Formal total synthesis of (+)-wortmannin using catalytic asymmetric intramolecular aldol condensation reaction

Article abstract of DOI:10.1016/j.tet.2005.03.038

A catalytic process for the synthesis of optically active C4-substituted tetrahydroindandiones using an asymmetric intramolecular aldol condensation reaction was developed. When 30 mol% of phenylalanine and 50 mol% of pyridinium p-toluenesulfonate were us

Full text of DOI:10.1016/j.tet.2005.03.038

Tetrahedron 61 (2005) 5057–5065
Formal total synthesis of (C)-wortmannin using catalytic
asymmetric intramolecular aldol condensation reaction
*
Hiroki Shigehisa, Takashi Mizutani, Shin-ya Tosaki, Takashi Ohshima
*
and Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 5 February 2005; revised 9 March 2005; accepted 9 March 2005
Available online 31 March 2005
Abstract—A catalytic process for the synthesis of optically active C4-substituted tetrahydroindandiones using an asymmetric intramolecular
aldol condensation reaction was developed. When 30 mol% of phenylalanine and 50 mol% of pyridinium p-toluenesulfonate were used
under highly concentrated conditions, a variety of C4-substituted tetrahydroindandiones and octahydronaphthalenediones were obtained
in high yield (up to 89% yield) and high enantiomeric excess (up to 94% ee). One of the products was successfully transformed into
the key intermediate for the synthesis of the phosphatidylinositol 3-kinase inhibitor wortmannin, achieving formal total synthesis of
(C)-wortmannin.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The challenging molecular structure of 1 (a bisallylic
quaternary carbon center and a highly reactive furano-
cyclohexadienone lactone unit on the steroid back-
bone)3,12,13 coupled with its exciting biological actions,
prompted us to attempt its total synthesis. In 1996, we
succeeded in the first chemical synthesis of 1 from
hydrocortisone.14 Later, the first direct total synthesis of
(G)-1 from simple cyclic diketone 3 was also achieved by
our group using an intramolecular Heck reaction of 6a and a
diosphenol Claisen rearrangement as key steps
(Scheme 1).15 Recently, Sorensen and co-workers reported
a racemic total synthesis of the related natural product
viridin (2), using rhodium-catalyzed cyclotrimerization, a
Phosphatidylinositol 3-kinase (PI 3-kinase) is an important
enzyme that functions in signal transduction pathways, and
its inhibitors are often used as a biological tool in cell
molecular biology.1 These agents have contributed greatly
to studies of intracellular signaling pathways in diabetes and
cancer research. Wortmannin (1) was isolated from
Penicillium wortmanniii2 and Myrothecium roridium3 as
an antifungal antibiotic, and later determined to be a potent
and specific covalent inhibitor of PI 3-kinase (Fig. 1).4–6 In
addition, it has potent inhibitory activity on smooth muscle
light chain kinase,7 anti-inflammatory activity comparable
to that of indomethacin,8,9 and other biological activities.10,11
Figure 1. Structures of wortmannin (1) and viridin (2).
Keywords: Enantioselective synthesis; (C)-Wortmannin; Intramolecular
aldol condensation reaction.
*
Corresponding authors. Tel.: C81 3 5684 0651; fax: C81 3 5684 5206;
e-mail: mshibasa@mol.f.u-tokyo.ac.jp
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.038

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H. Shigehisa et al. / Tetrahedron 61 (2005) 5057–5065
thermal electrocyclic rearrangement, and Donohoe
dihydroxylation.16
protostenediols synthetic intermediate 8e, in which
50 mol% of camphorsulfonic acid was used instead of 1 N
HClO4 with 1 equiv of L-phenylalanine (77% yield, 95%
ee).25 These stoichiometric reactions prompted us to
develop a more atom economical catalytic process for the
synthesis of C4-substituted tetrahydroindandione 8. Herein,
we describe the catalytic asymmetric intramolecular aldol
reaction of triketone 9 to 8 with broad substrate generality.
The concentrations, additive, and sonication were very
important to improve the reactivity of the reaction. More-
over, the product 8a was successfully converted to key
intermediates 5 and 7a, achieving formal total synthesis of
(C)-wortmannin.
From a medicinal viewpoint, syntheses of optically active
wortmannin (1) as well as its derivatives, which possess
more potent inhibitory activity and have less toxicity, are
highly desirable for the development of new antitumor
drugs. Other than our chemical transformation from (C)-
hydrocortisone, asymmetric synthesis of 1 has not been
reported, and a new versatile and direct method for the
asymmetric synthesis of 1 is in high demand. To address this
issue, we previously examined a kinetic resolution using an
asymmetric Heck reaction of 6 with several chiral ligands.17
All trials of this strategy, unfortunately, resulted in low
chemical yield although the enantiomeric excess of 7c was
excellent. These unsatisfactory results18 led us to search for
a more direct route to optically active 7a, namely an
asymmetric intramolecular aldol condensation reaction of
triketone 9a to 8a (Scheme 2).
2. Results and discussion
2.1. Catalytic asymmetric intramolecular aldol
condensation reaction
The substrate 9a for the aldol condensation was synthesized
in the following two steps (i) a palladium coupling reaction
of the alkylzinc prepared from 1026 with acryloyl chloride,
and (ii) a Michael reaction of diketone 3 to 10 (53% yield
for two steps) (Scheme 3).
Scheme 3. Reagents and conditions: (a) Zn–Cu, THF, reflux, then
Pd(OAc)2 (1 mol%), PPh3 (2.5 mol%), acryloyl chloride, 0 8C to rt; (b) 3,
NEt3 (30 mol%), DMF, 0 8C to rt, 53% for two steps.
As a preliminary experiment, Danishefsky’s condition was
first applied to the substrate 9a and the desired product 8a
was obtained in 47% yield and 58% ee (Table 1, Entry 1).
We first screened a variety of natural and synthetic amino
acids, including proline (Entry 2), and phenylalanine was
best in terms of total efficiency. Next, we investigated
additive effects. By changing the additive from HClO4 to
pyridinium p-toluenesulfonate (PPTS), the reactivity was
greatly improved to afford 8a in 78% yield within 10 h
(Entry 3). Enantioselectivity was also improved to 75% ee.
The use of other pyridinium salt derivatives of p-toluene-
sulfonic acid, such as salts of picoline, lutidine, collidine,
and 2,6-di-tert-butyl-4-methylpyridine, did not improve the
results. The effects of concentration were then examined.
Highly concentrated conditions improved not only the
chemical yield but also the enantioselectivity (Entries 4 to
6). The best yield was obtained under solvent free
conditions (Entry 6, 90% yield, 83% ee). Although
Swaminathan et al. previously reported a solvent-free
asymmetric aldol condensation of 9f (RZMe) using
L-phenylalanine and d-camphorsulfonic acid, in their case
phenylalanine did not work as a catalyst (59% yield and
79% ee using 1 equiv of phenylalanine).27 Under this
solvent free condition, however, there was some difficulty
performing the reaction due to the high viscosity of the
medium. The addition of 1 equiv of DMSO solved this
problem and gave better selectivity (Entry 7). This
optimized condition was effective for the catalytic process,
Scheme 2.
The asymmetric intramolecular aldol condensation reaction
is one of the most powerful methods to synthesize the
tetrahydroindandione skeleton corresponding to the
steroidal C-D ring. In the early-to-mid 1970s, Hajos
et al.19 and Wiechart et al.20 independently developed an
asymmetric intramolecular aldol condensation reaction
using a catalytic amount of proline to provide C4-
unsubstituted tetrahydroindandione 8b (RZH).21 Recently,
this proline-catalyzed asymmetric reaction was successfully
extended to several intermolecular reactions such as the
direct aldol reaction.22 On the other hand, the use of
stoichiometric amounts of amino acids is indispensable to
construct C4-substituted tetrahydroindandione. Danishefsky
et al. reported asymmetric synthesis of C4-substituted
tetrahydroindandione 8c, which was utilized for the total
synthesis of estrone and 19-norsteroids, using 1.2 equiv of
L-phenylalanine and 0.5 equiv of 1 N HClO4 (82% yield,
86% ee).23 Tsuji et al. reported similar conditions (1 equiv
of L-phenylalanine and 0.4 equiv of 1 N HClO4) for the
synthesis of 8d (85% yield, 76% ee), which was utilized for
the total synthesis of (C)-19-nortestosterone.24 Corey et al.
also reported the asymmetric synthesis of the

H. Shigehisa et al. / Tetrahedron 61 (2005) 5057–5065
5059
Table 1.
Entry
Amino acid
(mol%)
Additive (mol%)
Solvent
Temp (8C)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
L-Phe (100)
L-Pro (100)
L-Phe (100)
L-Phe (100)
L-Phe (100)
L-Phe (100)
L-Phe (100)
L-Phe (30)
L-Phe (30)
L-Phe (30)
L-Phe (30)
1 N HClO4 (50)
1 N HClO4 (50)
PPTS (100)
PPTS (100)
PPTS (100)
PPTS (100)
PPTS (100)
PPTS (50)
CH3CN (0.5 M)
CH3CN (0.5 M)
CH3CN (0.5 M)
CH3CN (1.0 M)
CH3CN (2.0 M)
—
DMSO (1 equiv)
DMSO (1 equiv)
DMSO (1 equiv)
DMSO (1 equiv)
DMSO (1 equiv)
80
80
80
80
80
80
80
60
50
50
50
168
168
10
10
10
10
10
8
47
13
78
80
84
90
81
78
55
64
73
58
38
75
78
80
83
85
86
94
94
94
9
PPTS (50)
PPTS (50)
PPTS (50)
24
24
24
10a
11a,b
a Sonication was used.
b 58 mmol scale.
and using 30 mol% of the catalyst, 8a was obtained in 78%
yield and 86% ee (Entry 8). Moreover, the enantiomeric
excess was increased to 94% at 50 8C although the chemical
yield was moderate (Entry 9). The chemical yield was then
improved to 64% using sonication (Entry 10). In addition,
the chemical yield of 8a was improved to 73% in large scale
(58 mmol) without loss of enantiomeric excess (Entry 11).
The fact that the reaction was performed under highly
concentrated conditions with minimal waste makes this
process desirable in terms of practicality and environmental
consciousness. When L-phenylalanine was used as a
catalyst, absolute configuration of the obtained product 8a
was determined to be the S configuration, as shown in
Scheme 2, by chemical transformation to the known
compound.28
asymmetric process was applicable to the synthesis of
various C4-substituted tetrahydroindandiones 8 and octa-
hydronaphthalenediones 13 (Entries 1–7). As shown in
entry 5, Tsuji’s synthetic intermediate 8d for (C)-19-
nortestosterone was obtained in better enantimomeric
excess (90% ee using 30 mol% of phenylalanine) compared
to the original result (76% ee using 100 mol% of
phenylalanine).24 Furthermore, when 9h was used as a
substrate, scale effects were again observed without loss of
enantiomeric excess (Entry 7). In the cases of 9b and 12b
(RZH), suitable substrates for the proline-catalyzed
reaction to provide C4-unsubstituted products 8b and
13b,19,20 very low enantiomeric excess was obtained
(Entries 8 and 9).
2.2. Formal total synthesis of (C)-wortmannin
After determining the optimized conditions, we examined
the scope and limitations using a variety of triketones 9
(nZ1) and 12 (nZ2) (Table 2). The present catalytic
We then focused on the transformation of tetrahydroindan-
dione 8a to the key intermediate of wortmannin synthesis
(Scheme 4). Chemo- and stereoselective reduction of 8a
(94% ee) with NaBH4 at low temperature and the following
esterification of the resulting hydroxyl group with pivaloyl
chloride gave 14 as a sole product. Next, we examined the
conversion of 14 to trans-hydrindane.29 Although Pd–C
hydrogenation is a common method for this purpose, in our
system the hydrogenation suffered from considerable over-
reduction of the carbonyl group to methylene and low
reproducibility. These problems were not overcome, even
after intensive studies to examine the effects of altering
temperature, solvent, and additive. The Ni boride reduction,
previously utilized in a similar system by Molander et al.,
successfully promoted the selective reduction of enone 14 to
trans-hydrindane in reasonable yield (ca. 50–60%).28 After
conversion of ketone to thioacetal (ca. 70–80%), the mixture
of desired 15 and inseparable impurity derived from the Ni
boride reduction was further purified by recrystallizaton to
provide chemically and optically pure 15 (21% yield
from 14) as a white needle crystalline (mp 114–115 8C,
[a]D C17.9, CHCl3). The reduction of 15 with LiAlH4,
Swern oxidation, and Wittig reaction of the resulting
aldehyde using NaHMDS led to terminal alkene 18 in
Table 2.
Entry
Substrate
Yield
(%)
ee
(%)
1
2
3
4
5
6
7b
8
9
9f: RZMe, nZ1
12f: RZMe, nZ2
9g: RZEt, nZ1
12g: RZEt, nZ2
87
83
79
57
93a
87a
91
80
9d: RZCH2CH2CHZCH2, nZ1 69
90a
91
9h: RZ(CH2)3OBz, nZ1
9h: RZ(CH2)3OBz, nZ1
9b: RZH, nZ1
65
89
73
75
90
11a
9a
12b: RZH, nZ2
a The absolute configuration was determined to be S.
b 3 mmol scale.

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3. Conclusion
A versatile asymmetric catalysis for the synthesis of C4-
substituted tetrahydroindandione 8 using catalytic amounts
of L-phenylalanine and PPTS was developed. Furthermore,
formal total synthesis of (C)-wortmannin was achieved.
4. Experimental
4.1. General
All reactions were performed under an argon atmosphere
with dry solvents, unless otherwise stated. Reagents were
purified by the usual methods. Reactions were monitored
using thin-layer chromatography with silica gel Merck 60
(230–400 mesh ASTM). Infrared (IR) spectra were recorded
on a JASCO FT/IR 410 Fourier transform infrared
spectrophotometer. NMR spectra were recorded on a
JEOL JNM-LA500 spectrometer, operating at 500 MHz
1
for H NMR and 125.65 MHz for 13C NMR and calibrated
using residual undeuterated solvent as an internal reference.
Optical rotation was measured on a JASCO P-1010
polarimeter. ESI mass spectra were measured on a Waters
micromass ZQ with a Waters 2695 Separation Module (for
LC-MS). HR-MS spectra were measured on a JEOL JMS-
MS700V in positive ion mode.
Scheme 4. Reagents and conditions: (a) NaBH4, EtOH, K78 8C, 92%;
(b) PivCl, pyridine, DMAP (30 mol%), 0 8C to rt, 90%; (c) NiCl2$ 6H2O,
NaBH4, MeOH, K78 8C; (d) ethanedithiol, BF3$Et2O (30 mol%), CH2Cl2,
0 8C to rt, 21% for two steps after recrystallization (O99% ee); (e) LiAlH4,
THF, 0 8C to rt, 99%; (f) oxalyl chloride, DMSO, CH2Cl2, K78 to K40 8C,
91%; (g) CH3PPh3Br, NaHMDS, THF, K78 to 0 8C, 93%; (h) 2-ethyl-2-
methyl-1,3-dioxolane, PTSA (10 mol%), rt, 78% (15% of 18 was
recovered); (i) PhI(CF3CO2)2, CH3CN–H2O, rt, 84%; (j) KHMDS,
TMSCl, THF, K78 8C; (k) KHCO3, mCPBA, CH2Cl2, K20 8C; (l) 1 N
NH4F, MeOH, 0 8C, 42% for three steps; (m) Cu(OAc)2, MeOH, 0 8C to rt;
(n) DBU, CH2Cl2, 0 8C; (o) Tf2O, i-Pr2NEt, CH2Cl2, K78 8C, 47% for
three steps; (p) NaBH4, CeCl3$7H2O, MeOH, 0 8C, 65%; (q) SEMCl, 2,6-
lutidine, TBAI (10 mol%), CH2Cl2, 40 8C, 87%; (r) 9-BBN, THF, 0 8C then
23, K3PO4, PdCl2(dppf) (3 mol%), THF–DMF, 60 8C, 64%; (s) Pd(OAc)2
(10 mol%), DPPP (20 mol%), K2CO3, TBAB, toluene, 100 8C, 65% (a:bZ
1:18).
4.2. Substrate synthesis for catalytic asymmetric
intramolecular aldol condensation reaction
4.2.1. Synthesis of 9a. A suspension of 10 (50 g, 0.172 mol)
and Zn–Cu (17 g, 0.259 mol) in THF (170 mL) was stirred
under reflux conditions for 90 min, affording alkylzinc
reagent. After cooling the reaction mixture to 0 8C, PPh3
(386 mg, 4.31 mmol) and Pd(OAc)2 (1.13 g, 1.72 mmol)
were added. Acryloyl chloride (15.4 mL, 0.190 mol) was
then slowly added to the mixture while maintaining the
reaction temperature below 10 8C. After stirring for 90 min
at room temperature, the reaction was quenched by the
addition of saturated aqueous NH4Cl solution, concentrated
under reduced pressure, and extracted with AcOEt. The
organic extract was washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated
to give crude enone 11. The slow addition of 2-methyl-1,3-
cyclopentanedione (3) (13 g, 0.172 mol) to a stirred solution
of the crude enone 11 and NEt3 (7.2 mL, 51.7 mmol) in
DMF (180 mL) maintained the reaction temperature below
10 8C (rapid addition of 3 promoted intramolecular aldol
reaction to afford racemic 9a). After stirring for 24 h at
room temperature, the reaction was quenched by the slow
addition of water while maintaining the temperature below
10 8C (rapid addition of water promoted the intramolecular
aldol reaction). The mixture was then extracted with AcOEt
and the organic extract was washed with water and brine,
dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (AcOEt–HexaneZ1:3) to give 9a (30.4 g,
53% for 2 steps) as a pale yellow oil. FT-IR (neat) nmax
2962, 1718, 1681, 1616, 1601, 1584, 1452, 1402, 1315,
excellent yield. When KHMDS or n-BuLi was used instead
of NaHDMS, the chemical yield was greatly decreased
because of dimer formation through the intermolecular aldol
reaction. Synthesis of the reported key intermediate 5 in an
optically pure manner was completed by acetal formation
under mild conditions using 2-ethyl-2-methyl-1,3-dioxo-
lane, followed by transformation of thioacetal to ketone
using freshly prepared [bis(trifluoroacetoxy)iodo-
benzene],30 resulting in formal total synthesis of (C)-
wortmannin (1). Compound 5 was further converted to the
more advanced intermediate 7a by following our racemic
synthesis. Compound 5 was converted to enol triflate 20
through (i) a-hydroxylation of ketone, (ii) a-keto enol
formation by Cu(II) oxidation and DBU treatment, and (iii)
triflation of the resulting enol.14 The subsequent Luche
reduction of 20 provided allylic alcohol 21 (a:bZca. 1:3,
64% yield of isolated b-isomer) and the following SEM-
ether formation afforded compound 22. After hydroboration
of 22 with 9-BBN, a Suzuki–Miyaura cross coupling
reaction was conducted with alkyl iodide 22 to provide
6a. Finally, an intramolecular Heck reaction of 6a gave the
optically pure tricyclic intermediate 7a ([a]D C28.0,
CHCl3).
1274, 1176, 1115, 1070, 1026, 983, 916, 712, 687, 674 cmK1
;
1H NMR (500 MHz, CDCl3) d 1.10 (s, 3H), 1.90 (t, 2H, JZ
7.1 Hz), 1.98–2.04 (m, 2H), 2.45 (t, 2H, JZ7.1 Hz), 2.53 (t,

H. Shigehisa et al. / Tetrahedron 61 (2005) 5057–5065
5061
2H, JZ7.1 Hz), 2.71–2.87 (m, 4H), 4.30 (t, 2H, JZ6.2 Hz),
7.44 (t, 2H, JZ7.6 Hz), 7.56 (br-dt, 1H), 8.01 (br-d, 2H);
13C NMR (125 MHz, CDCl3) d 19.1, 22.7, 27.8, 34.7, 36.7,
39.1, 55.1, 64.0, 128.4, 130.2, 133.0, 166.5, 208.9, 215.7;
MS [ESI(C)] m/z 353 (MCNaC); HR-MS [FAB(C)] Calcd
for C19H23OC5 (MCHC): 331.1540; Found 331.1544.
57.5 mmol), L-phenylalanine (2.84 g, 17.2 mmol), PPTS
(7.2 g, 28.8 mmol), and DMSO (4.4 mL, 57.5 mmol) was
stirred at room temperature for 1 min and then sonicated at
50 8C for 24 h. The reaction mixture was diluted with
AcOEt, poured into saturated aqueous NaHCO3 solution,
and extracted with AcOEt. The organic extract was washed
with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash silica gel
column chromatography (AcOEt–hexaneZ1:3) to give 8a
(11.6 g, 73%, 94% ee) as a pale yellow oil. [a]2D5 C180.8 (c
0.52, CHCl3, 94% ee) FT-IR (neat) nmax 2963, 1744, 1716,
1664, 1600, 1451, 1354, 1314, 1273, 1174, 1114, 1070,
4.2.2. Synthesis of 9g. Triketone 9g was synthesized in
65% yield by an intermolecular Michael addition of 3 to
1-hexene-3-one, similar to 9a. Pale yellow oil; FT-IR (neat)
nmax 2963, 2933, 1721, 1455, 1418, 1372, 1299, 1126, 1061,
1
993 cmK1; H NMR (500 MHz, CDCl3) d 0.83 (t, 3H, JZ
1
1025, 713 cmK1; H NMR (500 MHz, CDCl3) d 1.23 (s,
7.2 Hz), 1.05 (s, 3H), 1.45–1.53 (m, 2H), 1.83 (t, 2H, JZ
7.2 Hz), 2.28 (t, 2H, JZ7.2 Hz), 2.37 (t, 2H, JZ7.2 Hz),
2.64–2.86 (m, 4H); 13C NMR (125 MHz, CDCl3) d 13.5,
17.0, 19.0, 27.8, 34.6, 36.3, 44.7, 55.1, 210.2, 215.7; MS
[ESI(C)] m/z 232 (MCNaC); HR-MS [FAB(C)] Calcd for
C12H19OC3 (MCHC): 211.1329; Found 211.1331.
3H), 1.83 (td, 1H, JZ6.0, 13.4 Hz), 2.06 (ddd, 1H, JZ2, 5,
13.4 Hz), 2.15–2.23 (m, 1H), 2.49–2.57 (m, 2H), 2.60–2.69
(m, 1H), 2.71–2.81 (m, 3H), 2.99 (ddd, 1H, JZ2, 13,
17.2 Hz), 4.38–4.45 (m, 2H), 7.43 (t, 2H, JZ7.6 Hz), 7.56
(br-dt, 1H), 7.97 (br-dd, 2H); 13C NMR (125 MHz, CDCl3)
d 21.1, 24.6, 25.4, 28.7, 32.8, 35.5, 49.0, 63.1, 128.5, 129.4,
130.0, 130.1, 133.1, 165.2, 166.4, 197.1, 217.0; MS [ESI (C)]
m/z 335 (MCNaC); HR-MS [FAB(C)] Calcd for
C19H21OC4 (MCHC): 313.1434; Found 313.1448. The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis [DAICEL CHIRALPAK AD-H,
i-PrOH/Hexane 1/9, flow rate 1.0 mL/min, tR 16.0 min for
(R)-isomer and tR 18.5 min for (S)-isomer, detected at
254 nm]. The absolute configuration of 8a was determined
to be S by transformation to the known compound 2428 via
14, as shown below. [a]D25 C11.4 (c 1.02, CHCl3, 94% ee);
Reported data: [a]2D5 K11.6 (c 1.03, CHCl3, O99% ee) for
the R isomer.
4.2.3. Synthesis of 12g. Triketone 12g was synthesized in
73% yield by an intermolecular Michael addition of
2-methyl-1,3-cyclohexanedione to 1-hexene-3-one, similar
to 9a. Pale yellow oil; FT-IR (neat) nmax 2962, 1694, 1457,
1
1024 cmK1; H NMR (500 MHz, CDCl3) d 0.77–0.82 (m,
3H), 1.14–1.15 (m, 3H), 1.43–1.51 (m, 2H), 1.77–2.00 (m,
4H), 2.20–2.28 (m, 4H), 2.51–2.69 (m, 4H); 13C NMR
(125 MHz, CDCl3) d 13.5, 17.0, 17.4, 19.6, 29.5, 37.2, 37.6,
44.5, 64.2, 209.6, 209.9; MS [ESI(C)] m/z 247 (MCNaC);
HR-MS [FAB(C)] Calcd for C13H21OC3 (MCHC):
225.1485; Found 225.1495.
4.2.4. Synthesis of 9h. Triketone 9h was synthesized similar
to 9a. Starting from 4-iodobutyl benzoate,31 an I/Zn
exchange reaction followed by a palladium-catalyzed
coupling reaction with acryloyl chloride afforded the
corresponding enone in 52% yield as a colorless oil. FT-
IR (neat) nmax 2954, 1717, 1682, 1276, 1116, 713 cmK1; 1H
NMR (500 MHz, CDCl3) d 1.76–1.79 (m, 4H), 2.53–2.56
(m, 2H), 4.30–4.34 (m, 2H), 5.82 (d, 1H, JZ10.4 Hz), 6.22
(d, 1H, JZ17.7 Hz), 6.35 (dd, 1H, JZ10.4, 17.7 Hz), 7.43
(t, 2H, JZ7.4 Hz), 7.55 (t, 1H, JZ7.4 Hz), 8.03 (d, 2H, JZ
7.4 Hz); 13C NMR (125 MHz, CDCl3) d 20.3, 28.2, 38.9,
64.5, 128.1, 128.3, 129.5, 130.3, 132.8, 136.4, 166.6, 200.2;
MS [ESI(C)] m/z 255(MCNaC). Then, intermolecular
Michael addition of 3 to the enone gave 9h in 80% yield as a
white powder. Mp 58–59 8C; FT-IR (neat) nmax 2931, 1718,
4.3.2. Data for 8g.35 White powder; [a]2D3 C135.1 (c 1.96,
CHCl3, 86% ee) FT-IR (neat) nmax 2963, 2672, 1711, 1666,
1606, 1460, 1422, 1358, 1336, 1306, 1262, 1239, 1202,
1161, 1143, 1114, 1065, 1015, 945, 884, 859, 832, 729 cmK1
;
1H NMR (500 MHz, CDCl3) d 0.95 (t, 3H, JZ7.4 Hz), 1.28
(s, 3H), 1.82 (dt, 1H, JZ5.8, 13.7 Hz), 2.04–2.07 (m, 1H),
2.27 (q, 2H, JZ7.4 Hz), 2.37–2.84 (m, 3H), 2.88–2.95 (m,
3H); 13C NMR (125 MHz, CDCl3) d 13.5, 18.5, 21.2, 24.0,
28.7, 32.9, 35.5, 48.7, 135.9, 162.1, 197.3, 217.7; MS
[ESI(C)] m/z 215 (MCNaC); HR-MS [FAB(C)] Calcd for
1
1282, 710 cmK1; H NMR (500 MHz, CDCl3) d 1.10 (s,
3H), 1.65–1.77 (m, 4H), 1.90 (t, 2H, JZ7.2 Hz), 2.39–2.46
(q, 4H, JZ7.3 Hz), 2.71–2.89 (m, 4H), 4.31 (t, 2H, JZ
6.3 Hz), 7.44 (t, 2H, JZ7.4 Hz), 7.56 (t, 1H, JZ7.4 Hz),
8.03 (d, 2H, JZ7.4 Hz); 13C NMR (125 MHz, CDCl3)) d
19.2, 20.0, 27.8, 28.1, 34.7, 36.5, 42.2, 55.1, 64.5, 128.3,
129.5, 130.3, 132.8, 166.6, 209.6, 215.8; MS [ESI(C)] m/z
367 (MCNaC); HR-MS [FAB(C)] Calcd for C20H25O5C
(MCHC): 345.1702; Found 345.1711.
C12H17O2 (MCHC): 193.1229; Found 193.1232. The
C
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis [DAICEL CHIRALPAK OJ-H,
i-PrOH/Hexane 1:9, flow rate 1.0 mL/min, tR 12.8 min for
minor isomer and tR 14.3 min for major isomer, detected at
254 nm].
Triketones 9b,32 12b,32 9f,33 12f,34 and 9b24 are other
known compounds.
4.3.3. Data for 13g. White powder; [a]2D3 C58.8 (c 1.15,
CHCl3, 75% ee) FT-IR (neat) nmax 2966, 2932, 2872, 1744,
1664, 1448, 1371, 1354, 1311, 1260, 1173, 1120, 1058,
1
1009, 902, 853, 748 cmK1; H NMR (500 MHz, CDCl3) d
4.3. Catalytic asymmetric intramolecular aldol
condensation reaction
0.90–0.94 (dt, 3H), 1.43 (s, 3H), 1.58 (d, 1H, JZ2 Hz),
1.69–1.76 (m, 1H), 2.02–2.19 (m, 3H), 2.34 (m, 2H), 2.41–
2.53 (m, 3H), 2.65–2.72 (m, 1H), 2.90 (br-dt, 1H); 13C NMR
4.3.1. General procedure. A mixture of 9a (19.0 g,

5062
H. Shigehisa et al. / Tetrahedron 61 (2005) 5057–5065
(125 MHz, CDCl3) d 14.0, 18.8, 22.3, 23.5, 26.6, 29.5, 33.6,
37.3, 50.8, 136.9, 158.0, 197.3, 212.1; MS [ESI(C)] m/z
4.4. Formal total synthesis of (C)-wortmannin
229 (MCNaC); HR-MS [FAB(C)] Calcd for C13H19O2
C
4.4.1. Synthesis of 14. NaBH4 (1.00 g, 26.3 mmol) was
added over 30 min to a stirred solution of 8a (31.4 g,
0.101 mol, 94% ee) in absolute EtOH (500 mL) at K78 8C.
After stirring for 1 h at the same temperature, the reaction
mixture was poured into saturated aqueous NH4Cl solution,
concentrated under reduced pressure, and extracted with
AcOEt. The organic extract was washed with brine, dried
over Na2SO4, and concentrated to give crude b-alcohol.
DMAP (3.70 g, 30.3 mmol) and pivaloyl chloride (25 mL,
0.202 mol) were added to a stirred solution of the crude
b-alcohol in pyridine (200 mL) at 0 8C. After stirring for
48 h at room temperature, the reaction mixture was poured
into water and extracted with AcOEt. The organic extract
was washed with water, 1 N aqueous solution of HCl and
brine, dried over Na2SO4, and concentrated. The residue
was purified by flash silica gel column chromatography
(AcOEt–hexaneZ1:3) to afford pivaloyl ester 14 (33.0 g,
82% for 2 steps) as a pale yellow oil. [a]2D8 C17.0 (c 2.0,
CHCl3, 94% ee) FT-IR (neat) nmax 2973, 1722, 1665, 1601,
1479, 1453, 1420, 1396, 1375, 1355, 1314, 1274, 1154,
(MCHC): 207.1385; Found 207.1384. The enantiomeric
excess was determined by chiral stationary-phase HPLC
analysis [DAICEL CHIRALPAK OJ-H, i-PrOH/Hexane
1:9, flow rate 1.0 mL/min, tR 10.4 min for minor isomer and
tR 11.5 min for major isomer, detected at 254 nm].
4.3.4. Data for 8h. Pale yellow oil; [a]2D3 C153 (c 1.10,
CHCl3, 86% ee) FT-IR (KBr) nmax 2960, 1745, 1716, 1664,
1275, 1116, 715 cmK1; 1H NMR (500 MHz, CDCl3) d 1.27
(s, 3H), 1.81 (dd, 1H, JZ5.8, 13.8 Hz), 1.84–1.91 (m, 2H),
2.07 (ddd, 1H, JZ2.1, 5.2, 13.4 Hz), 2.34–2.60 (m, 5H),
2.72 (dd, 1H, JZ2.8, 10.8 Hz), 2.77–2.84 (m, 1H), 2.94 (dd,
1H, JZ2.8, 17.1 Hz), 4.29 (t, 2H, JZ7.4 Hz), 7.45 (t, 2H,
JZ7.4 Hz), 7.57 (t, 1H, JZ7.4 Hz), 8.04 (d, 2H, JZ
7.4 Hz); 13C NMR (125 MHz, CDCl3) d 21.2, 21.9, 24.3,
27.7, 28.9, 32.9, 35.5, 48.9, 64.3, 128.4, 129.5, 130.2, 132.9,
133.1, 163.6, 166.5, 197.3, 217.2; MS [ESI(C)] m/z 335
(MCNaC); HR-MS [FAB(C)] Calcd for C20H23O4C (MC
HC): 327.1597; Found 327.1583. The enantiomeric excess
was determined by chiral stationary-phase HPLC analysis
[DAICEL CHIRALPAK AD-H, i-PrOH/Hexane 1:9, flow
rate 1.0 mL/min, tR 20.1 min for major isomer and tR
22.8 min for minor isomer, detected at 254 nm].
1114, 1069, 1027, 1008, 937, 891, 769 cmK1; H NMR
1
(500 MHz, CDCl3) d 1.07 (s, 3H), 1.14 (s, 9H), 1.66–1.90
(m, 3H), 2.09–2.15 (m, 1H), 2.33–2.37 (m, 1H), 2.45–2.64
(m, 5H), 4.25–4.33 (m, 2H), 4.64 (dd, 1H, JZ7.6, 10.3 Hz),
7.36 (t, 2H, JZ7.6 Hz), 7.48 (t, 1H, JZ7.3 Hz), 7.91 (d, 2H,
JZ7.6 Hz); 13C NMR (125 MHz, CDCl3) d 16.5, 25.4, 25.5,
26.2, 27.0, 32.9, 33.7, 38.7, 44.7, 62.7, 80.4, 128.2, 129.2,
130.0, 132.7, 166.1, 168.3, 177.7, 197.2; MS [ESI(C)] m/z
421 (MCNaC); Anal. Calcd for C24H30O5: C 72.34, H 7.59;
Found C 72.05, H 7.61.
Other products shown in Table 2 are known compounds and
the absolute configuration of those compounds was
determined to be S by comparison of optical rotation.27
4.3.5. HPLC analysis of 8b, 13b, 8f, 13f, and 8d.
Compound 8b. The enantiomeric excess was determined
by chiral stationary-phase HPLC analysis [DAICEL
CHIRALPAK AD-H, i-PrOH/Hexane 1:50, flow rate
1.0 mL/min, tR 30.0 min for (R)-isomer and tR 34.9 min
for (S)-isomer, detected at 254 nm].
4.4.2. Synthesis of 15. NiCl2$6H2O (2.15 g, 9.03 mmol)
was added to a stirred solution of 14 (720 mg, 1.81 mmol) in
MeOH (18 mL) at room temperature. After NiCl2$6H2O
was dissolved in MeOH, NaBH4 (682 mg, 18.1 mmol) was
added over 30 min at K78 8C. After stirring for 20 min at
room temperature, silica gel was added to the reaction
mixture, which was then filtered and concentrated under
reduced pressure. The residue was purified by flash silica gel
column chromatography (AcOEt–hexaneZ1:9) to afford
trans-hydrindane compound with inseparable byproducts.
Ethanedithiol (0.10 mL, 1.21 mmol) was added to a stirred
solution of the residue in CH2Cl2 (3.6 mL), followed by the
addition of BF3$Et2O (0.076 mL, 0.606 mmol) at 0 8C.
After stirring for 18 h at room temperature, the reaction
mixture was poured into saturated aqueous NaHCO3
solution and extracted with AcOEt. The organic extract
was washed with brine, dried over Na2SO4, and concen-
trated. The residue was purified by flash silica gel column
chromatography (AcOEt–hexaneZ1:20) to give 15 with
inseparable byproducts, which was then further purified by
recrystallization (ether–hexane) to give chemically and
optically pure 15 (180 mg, 21% from 14, O99% ee) as a
white needle crystalline. Mp 114–115 8C; [a]2D8 C11.4 (c
2.6, CHCl3, O99% ee) FT-IR (KBr) nmax 3421, 2970, 2921,
2851, 1723, 1654, 1601, 1583, 1478, 1455, 1421, 1395,
1364, 1334, 1314, 1282, 1164, 1123, 1071, 1024, 991, 972,
936, 898 cmK1; 1H NMR (500 MHz, CDCl3) d 0.89 (s, 3H),
1.19 (s, 9H), 1.39–1.66 (m, 5H), 1.69–1.76 (m, 1H), 1.80–
1.85 (m, 1H), 1.92–1.97 (m, 1H), 2.11 (td, 1H JZ3.4,
14.4 Hz), 2.17–2.25 (m, 2H), 2.33–2.39 (m, 1H), 3.18–3.33
Compound 13b. The enantiomeric excess was determined
by chiral stationary-phase HPLC analysis [DAICEL
CHIRALPAK OD-H, i-PrOH/Hexane 1:50, flow rate
1.0 mL/min, tR 25.8 min for (R)-isomer and tR 28.6 min
for (S)-isomer, detected at 254 nm].
Compound 8f. The enantiomeric excess was determined by
chiral stationary-phase HPLC analysis [DAICEL CHIR-
ALPAK AS-H, i-PrOH/Hexane 1:9, flow rate 1.0 mL/min,
tR 20.0 min for (R)-isomer and tR 28.8 min (S)-isomer),
detected at 254 nm].
Compound 13f. The enantiomeric excess was determined by
chiral stationary-phase HPLC analysis [DAICEL
CHIRALPAK AS-H, i-PrOH/Hexane 1:9, flow rate
1.0 mL/min, tR 17.4 min for (R)-isomer and tR 20.4 min
for (S)-isomer, detected at 254 nm]. [a]2D3 C120.7 (c 0.49,
CHCl3, 80% ee).
Compound 8d. The enantiomeric excess was determined by
chiral stationary-phase HPLC analysis [DAICEL
CHIRALPAK AS-H, i-PrOH/Hexane 1:9, flow rate
1.0 mL/min, tR 15.7 min (R)-isomer] and tR 22.1 min (S)-
isomer), detected at 254 nm]. [a]2D3 C219.3 (c 1.67, CHCl3,
90% ee).

H. Shigehisa et al. / Tetrahedron 61 (2005) 5057–5065
5063
(m, 4H), 4.25–4.30 (m, 1H), 4.39–4.44 (m, 1H), 4.61 (dd,
1H, JZ7.7, 9.5 Hz), 7.44 (t, 2H, JZ7.7 Hz), 7.54–7.57 (m,
1H), 8.06–8.08 (m, 2H); 13C NMR (125 MHz, CDCl3) d
12.0, 24.9, 27.2, 27.4, 30.6, 36.0, 38.7, 38.8, 39.0, 42.2,
42.5, 42.9, 51.1, 64.9, 75.5, 81.5, 128.3, 129.6, 130.4, 132.8,
166.6, 178.4; MS [ESI(C)] m/z 499 (MCNaC); Anal.
Calcd for C26H36O4S2: C 65.51, H 7.61; Found C 65.23, H
7.52. The enantiomeric excess was determined by chiral
stationary-phase HPLC analysis [DAICEL CHIRALPAK
AD-H, i-PrOH/Hexane 1:9, flow rate 1.0 mL/min, tR
8.1 min for major isomer and tR 9.6 min for minor isomer,
detected at 254 nm].
(2.3 mL, 2.28 mmol) was added to a stirred suspension of
Ph3PCH3Br (1.08 g, 3.04 mmol, dried at 100 8C for 1 h
under reduced pressure prior to use) in THF (10 mL) at 0 8C.
After stirring for 30 min at the same temperature, a solution
of 17 (431 mg, 1.52 mmol) in THF (10 mL) was added at
K78 8C, which was gradually warmed to 0 8C within 4 h.
The reaction mixture was then quenched by the addition of
saturated aqueous NH4Cl at K78 8C and extracted with
AcOEt. The organic extract was washed with brine, dried
over Na2SO4, and concentrated. The residue was purified by
flash silica gel column chromatography (AcOEt–hexaneZ
1:20) to give 18 (400 mg, 93%) as a white powder. [a]D28
C111.5 (c 2.1, CHCl3, O99% ee) FT-IR (KBr) nmax 3454,
3071, 2962, 2924, 2857, 1732, 1637, 1473, 1457, 1431,
4.4.3. Synthesis of 16. Compound 15 (1.04 g, 2.19 mmol)
was added to a stirred suspension of LiAlH4 (311 mg,
6.56 mmol) in THF (10 mL) at 0 8C. After stirring for
90 min at room temperature, the reaction mixture was
quenched by the addition of water (0.3 mL) at 0 8C,
followed by 4 N aqueous solution of NaOH (0.3 mL) and
water (0.9 mL), which was then filtered and concentrated.
The residue was purified by flash silica gel column
chromatography (AcOEt–hexaneZ1:1) to afford 16
(689 mg, 99%) as a white powder. [a]2D8 C29.4 (c 0.36,
CHCl3, O99% ee) FT-IR (KBr) nmax 3292, 2920, 2876,
1637, 1445, 1428, 1383, 1353, 1278, 1241, 1205, 1160,
1407, 1378, 1282, 1251, 1089, 1039, 1011, 994, 923 cmK1
;
1H NMR (500 MHz, CDCl3) d 0.93 (s, 3H), 1.57–1.65 (m,
3H), 1.69–1.73 (m, 1H), 1.99–2.12 (m, 3H), 2.15–2.25 (m,
3H), 2.37–2.44 (m, 1H), 2.75–2.79 (m, 1H), 3.15–3.34 (m,
4H), 4.95–5.08 (m, 2H), 5.84–5.92 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 13.6, 23.7, 30.9, 35.3, 35.8, 39.0, 39.1,
41.9, 46.2, 47.8, 51.7, 75.1, 115.2, 138.9, 219.6; MS [ESI(C)]
m/z 305 (MCNaC); HR-MS [FAB(C)] Calcd for
C15H23OSC2 (MCHC): 283.1185; Found 283.1179.
4.4.6. Synthesis of 19. p-Toluenesulfonic acid (181 mg,
0.954 mmol) was added to a stirred solution of 18 (2.70 g,
9.54 mmol) in 2-ethyl-2-methyl-1,3-dioxolane at room
temperature. After stirring for 48 h at the same temperature,
the reaction mixture was poured into saturated aqueous
NaHCO3 solution and extracted with AcOEt. The organic
extract was washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by flash silica gel
column chromatography (AcOEt–hexaneZ1:20) to give 19
(2.43 g, 78%) as a colorless oil with recovery of 18 (398 mg,
15%). [a]2D1 C4.6 (c 0.70, CHCl3, O99% ee) FT-IR (neat)
nmax 3071, 2972, 2945, 2878, 1637, 1457, 1435, 1380, 1309,
1279, 1228, 1187, 1163, 1103, 1035, 995, 957, 907,
1
1135, 1033, 1018 cmK1; H NMR (500 MHz, CDCl3) d
0.57 (s, 3H), 1.24–1.30 (m, 1H), 1.38–1.59 (m, 8H), 1.92
(ddd, 1H, JZ2.3, 6.6, 11.8 Hz), 2.03–2.24 (m, 4H), 3.15–
3.35 (m, 4H), 3.51–3.57 (m, 1H), 3.66–3.73 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 10.9, 24.5, 30.1, 34.6, 35.7,
38.7, 38.8, 42.3, 42.4, 43.0, 51.4, 62.5, 75.9, 80.9; MS
[ESI(C)] m/z 311 (MCNaC); HR-MS [EI(C)] Calcd for
C14H24O2S2 (MC): 288.1218; Found 288.1230.
4.4.4. Synthesis of 17. A solution of DMSO (0.74 mL,
10.4 mmol) in CH2Cl2 (4.3 mL) was added to a stirred
solution of oxalyl chloride (0.45 mL, 5.21 mmol) in CH2Cl2
(4.3 mL) at K78 8C. After stirring for 20 min at the same
temperature, a solution of 16 (500 mg, 1.74 mmol) in
CH2Cl2 (9 mL) was added to the mixture. After stirring for
1 h at K40 8C, triethylamine (2.4 mL) was added and the
reaction mixture was stirred for 20 min at the same
temperature. The reaction mixture was poured into saturated
aqueous NH4Cl and extracted with CH2Cl2. The organic
extract was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was
purified by flash silica gel column chromatography (AcOEt–
hexaneZ1:4) to give 17 (449 mg, 91%) as a white powder.
[a]2D8 C109.8 (c 1.3, CHCl3, O99% ee) FT-IR (KBr) nmax
3443, 3416, 2997, 2919, 2883, 2858, 2841, 2716, 1710,
1473, 1462, 1427, 1398, 1377, 1351, 1336, 1305, 1281,
1262, 1243, 1225, 1206, 1161, 1130,1119, 1088, 1071,
1
855 cmK1; H NMR (500 MHz, CDCl3) d 0.91 (s, 3H),
1.25–1.40 (m, 2H), 1.71–1.97 (m, 6H), 2.07–2.21 (m, 3H),
2.54 (brdd, 1H), 3.14–3.33 (m, 4H), 3.80–3.96 (m, 4H), 4.90
(d, 1H, JZ10.1 Hz), 5.01 (d, 1H, JZ17.1 Hz), 5.83–5.91
(m, 1H); 13C NMR (125 MHz, CDCl3) d 14.1, 24.3, 30.0,
34.2, 36.0, 38.9, 39.0, 42.2, 46.2, 46.7, 51.0, 64.7, 65.2,
75.6, 114.5, 118.4, 139.6; MS [ESI(C)] m/z 349
C
(MCNaC); HR-MS [FAB(C)] Calcd for C17H27O2S2
(MCHC): 327.1447; Found 327.1449.
4.4.7. Synthesis of 5. Freshly prepared PhI(OCOCF3)2
(79 mg, 0.184 mmol) was added to a stirred solution of 19
(30.0 mg, 0.0920 mmol) in CH3CN (0.8 mL) and H2O
(0.1 mL) at room temperature. After stirring for 1 min at the
same temperature, the reaction mixture was quenched by the
addition of saturated aqueous NaHCO3 solution and
extracted with AcOEt. The organic extract was washed
with brine, dried over Na2SO4, and concentrated. The
residue was purified by flash silica gel column chromato-
graphy (AcOEt–hexaneZ1:9) to give 5 (19.3 mg, 84%) as a
colorless oil. [a]2D2 C17.9 (c 1.96, CHCl3, O99% ee) FT-IR
1
1053, 1031, 1013 cmK1; H NMR (500 MHz, CDCl3) d
0.97 (s, 3H), 1.53–1.62 (m, 3H), 1.72–1.80 (m, 2H), 2.05–
2.12 (m, 1H), 2.16–2.27 (m, 2H), 2.41–2.54 (m, 2H), 2.71–
2.76 (m, 1H), 2.96 (ddd, 1H, JZ1.9, 5, 17.4 Hz), 3.10–3.28
(m, 4H), 9.83 (t, 1H, JZ1.9 Hz); 13C NMR (125 MHz,
CDCl3) d 13.5, 22.9, 30.7, 35.5, 38.9, 39.0, 41.2, 41.4, 44.9,
47.6, 50.1, 74.1, 200.3, 219.7; MS [ESI(C)] m/z 307
(neat) nmax 3078, 2975, 2878, 1708, 1434, 1308, 1177 cmK1
;
(MCNaC); HR-MS [FAB(C)] Calcd for C14H21O2S2
C
1H NMR (500 MHz, CDCl3) d 1.13 (s, 3H), 1.37–1.45 (m,
1H), 1.52–1.56 (m, 1H), 1.73–1.80 (m, 1H), 1.83–1.89 (m,
1H), 1.92–2.02 (m, 2H), 2.03–2.09 (m, 1H), 2.21–2.44 (m,
5H), 3.81–3.92 (m, 4H), 4.93–5.02 (m, 2H), 5.80 (ddt, 1H);
(MCHC): 285.0977; Found 285.0990.
4.4.5. Synthesis of 18. A 1.0 M THF solution of NaHMDS

5064
H. Shigehisa et al. / Tetrahedron 61 (2005) 5057–5065
13C NMR (125 MHz, CDCl3) d 13.9, 23.2, 28.9, 30.9, 34.4,
37.4, 45.8, 48.2, 50.7, 64.5, 65.3, 116.1, 117.7, 136.5, 211.3;
MS [EI(C)] m/z 250 (MC); HR-MS [EI(C)] Calcd for
C15H22O3C (MC): 250.1569; Found 250.1571.
5.8, 14.3 Hz), 3.82–3.96 (m, 4H), 5.19 (d, 1H, JZ10.5 Hz),
5.20 (d, 1H, JZ16.0 Hz), 5.73 (ddt, 1H, JZ7.2, 10.5,
16.0 Hz); 13C NMR (125 MHz, CDCl3) d 14.6, 21.2, 33.2,
33.3, 45.0, 45.9, 48.5, 64.6, 65.6, 118.5 (q, coupling with F),
119.3, 131.1, 141.3, 150.6, 190.0; MS [EI(C)] m/z 386
(MC); HR-MS [EI(C)] Calcd for C16H20O6F3SC (MC):
397.0932; Found 397.0939.
4.4.8. Synthesis of 20. A solution of 5 (135 mg,
0.540 mmol) in THF (2.7 mL) was added dropwise to a
stirred solution of potassium hexamethyldisilazide (324 mg,
1.619 mmol) in THF (2.7 mL) at K78 8C. After stirring for
30 min at the same temperature, TMSCl (0.14 mL,
1.08 mmol) was added at K78 8C. After additional stirring
for 20 min at the same temperature, the reaction was
quenched by the addition of saturated aqueous NaHCO3
solution and extracted twice with Et2O. The combined
organic extracts were washed with brine, dried over
Na2SO4, and concentrated to give crude enol silyl ether.
m-Chloroperbenzoic acid (219 mg, 0.756 mmol) was added
by portions to a stirred suspension of the residual oil and
KHCO3 (270 mg, 2.70 mmol) in CH2Cl2 (2.7 mL) at
K20 8C. After stirring for 2 h at the same temperature, the
reaction mixture was diluted with CH2Cl2 and poured into
saturated aqueous NaHCO3 solution to give white precipi-
tate. Water was added to dissolve the precipitate and
extracted with CH2Cl2. The organic extract was washed
with saturated aqueous Na2S2O3 solution and brine, dried
over Na2SO4, and concentrated. A mixture of the residual
oil and 3 N aqueous solution of NH4F (0.54 mL) in MeOH
(2.7 mL) was stirred at 0 8C for 15 min, and then about half
of the MeOH was removed under reduced pressure. The
residual mixture was poured into a saturated aqueous
NaHCO3 solution, and extracted with EtOAc. The organic
extract was washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by flash silica gel
column chromatography (AcOEt–hexaneZ1:4) to give
a-hydroxy ketone (61 mg, 42%) as a colorless oil.
Cu(OAc)2$H2O (91 mg, 0.456 mmol) was added to a
solution of the a-hydroxy ketone in MeOH (1.1 mL) at
0 8C. After stirring for 15 h at room temperature, the
reaction mixture was quenched by the addition of water.
After additional stirring for 30 min, the mixture was
extracted with CH2Cl2. The organic extract was success-
ively washed with brine, 10% aqueous citric acid solution
and brine, dried over Na2SO4, and concentrated. A solution
of the residual oil and DBU (0.034 mL, 0.228 mmol) in
CH2Cl2 (1 mL) was stirred at 0 8C for 10 min, which was
then quenched by the addition of saturated aqueous NH4Cl
solution, and extracted with CH2Cl2. Organic extract was
washed with brine, dried over Na2SO4, and concentrated to
give crude diosphenol. Diisopropylethylamine (0.048 mL)
and Tf2O (0.038 mL) were added to a solution of the
residual oil in CH2Cl2 (1 mL) K78 8C. After stirring for
15 min at the same temperature, the reaction mixture was
quenched by the addition of saturated aqueous NaHCO3
solution and extracted with AcOEt. The organic extract was
washed with brine, dried over Na2SO4, and concentrated.
The residue was purified by silica gel column chromato-
graphy (AcOEt–hexaneZ1:20) to give 20 (42 mg, 47%) as
a colorless oil. [a]D22 C38.8 (c 0.17, CHCl3, O99% ee)
FT-IR (neat) nmax 1747, 1697, 1418, 1210, 1140, 1017,
4.4.9. Synthesis of 21. CeCl3$7H2O (699 mg) was added to
a solution of 20 (620 mg, 1.56 mmol) in MeOH (10 mL) at
room temperature and the mixture was stirred at the same
temperature until CeCl3$7H2O was dissolved. Then NaBH4
(77 mg, 2.03 mmol) was added to the mixture at 0 8C. After
stirring for 1 h at the same temperature, the reaction mixture
was quenched by the addition of acetone followed by water,
and extracted with AcOEt. The organic extract was washed
with brine, dried over Na2SO4, and concentrated. The
residue was purified by silica gel column chromatography
(AcOEt–hexaneZ5:1) to give 21 (403 mg, 65%) and the
diastereomer (about 130 mg) as white solids. [a]2D3 C43.8 (c
0.16, CHCl3, O99% ee) FT-IR (neat) nmax 3471, 2974,
1
2889, 1408, 1209, 1141, 1039 cmK1; H NMR (500 MHz,
CDCl3) d 1.06 (s, 3H), 1.57–1.66 (m, 1H), 1.81 (d, 1H, JZ
14.1 Hz), 1.83–1.96 (m, 2H), 2.11 (d, 1H, JZ6.4 Hz), 2.12–
2.22 (m, 2H), 2.71–2.80 (m, 2H), 3.16 (dd, 1H, JZ6.9,
14.6 Hz), 3.84–3.94 (m, 4H), 4.53 (t, 1H, JZ6.4 Hz), 5.09
(dd, 1H, JZ1.5, 10.5 Hz), 5.14 (dd, 1H, JZ1.5, 17.1 Hz),
5.68–5.76 (m, 1H); 13C NMR (125 MHz, CDCl3) d 15.2,
21.0, 32.1, 34.8, 37.0, 44.2, 46.2, 64.5, 65.4, 65.9, 117.4,
117.6, 132.8, 133.1, 143.3; MS [FAB(C)] m/z 381 (MK
H2OCHC); HR-MS [FAB(C)] Calcd for C16H20O5F3SC
(MC): 381.983; Found 381.994.
Spectroscopic data except for optical rotation of 22, 24, and
7a and experimental procedure for the syntheses of those
compounds were previously reported.15
4.4.10. Optical rotation of 22, 24 and 7a. Compound 22:
[a]2D3 C83.3 (c 0.12, CHCl3, O99% ee).
Compound 24: [a]2D1 C4.6 (c 0.70, CHCl3, O99% ee).
Compound 7a: [a]2D2 C28.0 (c 0.10, CHCl3, O99% ee,
diastreomixture, a:bZ1:18).
Acknowledgements
This work was supported by RFTF, Grant-in-Aid for
Encouragements for Young Scientists (A), and Grant-in-
Aid for Specially Promoted Research from the Japan
Society for the Promotion of Science (JSPS) and Ministry
of Education, Culture, Sports, Science and Technology
(MEXT).
Supplementary data
1
865 cmK1; H NMR (500 MHz, CDCl3) d 0.99 (s, 3H),
1.71–1.80 (m, 1H), 1.93–2.12 (m, 3H), 2.45 (d, 1H, JZ
16.5 Hz), 2.75 (d, 1H, JZ16.5 Hz), 2.96 (dd, 1H, JZ7.2,
13.5 Hz), 3.22 (dd, 1H, JZ7.2, 13.5 Hz), 3.32 (dd, 1H, JZ
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.03.
038

H. Shigehisa et al. / Tetrahedron 61 (2005) 5057–5065
5065
were unsatisfactory in terms of isolated yield and
enantioselectivity.
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