was added and the reaction mixture was warmed to rt for over 5 h.
After stirring for 1 h at ambient temperature, the reaction mixture
was diluted with Et2O, washed with saturated aqueous NH4Cl so-
lution, H2O and brine, and then dried. Removal of the solvent gave
a residue, which was purified by silica gel column chromatography
(hexane/AcOEt¼2:1) to generate epoxysulfone 3 (113 mg, 99%) as
(KBr) 3429, 2953, 1283, 1131 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
ppm: 7.88 (2H, m), 7.60 (1H, m), 7.51 (2H, m), 7.29 (2H, m), 7.20 (3H,
m), 5.75 (1H, d, J¼5.7 Hz), 3.79 (1H, dd, J¼12.4, 12.4 Hz), 3.03 (1H, d,
J¼5.7 Hz), 2.87 (1H, ddd, J¼13.7, 8.6, 8.6 Hz), 2.62 (1H, ddd, J¼13.7,
8.1, 8.1 Hz), 2.27 (1H, m), 2.06 (1H, m),1.93 (1H, m),1.80 (3H, m),1.64
a colorless viscous oil. IR (neat) 2929, 1305, 1146 cmꢀ1
;
1H NMR
ppm: 7.82 (2H, m), 7.62 (2H, m), 7.28 (2H, m),
(400 MHz, CDCl3)
d
7.19 (3H, m), 5.60 (1H, m), 5.28 (1H, dd, J¼10.3, 6.0 Hz), 5.03 (1H, dd,
J¼17.1, 6.0 Hz), 3.47 (1H, m), 2.82 (1H, m), 2.69 (2H, m), 2.07 (1H,
m), 1.84 (2H, m), 1.66 (1H, m), 1.58–1.24 (4H, m), 1.10 (3H, s); 13C
(1H, m),1.57 (3H, s),1.49 (1H, m); 13C NMR (100 MHz, CDCl3)
d ppm:
141.7, 139.2, 133.6, 129.6, 128.8, 128.5, 128.3, 126.0, 97.6, 82.9, 81.4,
59.1, 37.2, 33.6, 31.3, 30.6, 20.6; HRESIMS (m/z) calcd for C22H26O4S
(MꢀOH)þ 369.1524, found 369.1529.
NMR (100 MHz, CDCl3) d ppm: 141.2,137.3,133.6,130.2, 129.1,128.8,
128.4, 126.0, 123.7, 123.7, 69.8 (69.7), 62.8 (62.8), 60.5 (60.5), 38.0
(37.9), 32.6, 30.4 (30.4), 26.8, 22.1 (22.0), 16.4 (16.3); HRESIMS (m/z)
calcd for C23H28O3S (MþH)þ 385.1837, found 385.1823. Anal. Calcd
for C23H28O3S: C, 71.84; H, 7.34. Found: C, 71.57; H, 7.38.
To a solution of the above hemiacetal (5.0 mg, 13.0 mmol) in
CH2Cl2 (650
mL) were added 4 Å MS (6.5 mg), NMO (7.5 mg,
65.0 mol), and TPAP (0.5 mg, 1.30
m
m
mol) and the mixture was
stirred at rt for 30 min. The reaction mixture was diluted with Et2O
and then filtered through a silica gel pad. Removal of the solvent
gave a residue, which was purified by silica gel column chroma-
4.4. (S
*
)-1-[(1R
*
,2S
*
)-2-Benzenesulfonyl-1-methyl-2-vinyl-
)-1-[(1R ,2R )-
cyclopentyl]-3-phenylpropan-1-ol (2) and (S
*
*
*
tography (hexane/AcOEt¼2:1) to generate lactone
quantitative yield) as colorless plates. Mp 169–170 ꢁC. IR (KBr)
2935,1766,1306,1145 cmꢀ1; 1H NMR (400 MHz, CDCl3)
ppm: 7.84
8 (5.0 mg,
2-benzenesulfonyl-1-methyl-2-vinylcyclopentyl]-3-
phenylpropan-1-ol (6)
d
(2H, m), 7.68 (1H, m), 7.55 (2H, m), 7.32 (2H, m), 7.23 (3H, m), 4.80
(1H, dd, J¼10.5, 2.4 Hz), 3.00 (1H, ddd, J¼13.8, 10.9, 4.9 Hz), 2.76
(1H, ddd, J¼13.8, 10.5, 6.6 Hz), 2.56 (1H, m), 2.08 (1H, m), 1.89 (4H,
m), 1.72 (1H, m), 1.61 (3H, s), 1.58 (1H, m); 13C NMR (100 MHz,
To a solution of epoxysulfone 3 (30.4 mg, 0.079 mmol) in THF
(0.79 mL) was added nBuLi (0.087 mmol, hexane solution) at
ꢀ78 ꢁC. The mixture was stirred for 30 min at the same tempera-
ture. Me3Al (0.087 mmol, hexane solution) was added and the re-
action mixture was warmed to 0 ꢁC for over 5 h. After stirring for
1 h at the same temperature, the reaction mixture was diluted with
Et2O, washed with saturated aqueous NH4Cl solution, H2O and
brine, and then dried. Removal of the solvent gave a residue, which
was purified by silica gel column chromatography (hexane/
CDCl3)
d ppm: 172.8, 141.0, 137.4, 134.4, 130.2, 128.6, 128.6, 128.3,
126.3, 86.0, 80.0, 56.8, 35.7, 33.3, 32.8, 31.6, 23.0, 18.5; HRESIMS
(m/z) calcd for C22H24O4S (MþH)þ 385.1474, found 385.1492. Anal.
Calcd for C22H24O4S: C, 68.72; H, 6.29. Found: C, 68.68; H, 6.58.
4.6. (S
*
)-1-{(S )-2-[(E)-2-Benzenesulfonylethylidene]-1-
*
AcOEt¼4:1) to generate
(3.7 mg, 12%) as colorless solids. Compound 2: mp 154–157 ꢁC. IR
(neat) 3551, 2974, 1281, 1129 cmꢀ1 1H NMR (400 MHz, CDCl3)
ppm: 7.75 (2H, m), 7.54 (1H, m), 7.44 (2H, m), 7.26 (4H, m), 7.16
a-sulfone 2 (20.1 mg, 66%) and b-sulfone 6
methylcyclopentyl}-3-phenylpropan-1-ol (9)
;
To a solution of
b
-sulfone 6 (23.2 mg, 60.0
mmol) in CCl4 (600 mL)
d
was added BPO (1.2 mg, 3.60
mmol) and the mixture was refluxed

K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
8673
for 8 h. The reaction mixture was diluted with Et2O, washed with
aqueous NaOH solution (1 M), saturated aqueous Na2S2O3 solution,
H2O and brine, and then dried. Removal of the solvent gave a resi-
due, which was purified by TLC (hexane/AcOEt¼2:1) to generate
sulfone 9 (12.6 mg, 54% yield) as a colorless oil. IR (neat) 3520,
(3H, s); 13C NMR (100 MHz, CDCl3)
d
ppm: 143.4, 136.8, 134.9, 133.3,
130.7, 128.6, 128.3, 127.9, 125.5, 121.0, 99.3, 85.3, 81.0, 56.5, 56.2,
38.7, 36.3, 33.5, 31.3, 19.6, 19.1; HRESIMS (m/z) calcd for C25H32O4S
(MþNa)þ 451.1919, found 451.1928. Anal. Calcd for C25H32O4S: C,
70.06; H, 7.53. Found: C, 69.79; H, 7.54.
2956, 1306, 1147 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
ppm: 7.88 (2H,
To a solution of the above MOM ether (43.7 mg, 0.102 mmol) in
MeOH/THF (2.00 mL, 1:1) were added Na2HPO4 (870 mg) and 5%
Na–Hg (2.40 g). After stirring for 2 h at rt, the reaction mixture was
diluted with Et2O and filtered through silica gel. The filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/AcOEt¼20:1) to gener-
ate E-olefin 10 (30.2 mg, 99%) as a colorless viscous oil. IR (neat)
m), 7.66 (1H, m), 7.55 (2H, m), 7.29 (2H, m), 7.21 (3H, m), 5.16 (1H,
m), 3.85 (2H, m), 3.52 (1H, dd, J¼10.3, 10.3 Hz), 2.94 (1H, m), 2.61
(1H, m), 2.14 (1H, m), 1.88 (3H, m), 1.73 (1H, br s), 1.61 (2H, m), 1.32
(2H, m), 0.89 (3H, s); 13C NMR (100 MHz, CDCl3)
d ppm: 161.8,142.4,
139.0, 133.7, 129.2, 128.5, 128.4, 128.3, 125.8, 106.6, 76.5, 57.6, 51.5,
33.4, 33.1, 33.0, 31.2, 24.6, 22.7; HRESIMS (m/z) calcd for C23H28O3S
(MþH)þ 385.1837, found 385.1862.
2954 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d ppm: 7.23 (5H, m), 5.21
(1H, m), 4.68 (1H, d, J¼6.6 Hz), 4.61 (1H, d, J¼6.6 Hz), 3.41 (3H, s),
3.39 (1H, m), 2.86 (1H, m), 2.58 (1H, m), 2.37 (1H, m), 2.10–1.86 (4H,
m), 1.71 (2H, m), 1.58 (3H, d, J¼6.6 Hz),1.32 (1H, m), 0.98 (3H, s); 13C
4.7. (S
*
)-1-{(S )-2-[(E)-2-Benzenesulfonylethylidene]-1-
*
methylcyclopentyl}-3-phenylpropan-1-ol (9)
NMR (100 MHz, CDCl3)
d ppm: 149.9, 142.8, 128.4, 128.3, 125.7,
To a solution of
was added BPO (1.3 mg, 3.90
a
-sulfone 2 (25.0 mg, 65.0
m
mol) in CCl4 (650
m
L)
114.7, 98.2, 84.5, 55.9, 50.0, 35.8, 33.8, 33.4, 30.1, 24.3, 22.6, 14.7;
HRESIMS (m/z) calcd for C19H28O2 (MþNa)þ 311.1987, found
311.2011. Anal. Calcd for C19H28O2: C, 79.12; H, 9.78. Found: C,
78.84; H, 9.71.
mmol) and the mixture was refluxed
for 8 h. The reaction mixture was diluted with Et2O, washed with
aqueous NaOH solution (1 M), saturated aqueous Na2S2O3 solution,
H2O and brine, and then dried. Removal of the solvent gave a resi-
due, which was purified by TLC (hexane/AcOEt¼2:1) to generate
sulfone 9 (13.7 mg, 55% yield) as a colorless oil.
4.10. (S
*
)-1-{(1R
*
,2S
*
)-2-[(S )-1-Methoxymethoxy-3-
*
phenylpropyl]-2-methylcyclopentyl}ethanol (11)
4.8. (S
*
)-1-[(1R
*
,2S
*
)-2-Benzenesulfonyl-1-methyl-2-vinyl-
)-1-[(1R ,2R )-
To a solution of E-olefin 10 (10.8 mg, 0.036 mmol) in THF
(0.36 mL) was added BH3/THF (0.109 mmol, THF solution) at 0 ꢁC.
The reaction mixture was warmed to 45 ꢁC and stirred for 2 h. To
cyclopentyl]-3-phenylpropan-1-ol (2) and (S
2-benzenesulfonyl-1-methyl-2-vinylcyclopentyl]-3-
phenylpropan-1-ol (6) (one-pot procedure)
*
*
*
the resulting solution were added 1 M NaOH solution (73
mL) and
35% aqueous H2O2 solution (73 L) at rt. After stirring for 1 h, the
m
To a solution of allyl phenyl sulfone (133 mg, 0.730 mmol) in
THF (4.50 mL) was added nBuLi (0.700 mmol, hexane solution) at
ꢀ78 ꢁC and the mixture was warmed to 0 ꢁC. The mixture was
stirred for 30 min at the same temperature. After cooling to ꢀ78 ꢁC,
a solution of epoxyiodide 5 (102 mg, 0.310 mmol) in THF (1.50 mL)
was added and the reaction mixture was warmed to ꢀ20 ꢁC for over
5 h. The mixture was stirred for 1 h at the same temperature. After
cooling to ꢀ78 ꢁC, nBuLi (0.640 mmol, hexane solution) was added
and the reaction mixture was warmed to ꢀ20 ꢁC. The mixture was
stirred for 30 min at the same temperature. After cooling to ꢀ78 ꢁC,
Me3Al (0.680 mmol, hexane solution) was added. After stirring for
30 min at the same temperature, the reaction mixture was diluted
with Et2O, washed with saturated aqueous NH4Cl solution, H2O and
brine, and then dried. Removal of the solvent gave a residue, which
was purified by silica gel column chromatography (hexane/
resultant mixture was diluted with Et2O, washed with H2O and
brine, and then dried. Removal of the solvent gave a residue, which
was purified by silica gel column chromatography (hexane/
AcOEt¼4:1) to generate alcohol 11 (9.6 mg, 87%) as a colorless
viscous oil. IR (neat) 3432 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d ppm:
7.41–7.23 (5H, m), 4.82 (2H, dd, J¼15.9, 6.8 Hz), 4.01 (1H, m), 3.92
(1H, br s), 3.51 (3H, s), 3.46 (1H, m), 2.98 (1H, m), 2.65 (1H, m), 2.14–
1.98 (2H, m), 1.79–1.31 (7H, m), 1.25 (3H, s), 1.19 (3H, d, J¼6.2 Hz);
13C NMR (100 MHz, CDCl3)
d ppm: 142.1, 128.5, 128.4, 125.9, 98.3,
88.3, 68.8, 59.1, 56.3, 49.1, 38.8, 35.2, 34.8, 32.0, 30.2, 23.0, 22.9;
HRESIMS (m/z) calcd for C19H30O3 (MþNa)þ 329.2093, found
329.2098. Anal. Calcd for C19H30O3: C, 74.47; H, 9.87. Found: C,
74.18; H, 9.79.
4.11. (2S
*
,3S )-2-Ethyl-2-(3-iodopropyl)-3-methyl-3-
*
AcOEt¼4:1) to generate
a
-sulfone 2 (78.7 mg, 66%) and
b-sulfone 6
phenethyloxirane (12)
(21.5 mg, 18%) as colorless solids.
To a solution of 2-bromobut-1-ene (3.29 g, 24.4 mmol) in Et2O
(97.6 mL) was added tBuLi (26.8 mmol, hexane solution) at ꢀ78 ꢁC.
After stirring for 15 min at the same temperature, commercially
available 3-phenylpropanal (3.47 g, 25.6 mmol) was added and the
mixture was warmed to rt. The mixture was stirred for 1.5 h at the
same temperature. The reaction mixture was diluted with Et2O,
washed with saturated aqueous NH4Cl solution, H2O and brine,
dried, and then concentrated to afford the crude alcohol. To the
crude alcohol were added triethyl orthoacetate (15.8 g, 97.7 mmol)
and propionic acid (180.7 mg, 2.44 mmol) at rt and the mixture was
warmed to 140 ꢁC. The mixture was stirred for 38 h under reflux
and then heated to 160 ꢁC. Following removal of excess triethyl
orthoacetate, the residue was filtered through a silica gel pad
(hexane/AcOEt¼20:1). The filtrate was concentrated under reduced
pressure to give the crude ester. To a solution of the crude ester in
Et2O (122 mL) was added LiAlH4 (1.85 g, 48.8 mmol) at 0 ꢁC. After
stirring for 30 min at the same temperature, the reaction mixture
was diluted with Et2O and Na2SO4$10H2O was added. The mixture
was dried over MgSO4 and Na2SO4. Removal of the solvent gave
4.9. (S
*
)-[(1S ,2E)-3-(2-Ethylidene-1-methylcyclopentyl)-
*
3-methoxymethoxypropyl]benzene (10)
To a solution of
a-sulfone 2 (60.2 mg, 0.157 mmol) in 1,2-di-
chloroethane (1.60 mL) were added N,N-diisopropylethylamine
(0.136 mL, 0.785 mmol), chloromethyl methyl ether (0.060 mL,
0.785 mmol), and DMAP (19.1 mg, 0.157 mmol) and the mixture
was stirred at 60 ꢁC for 2 h. The reaction mixture was diluted with
Et2O, washed with saturated aqueous NaHCO3 solution, H2O and
brine, and then dried. Removal of the solvent gave a residue, which
was purified by silica gel column chromatography (hexane/
AcOEt¼4:1) to generate the MOM ether (66.7 mg, 99%) as a color-
less solid. Mp 119–121 ꢁC. IR (KBr) 2937 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) d ppm: 7.72 (2H, m), 7.51 (1H, m), 7.39 (2H, m), 7.24 (4H, m),
7.13 (1H, m), 6.31 (1H, dd, J¼17.4, 11.0 Hz), 5.15 (1H, d, J¼11.0 Hz),
4.83 (1H, d, J¼6.3 Hz), 4.74 (1H, d, J¼6.3 Hz), 4.65 (1H, d, J¼17.4 Hz),
4.43 (1H, d, J¼9.1 Hz), 3.41 (3H, s), 2.89 (1H, m), 2.78 (1H, m), 2.59
(1H, m), 2.29 (1H, m), 2.09–1.98 (2H, m), 1.86–1.72 (4H, m), 0.87

8674
K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
a residue, which was purified by silica gel column chromatography
(hexane/AcOEt¼5:1) to generate the alcohol (413.1 mg, 8% yield) as
a colorless oil. IR (neat) 3349,1453 cmꢀ1; 1H NMR (400 MHz, CDCl3)
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d ppm: 143.0, 138.0, 135.6,
133.4, 130.5, 128.7, 128.3, 128.0, 125.7, 119.3, 82.0, 73.8, 61.1, 34.9,
33.6, 33.6, 32.4, 28.1, 21.1, 9.8; HRESIMS (m/z) calcd for C24H31O3S
(MþH)þ 399.1994, found 399.1980.
d
ppm: 7.30–7.27 (2H, m), 7.20–7.16 (3H, m), 5.18 (1H, t, J¼7.1 Hz),
3.61 (2H, br t), 2.65 (2H, dd, J¼7.4, 8.2 Hz), 2.33 (2H, dd, J¼7.6,
15.4 Hz), 2.07 (2H, dd, J¼7.5, 7.7 Hz), 2.01 (2H, q, J¼7.6 Hz), 1.65 (2H,
m), 1.28 (1H, br s), 0.92 (3H, t, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
4.13. (2R
*
,3S )-2-(3-Iodopropyl)-3-methyl-3-phenethyl-2-
*
phenyloxirane (14)
d
ppm: 142.3, 141.2, 128.4, 128.2, 125.7, 123.4, 62.9, 36.4, 32.7, 31.0,
29.6, 23.0, 13.1; HRESIMS (m/z) calcd for C15H22ONa (MþNa)þ
241.1568, found 241.1585. Anal. Calcd for C15H22O: C, 82.52; H,10.16.
Found: C, 82.24; H, 10.02.
To a solution of a-bromostylene (5.00 g, 24.6 mmol) in Et2O
(98.4 mL) was added tBuLi (27.1 mmol, hexane solution) at ꢀ78 ꢁC.
After stirring for 15 min at the same temperature, commercially
available 3-phenylpropanal (3.47 g, 25.6 mmol) was added and the
reaction mixture was warmed to rt. The mixture was stirred for
1.5 h at the same temperature. The reaction mixture was diluted
with Et2O, washed with saturated aqueous NH4Cl solution, H2O and
brine, dried, and then concentrated to afford the crude alcohol. To
the crude alcohol were added triethyl orthoacetate (15.9 g,
98.0 mmol) and propionic acid (182.2 mg, 2.46 mmol) at rt and the
mixture was warmed to 140 ꢁC. The mixture was stirred for 22 h
under reflux and then heated to 160 ꢁC. Following removal of ex-
cess triethyl orthoacetate, the residue was filtered through a silica
gel pad (hexane/AcOEt¼15:1). The filtrate was concentrated under
reduced pressure to give the crude ester. To a solution of the crude
ester in Et2O (123 mL) was added LiAlH4 (1.90 g, 49.2 mmol) at 0 ꢁC.
After stirring for 35 min at the same temperature, the reaction
mixture was diluted with Et2O and Na2SO4$10H2O was added. The
mixture was dried over MgSO4 and Na2SO4. Removal of the solvent
gave a residue, which was purified by silica gel column chroma-
tography (hexane/AcOEt¼4:1) to generate the alcohol (533.6 mg,
To a solution of the above alcohol (410 mg, 1.88 mmol) in CH2Cl2
(37.6 mL) were added DMAP (528 mg, 4.32 mmol) and p-toluene-
sulfonyl chloride (430 mg, 2.26 mmol) at 0 ꢁC. The mixture was
stirred for 3 h at rt. The reaction mixture was diluted with Et2O,
washed with saturated aqueous NaHCO3 solution, H2O and brine,
dried, and then concentrated to afford the crude tosylate. To a so-
lution of the crude tosylate in CH2Cl2 (37.6 mL) were added NaHCO3
(474 mg, 5.64 mmol) and m-CPBA (749 mg, 2.82 mmol) at rt. The
mixture was stirred for 20 min at the same temperature. The re-
action mixture was diluted with Et2O, washed with saturated
aqueous NaHCO3 solution, H2O and brine, dried, and then con-
centrated to afford the crude epoxytosylate. To a solution of the
crude epoxytosylate in acetone (37.6 mL) were added NaHCO3
(237 mg, 2.82 mmol) and NaI (1.41 g, 9.41 mmol) at rt. The mixture
was stirred for 3 h at 50 ꢁC. The reaction mixture was diluted with
Et2O and filtered through a silica gel pad. The filtrate was con-
centrated to give a residue, which was purified by silica gel col-
umn chromatography (hexane/AcOEt¼15:1) to generate
epoxyiodide 12 (67.7 mg, 11% yield) as a colorless oil. IR (neat)
8% yield) as a colorless oil. IR (neat) 3343, 1448 cmꢀ1
;
1H NMR
2968 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
ppm: 7.32–7.28 (2H, m),
(400 MHz, CDCl3)
d
ppm: 7.32–7.18 (6H, m), 7.11 (2H, d, J¼7.2 Hz),
7.22–7.19 (3H, m), 3.17 (2H, ddd, J¼6.8, 6.8, 3.4 Hz), 2.88–2.69 (2H,
m), 2.78 (1H, dd, J¼6.5, 5.8 Hz), 1.92–1.80 (4H, m), 1.67–1.58 (3H,
m), 1.46–1.37 (1H, m), 0.96 (3H, t, J¼7.6 Hz); 13C NMR (100 MHz,
7.04 (2H, d, J¼7.0 Hz), 5.53 (1H, t, J¼7.2 Hz), 3.60 (2H, br t), 2.65
(2H, dd, J¼7.4, 7.8 Hz), 2.42 (2H, dd, J¼7.4, 7.5 Hz), 1.56 (2H, m),
1.29 (1H, br s); 13C NMR (100 MHz, CDCl3)
d ppm: 141.8, 141.1,
CDCl3)
d
ppm: 141.3, 128.5, 128.4, 126.1, 63.5, 63.0, 35.4, 32.9, 30.1,
140.8, 128.5, 128.3, 128.2, 128.0, 126.7, 126.5, 125.7, 62.4, 36.2, 35.5,
31.0, 30.7; HRESIMS (m/z) calcd for C19H23O (MþH)þ 267.1749,
found 267.1744. Anal. Calcd for C19H22O: C, 85.67; H, 8.32. Found:
C, 85.54; H, 8.40.
28.8, 23.2, 9.3, 6.4; HRESIMS (m/z) calcd for C15H22OI (MþH)þ
345.0715, found 345.0698. Anal. Calcd for C15H21OI: C, 52.34; H,
6.15. Found: C, 52.50; H, 6.31.
To a solution of the above alcohol (467 mg, 1.75 mmol) in CH2Cl2
(17.5 mL) were added DMAP (492 mg, 4.03 mmol) and p-toluene-
sulfonyl chloride (400 mg, 2.10 mmol) at 0 ꢁC and the mixture was
warmed to rt. The mixture was stirred for 3 h at the same tem-
perature. The reaction mixture was diluted with Et2O, washed with
saturated aqueous NaHCO3 solution, H2O and brine, dried, and then
concentrated to afford the crude tosylate. To a solution of the crude
tosylate in CH2Cl2 (17.5 mL) were added NaHCO3 (441 mg,
5.25 mmol) and m-CPBA (697 mg, 2.63 mmol) at 0 ꢁC and the
mixture was warmed to rt. The mixture was stirred for 2 h at the
same temperature. The reaction mixture was diluted with Et2O,
washed with 10% aqueous NaOH solution, H2O and brine, dried, and
then concentrated to afford the crude epoxytosylate. To a solution
of the crude epoxytosylate in acetone (17.5 mL) were added
NaHCO3 (221 mg, 2.63 mmol) and NaI (1.31 g, 8.74 mmol) at rt. The
mixture was warmed to 50 ꢁC and then stirred for 12 h at the same
temperature. The reaction mixture was diluted with Et2O and fil-
tered through a silica gel pad. Removal of the solvent gave a residue,
which was purified by silica gel column chromatography (hexane/
AcOEt¼15:1) to generate epoxyiodide 14 (568.4 mg, 83% yield) as
4.12. (S
*
)-1-[(1R
*
,2R )-2-Benzenesulfonyl-1-ethyl-2-
*
vinylcyclopentyl]-3-phenylpropan-1-ol (13)
To a solution of allyl phenyl sulfone (87.5 mg, 0.480 mmol) in
THF (3.00 mL) was added nBuLi (0.479 mmol, hexane solution) at
ꢀ78 ꢁC and the mixture was warmed to 0 ꢁC. The mixture was
stirred for 30 min at the same temperature. After cooling to ꢀ78 ꢁC,
a
solution of epoxyiodide 12 (53.2 mg, 0.155 mmol) in THF
(1.00 mL) was added and the reaction mixture was warmed to
ꢀ20 ꢁC. The mixture was stirred for 30 min at the same tempera-
ture. After cooling to ꢀ78 ꢁC, nBuLi (0.417 mmol, hexane solution)
was added and the reaction mixture was warmed to ꢀ20 ꢁC and
then stirred for 30 min at the same temperature. After cooling to
ꢀ78 ꢁC, Me3Al (0.448 mmol, hexane solution) was added. After
stirring for 2 h at the same temperature, the reaction mixture was
diluted with Et2O, washed with saturated aqueous NH4Cl solution,
H2O and brine, and then dried. Removal of the solvent gave a resi-
due, which was purified by silica gel column chromatography
(hexane/AcOEt¼3:1) to generate
a colorless viscous oil. IR (neat) 3423 cmꢀ1
CDCl3)
ppm: 7.78 (2H, d, J¼7.4 Hz), 7.60 (1H, t, J¼7.4 Hz), 7.48 (2H,
a
-sulfone 13 (23.6 mg, 38%) as
;
1H NMR (400 MHz,
a colorless oil. IR (neat) 3026 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
d
ppm: 7.35–7.22 (7H, m), 7.17 (1H, m), 7.04 (2H, m), 3.13 (2H, dt,
t, J¼7.8 Hz), 7.32–7.18 (5H, m), 6.39 (1H, dd, J¼18.0, 11.4 Hz), 5.21
(1H, d, J¼10.8 Hz), 4.78 (1H, d, J¼17.4 Hz), 4.55 (1H, dd, J¼9.3,
4.5 Hz), 3.57 (1H, d, J¼5.4 Hz), 3.08 (1H, dt, J¼8.6, 2.3 Hz), 2.76 (1H,
dt, J¼7.7, 2.6 Hz), 2.58 (1H, dt, J¼7.5, 3.1 Hz), 2.28 (1H, dt, J¼8.0,
3.1 Hz), 2.05–1.97 (2H, m), 1.91–1.85 (2H, m), 1.63 (1H, quint.,
J¼7.6 Hz), 1.56 (2H, m), 1.43 (1H, quint., J¼7.6 Hz), 1.01 (3H, t,
J¼2.7, 6.8 Hz), 3.10 (1H, t, J¼6.1 Hz), 2.66 (2H, m), 2.31 (1H, m), 1.91
(1H, m), 1.75 (1H, m), 1.63 (1H, m), 1.48 (2H, m); 13C NMR (100 MHz,
CDCl3)
d ppm: 141.1, 137.6, 128.4, 128.3, 128.1, 127.4, 126.8, 125.9,
65.2, 64.0, 38.5, 32.3, 30.4, 28.9, 6.5; HRESIMS (m/z) calcd for
C19H22OI (MþH)þ 393.0715, found 393.0731. Anal. Calcd for
C19H21OI: C, 58.17; H, 5.40. Found: C, 58.21; H, 5.48.

K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
8675
4.14. (2R
*
,3S
*
)-2-Iodomethyl-2,3-dimethyl-3-
reaction mixture was diluted with Et2O, and to this was added
saturated aqueous NH4Cl solution. The mixture was filtered
through a Celite pad (Et2O). The filtrate was washed with H2O and
brine and then dried over MgSO4. Removal of the solvent gave
a residue, which was purified by silica gel column chromatography
(hexane only) to generate the diene (358.6 mg, 27% yield) as a col-
orless oil.
To a solution of cyclohexene (102.1 mg, 1.24 mmol) in THF
(2.0 mL) was added BH3/THF (0.62 mmol, THF solution) dropwise at
0 ꢁC. The mixture was stirred for 1 h at the same temperature and
a solution of the above diene (97.3 mg, 0.56 mmol) in THF (1.0 mL)
was added dropwise at rt. After stirring for 12 h, 3 M NaOH solution
phenethyloxirane (16)
To a solution of (E)-2-methyl-5-phenylpent-2-en-1-ol11 (966 mg,
5.48 mmol) in CH2Cl2 (55.0 mL) were added NaHCO3 (2.30 g,
27.4 mmol) and m-CPBA (2.18 g, 8.20 mmol) at 0 ꢁC. The mixture
was stirred for 15 min at the same temperature. The reaction
mixture was diluted with Et2O, washed with saturated aqueous
NaHCO3 solution, H2O and brine, dried, and then concentrated to
afford the crude epoxyalcohol. To a solution of the crude epoxy-
alcohol in CH2Cl2 (25.0 mL) were added imidazole (1.10 g,
16.2 mmol), Ph3P (2.25 g, 8.59 mmol), I2 (2.18 g, 8.59 mmol), and 2-
methyl-but-2-ene (2.70 mL, 25.3 mmol) at 0 ꢁC. The mixture was
stirred for 3 h at the same temperature. The reaction mixture was
diluted with Et2O, washed with saturated aqueous Na2S2O3 solu-
tion, H2O and brine, and then dried. Removal of the solvent gave
a residue, which was purified by silica gel column chromatography
(hexane/AcOEt¼15:1) to generate epoxyiodide 16 (808.8 mg, 49%
(1.1 mL) and 35% aqueous H2O2 solution (210 mL) were added to the
mixture at rt. After stirring for 30 min, the resultant mixture was
diluted with Et2O, washed with H2O and brine, and then dried.
Removal of the solvent gave a residue, which was purified by silica
gel column chromatography (hexane/AcOEt¼4:1) to give the alco-
hol (103.5 mg, 96% yield) as a colorless oil.
yield) as a colorless oil. IR (neat) 2963 cmꢀ1
CDCl3) ppm: 7.36–7.23 (5H, m), 3.24 (1H, m), 3.11 (1H, m), 2.96
(1H, t, J¼6.3 Hz), 2.91–2.74 (2H, m), 1.99–1.83 (2H, m), 1.41 (3H, s);
13C NMR (100 MHz, CDCl3)
ppm: 140.9, 128.5, 128.4, 126.2, 65.9,
60.2, 32.5, 30.9, 16.0, 13.9; HRESIMS (m/z) calcd for C12H15OINa
(MþNa)þ 325.0065, found 325.0088. Anal. Calcd for C12H15OI: C,
47.70; H, 5.00. Found: C, 47.81; H, 5.22.
;
1H NMR (400 MHz,
To a solution of the above alcohol (269.0 mg, 1.41 mmol) in
CH2Cl2 (3.50 mL) were added DMAP (396 mg, 3.24 mmol) and p-
toluenesulfonyl chloride (323 mg, 1.69 mmol) at 0 ꢁC. The mixture
was stirred for 30 min at rt. The reaction mixture was diluted with
Et2O, washed with saturated aqueous NaHCO3 solution, H2O and
brine, dried, and then concentrated to afford the crude tosylate. To
a solution of the crude tosylate in CH2Cl2 (14.1 mL) were added
NaHCO3 (592 mg, 7.05 mmol) and m-CPBA (562 mg, 2.12 mmol) at
0 ꢁC. The mixture was stirred for 30 min at rt. The reaction mixture
was diluted with Et2O, washed with saturated aqueous NaHCO3
solution, H2O and brine, dried, and then concentrated to afford the
crude epoxytosylate. To a solution of the crude epoxytosylate in
acetone (7.1 mL) were added NaHCO3 (178 mg, 2.12 mmol) and NaI
(1.10 g, 7.05 mmol) at rt. The mixture was stirred for 4 h at the same
temperature. The reaction mixture was diluted with Et2O and then
filtered through a silica gel pad. Removal of the solvent gave a res-
idue, which was purified by silica gel column chromatography
(hexane/AcOEt¼10:1) to generate epoxyiodide 18 (214.9 mg, 48%
d
d
4.15. (S
*
)-1-[(1R
*
,2S )-2-Benzenesulfonyl-1-methyl-2-
*
vinylcyclopropyl]-3-phenylpropan-1-ol (17)
To a solution of allyl phenyl sulfone (242 mg, 1.34 mmol) in THF
(6.00 mL) was added nBuLi (1.27 mmol, hexane solution) at ꢀ78 ꢁC
and the mixture was warmed to 0 ꢁC. The mixture was stirred for
30 min at the same temperature. After cooling to ꢀ78 ꢁC, a solution
of epoxyiodide 16 (183 mg, 0.604 mmol) in THF (6.10 mL) was
added and the reaction mixture was warmed to ꢀ20 ꢁC. The mix-
ture was stirred for 1 h at the same temperature. After cooling to
ꢀ78 ꢁC, nBuLi (0.664 mmol, hexane solution) was added and the
mixture was warmed to 0 ꢁC. After stirring for 3 h at the same
temperature, the mixture was diluted with Et2O, washed with
saturated aqueous NH4Cl solution, H2O and brine, and then dried.
Removal of the solvent gave a residue, which was purified by silica
gel column chromatography (hexane/AcOEt¼3:1) to generate cy-
clopropane 17 (195 mg, 91%) as a colorless viscous oil. IR (neat)
yield) as a colorless oil. IR (neat) 2925 cmꢀ1
CDCl3) ppm: 7.32–7.19 (5H, m), 3.14 (2H, m), 2.90–2.71 (2H, m),
2.85 (1H, t, J¼6.2 Hz), 2.20 (1H, m), 1.98 (1H, m), 1.87 (2H, m), 1.17
(3H, s); 13C NMR (100 MHz, CDCl3)
ppm: 141.2, 128.5, 128.4, 126.1,
;
1H NMR (400 MHz,
d
d
62.8, 61.1, 42.6, 32.7, 30.4, 15.9, ꢀ0.8; HRESIMS (m/z) calcd for
C13H18OI (MþH)þ 317.0402, found 317.0396. Anal. Calcd for
C13H17OI: C, 49.38; H, 5.42. Found: C, 49.44; H, 5.58.
3522, 2937,1303,1147 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d ppm: 7.77
(2H, m), 7.60 (1H, m), 7.48 (2H, m), 7.33–7.15 (5H, m), 5.90 (1H, dd,
J¼17.2, 10.2 Hz), 5.19 (1H, d, J¼10.2 Hz), 4.85 (1H, d, J¼17.2 Hz), 4.71
(1H, m), 2.99–2.75 (2H, m), 2.23 (1H, m), 1.95 (3H, m), 1.19 (1H, d,
4.17. (1R
*
,2S
*
,3R )-3-Benzenesulfonyl-1-methyl-2-phenethyl-
*
3-vinylcyclopentanol (20)
J¼4.1 Hz), 1.10 (3H, s); 13C NMR (100 MHz, CDCl3)
d
ppm: 142.3,
To a solution of allyl phenyl sulfone (140 mg, 0.770 mmol) in
THF (4.50 mL) was added nBuLi (0.752 mmol, hexane solution) at
ꢀ78 ꢁC and the mixture was warmed to 0 ꢁC. The mixture was
stirred for 30 min at the same temperature. After cooling to ꢀ78 ꢁC,
a solution of epoxyiodide 18 (116 mg, 0.367 mmol) in THF (2.80 mL)
was added and the reaction mixture was warmed to ꢀ20 ꢁC. The
mixture was stirred for 1 h at the same temperature. After cooling
to ꢀ78 ꢁC, nBuLi (0.550 mmol, hexane solution) was added. After
the mixture was stirred for 1 h at the same temperature, Me3Al
(0.734 mmol, hexane solution) was added. After stirring for 1.5 h at
the same temperature, the reaction mixture was diluted with Et2O,
washed with saturated aqueous NH4Cl solution, H2O and brine, and
then dried. Removal of the solvent gave a residue, which was pu-
rified by silica gel column chromatography (hexane/AcOEt¼2:1) to
generate cyclopentane 20 (129 mg, 95%) as a colorless viscous oil. IR
140.0, 133.1, 130.6, 128.8, 128.6, 128.5, 128.3, 125.7, 124.1, 71.8, 54.3,
38.3, 37.0, 33.3, 24.8, 15.3; HRESIMS (m/z) calcd for C21H24O3S
(MþNa)þ 379.1344, found 379.1357.
4.16. (2S
*
,3S )-2-(2-Iodoethyl)-2,3-dimethyl-3-
*
phenethyloxirane (18)
To a solution of (E)-2-methyl-5-phenylpent-2-en-1-ol11 (1.38 g,
7.80 mmol) in CH2Cl2 (78.0 mL) were added 4 Å MS (2.34 g), NMO
(1.19 g, 10.1 mmol), and TPAP (95.9 mg, 0.27 mmol) at rt. The mix-
ture was stirred for 1 h at the same temperature. The reaction
mixture was diluted with Et2O, filtered through a silica gel pad
(AcOEt only), and then concentrated to afford the crude aldehyde.
To a solution of methyltriphenylphosphonium iodide (28.4 g,
70.2 mmol) in THF (100 mL) was added nBuLi (62.4 mmol, hexane
solution) at 0 ꢁC. The mixture was stirred for 30 min at the same
temperature and a solution of the above crude aldehyde in THF
(11.0 mL) was added dropwise at rt. After stirring for 30 min, the
(neat) 3501, 2965 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d ppm: 7.76 (2H,
m), 7.59 (1H, m), 7.47 (2H, m), 7.28 (4H, m), 7.18 (1H, m), 6.28 (1H,
dd, J¼17.4, 10.7 Hz), 5.16 (1H, d, J¼10.7 Hz), 4.82 (1H, d, J¼17.4 Hz),
2.92 (2H, m), 2.61 (1H, m), 2.26 (2H, m), 2.05 (2H, m), 1.72 (2H, m),

8676
K. Ota et al. / Tetrahedron 65 (2009) 8668–8676
1.64 (1H, br s),1.59 (3H, s); 13C NMR (100 MHz, CDCl3)
d ppm: 142.2,
3. Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron Lett. 1998, 39, 621–624.
4. Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron 2000, 56, 8083–8094.
5. Miyaoka, H.; Shigemoto, T.; Yamada, Y. Tetrahedron Lett. 1996, 37, 7407–7408.
6. Miyaoka, H.; Shigemoto, T.; Yamada, Y. Heterocycles 1998, 47, 415–428.
7. Kashman, Y.; Hirsch, S.; Koehn, F.; Cross, S. Tetrahedron Lett. 1987, 28, 5461–
5464.
137.4, 137.1, 133.4, 130.4, 128.6, 128.3, 128.1, 125.7, 116.5, 81.3, 76.6,
60.2, 40.4, 35.3, 29.5, 27.6, 23.6; HRESIMS (m/z) calcd for C22H26O3S
(MþNa)þ 393.1500, found 393.1480.
8. Peng, J.; Walsh, K.; Weedman, V.; Bergthold, J. D.; Lynch, J.; Lieu, K. L.; Braude, I.
A.; Kelly, M.; Hamann, M. T. Tetrahedron 2002, 58, 7809–7819.
9. Iguchi, K.; Fujita, M.; Nagaoka, H.; Mitome, H.; Yamada, Y. Tetrahedron Lett.
1993, 34, 6277–6280.
10. Abouabdellah, A.; Bonnet-Delpon, D. Tetrahedron 1994, 50, 11921–11932.
11. Browder, C. C.; Marmsaeter, F. P.; West, F. G. Org. Lett. 2001, 3, 3033–3035.
References and notes
1. Simokin, N. S. Sulphones in Organic Synthesis; Pergamon: Oxford, 1993.
2. Miyaoka, H.; Shigemoto, T.; Shinohara, I.; Suzuki, A.; Yamada, Y. Tetrahedron
2000, 56, 8077–8081.