Stereoselective conjugate addition of alkyl groups to (S)-4-(tert-butyldimethylsilyloxy)-2-cyclopentenone derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00686-4

Reaction of (S)-2-benzenesulfonyl-4-(tert-butyldimethylsilyloxy)-2-cyclopentenone (2) and a 2-methoxycarbonyl congener (3) with R₂CuLi or RMgBr-CuI stereoselectively gave (2S,3R,4S)-3-alkyl-2-benzenesulfonyl-4-(tert-butyldimethysilyloxy)cyclopentan one (4) and its (2S,3S,4S)-2-methoxycarbonyl derivative (5) as a major diastereoisomer. On the other hand, reaction with R₃Al in toluene exclusively gave the corresponding 3,4-cis-adducts 6 and 7. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00686-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7715±7721
Stereoselective Conjugate Addition of Alkyl Groups to
(S)-4-(tert-Butyldimethylsilyloxy)-2-cyclopentenone Derivatives
*
Takayuki Yakura, Kenji Tanaka, Tomoko Kitano, Jun'ichi Uenishi and Masazumi Ikeda
*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
Received 27 June 2000; accepted 31 July 2000
AbstractÐReaction of (S)-2-benzenesulfonyl-4-(tert-butyldimethylsilyloxy)-2-cyclopentenone (2) and a 2-methoxycarbonyl congener (3)
with R2CuLi or RMgBr-CuI stereoselectively gave (2S,3R,4S)-3-alkyl-2-benzenesulfonyl-4-(tert-butyldimethylsilyloxy)cyclopentanone (4)
and its (2S,3S,4S)-2-methoxycarbonyl derivative (5) as a major diastereoisomer. On the other hand, reaction with R3Al in toluene exclusively
gave the corresponding 3,4-cis-adducts 6 and 7. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
The chiral building block O-tert-butyldimethylsilyl-
(TBDMS)-protected 4-hydroxy-2-cyclopentenone (1) has
been widely used as a valuable precursor for the synthesis
of prostaglandins, endiyne antitumor agents, and other
important bioactive compounds in an optically active
form.1±3 Recently, we reported a simple preparation of
new (S)-4-(TBDMSoxy)-2-cyclopentenone derivatives,
(S)-2-benzenesulfonyl-4-(TBDMSoxy)-2-cyclopentenone
(2)4a,5 and 2-methoxycarbonyl derivative (3),4 starting from
(S)-malic acid. Since 2 and 3 have an additional functional
group at the C-2 position, they are expected to be useful new
chiral cyclopentenone building blocks. As a synthetic appli-
cation of 2 and 3, we examined the conjugate addition of
organocopper and trialkylaluminum reagents to 2 and 3. We
found that the reactions of 2 and 3 with organocopper
reagents proceeded cleanly to give 3-alkyl-2-benzene-
sulfonyl-4-(TBDMSoxy)cyclopentanones 4a±d or 2-meth-
oxycarbonyl derivatives 5a,b with a 3,4-trans relationship,
whereas 2 and 3 reacted with trialkylaluminums to give the
corresponding 3,4-cis cyclopentanones 6a±c and 7a.6
(Scheme 1)
Conjugate addition reaction of organocopper reagents to
2 and 3.
The conjugate addition reaction7 of carbon nucleophiles to
a,b-unsaturated ketones is one of the most important
carbon±carbon bond-forming reactions. This reaction is
usually carried out using lithium dialkylcuprates or
Grignard reagents in the presence of copper(I) salt.
(Scheme 2)
We ®rst examined the reaction of organocopper reagents
with 2 and 3 (Table 1). Treatment of 2 with lithium
dimethylcuprate prepared from methyllithium and copper(I)
iodide at 2788C for 15 min gave (2S,3R,4S)-2-benzene-
sulfonyl-4-(TBDMSoxy)-3-methylcyclopentanone (4a) in
90% yield as a sole diastereoisomer, as expected.8 The
relative stereochemistry of the trans 2,3-substituents of 4a
was assigned on the basis of the large J value between H-2
and H-3 (10.5 Hz).9,10 The 3,4-trans-stereochemistry was
con®rmed by conversion of 4a by desulfonylation with
samarium(II) iodide (SmI2)11 in THF to 8, which was
Scheme 1.
Keywords: Michael reactions; aluminum and compounds; copper and compounds; cyclopentenones.
* Corresponding authors. Tel.: 181-75-595-4666; fax: 181-75-595-4763; e-mail: yakura@mb.kyoto-phu.ac.jp; juenishi@mb.kyoto-phu.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00686-4

7716
T. Yakura et al. / Tetrahedron 56 (2000) 7715±7721
Scheme 2.
Table 1. Conjugate addition of organocopper reagents to 2 and 3 (all reactions were carried out in THF at 2788C.)
Entry
Enone
Reagent
Time (min)
Total yield (%)
Products (ratio)a
1
2
3
2
2
2
2
3
3
Me2CuLi
15
15
15
20
30
30
90
85
82
98
71
59
4a
4b
4c
4d
EtMgBr, CuI
i-BuMgBr, CuI
CH2vCHMgBr, CuI
Me2CuLi
4
5b
6
5a17a (8:1)
5b17b (8:1)c
n-Bu2CuLi
a Determined by 1H NMR spectroscopy.
b Ref. 4.
c 13% of unreacted 3 was recovered.
identical with a racemic authentic sample.10 Similar reac-
tions of 2 with Grignard reagents in the presence of CuI
stereoselectively proceeded to provide 4b±d in 82±98%
yields (Table 1, entries 2±4). The ester congener 3, upon
treatment with Me2CuLi in THF at 2788C for 30 min, gave
an 8:1 mixture of the 3,4-trans adduct 5a and the 3,4-cis
adduct 7a in a combined yield of 71%.4 Similarly, 3 was
treated with lithium dibutylcuprate to give a mixture of 5b10
and 7b10 in a combined yield of 59% in a ratio of 8:1
alkylaluminums are known to be less reactive than
organocopper reagents for conjugate addition reactions to
a,b-unsaturated ketones, so that the reactions require an
additive such as a radical initiator,13 Ni(I),14 or Cu(I)
salt,15 or a doubly activated alkene as an electrophile.16
We anticipated that 2 and 3 could react with trialkyl-
aluminums, since these are activated as b-ketosulfone or
b-ketoester (Scheme 3).
1
(determined by H NMR spectroscopy) along with 13% of
A solution of 2.2 equiv. of Me3Al in hexane was added to a
solution of 2 in toluene at 2788C and the mixture was
stirred at the same temperature for 30 min to give
(2R,3S,4S)-2-benzenesulfonyl-4-(TBDMSoxy)-3-methyl-
cyclopentanone (6a) in 86% yield as a sole diastereoisomer
(Table 2, entry 1). The 2,3-trans- and 3,4-cis-stereo-
chemistries of 6a were determined by the J value between
the starting enone 3. These reactions proceed by the addition
of an alkyl group to the C-3 position from the less-hindered
a-side to give copper enolates A, which are then protonated
to produce the thermodynamically stable 2,3-trans-3,4-
trans adduct after work-up.
1
Conjugate addition reaction of trialkylaluminums to 2
and 3.
H-2 and H-3 (10.0 Hz) in H NMR spectroscopy and its
desulfonylation with SmI2 to 910 (72%). When 1 equiv. of
Me3Al was used, the reaction was not completed even after
stirring for 1.5 h; 6a was obtained in 49% yield along with
49% of unreacted 2 (Table 2, entry 2). Solvent effects were
observed in this reaction: the reaction in dichloromethane
Organoaluminum reagents are used as nucleophiles and
offer some advantages such as the availability of lower
alkyl ligands, ease of handling, and low toxicity.12 Tri-
Scheme 3.

T. Yakura et al. / Tetrahedron 56 (2000) 7715±7721
Table 2. Conjugate addition of organoaluminum reagents to 2, 3, 10, and 11
7717
Entry
Enone
Reagent (equiv.)
Solvent
Conditions
Total yield (%)
Products (ratio)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
10
11
3
Me3Al (2.2)
Me3Al (1)
Me3Al (2.2)
Me3Al (2.2)
Et3Al (2.2)
i-Bu3Al (2.2)
Et2Al±CuCTMS (2.2)
Me3Al (2.2)
Me3Al (2.2)
Me3Al (2.2)
Me3Al (4)
Toluene
Toluene
CH2Cl2
Et2O
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
2788C, 30 min
2788C, 1.5 h
2788C, 30 min
2788C, 3 h
2788C, 30 min
2788C, 30 min
2788C, 30 min
2788C, 30 min
2788C, 30 min
2788C, 30 min
2788C, 30 min
86
49a
74
6a
6a
6a
±
6b
6c
0b
65
32
Quant.
62d
0e
4e16d16b (51:31:18)c
12
±
7a
7a
9
10
11
22f
66
3
a 49% of unreacted 1b was recovered.
b 81% of unreacted 1b was recovered.
c Determined by 1H NMR spectroscopy.
d 24% of unreacted 10 was recovered.
e 22% of unreacted 11 was recovered.
f 22% of unreacted 3 was recovered.
gave 6a in a slightly lower yield (74%), while ether was not
effective; only unreacted 2 (81%) was recovered (Table 2,
entries 3 and 4).
position is important for both the reactivity and high stereo-
selectivity.
The ester congener 3, upon treatment with 2.2 equiv. of
Me3Al in toluene at 2788C for 30 min, gave the 3,4-cis
adduct 7a as a single diastereoisomer but in only 22%
yield, along with 22% of unreacted 3. The spectroscopic
data of 7a were identical to those of a racemic authentic
sample.10 The use of 4 equiv. of Me3Al increased the yield to
66%. In contrast, no reaction took place when the cyclo-
pentenone 1 was treated with Me3Al under the same
conditions. These results show that an additional electron-
withdrawing group at the C-2 position is necessary for the
reaction.
A similar reaction of 2 with 2.2 equiv. of triethylaluminum
proceeded exclusively to provide 6b in 65% yield. The
reaction of 2 with triisobutylaluminum gave 6c in 32%
yield as a sole stereoisomer. The stereochemistry of the
products 6b and 6c was determined by a comparison of
the coupling constants of H-2 and H-3, and H-3 and H-4
(J2,3ˆ9.6, 9.8 Hz and J3,4ˆ3.6, 3.7 Hz, respectively) in the
1H NMR spectra with those of 6a (J2,3ˆ10.0 Hz and
J3,4ˆ3.7 Hz). In contrast, a similar reaction of diethyl(tri-
methylsilylethynyl)aluminum17 in toluene gave an insepar-
able 51:31:18 mixture of 4e, 6d and 6b in quantitative yield
(see Experimental).
One possible explanation for the high diastereoselectivity in
the reaction of 2 and 3 with R3Al is based on the assumption
of a 1:2 complex of B and C, respectively. Thus, the ®rst
alane combines with the keto and sulfonyl or ester groups as
a Lewis acid to activate the enone 2 or 3. The second R3Al
chelates an oxygen atom of the TBDMSO group to form the
intermediate B or C.18 The alkyl group is then transferred
intramolecularly from the chelated R3Al to give the 3,4-cis
adducts 6a±d and 7a. The nucleophilicity of the alkyl group
of the resulting ate-complex is higher than that for a
noncoordinated R3Al.13a,19 A bulky alane such as triiso-
butylaluminum and/or a bulky silyloxy group such as a
TIPSO group at the C-4 position would retard the formation
of the intermediate B to reduce the yield of the conjugate
addition. The high reactivity of diethyl(trimethylsilyl-
ethynyl)aluminum to enones20 would allow the reaction
To study the reaction mechanism, the TBDMSO group at
the C-4 position was replaced by triisopropylsilyl(TIPS)oxy
and methyl groups. Thus, 2-benzenesulfonyl-4-(TIPSoxy)-
2-cyclopentenone (10) and 2-benzenesulfonyl-4-methyl-2-
cyclopentenone (11) were treated with Me3Al (Table 2,
entries 8 and 9). Reaction of 10 with 2.2 equiv. of Me3Al
in toluene for 30 min gave the 3,4-cis adduct 12 in 62%
yield as a sole diastereoisomer along with 24% of unreacted
10. The 1H NMR spectrum of 12 indicated the 2,3-trans and
3,4-cis relationships (J2,3ˆ9.5 Hz and J3,4ˆ4.0 Hz). On the
other hand, the conjugate addition reaction of compound 11
with 4 equiv. of Me3Al completely failed; 22% of unreacted
11 and complex mixtures were isolated. These results
indicate that the presence of the silyloxy group at the C-4
Figure 1.

7718
T. Yakura et al. / Tetrahedron 56 (2000) 7715±7721
to proceed through a non-chelated intermediate D, in
which the nucleophile attacks from the less-hindered side
to give the 3,4-trans isomer 3. In ether, complexation of
R3Al with ether would make it unable to form intermediate
B.
EtOAc, 20:1) to give (S)-1-benzenesulfonyl-4,5-bis(tert-
butyldimethylsilyloxy)-1-diazo-2-pentanone (720 mg,
95%) as a pale yellow oil: [a]2D6ˆ248.2 (c 1.00, CHCl3);
1
IR (CCl4) n 2120, 1670, 1340, 1150 cm21; H NMR d:
20.16, 20.02, 0.01, 0.02 (all 3H, s), 0.75, 0.85 (both 9H,
s), 2.68 (1H, d of ABq, Jˆ7.8, 14.5 Hz), 2.75 (1H, d of ABq,
Jˆ4.4, 14.5 Hz), 3.34 (1H, dd, Jˆ10.1, 6.9 Hz), 3.53 (1H,
dd, Jˆ10.1, 4.6 Hz), 4.07±4.17 (1H, m), 7.52±7.59 (2H, m),
7.61±7.68 (1H, m), 8.00±8.06 (2H, m). Anal. Calcd for
C23H40N2O5SSi2: C, 53.87; H, 7.86; N, 5.46. Found: C,
53.57; H, 7.27; N, 5.87. A solution of the diazoketosulfone
(890 mg, 1.74 mmol) in CH2Cl2 (2 mL) was added to a
boiling solution of Rh2(OAc)4 (8 mg, 0.017 mmol) in
CH2Cl2 (15 mL), and the mixture was re¯uxed for 15 min.
After evaporation of the solvent, the crude material was
chromatographed on silica gel (hexane/EtOAc, 7:1) to
give 2 (443 mg, 72%) as colorless crystals: mp 90±91.58C
(hexane/EtOAc); [a]D26ˆ280.1 (c 1.02, CHCl3); IR (CCl4)
In summary, this study revealed the stereoselective conju-
gate addition of alkyl groups to optically active (S)-4-
(TBDMSoxy)-2-cyclopentenone derivatives 2 and 3 by
means of organocopper reagents and trialkylaluminums.
Reaction of 2 and 3 with organocopper reagents stereo-
selectively gave the corresponding 3,4-trans adduct, while
trialkylaluminum led to the 3,4-cis adduct as a single
diastereoisomer. (Fig. 1)
Experimental
1
n 1740, 1630, 1320, 1150 cm21; H NMR d: 0.12, 0.14
All melting points are uncorrected. IR spectra were recorded
using a JASCO IR-1 spectrophotometer. H NMR spectra
1
(both 3H, s), 0.90 (9H, s), 2.43 (1H, dd, Jˆ18.5, 2.6 Hz),
2.88 (1H, dd, Jˆ18.5, 6.2 Hz), 5.00 (1H, dt, Jˆ6.2, 2.4 Hz),
7.52±7.61 (2H, m), 7.63±7.70 (1H, m), 8.05±8.10 (2H, m),
8.13 (1H, d, Jˆ2.3 Hz). Anal. Calcd for C17H24O4SSi: C,
57.92; H, 6.86. Found: C, 57.82; H, 6.94.
were determined with a Varian XL-300 (300 MHz) spectro-
meter using CDCl3 as a solvent and tetramethylsilane as an
internal standard. Speci®c rotations were recorded on a
JASCO DIP-360 polarimeter. High-resolution mass spectra
(Exact FAB-MS) were obtained with a JEOL JMS-SX 102A
instrument. Column chromatography was carried out on
Silica gel 60 PF254 (Nacalai Tesque, Inc.) under pressure.
Known cyclpentenone 3 was prepared according to the
reported procedure.4b
Conjugate addition of lithium dimethylcuprate to 2. A
solution of methyllithium in Et2O (1.14 M, 1.1 mL,
1.19 mmol) was added to a suspension of CuI (113 mg,
0.59 mmol) in THF (5 mL) at 2788C under a nitrogen
atmosphere and the mixture was stirred at 2208C for
5 min. The mixture was recooled to 2788C, a solution of
2 (100 mg, 0.30 mmol) in THF (2 mL) was added to the cold
mixture. The whole was stirred for further 15 min, and then
aq. NH4Cl was added. The organic layer was separated, and
the aqueous layer was extracted with Et2O and the combined
extracts were washed with brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica
gel (hexane/EtOAc, 20:1) to give (2S,3R,4S)-2-benzene-
sulfonyl-4-(tert-butyldimethylsilyloxy)-3-methylcyclo-
pentanone (4a) (99 mg, 90%) as colorless crystals: mp 107±
1088C (hexane); [a]D23ˆ1144.4 (c 1.09, CHCl3); IR (CCl4)
n 1760, 1320, 1150 cm21; 1H NMR d: 0.04, 0.08 (both 3H,
s), 0.89 (9H, s), 1.31 (3H, d, Jˆ6.6 Hz), 2.43 (1H, dd,
Jˆ17.1, 10.3 Hz), 2.57 (1H, ddd, Jˆ17.1, 6.6, 1.0 Hz),
2.78 (1H, ddq, Jˆ10.5, 8.5, 6.6 Hz), 3.40 (1H, br d,
Jˆ10.5 Hz), 3.79 (1H, ddd, Jˆ10.3, 8.5, 6.6 Hz), 7.75±
7.62 (2H, m), 7.66±7.73 (1H, m), 7.87±7.92 (2H, m).
Anal. Calcd for C18H28O4SSi: C, 58.66; H, 7.66. Found:
C, 58.40; H, 7.56.
(S)-2-Benzenesulfonyl-4-(tert-butyldimethylsilyloxy)-2-
cyclopentenone (2). A solution of methyl phenyl sulfone
(1.28 g, 8.19 mmol) in THF (10 mL) was added to a solution
of LDA in THF (20 mL), prepared from diisopropylamine
(954 mg, 9.43 mmol) and butyllithium (1.6 M in hexane,
5.38 mL, 8.60 mmol), at 2788C under a nitrogen
atmosphere and the mixture was stirred for 1 h. Then a
solution of methyl (S)-3,4-bis(tert-butyldimethylsilyloxy)-
butanoate4b (1.49 g, 4.10 mmol) in THF (16 mL) was
added to the solution of the anion at the same temperature.
The whole mixture was stirred for 10 min, and then aq.
NH4Cl was added. The organic layer was separated, and
the aqueous layer was extracted with EtOAc and the
combined extracts were washed with brine, dried
(MgSO4), and concentrated. The residue was chromato-
graphed on silica gel (hexane/EtOAc, 20:1) to give (S)-1-
benzenesulfonyl-4,5-bis(tert-butyldimethylsilyloxy)-2-
pentanone (1.46 g, 75%) as a pale yellow oil: [a]2D4ˆ219.1
1
(c 1.01, CHCl3); IR (CCl4) n 1720, 1320, 1150 cm21; H
NMR d: 0.015, 0.024, 0.03, 0.06 (all 3H, s), 0.84, 0.87 (both
9H, s), 2.78 (1H, d of ABq, Jˆ6.9, 15.6 Hz), 2.94 (1H, d of
ABq, Jˆ4.9, 15.6 Hz), 3.38 (1H, dd, Jˆ10.0, 6.9 Hz), 3.55
(1H, dd, Jˆ10.0, 4.8 Hz), 4.06±4.16 (1H, m), 4.20, 4.26
(each 1H, ABq, Jˆ13.5 Hz), 7.53±7.61 (2H, m), 7.64±
7.71 (1H, m), 7.87±7.92 (2H, m). HRMS (FAB) Calcd for
C23H43O5SSi2 [(M1H)1]: 487.2370. Found: 487.2361. The
mixture of the ketosulfone (716 mg, 1.47 mmol), p-toluene-
sulfonyl azide (304 mg, 1.54 mmol) and Et3N (521 mg,
5.15 mmol) in MeCN (15 mL) was stirred at room tempera-
ture for 1 h. The solution was concentrated and the residue
was diluted with Et2O (30 mL). The solution was washed
with 9% KOH and brine, dried (MgSO4), and concentrated.
The residue was chromatographed on silica gel (hexane/
(3S,4S)-3-(tert-Butyldimethylsilyloxy)-4-methylcyclo-
pentanone (8). According to the procedure of Molander and
Hahn,11 a solution of SmI2 in THF (0.1 M, 3.3 mL,
0.33 mmol) was added to a solution of 4a (40 mg,
0.11 mmol) in THF (1 mL) and MeOH (0.5 mL) at 2788C
under a nitrogen atmosphere and the mixture was stirred at
the same temperature for 10 min and at room temperature
for 30 min. The mixture was poured into sat. aq. K2CO3
(10 mL), and extracted with Et2O. The extract was dried
(MgSO4) and concentrated. The residue was chromato-
graphed on silica gel (hexane/EtOAc, 20:1) to give 8
(22 mg, 88%) as a colorless oil, whose spectroscopic data
were identical with those of an authentic sample.10

T. Yakura et al. / Tetrahedron 56 (2000) 7715±7721
7719
Conjugate addition of ethylmagnesium bromide and
copper(I) iodide to 2. A solution of ethylmagnesium
bromide in THF (0.96 M, 0.83 mL, 0.8 mmol) was added
to a solution of CuI (76 mg, 0.4 mmol) in THF (4 mL) at
2788C under a nitrogen atmosphere and the mixture was
stirred at 2208C for 10 min. The mixture was recooled to
2788C, and a solution of 2 (67 mg, 0.2 mmol) in THF
(2 mL) was added to the cold mixture. The whole was
stirred for further 15 min, and then aq. NH4Cl was added.
The organic layer was separated, and the aqueous layer was
extracted with EtOAc and the combined extracts were
washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (hexane/EtOAc,
10:1) to give (2S,3R,4S)-2-benzenesulfonyl-4-(tert-butyl-
dimethylsilyloxy)-3-ethylcyclopentanone (4b) (65 mg,
85%) as colorless crystals: mp 118±1208C (hexane/
EtOAc); [a]2D7ˆ227.6 (c 0.21 CHCl3); IR (KBr) n 1750,
1320, 1140 cm21; 1H NMR d: 0.03, 0.08 (both 3H, s), 0.89
(9H, s), 0.99 (3H, t, Jˆ7.5 Hz), 1.73 (2H, qd, Jˆ7.5,
5.9 Hz), 2.50 (1H, dd, Jˆ16.9, 9.2 Hz), 2.57 (1H, ddd,
Jˆ16.9, 6.6, 1.0 Hz), 2.85 (1H, ddt, Jˆ9.2, 7.3, 5.9 Hz),
3.73 (1H, br d, Jˆ9.2 Hz), 3.99 (1H, dt, Jˆ9.2, 7.0 Hz),
7.52±7.61 (2H, m), 7.64±7.71 (1H, m), 7.85±7.91 (2H,
m). HRMS (FAB) Calcd for C19H31O4SSi [(M1H)1]:
383.1712. Found: 383.1707.
Conjugate addition of lithium dibutylcuprate to 3.
According to a procedure similar to that described for the
reaction of 2 with lithium dimethylcuprate, treatment of 3
(119 mg, 0.44 mmol) with lithium dibutylcuprate prepared
by butyllithium (1.6 M, 1.1 mL, 1.76 mmol) and CuI
(168 mg, 0.88 mmol) gave an oily mixture of 5b and 7b
(total 85 mg, 59%). The ratio of 5b and 7b was estimated
to be 8:1 by an integrated intensity of the peak heights of the
signals due to the methine proton at the 1-position appeared
at d 2.88 (d) and 3.15 (d), respectively.8 The mixture was
rechromatographed on silica gel (hexane/EtOAc, 50:1). The
®rst fraction gave methyl (1S,2S,3S)-3-(tert-butyldimethyl-
silyloxy)-2-butyl-5-oxocyclopentanecarboxylate (5b) as an
oil, whose spectroscopic data were identical with those of an
authentic sample.10 The second fraction gave methyl
(1R,2R,3S)-3-(tert-butyldimethylsilyloxy)-2-butyl-5-oxo-
cyclopentanecarboxylate (7b) as an oil, whose spectro-
scopic data were identical with those of an authentic
sample.10
Conjugate addition of trimethylaluminum to 2. General
procedure. A 1.0 M solution of Me3Al in hexane (0.63 mL,
0.63 mmol) was added to a solution of 2 (100 mg,
0.28 mmol) in toluene (6 mL) at 2788C under a nitrogen
atmosphere. The mixture was stirred at the same tempera-
ture for 30 min and quenched with sat. aq. NH4Cl. The
mixture was allowed to warm to room temperature and
extracted with EtOAc. The extract was washed with brine,
dried (MgSO4), and concentrated. The residue was chroma-
tographed on silica gel (hexane/EtOAc, 10:1) to give
(2R,3S,4S)-2-benzenesulfonyl-4-(tert-butyldimethylsilyloxy)-
3-methylcyclopentanone (6a) (89 mg, 86%) as colorless
crystals: mp 111±113.58C (hexane); [a]2D4ˆ296.9 (c 1.08,
Conjugate addition of isobutylmagnesium bromide and
copper(I) iodide to 2. According to a procedure similar to
that described for the reaction of 2 with EtMgBr and CuI,
treatment of 2 (67 mg, 0.2 mmol) with isobutylmagnesium
bromide in Et2O (2.0 M, 0.4 mL, 0.8 mmol) and CuI
(67 mg, 0.4 mmol) gave (2S,3R,4S)-2-benzenesulfonyl-4-
(tert-butyldimethylsilyloxy)-3-(2-methylpropyl)cyclo-
pentanone (4c) (67 mg, 82%) as colorless crystals: mp 69±
728C (hexane); [a]2D7ˆ113.2 (c 0.41 CHCl3); IR (KBr) n
1755, 1310, 1140 cm21; 1H NMR d: 0.03, 0.08 (both 3H, s),
0.89 (9H, s), 0.66 (3H, d, Jˆ 6.6 Hz), 0.96 (3H, d,
Jˆ6.4 Hz), 1.35±1.57 (2H, m), 1.79±1.96 (1H, m), 2.51
(1H, dd, Jˆ16.9, 8.3 Hz), 2.59 (1H, dd, Jˆ17.1,
6.6 Hz), 2.89±3.01 (1H, m), 3.41 (1H, d, Jˆ7.7 Hz),
3.95 (1H, dt, Jˆ8.4, 6.6 Hz), 7.53±7.62 (2H, m),
7.64±7.72 (1H, m), 7.85±7.92 (2H, m). HRMS (FAB)
Calcd for C21H35O4SSi [(M1H)1]: 411.2025. Found:
411.2020.
1
CHCl3); IR (CCl4) n 1760, 1320, 1140 cm21; H NMR d:
0.02, 0.05 (both 3H, s), 0.82 (9H, s), 1.30 (3H, d, Jˆ6.8 Hz),
2.31 (1H, dt, Jˆ16.8, 1.0 Hz), 2.54 (1H, dd, Jˆ16.8,
3.9 Hz), 2.96 (1H, dqd, Jˆ10.0, 6.8, 3.5 Hz), 3.48 (1H, d,
Jˆ10.0 Hz), 4.31 (1H, t, Jˆ3.7 Hz), 7.54±7.61 (2H, m),
7.65±7.71 (1H, m), 7.86±7.91 (2H, m). Anal. Calcd for
C18H28O4SSi: C, 58.66; H, 7.66. Found: C, 58.87; H, 7.51.
Use of CH2Cl2 as a solvent: Compound 2 (100 mg,
0.28 mmol) was treated with Me3Al (1.0 M solution in
hexane, 0.63 mL, 0.63 mmol) in CH2Cl2 (6 mL) to give 6a
(77 mg, 74%).
Conjugate addition of vinylmagnesium bromide and
copper(I) iodide to 2. According to a procedure similar to
that described for the reaction of 2 with EtMgBr and CuI,
treatment of 2 (94 mg, 0.28 mmol) with vinylmagnesium
bromide in Et2O (1.14 M, 1.1 mL, 1.12 mmol) and CuI
(106 mg, 0.56 mmol) gave (2S,3R,4S)-2-benzenesulfonyl-
4-(tert-butyldimethylsilyloxy)-3-vinylcyclopentanone (4d)
(100 mg, 98%) as colorless crystals: mp 85±868C (hexane);
[a]2D3ˆ1147.7 (c 1.00, CHCl3); IR (CCl4) n 1760, 1320,
(3S,4R)-3-(tert-Butyldimethylsilyloxy)-4-methylcyclo-
pentanone (9). According to a procedure similar to that
described for the preparation of 8, treatment of 6a (40 mg,
0.11 mmol) with SmI2 (0.1 M in THF, 3.3 mL, 0.33 mmol)
gave 9 (18 mg, 72%) as a colorless oil, whose spectroscopic
data were identical with those of an authentic sample.10
Conjugate addition of triethylaluminum to 2. Following
the general procedure, 2 (83 mg, 0.24 mmol) was treated
with Et3Al (1.0 M in hexane, 0.52 mL, 0.52 mmol) in
toluene (6 mL) to give (2R,3S,4S)-2-benzenesulfonyl-4-
1
1150 cm21; H NMR d: 0.02, 0.03 (both 3H, s), 0.87 (9H,
s), 2.54 (1H, dd, Jˆ17.1, 10.0 Hz), 2.64 (1H, ddd, Jˆ17.1,
7.0, 0.9 Hz), 3.33 (1H, dt, Jˆ10.0, 8.0 Hz), 3.68 (1H, dd,
Jˆ10.2, 0.9 Hz), 3.98 (1H, ddd, Jˆ10.1, 8.2, 6.9 Hz), 5.13
(1H, dt, Jˆ10.2, 1.0 Hz), 5.17 (1H, dt, Jˆ17.0, 1.0 Hz), 5.69
(1H, ddd, Jˆ17.1, 10.2, 7.8 Hz), 7.53±7.61 (2H, m, ArH),
7.64±7.71 (1H, m, ArH), 7.85±7.90 (2H, m, ArH). Anal.
Calcd for C19H28O4SSi: C, 59.96; H, 7.42. Found: C, 59.60;
H, 7.45.
(tert-butyldimethylsilyloxy)-3-ethylcyclopentanone (6b)
(58 mg, 65%) as colorless crystals: mp 102±1078C
(hexane); [a]2D3ˆ260.1 (c 1.14, CHCl3); IR (CCl4) n
1
1760, 1320, 1140 cm21; H NMR d: 0.03, 0.07 (both 3H,
s), 0.81 (9H, s), 1.01 (3H, t, Jˆ7.4 Hz), 1.70±1.93 (2H, m),
2.34 (1H, br d, Jˆ16.6 Hz), 2.55 (1H, dd, Jˆ16.6, 3.9 Hz),

7720
T. Yakura et al. / Tetrahedron 56 (2000) 7715±7721
2.76 (1H, tt, Jˆ10.0, 4.0 Hz), 3.48 (1H, br d, Jˆ9.6 Hz),
4.50 (1H, t, Jˆ3.6 Hz), 7.54±7.62 (2H, m), 7.65±7.72 (1H,
m), 7.85±7.90 (2H, m). Anal. Calcd for C19H30O4SSi: C,
59.65; H, 7.90. Found: C, 59.37; H, 7.90.
Conjugate addition of trimethylaluminum to 10. Follow-
ing the general procedure, 10 (25 mg, 0.063 mmol) was
treated with Me3Al (1.0 M in hexane, 0.14 mL,
0.14 mmol) in toluene (3 mL) to give unreacted 10 (6 mg,
24%) and (1R,2S,3S)-2-benzenesulfonyl-3-methyl-4-(tri-
isopropylsilyloxy)cyclopentanone (12) (16 mg, 62%) as a
colorless oil: [a]D26ˆ266.4 (c 1.01, CHCl3); IR (CCl4) n
Conjugate addition of triisobutylaluminum to 2. Follow-
ing the general procedure, 2 (100 mg, 0.28 mmol) was
treated with iBu3Al (15% in hexane, 0.86 mL, 0.62 mmol)
in toluene (6 mL) to give (2R,3S,4S)-2-benzenesulfonyl-4-
(tert-butyldimethylsilyloxy)-3-(2-methylpropyl)cyclo-
pentanone (6c) (38 mg, 32%) as colorless crystals: mp 102±
1
1760, 1320, 1150 cm21; H NMR d: 0.99±1.05 (21H, m),
1.37 (3H, d, Jˆ6.8 Hz), 2.43 (1H, dt, Jˆ16.8, 1.5 Hz), 2.58
(1H, dd, Jˆ16.8, 4.0 Hz), 3.01 (1H, dqd, Jˆ9.5, 6.8,
4.0 Hz), 3.50 (1H, dt, Jˆ9.5, 0.6 Hz), 4.53 (1H, td, Jˆ4.0,
1.3 Hz), 7.56±7.61 (2H, m), 7.67±7.72 (1H, m), 7.87±7.90
(2H, m). Anal. Calcd for C21H34O4SSi: C, 61.42; H, 8.35.
Found: C, 61.00; H, 8.28.
1
1078C (hexane); IR (CCl4) n 1760, 1310, 1140 cm21; H
NMR d: 0.01, 0.06 (both 3H, s), 0.81 (9H, s), 0.93 (3H, d,
Jˆ6.5 Hz), 0.98 (3H, d, Jˆ6.4 Hz), 1.36±1.49 (1H, m),
1.60±1.86 (2H, m), 2.34 (1H, d, Jˆ16.6 Hz), 2.55 (1H,
dd, Jˆ16.6, 3.7 Hz), 2.92 (1H, tt, Jˆ10.2, 3.9 Hz), 3.46
(1H, d, Jˆ9.8 Hz), 4.43 (1H, t, Jˆ3.5 Hz), 7.54±7.62 (2H,
m), 7.65±7.72 (1H, m), 7.85±7.90 (2H, m). HRMS (FAB)
Calcd for C21H35O4SSi [(M1H)1]: 411.2025. Found:
411.2017.
Conjugate addition of trimethylaluminum to 3. Follow-
ing the general procedure, 3 (526 mg, 0.91 mmol) was
treated with Me3Al (1.0 M in hexane, 3.64 mL,
3.64 mmol) in toluene (10 mL) to give methyl (1R,2R,3S)-
3-(tert-butyldimethylsilyloxy)-2-methyl-5-oxocyclopentane-
carboxylate (7a) (172 mg, 66%) as colorless crystals: mp
64±658C (pentane); [a]2D4ˆ232.2 (c 1.06, CHCl3), whose
spectroscopic data were identical with a racemic authentic
sample.10
Conjugate addition of alkynylaluminum to 2. According
to the procedure reported by CarrenÄo et al.,17 a solution of
butyllithium (1.6 M in hexane, 0.44 mL, 0.71 mmol) was
added to a solution of (trimethylsilyl)acetylene (70 mg,
0.71 mmol) in toluene (5 mL) at 08C, and the mixture was
stirred at room temperature for 30 min. A solution of
diethylaluminum chloride (1 M in hexane, 0.71 mL,
0.71 mmol) was added at 08C and then stirred for 30 min
at the same temperature to give a solution of diethyl[(tri-
methylsilyl)ethynyl]aluminum in toluene-hexane. Follow-
References
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Chem. Int. Ed. Engl. 1984, 23, 847±876; Corey, E. J.; Cheng,
X.-M. The Logic of Chemical Synthesis; John Wiley & Sons:
New York, 1989.
ing the general procedure from here,
2 (100 mg,
0.28 mmol) was treated with the above prepared aluminun
reagent in toluene±hexane to give a 51:31:18 inseparable
mixture of (2S,3R,4S)-2-benzenesulfonyl-4-(tert-butyl-
dimethylsilyloxy)-3-[(trimethylsilyl)ethynyl]cyclopentanone
(4e), its (2R,3S,4S)-isomer 6d, and 6b (total 124 mg, quant.)
2. For the recent syntheses of endiyne antitumor agents starting
from 1, see; Myers, A. G.; Hammond, M.; Wu, Y.; Xiang, J.-N.;
Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1996, 118,
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as colorless crystals; IR (CCl4) n 1760, 1320, 1150 cm21
;
1H NMR for 4e d: 0.04 (9H, s), 0.09, 0.13 (both 3H, s), 0.90
(9H, s), 2.50±2.75 (2H, m), 3.48 (1H, dd, Jˆ9.8, 8.0 Hz),
3.84 (1H, d, Jˆ9.7 Hz), 4.23 (1H, ddd, Jˆ10.1, 7.9, 6.8 Hz),
7.75±7.62 (2H, m), 7.66±7.73 (1H, m), 7.85±7.97 (2H, m).
Selected signals for 6d d: 0.84 (9H, s), 2.43 (1H, dt, Jˆ16.8,
1.3 Hz), 3.64 (1H, dd, Jˆ9.4, 3.8 Hz), 3.95 (1H, d,
Jˆ9.3 Hz). HRMS (FAB) for 4e and 6d Calcd for
C22H35O4SSi2 [(M1H)1]: 451.1796. Found: 451.1791.
The ratio of 4e, 6d and 6b was estimated to be 51:31:18
by an integrated intensity of the peak heights of the signals
due to the protons of the tert-butyl group appeared at d 0.90,
0.84 and 0.81, respectively.
3. For the synthesis of optically active 1, see; Paquette, L. A.;
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Ikeda, M. Chem. Pharm. Bull. 1998, 46, 1182±1183. (b) Yakura,
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5. Although racemic 2 was reported in the literature, its spectral
data are not available, see: Donaldson, R. E.; Saddler, J. C.; Byrn,
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(S)-2-Benzenesulfonyl-4-(triisopropylsilyloxy)-2-cyclo-
pentenone (10). According to a procedure similar to that
described for the preparation of 2, alkylation of the TIPS
ether of methyl (S)-3,4-dihydroxybutanoate, followed by
diazotransfer reaction and Rh(II)-catalyzed reaction gave
10 as a colorless oil: [a]2D3ˆ243.3 (c 1.08, CHCl3); IR
6. Part of this work has appeared in a preliminary communication:
Yakura, T.; Tanaka, K.; Iwamoto, M.; Nameki, M.; Ikeda, M.
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7. Perlmutter, P. Conjugate Addition in Organic Synthesis,
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8. Although Fuchs and co-workers5 reported a similar stereo-
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1
(CCl4) n 1730, 1630, 1320, 1160 cm21; H NMR d: 1.04±
1.09 (21H, m), 2.49 (1H, dd, Jˆ18.5, 2.5 Hz), 2.92 (1H, dd,
Jˆ18.5, 6.1 Hz), 5.09 (1H, dt, Jˆ6.0, 2.4 Hz), 7.54±7.59
(2H, m), 7.64±7.69 (1H, m), 8.06±8.10 (2H, m), 8.17 (1H,
d, Jˆ2.4 Hz). HRMS (FAB) Calcd for C20H31O4SSi
[(M1H)1]: 395.1712. Found: 395.1718.

T. Yakura et al. / Tetrahedron 56 (2000) 7715±7721
7721
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