A novel method for the asymmetric synthesis of 4,4-disubstituted 2-cyclopentenones from optically active 1-chlorovinyl p-tolyl sulfoxides and its application to the asymmetric total synthesis of (+)-α-cuparenone

Article abstract of DOI:10.1016/S0957-4166(02)00797-8

Enantiomerically pure 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position were synthesized from unsymmetrical ketones and (R)-(-)-chloromethyl p-tolyl sulfoxide in three steps. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium at -78°C to room temperature gave optically active 2-amino-1-cyano-5,5-disubstituted-1,3-cyclopentadienes in high yields with very high asymmetric induction from the stereogenic center of the sulfoxide moiety. A mechanism for the asymmetric induction is proposed. The products were treated with phosphoric acid in acetic acid at reflux temperature to give enantiomerically pure 4,4-disubstituted 2-cyclopentenones in good yields. As an application of this synthetic method, a relatively short (seven steps) total asymmetric synthesis of (+)-α-cuparenone from methyl 4-methylphenyl ketone is described.

Full text of DOI:10.1016/S0957-4166(02)00797-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 281–288
A novel method for the asymmetric synthesis of 4,4-disubstituted
2-cyclopentenones from optically active 1-chlorovinyl p-tolyl
sulfoxides and its application to the asymmetric total synthesis
of (+)-a-cuparenone
Tsuyoshi Satoh,* Masaaki Yoshida, Yasuhiro Takahashi and Hiroyuki Ota
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 6 November 2002; accepted 21 November 2002
Abstract—Enantiomerically pure 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position were
synthesized from unsymmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps. Treatment of the 1-chlorovinyl
p-tolyl sulfoxides with cyanomethyllithium at −78°C to room temperature gave optically active 2-amino-1-cyano-5,5-disubstituted-
1,3-cyclopentadienes in high yields with very high asymmetric induction from the stereogenic center of the sulfoxide moiety. A
mechanism for the asymmetric induction is proposed. The products were treated with phosphoric acid in acetic acid at reflux
temperature to give enantiomerically pure 4,4-disubstituted 2-cyclopentenones in good yields. As an application of this synthetic
method, a relatively short (seven steps) total asymmetric synthesis of (+)-a-cuparenone from methyl 4-methylphenyl ketone is
described. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
On the other hand, the construction of a quaternary
carbon center is known to be a formidable task. In
particular the asymmetric synthesis of a stereogenic
quaternary carbon center is an interesting and challeng-
ing target in its own right.5
Cyclopentenones are important intermediates in
organic synthesis. In addition, the cyclopentenone ring
system is an abundantly distributed carbon skeletal
structure in natural and unnatural organic compounds.
Accordingly, new methods for the synthesis of
cyclopentenones, including the optically active form,
have been eagerly sought in recent years.1
We recently reported a novel method for the synthesis
of 4,4-disubstituted 2-cyclopentenones 6 from ketones 1
and chloromethyl p-tolyl sulfoxide 2 via 1-chlorovinyl
p-tolyl sulfoxides 3 and enaminonitrile 5 (Scheme 1).6
The mechanism for the reaction of 3 with cyanomethyl-
lithium giving the enaminonitrile 5 was shown to be as
follows.6 First, cyanomethyllithium adds to the b-car-
bon of the alkenylsulfoxide 3 to afford the carbenoid 4
as an intermediate. Reaction of 4 with a second
cyanomethyllithium followed by the Thorpe–Ziegler
reaction7 then gives the enaminonitrile 5.
Two famous recent methods for the construction of
cyclopentenones are the Nazarov cyclization2 and the
Pauson–Khand reaction.3 The Nazarov cyclization,
however, is not usually useful for the synthesis of
optically active cyclopentenones. On the contrary, the
Pauson–Khand reaction has recently been extensively
studied and the reaction has been extended to the
synthesis of optically active cyclopentenones3g by using,
for example, brucine N-oxide,4b (S)-methionine-derived
amides,4c BINAP,4d and chiral phosphino-oxazoline
ligand4e as chiral sources.4
From this mechanism, it is expected that, if unsymmet-
rical ketones 1 and chiral chloromethyl p-tolyl sulfoxide
2 were used in this reaction, optically active enaminon-
itriles 5 and 4,4-disubstituted 2-cyclopentenones 6 could
be synthesized. This expectation was already verified,
and we have previously communicated a novel asym-
metric synthesis of cyclopentenones having a quater-
nary stereogenic carbon 6.8 We report herein the details
of the asymmetric synthesis of 4,4-disubstituted 2-
cyclopentenones and, as an application of this method,
* Corresponding author. Fax: 81-3-3235-2214; e-mail: tsatoh@
ch.kagu.sut.ac.jp
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00797-8

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a relatively short asymmetric total synthesis of (+)-a-
cuparenone 7.
96% yield as a mixture of two diastereomers. Deace-
toxylation of the acetates was successfully conducted
with dimsylsodium in DMSO at room temperature to
afford the optically active 10 and 11 (in a ratio of 4:1)
in 90% yield. The isomers could be separated by silica
gel flash column chromatography.10 The geometry of
the two isomers could be easily determined by 1H
NMR.11
2. Results and discussion
2.1. Synthesis of optically active 1-chlorovinyl p-tolyl
sulfoxides and the reaction with cyanomethyllithium
The synthesis of optically active 1-chlorovinyl p-tolyl
sulfoxides 10 and 11 was first investigated, starting
from acetophenone and (R)-(−)-chloromethyl p-tolyl
sulfoxide 29 (Scheme 2). According to the previous
paper,6 (R)-2 was treated with LDA at −50°C followed
by acetophenone to give the adduct 8 in 99% yield as a
mixture of two diastereomers. This mixture was acetyl-
ated with acetic anhydride in pyridine in the presence of
DMAP at room temperature to afford the acetate 9 in
With the desired optically active 1-chlorovinyl p-tolyl
sulfoxides in hand, we first investigated the reaction of
10 with cyanomethyllithium at −78°C to room tempera-
ture (Scheme 3). The reaction proceeded smoothly to
afford the optically active enaminonitrile (−)-12 in 93%
yield. The enantiomeric purity was determined by
HPLC using a chiral stationary column (Daisel CHI-
RALCEL OD, 10% 2-propanol in hexane) and we
found that the enantiomeric purity was surprisingly
Scheme 1.
Scheme 2.
Scheme 3.

T. Satoh et al. / Tetrahedron: Asymmetry 14 (2003) 281–288
283
high (98.8%). The same reaction of 11 gave the enam-
inonitrile (+)-12, which was found to be the enantiomer
of the product derived from 10. The enantiomeric
purity of (+)-12 was found to be 94.4%. Interestingly,
the geometrical isomers 10 and 11 gave the enantiomers
of the enaminonitrile 12, respectively, in high ee value.
At this stage, the absolute configuration of (−)-12 and
(+)-12 was not known.
Comparing the sign of the specific rotation of the
product enone (−)-13 with that of the reported optically
active 13,12 the absolute configuration of (−)-13 was
unambiguously determined to be S. At the same time,
the absolute configuration of the enaminonitrile (−)-12
was determined to be S.
As shown in Scheme 4, (S)-(−)-12 was derived from the
adduct of (E)-1-chlorovinyl p-tolyl sulfoxide 10 with
cyanomethyllithium, and the cyanomethyllithium must
be selectively introduced from the re face of the vinyl
sulfoxide. The observed high selectivity is most conve-
niently explained by assuming the formation of a five-
membered chelate with the lithium ion between the
oxygen of the sulfoxide and the chlorine, where the
approach of the cyanomethyl anion takes place from
the less-hindered re face avoiding the bulky p-tolyl
group. This is the first example of asymmetric synthesis
by conjugate addition to an a,b-unsaturated sulfoxide
bearing a halogen atom on the a-position.13
2.2. Hydrolytic decyanation of the enaminonitriles giv-
ing 4,4-disubstituted-2-cyclopentenones and determina-
tion of the absolute configuration
To ascertain the absolute configuration of the products
((−)-12 and (+)-12), and to transform the products to
the synthetically useful compound, 4,4-disubstituted-2-
cyclopentenone, we investigated the hydrolytic decya-
nation of (−)-12 (Table 1). The enaminonitrile (−)-12
was heated at reflux in 1,4-dioxane with 5% H2SO4. The
reaction gave the hydrolyzed cyano-enone 14 within 1
h; however, hydrolysis of the cyano group was found to
be difficult (entry 1). After some investigation we found
that phosphoric acid is effective for our purpose
(entries 2 and 3). Finally, phosphoric acid in acetic acid
containing a small amount of water was found to be the
conditions of choice of this reaction (entries 4 and 5),
and (−)-4-methyl-4-phenyl-2-cyclopentenone (−)-13 was
obtained in 86% yield. The conditions in entry 5 seem
to be somewhat harsh; however, the reaction was com-
paratively clean and the mass balance was good (total
yield 94%).
To investigate the generality of these reactions, we
studied this procedure further, starting from 2-hex-
anone (Scheme 5). The vinyl sulfoxides (E)-15 and
(Z)-16 were synthesized from 2-hexanone in a similar
way as described for the synthesis of 10 and 11. In the
deacetylation step, in this case, the ratio of 15 and 16
was almost 1:1. The vinyl sulfoxide 15 was treated with
cyanomethyllithium in the same way as described above
to obtain the desired enaminonitrile (−)-17 in 97% yield
with higher enantiomeric excess (99.2% ee) than the
case of (S)-(−)-12.
Table 1. Hydrolytic decyanation of (−)-12 with acids under reflux conditions
Entry
Acid
Solvent
Time (h)
Yield (%)
(S)-(−)-13
14
1
2
3
4
5
5% H2SO4
AcOH, H3PO4
H3PO4
H3PO4
H3PO4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
AcOH
77
77
77
16
44
65
78
33
39
8
Trace
Trace
42
50
86
AcOH
Scheme 4.

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T. Satoh et al. / Tetrahedron: Asymmetry 14 (2003) 281–288
Scheme 5.
The enaminonitrile (−)-17 was heated in a solution of
phosphoric acid in acetic acid to give the enone (−)-18
in 83% yield. Comparing the sign of the specific rota-
tion of the enone (−)-18 with that of the reported
optically active 18,12 the absolute configuration of the
enone was determined to be S. The result from the
vinyl sulfoxide 16 is shown in Scheme 5. Again, the
asymmetric induction is explained by the chelate model
shown in Scheme 4. It is worth noting that the level of
asymmetric induction reported in this paper is one of
the highest attained in asymmetric synthesis using chiral
sulfoxide.13
In order to refine this step and to determine whether we
could obtain the desired isomer 21 with higher selectiv-
ity, the reaction was investigated with other bases, and
the results are shown in Scheme 6. The alkoxides
worked; however, the yields were usually lower than
those obtained using dimsylsodium. Finally, lithium
diphenylamide was found to be the reagent of choice
for this elimination. The reaction of the acetate with
lithium diphenylamide gave over 93% yield of the
desired 1-chlorovinyl p-tolyl sulfoxide 21 and 22 with
good reproducibility. Despite the fact that we could not
improve the ratio of 21:22, the two isomers were easily
separable by silica gel flash chromatography.10
2.3. An application of this chiral synthesis of 4,4-disub-
stituted-2-cyclopentenone to an asymmetric synthesis of
(+)-a-cuparenone
The major isomer 21 was treated with 5 equiv. of
cyanomethyllithium to give optically active enaminoni-
trile 23 in 75% yield and the enantiomeric purity was
found to be 96% by HPLC. One recrystallization of the
product from ethyl acetate–hexane gave enantiomeri-
cally pure 23 ([h]2D0 −373.6). The enaminonitrile 23 was
heated under reflux with H3PO4 in acetic acid to give
the desired cyclopentenone 24 in 93% yield, which was
treated with excess sodium hydride and iodomethane in
DMF at room temperature to afford the dimethylated
product 25 ([h]2D7 +35.6) in 72% yield. Finally, 25 was
hydrogenated in ethyl acetate with catalytic Pd–C
under atmospheric pressure of hydrogen to give a quan-
titative yield of (+)-a-cuparenone 7 as a crystalline solid
(mp 51.5–52°C; [h]D28 +172.5 (c 0.49 CHCl3; over 99%
ee); lit.14 mp 52–53°C, [h]D30 +177.1; lit.18c mp 53–54°C,
[h]2D3 +163 (c 0.82, CHCl3).
(+)-a-Cuparenone 7 was isolated from Mayur Pankhi,14
and the absolute configuration was determined by Irie
et al.15 Interestingly, the enantiomer (−)-7 was also
isolated from the liverwort Mannia fragrans.16 Several
papers have been published for the synthesis of racemic
a-cuparenone;17 however, only few methods have been
applied to the asymmetric synthesis of (+)-a- and (−)-a-
cuparenone 7.18
As an application of our above-mentioned method to
synthesis of optically active natural products, we inves-
tigated a synthesis of enantiomerically pure (+)-a-
cuparenone
7 (Scheme 6). Enantiomerically pure
(R)-(−)-2 was treated with LDA at −50°C followed by
commercially available methyl 4-methylphenyl ketone
to afford the adduct 19 in 98% yield as a mixture of
two diastereomers. The hydroxyl group in 19 was acetyl-
ated to afford the acetate 20 in 95% yield. As men-
tioned above, in order to obtain the 1-chlorovinyl p-
tolyl sulfoxide 21, the acetate 20 was treated with base
(see Table in Scheme 6). First, 20 was treated with
dimsylsodium in DMSO under similar conditions to
those described above; however, we came across a
problem in this step: the reaction gave a mixture of 21
and 22 in up to 81% yield, but the outcome of the
reaction was found to be quite sensitive to the condi-
tions employed, especially with regard to the base
employed. Sometimes, the reaction gave complex mix-
tures of products and low yields.
3. Experimental
1
All melting points are uncorrected. H NMR spectra
were measured in a CDCl3 solution with JEOL JNM-
LA 400 and 500 spectrometer. Electron-impact mass
spectra (MS) were obtained at 70 eV by direct insertion.
Silica gel 60 (Merck) containing 0.5% fluorescence
reagent 254 and a quartz column were used for column
chromatography and the products having UV absorp-
tion were detected by UV irradiation. In experiments
requiring a dry reagent and solvent, diisopropylamine,
acetonitrile, pyridine, DMF and DMSO were distilled
from CaH2 and THF was distilled from diphenylketyl.
Acetone was dried over CaSO4 and distilled before use.

T. Satoh et al. / Tetrahedron: Asymmetry 14 (2003) 281–288
285
Scheme 6.
3.1. (RS)-(E)-1-Chloro-2-phenyl-1-(p-tolylsulfinyl)-1-
propene, 10 and (RS)-(Z)-isomer, 11
4-(Dimethylamino)pyridine (489 mg, 0.4 mmol) was
added to a solution of 8 (612 mg, 2.0 mmol) in a
mixture of acetic anhydride (3 ml) and pyridine (3 ml).
The mixture was stirred at room temperature for 11 h.
The acetic anhydride and pyridine were evaporated
under vacuum and the residue was purified by silica gel
column chromatography to give 667 mg (96%) of 9 as
a colorless oil (a mixture of two diastereomers). IR
(neat) 1746 (CO), 1241 (COC), 1059 (SO) cm−1.
A solution of (R)-2 (377 mg; 2.0 mmol) in the minimum
amount of dry THF (about 2 ml) was added dropwise
with stirring to a solution of LDA (2.4 mmol) in 6.0 ml
of THF in a flame-dried flask at −50°C. After 5 min, a
solution of acetophenone (0.28 ml, 2.4 mmol) in THF
was added to the reaction mixture and the reaction
mixture was stirred for 3 min. The reaction was
quenched with sat aq. NH4Cl. The whole was extracted
with AcOEt–hexane. The organic layer was dried over
MgSO4, and the solvent was evaporated to leave color-
less crystals, which were purified by silica gel column
chromatography to give 612 mg (99%) of 8 as colorless
crystals (a mixture of two diastereomers). IR (KBr)
3332 (OH), 1036 (SO) cm−1.
NaH (33 mg, 0.83 mmol) was added to DMSO (2.9 ml)
and the suspension was stirred at room temperature for
4 h to afford dimsylsodium. To this was added with
stirring a solution of 9 (100 mg, 0.29 mmol) in mini-
mum amount (about 0.5 ml) of dry THF. After 8 min,
the solution was diluted with ether (4 ml) and cooled in
an ice bath. The reaction was quenched by adding a

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T. Satoh et al. / Tetrahedron: Asymmetry 14 (2003) 281–288
solution of acetic acid (1 ml) in 10 ml of ether. The
whole was extracted with AcOEt–hexane, washed once
with sat aq. NH4Cl. The organic layer was dried over
MgSO4 and the products were purified by column
chromatography to give 10 (60 mg; 72%) and 11 (15
mg; 18%). 10: Colorless crystals; mp 82–83°C (AcOEt–
hexane). IR (KBr) 1594, 1086, 1060 (SO), 813, 760, 700,
520 cm−1; 1H NMR l 2.32 (3H, s, vinyl-CH3), 2.40 (3H,
s), 7.28–7.46 (9H, m). Anal. calcd for C16H15ClOS: C,
66.19; H, 5.21; Cl, 12.05; S, 11.04. Found: C, 66.35; H,
5.21; Cl, 12.05; S, 11.04%. [h]2D1 +280.5 (c 0.40, acetone).
11: Colorless crystals; mp 77–78°C (AcOEt–hexane). IR
(KBr) 1596, 1088, 1055 (SO), 892, 807, 705, 525 cm−1;
1H NMR l 2.43 (3H, s), 2.62 (3H, s, vinyl-CH3),
7.24–7.58 (9H, m). Anal. calcd for C16H15ClOS: C,
66.19; H, 5.21; Cl, 12.05; S, 11.04. Found: C, 66.28; H,
5.14; Cl, 12.00; S, 10.98%. [h]2D7 −9.3 (c 0.20, acetone).
3.4. (RS)-(E)-1-Chloro-2-methyl-1-(p-tolylsulfinyl)-1-
hexene, 15 and (RS)-(Z)-isomer, 16
These 1-chrolovinyl p-tolyl sulfoxides were synthesized
from 2-hexanone and (R)-(−)-2 according to the proce-
dure described above in similar yields. 15: Light yellow
oil; IR (neat) 2957, 2930, 1603, 1465, 1083, 1057 (SO),
1
807, 520 cm−1; H NMR l 0.98 (3H, t, J=7.2 Hz), 1.44
(2H, sextet, J=7.2 Hz), 1.49–1.57 (1H, m), 1.58–1.66
(1H, m), 2.00 (3H, s), 2.41 (3H, s), 2.70–2.77 (2H, m),
7.31, 7.48 (each 2H, d, J=8.3 Hz). MS m/z (%) 270
(M+, 18), 255 (38), 253 (100), 175 (28), 91 (33). Calcd
for C14H19ClOS: M, 270.0843. Found: m/z 270.0841.
[h]2D4 +187.6 (c 0.40, acetone). 16: Colorless crystals; mp
68–70°C (AcOEt–hexane). IR (KBr) 2954, 2927, 1684,
1
1085, 1054 (SO), 884, 809 cm−1; H NMR l 0.91 (3H,
t, J=7.3 Hz), 1.29–1.37 (2H, m), 1.40–1.51 (2H, m),
2.31 (3H, s), 2.34 (2H, t, J=7.8 Hz), 2.41 (3H, s), 7.31,
7.46 (each 2H, d, J=8.1 Hz). MS m/z (%) 270 (M+, 85),
253 (93), 211 (62), 140 (72), 92 (96), 89 (100). Anal.
calcd for C14H19ClOS: C, 62.09; H, 7.07; Cl, 13.09; S,
11.84. Found: C, 62.22; H, 6.89; Cl, 12.98; S, 11.89%.
High Mass: M, 270.0845. Found: m/z 270.0851. [h]D27
+133.4 (c 0.40, acetone).
3.2. (S)-(−)-2-Amino-1-cyano-5-methyl-5-phenyl-1,3-
cyclopentadiene, 12
Acetonitrile (0.094 ml, 1.8 mmol) was added to a
solution of n-BuLi (1.5 mmol) in 3 ml of dry THF at
−78°C with stirring. The solution was stirred for 15
min, then a solution of 10 (87 mg, 0.3 mmol) in THF (1
ml) was added. The temperature of the reaction mixture
was gradually allowed to warm to room temperature
for 2 h and the reaction mixture was stirred at room
temperature for 15 min. The reaction was quenched by
sat aq. NH4Cl. The whole was extracted with AcOEt–
hexane. The organic layer was washed once with sat aq.
NH4Cl. The product was isolated by silica gel column
chromatography to give (S)-12 as colorless crystals (55
mg, 93%); mp 114–116°C (AcOEt–hexane). IR (KBr)
3454, 3423, 3353, 3231, 2168 (CN), 1642, 1610, 1544,
3.5. (R)-2-Amino-5-butyl-1-cyano-5-methyl-1,3-
cyclopentadiene, 17
Colorless crystals; mp 56–58°C (AcOEt–hexane). IR
(KBr) 3451, 3350, 3236, 2929, 2169 (CN), 1660, 1640,
1
1610, 1547, 1420, 782 cm−1; H NMR l 0.85 (3H, t,
J=7.3 Hz), 1.08–1.16 (2H, m), 1.21–1.28 (2H, m), 1.25
(3H, s), 1.61–1.66 (2H, m), 4.51 (2H, s, NH), 6.00, 6.42
(each 1H, d, J=5.5 Hz). MS m/z (%) 176 (M+, 27), 133
(50), 120 (66), 119 (100). Anal. calcd for C11H16N2: C,
74.96; H, 9.15; N, 15.89. Found: C, 75.06; H, 8.98; N,
15.78%. High Mass: M, 176.1313. Found: m/z
176.1323. [h]2D9 −176.5 (c 0.40, acetone). (S)-17: [h]2D8
+172.7 (c 0.40, acetone).
1
1420, 780, 766, 700 cm−1; H NMR l 1.68 (3H, s), 4.69
(2H, br s), 6.07, 6.67 (each 1H, d, J=5.5 Hz), 7.2–7.3
(5H, m). 13C NMR l 22.2, 59.0, 88.0, 118.1, 125.1,
125.8, 126.9, 128.6, 140.4, 153.6, 158.9. MS m/z (%) 196
(M+, 100), 181 (89), 152 (12). Calcd for C13H12N2: M,
196.1000. Found: m/z 196.1004. [h]2D1 −428.5 (c 0.40,
acetone; over 99% ee). (R)-12: [h]3D1 +418.8 (c 0.40,
acetone; 98.1% ee).
3.6. (S)-4-Butyl-4-methyl-2-cyclopentenone, 18
Colorless oil; IR (neat) 2959, 2930, 2872, 1716, 1586,
1
1459, 1411, 802 cm−1; H NMR l 0.89 (3H, t, J=7.0
3.3. (S)-4-Methyl-4-phenyl-2-cyclopntenone, 13
Hz), 1.14–1.33 (4H, m), 1.21 (3H, s), 1.42–1.56 (2H, m),
2.12, 2.30 (each 1H, d, J=18.8 Hz), 6.03, 7.44 (each
1H, d, J=5.6 Hz). MS m/z (%) 152 (M+, 28), 96 (82),
95 (100), 67 (65), 41 (50), 18 (76). Calcd for C10H16O:
M, 152.1200. Found: m/z 152.1205. [h]3D2 −43.1 (c 0.40,
toluene). (R)-18: [h]3D0 +41.6 (c 0.35, toluene).
To a solution of (S)-12 (29 mg, 0.15 mmol) in 10 ml of
acetic acid was added phosphoric acid (85%, 4 ml) and
water (0.6 ml). The reaction mixture was stirred and
heated under reflux for 44 h. The reaction mixture was
neutralized with 5% aq. NaOH followed by sat aq.
NH4Cl and the whole was extracted with AcOEt–hex-
ane. The organic layer was dried over MgSO4 and the
solvent was evaporated to give an oil, which was
purified by silica gel column chromatography to afford
22 mg (86%) of (S)-13 as a colorless oil; IR (neat) 1714,
1588, 1495, 805, 762, 700 cm−1; 1H NMR l 1.64 (3H, s),
2.57, 2.65 (each 1H, d, J=18.8 Hz), 6.21 (1H, d, J=5.5
Hz), 7.23–7.37 (5H, m), 7.69 (1H, d, J=5.5 Hz). MS
m/z (%) 172 (M+, 89), 157 (100), 129 (49), 43 (37).
Calcd For C12H12O: M, 172.0888. Found: m/z
172.0883. [h]2D7 −119.0 (c 0.40, toluene; over 99% ee).
(R)-13: [h]3D2 +115.1 (c 0.30, toluene; 94.4% ee).
3.7. (RS)-(E)-1-Chloro-2-(4-methylphenyl)-1-(p-tolyl-
sulfinyl)-1-propene, 21 and (RS)-(Z)-isome, 22
A solution of (R)-2 (1.89 g, 10.0 mmol) in dry THF (7
ml) was added dropwise with stirring to a solution of
LDA (12.0 mmol) in THF (30 ml) in a flame-dried flask
at −50°C. After 5 min, a solution of 4%-methylacetophe-
none (1.6 ml, 12.0 mmol) in THF was added to the
reaction mixture and the reaction mixture was stirred
for 2 min. The reaction was quenched with sat aq.
NH4Cl. The whole was extracted with AcOEt–hexane.
The organic layer was dried over MgSO4, and the

T. Satoh et al. / Tetrahedron: Asymmetry 14 (2003) 281–288
287
solvent was evaporated to leave a colorless oil, which
3.9. (S)-4-Methyl-4-(4-methylphenyl)-2-cyclopntenone,
24
was purified by silica gel column chromatography to
give 19 as a colorless oil (3.16 g, 98% mixture of two
diastereomers). IR (neat) 3313 (OH), 1041 (SO), 819
cm−1.
To a solution of 23 (336 mg, 1.59 mmol) in acetic acid
(112 ml) was added phosphoric acid (85%, 43 ml) and
water (6.4 ml). The reaction mixture was stirred and
heated under reflux for 50 h. The reaction mixture was
neutralized with 3% aq. NaOH followed by sat aq.
NH4Cl and the whole was extracted with AcOEt–hex-
ane. The organic layer was dried over MgSO4 and the
solvent was evaporated to give an oil, which was
purified by silica gel column chromatography to afford
275 mg (93%) of 24 as a colorless oil; IR (neat) 2965,
2923, 1713, 1588, 1514, 1408, 1339, 1203, 1169, 1054,
4-(Dimethylamino)pyridine (208 mg, 1.7 mmol) was
added to a solution of 19 (3.1 g, 9.54 mmol) in a
mixture of acetic anhydride (13 ml) and pyridine (13
ml). The mixture was stirred at room temperature for
19.5 h. The acetic anhydride and pyridine were evapo-
rated under vacuum and the residue was purified by
silica gel column chromatography to give 20 as a
colorless oil (3.32 g, 95%
a
mixture of two
1
818, 763 cm−1; H NMR l 1.62 (3H, s), 2.33 (3H, s),
diastereomers). IR (neat) 1749 (CO), 1239 (COC), 1059
(SO), 812 cm−1.
2.55, 2.63 (each 1H, d, J=8.8 Hz), 6.19 (1H, d, J=5.5
Hz, d), 7.15 (4H, s), 7.66 (1H, d, J=5.5 Hz). MS m/z
(%) 186 (M+, 43), 171 (100), 143 (20), 128 (25), 115 (14),
91 (8). Calcd for C13H14O: M, 186.1044. Found: m/z
186.1053. [h]2D7 −134.3 (c 0.46, toluene; over 99% ee).
A solution of 20 (624 mg, 1.71 mmol) in 11 ml of dry
THF was added dropwise with stirring to a solution of
Ph2NLi (2.4 mmol) in 11 ml of THF in a flame-dried
flask at 0°C. After 8 min, the reaction was quenched by
adding sat aq. NH4Cl. The whole was extracted with
AcOEt–hexane, washed once with sat. aq. NH4Cl. The
organic layer was dried over MgSO4. The products
were purified by column chromatography to give a
mixture of 21 and 22 (484 mg, 93%). These were
separated on silica gel flash column chromatography
and the ratio of 21 and 22 was found to be 3:1. 21:
Colorless oil. IR (neat) 2923, 1589, 1492, 1274, 1084,
1048 (SO), 808, 754 cm−1; 1H NMR l 2.30 (3H, s,
vinyl-CH3), 2.39 (3H, s) 2.40 (3H, s), 7.19–7.44 (8H, m).
MS m/z (%) 304 (M+, 42), 256 (48), 195 (19), 153. (41),
129 (100), 115 (45), 91 (32). Calcd for C17H17ClOS: M,
304.0687. Found: m/z 304.0685. [h]2D1 +369 (c 0.60,
acetone). 22: Colorless oil. IR (neat) 2921, 1588, 1494,
3.10. (S)-4,5,5-Trimethyl-4-(4-methylphenyl)-2-cyclopen-
tenone, 25
A solution of cyclopentenone 24 (132 mg, 0.71 mmol)
in the minimum amount (about 0.2 ml) of dry DMF
wad added over 0.25 h to a stirred solution of NaH
(60% in mineral oil, 67.2 mg) in DMF (0.6 ml). The
reaction was stirred for 30 min, and CH3I was added
dropwise (0.31 ml, 1.68 mmol). The mixture was stirred
for 24 h at 20°C. The reaction was quenched with sat
aq. NH4Cl. The whole was extracted with AcOEt–hex-
ane, washed once with sat aq. NH4Cl. The organic
layer was dried over MgSO4 and the product was
purified by column chromatography to give 109 mg
(72%) of 25 as a colorless oil. IR (neat) 2972, 2923,
1709, 1588, 1512, 1450, 1385, 1264, 1185, 1122, 815
cm−1; 1H NMR l 0.53 (3H, s), 1.19 (3H, s), 1.45 (3H, s)
2.34 (3H, s), 6.22 (1H, d, J=5.8 Hz), 7.05, 7.14 (each
2H, d, J=5.5 Hz), 7.75 (1H, d, J=5.8 Hz). MS m/z (%)
214 (M+, 34), 199 (100), 185 (20), 171 (10), 156 (11), 141
(20), 128 (20). Calcd for C15H18O: M, 214.1356. Found:
m/z 214.1354. [h]2D7 +35.6 (c 0.40, acetone; over 99% ee).
1
1089, 1061 (SO), 891, 811 cm−1; H NMR l 2.35 (3H,
s, vinyl-CH3), 2.42 (3H, s), 2.60 (3H, s) 7.15–7.57 (8H,
m). [h]2D1 −18.8 (c 0.40, acetone).
3.8. (S)-(−)-2-Amino-1-cyano-5-methyl-5-(4-methyl-
phenyl)-1,3-cyclopentadiene, 23
Acetonitrile (0.105 ml, 2.0 mmol) was added to a
solution of n-BuLi (2.0 mmol) in 6 ml of dry THF at
−78°C with stirring. The solution was stirred for 15
min, then a solution of 21 (120 mg, 0.4 mmol) in THF
(1 ml) was added dropwise. The temperature of the
reaction mixture was gradually allowed to warm to
room temperature for 2 h and the reaction mixture was
stirred at room temperature for 30 min. The reaction
was quenched by sat aq. NH4Cl. The whole was
extracted with AcOEt–hexane. The organic layer was
washed once with sat aq. NH4Cl. The product was
isolated by silica gel column chromatography to give
62.4 mg (75%) of (S)-23 as colorless crystals; mp 85–
86°C (AcOEt–hexane). IR (KBr) 3463, 3344, 2925, 2172
(CN), 1646, 1609, 1541, 1514, 1420, 1237, 1088, 1060,
3.11. (S)-(+)-a-Cuparenone, 7
A solution of the cyclopentenone 25 (122 mg, 0.57
mmol) and 10% Pd–C (174 mg) in ethyl acetate (6 ml)
was evacuated and purged three times with hydrogen
and then stirred under 1 atm of hydrogen for 1 h. The
catalyst was then filtered off through a short pad of
silica gel and the solution was concentrated and the
product was purified by silica gel column chromatogra-
phy to yield a-cuparenone (120 mg, 97%): mp 51.5–
52°C (hexane). IR (KBr) 2968, 2923, 2868, 1731, 1512,
1
1
822, 780 cm−1; H NMR l 1.66 (3H, s), 2.31 (3H, s),
1463, 1407, 1378, 1259, 1096, 1059, 817 cm−1; H NMR
4.60 (2H, brs, NH), 6.06, 6.67 (each 1H, d, J=5.5 Hz),
4.10, 7.20 (each 2H, d, J=7.9 Hz). MS m/z (%) 211
(M+, 18), 210 (100), 209 (20), 195 (90), 168 (11). Anal.
calcd for C14H14N2: C, 79.97; H, 6.71; N, 13.32. Found:
C, 79.79; H, 6.57; N, 13.20%. [h]2D0 −373.6 (c 0.40,
acetone; over 99% ee).
l 0.62 (3H, s), 1.17 (3H, s), 1.90 (1H, m), 1.26 (3H, s),
2.34 (3H, s), 2.40 (2H, m), 2.60 (1H, m) 7.15–7.28 (4H,
m). MS m/z (%) 216 (M+, 16), 145 (20), 132 (11), 97
(11), 85 (11), 71 (16), 57 (24), 43 (16), 28 (19), 18 (100),
17 (22). Calcd for C15H20O: M, 216.1516. Found: m/z
216.1514. [h]2D8 +172.5 (c 0.49, CHCl3; over 99% ee).

288
T. Satoh et al. / Tetrahedron: Asymmetry 14 (2003) 281–288
7. (a) Baldwin, S. J. Org. Chem. 1961, 26, 3280; (b) Bald-
Acknowledgements
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This work was supported by a Grant-in-Aid for Scien-
tific Research No. 11640545 from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan,
which is gratefully acknowledged.
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