Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Article abstract of DOI:10.1016/S0040-4020(03)00119-4

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (-)-theobroxide 19, (-)-phyllostine 22, (+)-herveynone 27 and (-)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.

Full text of DOI:10.1016/S0040-4020(03)00119-4

Tetrahedron 59 (2003) 1773–1780
Total synthesis of (1)-epiepoformin, (1)-epiepoxydon and
(1)-bromoxone employing a useful chiral building block, ethyl
(1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate
Toru Tachiharaa and Takeshi Kitaharab
,
*
aTechnical Research Center, T. Hasegawa Co., Ltd., 335 Kariyado, Nakahara-ku, Kawasaki-shi, Kanagawa 211-0022, Japan
bDepartment of Applied Biological Chemistry, Graduate School of Agricultural an dLife Sciences, The University of Tokyo,
1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Received 20 November 2002; accepted 14 January 2003
Abstract—Enantioselective total synthesis of (þ)-epiepoformin 1, (þ)-epiepoxydon 2 and (þ)-bromoxone 3 using a chiral building block,
ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25,
it accomplished a formal synthesis of (2)-theobroxide 19, (2)-phyllostine 22, (þ)-herveynone 27 and (2)-asperpentyn 28. The usefulness of
6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Our synthetic plan is shown in Scheme 1. We thought that
all target compounds could be synthesized from the
common intermediate, phenylselenoketone 4, via introduc-
tion of the proper substituent and deprotection. The key
intermediate 4 must be obtained from enone 5 by
stereoselective epoxidation and regioselective introduction
of the phenylselenyl group. The enone 5 could be derived
from the chiral building block 6 via modification of
functional groups including decarboxylation. We started
the synthesis according to this plan.
Epiepoformin 1, epiepoxydon 2 and bromoxone 3 are well
known as typical oxygenated cyclohexenones with remark-
able biological activities (Fig. 1). For example, epiepo-
formin 1 and epiepoxydon 2 being inhibitors of lettuce seed
germination were isolated from the culture broth of an
unidentified fungus separated from a diseased crapemyrtle
leaf by Nagasawa and co-workers in 1978.1 On the other
hand, bromoxone 3 was isolated from marine acorn worm
with its acetate by Higa and co-workers in 1987.2 The
acetate of bromoxone 3 shows potent antitumor activity
against P388 cells in vitro. Several methods for their
synthesis have already been reported.3–5 In this paper, we
describe a novel synthesis of epiepoformin 1, epiepoxydon 2
and bromoxone 3, using a common chiral building block,
ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexane-
carboxylate 6.
The chiral building block 6 as the starting material was first
synthesized in our laboratory in 1985,6 and is now available
in large quantities by simple operation via the high
enantiomeric reduction with baker’s yeast of b-ketoester
7. We have already succeeded in total syntheses of a series
of natural products using this building block; e.g. sporogen
AO1,7 polyoxygenated eremophilanes,8 dendryphiellin C,9
Figure 1.
Keywords: total synthesis; natural epoxycyclohexene derivatives; chiral building block.
*
Corresponding author. Tel.: þ81-3-5841-5119; fax: þ81-3-5841-8019; e-mail: atkita@mail.ecc.u-tokyo.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00119-4

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T. Tachihara, T. Kitahara / Tetrahedron 59 (2003) 1773–1780
Scheme 1.
Scheme 2.
pironetin10 and key intermediates of both enantiomers of
epibatidine11 (Scheme 2).
proceeded stereoselectively by using Triton B as a base3e,14
to give epoxyketone 13. Next, we investigated regioselec-
tive introduction of the phenylselenyl group to the a-
position of the ketone 13. At first, enolate was prepared with
lithium diisopropylamide (LDA), then we attempted to
introduce the phenylselenyl group to enolate directly. But,
only a complex mixture was obtained. Therefore, we
attempted stepwise introduction of the phenylselenyl
group. Trapping the enolate with trimethylsilyl chloride
(TMSCl) gave silyl enol ether 15, which was treated with
phenylselenenyl chloride in dichloromethane to afford
phenylselenyl compound 16 as a diastereomeric mixture
(Scheme 4).
2. Results and discussion
Hydrolysis of 6, followed by acetylation of the hydroxyl
group gave carboxylic acid 8. Oxidative decarboxylation12
of 8 with iodobenzene diacetate (IBDA) and iodine in
carbon tetrachloride afforded iodide 9 as an inseparable
diastereomeric mixture of 1:1. Dehydroiodination with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and subsequent
hydrolysis of 9 gave allylic alcohol 10. After TBS protection
of the hydroxyl group of 10, epoxidation of the resulting
compound 11 with m-chloroperbenzoic acid (mCPBA) gave
epoxide 12. Deacetalization of 12 under various conditions
afforded no desired compound (Scheme 3).
Introduction of a methyl group to 16 with sodium hydride as
a base and methyl iodide gave compound 17. Successive
oxidative elimination of the phenylselenenyl group with
35% hydrogen peroxide in the presence of sodium hydrogen
carbonate gave enone 18. Finally, deprotection of the TBS
group15 with 40% hydrofluoric acid in acetonitrile gave
epiepoformin. The overall yield of epiepoformin was 13.5%
On the other hand, deacetalization of compound 11 with
pyridinium p-toluenesulfonate (PPTS) in aqueous acetone
gave enone 1413 in excellent yield. Epoxidation of enone 14
Scheme 3.

T. Tachihara, T. Kitahara / Tetrahedron 59 (2003) 1773–1780
1775
Scheme 4.
Scheme 5.
in total 13 steps. The analytical data of our synthetic
epiepoformin were identical with those of the authentic
product.3 The conversion from the intermediate 18 to
theobroxide 19,16 a potato micro-tuber inducing substance,
was reported by Ogasawara and co-workers in 1995.3c Thus,
we accomplished total synthesis of (þ)-epiepoformin and
the formal synthesis of (2)-theobroxide (Scheme 5).
phyllostine 22,17 a phytotoxin, was reported by Ogasawara
and co-workers in 1996.4f Now, we have achieved total
synthesis of (þ)-epiepoxydon and the formal synthesis of
(2)-phyllostine, too (Scheme 6).
On the other hand, treatment of 16 with DBU and bromine
gave bromo analog 23. In the same manner, oxidative
elimination gave enone 24. Then deprotection of the TBS
group afforded bromoxone 3, which was synthesized in
17.5% overall yield through 13 steps. The analytical data of
our synthetic bromoxone were identical with those of the
authentic product5 (Scheme 7).
On the other hand, treatment of 16 with DBU as a base and
35% formalin gave hydroxymethyl compound 20. Oxidative
elimination of the resulting compound 20 was achieved in a
similar manner as above to give enone 21. Then deprotec-
tion of the TBS group gave epiepoxydon. Epiepoxydon was
yielded 10.4% overall in 13 steps. The analytical data of our
synthetic epiepoxydon were identical with those of the
authentic product.4 The conversion from epiepoxydon to
Oxidative elimination of phenylselenoketone 16 gave enone
25. The analytical data of our synthetic enone were identical
with those of the authentic product.3d The conversion from
Scheme 6.

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T. Tachihara, T. Kitahara / Tetrahedron 59 (2003) 1773–1780
Scheme 7.
Scheme 8.
enone 25 to harveynone 274e and asperpentyn 28,18 which
are phytotoxins, was reported by Barros and co-workers.3d
Thus, the formal synthesis of (þ)-harveynone and
(2)-asperpentyn was established (Scheme 8).
by ultraviolet light (254 nm), iodine vapor or phosphomo-
lybdic acid spray reagent. Preparative TLC was carried out
using 0.5 mm Merck silica gel 60 F254 precoated glass-
backed plates. Column chromatography was performed on
Merck silica gel 60 or Kanto Chemical silica gel 60N
(neutral). All solvents were reagent grade. Tetrahydrofuran
(THF) and diethyl ether were freshly distilled from
sodium/benzophenone under argon. Dichloromethane was
freshly distilled from calcium hydride under argon. Carbon
tetrachloride, toluene and N,N-dimethylformamide were
dried over 4A-molecular sieves. Methanol, acetonitrile and
acetone were used without purification.
In conclusion, we have succeeded in enantioselective total
synthesis of (þ)-epiepoformin, (þ)-epiepoxydon and
(þ)-bromoxone, using the common chiral building block.
Also, we could indicate the formal synthesis of
(2)-theobroxide, (2)-phyllostine, (þ)-herveynone and
(2)-asperpentyn. As a result, our chiral building block 6
have been established to be a extremely versatile material
for the synthesis of highly oxygenated cyclohexane natural
products.
3.1.1. (1R,2S)-2-Acetoxy-5,5-ethylenedioxycyclohexane-
carboxylic acid (8). To a solution of 6 (15.0 g, 65 mmol) in
methanol (225 mL) at 08C was added 1 M aqueous lithium
hydroxide (75 mL, 75 mmol) over 10 min. After being
stirred at room temperature for 3 h, the reaction mixture was
concentrated in vacuo. The residue was diluted with toluene
and concentrated in vacuo 3 times to give carboxylic acid
lithium salt (15.7 g) as a white solid. This was employed in
the next step without further purification.
3. Experimental
3.1. General
All melting points (mps) were uncorrected. Melting points
were recorded on a Yazawa BY-2. Infrared spectra (IR)
were measured on a Jasco FT/IR-300E spectrometer. Proton
magnetic resonance spectra (1H NMR) were recorded on a
JEOL JNM-AL 300 or a JEOL JNM-LA 400 spectrometer.
Chemical shifts are reported in parts per million (d) relative
To a solution of crude carboxylic acid lithium salt (15.7 g)
in pyridine (52 g) at 08C was added acetic anhydride (20 g,
196 mmol) over 10 min. After being stirred at room
temperature for 3 days, the reaction mixture was concen-
trated in vacuo. The residue was added dil. hydrochloric
acid to adjust pH 4, and extracted with ethyl acetate
(200 mL£3). The combined organic phase was washed with
brine (300 mL), dried over anhydrous magnesium sulfate
and concentrated in vacuo. The residue was washed with
1
to internal chloroform (d 7.26 for H). Optical rotations
were measured on a HORIBA SEPA 200 polarimeter.
HRMS were recorded with a HITACHI M-80B mass
spectrometer. Analytical thin-layer chromatography (TLC)
was carried out using 0.25 mm Merck silica gel 60 F254
precoated glass-backed plates. Compounds were visualized

T. Tachihara, T. Kitahara / Tetrahedron 59 (2003) 1773–1780
1777
n-hexane to give 8 (13.8 g, 87% from 6); colorless plates;
mp 134–1358C; [a]2D0¼þ37.98 (c 0.19, CHCl3); IR (KBr)
methylsilyl chloride (131 mL, 0.87 mmol). After being
stirred at room temperature overnight, the mixture was
poured into cold aqueous sodium hydrogen carbonate
(5 mL) and extracted with diethyl ether (10 mL£2). The
combined organic phase was washed with brine (20 mL),
dried over anhydrous magnesium sulfate and concentrated
in vacuo. The residue was chromatographed on silica gel
(20 g) and eluted with n-hexane/ethyl acetate (20:1–5:1) to
give 11 (191 mg, 98%); colorless oil; [a]2D0¼254.98 (c 0.70,
CHCl3); IR (film) nmax 2953, 2857, 1395, 1253, 1116, 1082,
n
max 2991, 1726, 1684, 1444, 1384, 1293, 1219, 1146, 1082,
1
1033, 972, 945, 913 cm21; H NMR (300 MHz, CDCl3) d
1.57–2.10 (6H, m), 2.04 (3H, s), 2.90 (1H, ddd, J¼2.4, 2.7,
12.9 Hz), 3.90–4.04 (4H, m), 5.44 (1H, br s); HRMS (m/z)
calcd for C9H12O4 [M2AcOH]þ, 184.0736, found
184.0672.
3.1.2. (1S)-4,4-Ethylenedioxy-2-iodo-1-cyclohexyl acetate
(9). A mixture of 8 (7.5 g, 31 mmol), iodobenzenediacetate
(11.1 g, 34 mmol) and iodine (7.8 g, 31 mmol) in carbon
tetrachloride (750 mL) was stirred and irradiated with
tungsten-filament lamps at 608C for 1.5 h. After cooling,
the mixture was washed with aqueous sodium thiosulfate
(300 mL£2), aqueous sodium hydrogen carbonate (300 mL)
and brine (300 mL). The organic phase was dried over
anhydrous magnesium sulfate and concentrated in vacuo.
The residue was chromatographed on silica gel (300 g) and
eluted with n-hexane/ethyl acetate (10:1–4:1) to give 9
(9.12 g, 91%) as an inseparable diastereomeric mixture;
colorless needles; mp 54–558C; IR (KBr) nmax 2959, 2885,
1
1021, 870, 836, 775 cm21; H NMR (300 MHz, CDCl3) d
0.06 (6H, s), 0.88 (9H, s), 1.71–1.79 (2H, m), 1.93–1.97
(2H, m), 3.89–4.01 (4H, m), 4.17–4.25 (1H, m), 5.55 (1H,
d, J¼10.0 Hz), 5.86 (1H, dd, J¼2.4, 10.0 Hz); HRMS (m/z)
calcd for C12H22O3Si [M2C2H4]þ, 242.1338, found
242.1374.
3.1.5. (1S,2S,3R)-1-tert-Butyldimethylsilyloxy-2,3-epoxy-
4,4-ethylenedioxycyclohexane (12). To a solution of 11
(500 mg, 1.85 mmol) and sodium hydrogen carbonate
(840 mg, 10 mmol) in dichloromethane (50 mL) at 08C
was added m-chloroperbenzoic acid (1.6 g, 9.27 mmol).
After being stirred at room temperature for 5 days, the
mixture was poured into cold aqueous sodium hydrogen
carbonate (50 mL) and extracted with diethyl ether
(100 mL£2). The combined organic phase was washed
with brine (200 mL), dried over anhydrous magnesium
sulfate and concentrated in vacuo. The residue was
chromatographed on silica gel (20 g) and eluted with
n-hexane/ethyl acetate (20:1–8:1) to give 12 (289 mg,
1
1739, 1363, 1245, 1070, 1045 cm21; H NMR (300 MHz,
CDCl3) d 1.11–2.58 (6H, m), 2.09 and 2.13 (total 3H, each
s), 3.90–3.96 (4H, m), 4.18 and 4.39 (total 1H, each ddd,
J¼4.6, 10.7, 13.0 Hz and 2.7, 4.5, 13.0 Hz), 4.90 and 5.19
(total 1H, dt J¼4.7, 10.5 Hz and d, J¼2.6 Hz); HRMS (m/z)
calcd for C10H15O4 [M2I]þ, 199.0970, found 199.0863.
3.1.3. (1S)-4,4-Ethylenedioxy-2-cyclohexen-1-ol (10). A
mixture of 9 (11.9 g, 37 mmol) and DBU (27.8 g,
183 mmol) in toluene (100 mL) was stirred at 1008C for
3.5 h. After cooling, the mixture was poured into cold water
(100 mL) and extracted with ethyl acetate (200 mL£2). The
combined organic phase was washed with brine (200 mL),
dried over anhydrous magnesium sulfate and concentrated
in vacuo. The residue was chromatographed on silica gel
(200 g) and eluted with n-hexane/ethyl acetate (20:1–4:1)
to give acetate (6.58 g, 91%); colorless oil; [a]2D0¼21168
(c 1.40, CHCl3); IR (film) nmax 2958, 2883, 1733, 1372,
1
55%); colorless oil; H NMR (300 MHz, CDCl3) d 0.08
(3H, s), 0.09 (3H, s), 0.89 (9H, s), 1.54–1.60 (3H, m), 1.74–
1.78 (1H, m), 3.03 (1H, d, J¼3.6 Hz), 3.17 (1H, d, J¼
3.6 Hz), 3.97–4.10 (5H, m).
3.1.6. (4S)-4-tert-Butyldimethylsilyloxy-2-cyclohexen-1-
one (14). A mixture of 11 (300 mg, 1.11 mmol) and
pyridinium p-toluenesulfonate (15 mg) in 90% aqueous
acetone (5 mL) was stirred at reflux for 1 h. After cooling,
the mixture was concentrated in vacuo. The residue was
chromatographed on silica gel (20 g) and eluted with
n-hexane/ethyl acetate (20:1–8:1) to give 14 (226 mg,
90%); colorless oil; [a]2D0¼2116.08 (c 0.70, CHCl3), lit.
[a]D¼2115.948 (c 1.06, CHCl3);13c IR (film) nmax 2954,
1
1117, 1019, 1093 cm21; H NMR (300 MHz, CDCl3) d
1.76–2.15 (4H, m), 2.05 (3H, s), 3.93–4.02 (4H, m), 5.26
(1H, br s), 5.73 (1H, d, J¼10.3 Hz), 5.88 (1H, dd, J¼3.2,
10.3 Hz); HRMS (m/z) calcd for C8H10O2 [M2AcOH]þ,
138.0681, found 138.0630.
1
2857, 1691, 1472, 1382, 1253, 1102, 860, 838 cm21; H
NMR (400 MHz, CDCl3) d 0.11 (3H, s), 0.12 (3H, s), 0.92
(9H, s), 2.00 (1H, ddt, J¼4.0, 8.8, 12.8 Hz), 2.21 (1H, dqd,
J¼1.6, 4.4, 12.8 Hz), 2.34 (1H, ddd, J¼4.4, 12.4, 16.8 Hz),
2.57 (1H, dtd, J¼0.8, 4.4, 16.8 Hz), 4.52 (1H, ddd, J¼2.4,
4.4, 9.2 Hz), 5.92 (1H, ddd, J¼1.2, 2.0, 10.4 Hz), 6.83 (1H,
dt, J¼2.0, 10.4 Hz); HRMS (m/z) calcd for C11H19O2Si
[M2CH3]þ, 211.1154, found 211.1186.
A mixture of acetate (7.4 g, 37 mmol) and potassium
carbonate (100 mg) in methanol (100 mL) was stirred at
room temperature for 4.5 h. The mixture was concentrated
in vacuo. The residue was chromatographed on silica gel
(200 g) and eluted with n-hexane/ethyl acetate (4:1–2:3) to
give 10 (5.02 g, 86%); colorless oil; [a]2D0¼240.58 (c 1.24,
CHCl3); IR (film) nmax 3399, 2951, 2882, 1114, 1011,
1
936 cm21; H NMR (300 MHz, CDCl3) d 1.57–1.62 (1H,
3.1.7. (2R,3S,4S)-4-tert-Butyldimethylsilyloxy-2,3-epoxy-
cyclohexan-1-one (13). To a solution of 14 (5.27 g,
23.3 mmol) in tetrahydrofuran (30 mL) at 08C was added
35% hydrogen peroxide (11.3 g,.117 mmol) and triton B
(1.05 mL, 2.33 mmol) over 10 min. After being stirred at
the same temperature for 1.5 h, the mixture was poured into
cold aqueous ammonium chloride (30 mL) and extracted
with diethyl ether (50 mL£2). The combined organic phase
was washed with aqueous sodium hydrogen carbonate
(100 mL) and brine (100 mL), dried over anhydrous
m), 1.73–1.82 (2H, m), 1.93–1.99 (1H, m), 2.08–2.16 (1H,
m), 3.90–4.03 (4H, m), 4.22 (1H, br s), 5.63 (1H, d,
J¼10.1 Hz), 5.95 (1H, dd, J¼1.9, 10.1 Hz); HRMS (m/z)
calcd for C8H10O2 [M2H2O]þ, 138.0681, found 138.0685.
3.1.4. (1S)-1-tert-Butyldimethylsilyloxy-4,4-ethylene-
dioxy-2-cyclohexene (11). To a solution of 10 (113 mg,
0.72 mmol) and imidazole (118 mg, 1.74 mmol) in N,N-di-
methylformamide (3 mL) at 08C was added tert-butyldi-

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T. Tachihara, T. Kitahara / Tetrahedron 59 (2003) 1773–1780
magnesium sulfate and concentrated in vacuo. The residue
was chromatographed on silica gel (200 g) and eluted with
n-hexane/ethyl acetate (20:1) to give 13 (4.52 g, 80%);
colorless oil; [a]D20¼þ57.38 (c 1.97, CHCl3); IR (film) nmax
2954, 2858, 1718, 1472, 1362, 1254, 1092, 982, 838,
777 cm21; 1H NMR (400 MHz, CDCl3) d 0.10 (3H, s), 0.12
(3H, s), 0.89 (9H, s), 1.70 (1H, ddd, J¼4.0, 10.4, 14.0 Hz),
2.09 (1H, tq, J¼3.2, 14.0 Hz), 2.29–2.44 (2H, m), 3.26 (1H,
d, J¼4.0 Hz), 3.46 (1H, dt, J¼0.8, 3.4 Hz), 4.45 (1H, dd, J¼
3.2, 6.8 Hz); HRMS (m/z) calcd for C11H19O3Si [M2
CH3]þ, 227.1103, found 227.1075.
CHCl3),3c [a]D¼þ251.38 (c 1.40, CHCl3),3d [a]D31¼þ2528
(c 0.815, CHCl3);3e IR (film) nmax 2954, 2930, 2858, 1685,
1
1092, 1074, 837, 778 cm21; H NMR [300 MHz, CDCl3,
compound 18 could be assigned] d 0.15 (3H, s), 0.17 (3H, s),
0.92 (9H, s), 1.84 (3H, s), 3.48 (1H, dd, J¼1.2, 3.6 Hz),
3.62–3.64 (1H, m), 4.64 (1H, dd, J¼1.2, 4.8 Hz), 6.27–6.30
(1H, m); HRMS (m/z) calcd for C12H19O3Si [M2CH3]þ,
239.1103, found 239.1129.
3.1.10. (2R,3R,4S)-2,3-Epoxy-4-hydroxy-6-methyl-5-
cyclohexen-1-one (epiepoformin 1). To a solution of 18
(8.8 mg, 0.035 mmol) in acetonitrile (1 mL) at 08C was
added 40% aqueous hydrofluoric acid (1 mL). After being
stirred at room temperature for 1.5 h, the mixture was
poured into aqueous sodium hydrogen carbonate (5 mL) and
extracted with ethyl acetate (5 mL£5). The combined
organic phase was washed with aqueous sodium hydrogen
carbonate (10 mL) and brine (10 mL), dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue
was purified by preparative TLC developed with n-hexane/
ethyl acetate (3:1) to give a white solid (5 mg), which was
recrystallized from n-hexane/ethyl acetate to give 1 (3 mg,
62%); colorless plates; mp 80–818C; lit. mp 87.5–88.58C,3c
84–858C;3d [a]D20¼þ320.08 (c 0.06, EtOH); lit. [a]Dþ
316.08 (c 0.37, EtOH),3c [a]D¼þ315.08 (c 0.49, EtOH),3d
[a]D27¼þ3108 (c 0.46, EtOH);3e IR (KBr) nmax 3416, 1667,
3.1.8. (2R,3S,4S)-4-tert-Butyldimethylsilyloxy-2,3-epoxy-
6-phenylselenylcyclohexan-1-one (16). To a solution of 13
(1.0 g, 4.13 mmol) in tetrahydrofuran (10 mL) at-788C was
added 1 M lithium hexamethyldisilazane (4.95 mL,
4.95 mmol) over 30 min and the mixture was stirred for
30 min. Then to the mixture was added chlorotrimethyl-
silane (1.05 mL, 8.26 mmol) over 15 min and the mixture
was stirred for 30 min. After being stirred at room
temperature for 1 h, the mixture was concentrated in
vacuo and dry n-pentane was added to the mixture. The
pentane solution was filtered through a celitew pad and then
concentrated in vacuo to give crude silyl enol ether 15
(1.33 g) as a pale-yellow oil. This was employed in the next
step without further purification.
1
1436, 1376, 1274, 1129, 1040, 824, 725, 597 cm21; H
To a solution of crude 15 (1.33 g) in dichloromethane
(50 mL) at 2788C was added a mixture of phenylselenenyl
chloride (870 mg, 4.54 mmol) and dichloromethane
(10 mL) over 30 min and the whole was stirred for
15 min. After being stirred at room temperature for
15 min, the mixture was concentrated in vacuo to give 16
(2.18 g) as a pale-yellow oil. This was employed in the next
step without further purification.
NMR (400 MHz, CDCl3) d 1.86 (3H, s), 3.52 (1H, dd, J¼
1.2, 3.6 Hz), 3.77–3.79 (1H, m), 4.67 (1H, dd, J¼1.2,
4.8 Hz), 6.44–6.47 (1H, m); HRMS (m/z) calcd for C7H8O3
[M]þ, 140.0473, found 140.0567.
3.1.11. (2R,3S,4S)-4-tert-Butyldimethylsilyloxy-2,3-epoxy-
6-hydroxymethyl-5-cyclohexen-1-one (21). To a suspen-
sion of crude 16 (100 mg) in tetrahydrofuran (1 mL) at 08C
was added DBU (76 mg, 0.5 mmol) and 35% formalin
(108 mg, 1.25 mmol). After being stirred at the same
temperature for 30 min, the mixture was poured into cold
water (3 mL) and extracted with diethyl ether (5 mL£2).
The combined organic phase was washed with aqueous
sodium hydrogen carbonate (10 mL) and brine (10 mL),
dried over anhydrous magnesium sulfate and concentrated
in vacuo to give crude 20 as a pale-yellow oil. This was
employed in the next step without further purification.
3.1.9. (2R,3S,4S)-4-tert-Butyldimethylsilyloxy-2,3-epoxy-
6-methyl-5-cyclohexen-1-one (18). To a suspension of
sodium hydride (25 mg, 0.65 mmol) in tetrahydrofuran
(1 mL) at 08C was added a mixture of crude 16 (82 mg) and
tetrahydrofuran (1 mL) over 10 min. Then to the mixture
at 08C was added iodomethane (70 mL, 1.12 mmol) over
10 min. After being stirred at the same temperature
overnight, the mixture was poured into cold water (3 mL)
and extracted with diethyl ether (5 mL£2). The combined
organic phase was washed with aqueous sodium hydrogen
carbonate (10 mL) and brine (10 mL), dried over anhydrous
magnesium sulfate and concentrated in vacuo to give crude
17 as a pale-yellow oil. This was employed in the next step
without further purification.
To a suspension of crude 20 and sodium hydrogen carbonate
(100 mg, 1.2 mmol) in tetrahydrofuran (2 mL) at 08C was
added 35% hydrogen peroxide (100 mL, 1.0 mmol) over
10 min. After being stirred at room temperature for 2 h, the
mixture was poured into water (5 mL) and extracted with
diethyl ether (5 mL£2). The combined organic phase was
washed with brine (10 mL), dried over anhydrous mag-
nesium sulfate and concentrated in vacuo. The residue was
chromatographed on silica gel (20 g) and eluted with
n-hexane/ethyl acetate (20:1–4:1) to give a white solid
(31 mg), which was recrystallized from n-hexane to give 21
(23 mg, 45% from 13); colorless needles; mp 40–418C;
lit. mp 39.5–418C;4f [a]D20¼þ245.08 (c 0.49, CHCl3); lit.
[a]2D9¼þ233.58 (c 0.9, CHCl3);4f IR (KBr) nmax 3438, 2929,
To a suspension of crude 17 and sodium hydrogen carbonate
(50 mg, 0.6 mmol) in tetrahydrofuran (3 mL) at 08C was
added 35% hydrogen peroxide (50 mL, 0.5 mmol) over
10 min. After being stirred at room temperature for 1.5 h,
the mixture was poured into water (5 mL) and extracted
with diethyl ether (5 mL£2). The combined organic phase
was washed with brine (10 mL), dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue
was purified by preparative TLC developed with n-hexane/
ethyl acetate (5:1) to give 18 (20 mg, 50% from 13) with
inseparable unknown by-products; colorless oil; [a]2D0¼
þ124.08 (c 0.59, CHCl3); lit. [a]Dþ251.08 (c 1.17,
1
1685, 1472, 1389, 1253, 1075, 843, 777, 717 cm21; H
NMR (300 MHz, CDCl3) d 0.16 (3H, s), 0.19 (3H, s), 0.92
(9H, s), 1.98 (1H, br s), 3.48 (1H, dd, J¼1.2, 3.6 Hz), 3.66–
3.67 (1H, m), 4.26 (1H, d, J¼14.4 Hz), 4.36 (1H, d,

T. Tachihara, T. Kitahara / Tetrahedron 59 (2003) 1773–1780
1779
J¼14.4 Hz), 4.72 (1H, d, J¼4.8 Hz), 6.50–6.51 (1H, m);
HRMS (m/z) calcd for C9H13O4Si [M2C4H9]þ, 213.0583,
found 213.0593.
3.1.15. (2R,3S,4S)-4-tert-Butyldimethylsilyloxy-2,3-
epoxy-5-cyclohexen-1-one (25). To a solution of crude
16 (50 mg, 0.13 mmol) and sodium hydrogen carbonate
(50 mg, 0.6 mmol) in tetrahydrofuran (1 mL) at 08C was
added 35% hydrogen peroxide (50 mL, 0.5 mmol) over
10 min. After being stirred at room temperature for 2 h, the
mixture was poured into water (5 mL) and extracted with
diethyl ether (5 mL£2). The combined organic phase was
washed with brine (10 mL), dried over anhydrous mag-
nesium sulfate and concentrated in vacuo. The residue was
purified by preparative TLC developed with n-hexane/ethyl
acetate (6:1) to give 25 (15.5 mg, 68% from 13); colorless
oil; [a]2D0¼þ335.98 (c 0.88, CHCl3); lit. [a]2D8¼þ331.58
(c 1.22, CHCl3);3d IR (film) nmax 2955, 2930, 2858, 1692,
3.1.12. (2R,3R,4S)-2,3-Epoxy-4-hydroxy-6-hydroxy-
methyl-5-cyclohexen-1-one (epiepoxydon 2). The depro-
tection of 21 (13 mg, 0.048 mmol) was performed as
described above for 1 to give 2 (4 mg, 53%); colorless oil;
[a]2D0¼þ256.18 (c 0.95, EtOH); lit. [a]D¼þ1948 (c 1.57,
EtOH),1 [a]D27¼þ256.48 (c 0.8, EtOH);4f IR (film) nmax
1
3355, 1680, 1397, 1242, 1112, 1032, 821, 716 cm21; H
NMR (300 MHz, CDCl3) d 3.52 (1H, dd, J¼1.2, 3.6 Hz),
3.81–3.84 (1H, m), 4.25 (1H, d, J¼14.4 Hz), 4.43 (1H, d,
J¼14.4 Hz), 4.77 (1H, d, J¼4.8 Hz), 6.67–6.70 (1H, m);
HRMS (m/z) calcd for C7H8O4 [M]þ, 156.0423, found
156.0438.
1260, 1090, 839, 806, 779 cm21 1H NMR (300 MHz,
;
CDCl3) d 0.15 (3H, s), 0.18 (3H, s), 0.92 (9H, s), 3.44–3.46
(1H, m), 3.63–3.65 (1H, m), 4.66 (1H, dd, J¼1.2, 4.2 Hz),
5.95 (1H, dt, J¼1.6, 10.8 Hz), 6.52 (1H, ddd, J¼2.8, 4.8,
10.8 Hz); HRMS (m/z) calcd for C12H20O3Si [M]þ,
240.1182, found 240.1090.
3.1.13. (2R,3S,4S)-6-Bromo-4-tert-butyldimethylsilyl-
oxy-2,3-epoxy-5-cyclohexen-1-one (24). To a suspension
of crude 16 (80 mg) in tetrahydrofuran (1 mL) at 08C was
added DBU (61 mg, 0.4 mmol) and bromine (32 mg,
0.2 mmol). After being stirred at the same temperature for
30 min, the mixture was poured into cold water (3 mL) and
extracted with diethyl ether (5 mL£2). The combined
organic phase was washed with aqueous sodium hydrogen
carbonate (10 mL) and brine (10 mL), dried over anhydrous
magnesium sulfate and concentrated in vacuo to give crude
23 as a pale-brown oil. This was employed in the next step
without further purification.
Acknowledgements
We thank Dr Tetsuya Yanai of Hasegawa Co., Ltd. for
HRMS analyses. This work was supported in part by a
Grant-in Aid from the Ministry of Education, Science,
Sports, Culture and Technology of Japan.
To a suspension of crude 23 and sodium hydrogen carbonate
(80 mg, 1.0 mmol) in tetrahydrofuran (2 mL) at 08C was
added 35% hydrogen peroxide (80 mL, 0.8 mmol) over
10 min. After being stirred at room temperature for 2 h,
the mixture was poured into water (5 mL) and extracted
with diethyl ether (5 mL£2). The combined organic phase
was washed with brine (10 mL), dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue
was chromatographed on silica gel (20 g) and eluted with
n-hexane/ethyl acetate (20:1–4:1) to give a white solid
(39 mg), which was recrystallized from n-hexane/CHCl3
to give 24 (33 mg, 68% from 13); colorless needles; mp
49–508C; [a]D20¼þ98.98 (c 0.79, CHCl3), IR (KBr) nmax
References
1. Nagasawa, H.; Suzuki, A.; Tamura, S. Agric. Biol. Chem.
1978, 42, 1303.
2. Higa, T.; Okuda, R. K.; Severns, R. M.; Scheur, P. J.; He,
C.-H.; Changfu, X.; Clardy, J. Tetrahedron 1987, 43, 1063.
3. Epiepoformin; (a) Ichihara, A.; Kimura, R.; Oda, K.;
Moriyasu, K.; Sakamura, S. Agric. Biol. Chem. 1982, 46,
1879. (b) Ichihara, A. Synthesis 1987, 207. (c) Kamikubo, T.;
Ogasawara, K. Tetrahedron Lett. 1995, 36, 1685. (d) Barros,
M. T.; Maycock, C. D.; Ventura, M. R. Chem. Eur. J. 2000, 6,
3991. (e) Shimizu, H.; Okamura, H.; Yamashita, N.; Iwagawa,
T.; Nakatani, M. Tetrahedron Lett. 2001, 42, 8649, and
references therein.
1
2953, 2858, 1703, 1253, 1091, 877, 841, 778 cm21; H
NMR (300 MHz, CDCl3) d 0.15 (3H, s), 0.17 (3H, s), 0.93
(9H, s), 3.67–3.69 (1H, m), 3.65 (1H, dd, J¼1.2, 3.6 Hz),
4.70 (1H, dt, J¼1.2, 5.1 Hz), 6.96 (1H, dd, J¼2.1, 5.1 Hz);
HRMS (m/z) calcd for C8H10BrO3Si [M2C4H9]þ,
260.9583, found 260.9621.
4. Epiepoxydon; (a) Ichihara, A.; Kimura, R.; Oda, K.;
Sakamura, S. Tetrahedron Lett. 1976, 17, 4741. (b) The-Wei
Chou, D.; Ganem, B. J. Am. Chem. Soc. 1980, 102, 7987.
(c) Ichihara, A.; Kimura, R.; Oda, K.; Moriyasu, K.;
Sakamura, S. Agric. Biol. Chem. 1982, 46, 1879. (d) Ichihara,
A. Synthesis 1987, 207. (e) Nagata, T.; Ando, Y.; Hiroto, A.
Biosci. Biotechnol. Biochem. 1992, 56, 810. (f) Kamikubo, T.;
Hiroya, K.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 499.
(g) Genski, T.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43,
3573, and references therein.
3.1.14. (2R,3R,4S)-6-Bromo-2,3-epoxy-4-hydroxy-5-
cyclohexen-1-one (bromoxone 3). The deprotection of 24
(7.9 mg, 0.025 mmol) was performed as described above for
1 to give a brown solid (5 mg), which was recrystallized
from n-hexane/chloroform to give 3 (3 mg, 59%); pale-
yellow needles; mp 124–1258C; lit. 123–1278C,2 138–
1398C,5b 131–1328C;5e [a]2D0¼þ204.08 (c 0.21, acetone);
lit. [a]2D2¼þ2208 (c 0.09, CHCl3),2 [a]2D5¼þ2038 (c 2.5,
acetone);5e IR (KBr) nmax 3467, 1688, 1610, 1254, 1046,
5. Bromoxone; (a) Gautier, E. C. L.; Lewis, N.; McKillop, A.;
Taylor, R. J. K. Tetrahedron Lett. 1994, 35, 8759. (b) Johnson,
C. R.; Miller, M. W. J. Org. Chem. 1995, 60, 6674. (c) Adelt,
S.; Plettenburg, O.; Stricker, R.; Reiser, G.; Altenbach, H.-J.;
Vogel, G. J. Med. Chem. 1999, 42, 1262. (d) Altenbach, H.-J.
In Antibiotics and Antiviral Compounds; Krohn, K., Kirst, H.,
Maas, H., Eds.; VCH: Weinheim, 1993; pp 359–372.
1
791, 613, 546 cm21; H NMR (400 MHz, CDCl3) d 3.68
(1H, dd, J¼1.2, 3.6 Hz), 3.84 (1H, br s), 4.75 (1H, d, J¼
5.2 Hz), 7.14 (1H, dd, J¼2.4, 5.2 Hz); HRMS (m/z) calcd
for C6H5BrO3 [M]þ, 203.9422, found 203.9407.

1780
T. Tachihara, T. Kitahara / Tetrahedron 59 (2003) 1773–1780
(e) Block, O.; Klein, G.; Altenbach, H.-J.; Brauer, D. J. Org.
Chem. 2000, 65, 716, and references therein.
Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem.
1989, 54, 3738, and references therein. For the recent synthesis
of enantiomer of compound 14 (d) Evarts, J. B.; Fuchs, P. L.
Tetrahedron Lett. 2001, 42, 3673. (e) Hashiguchi, S.; Fujii, A.;
Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew.
Chem. Int. Ed. Engl. 1997, 36, 288. (f) Hiroya, K.; Kurihara,
Y.; Ogasawara, K. Angew. Chem. Int. Ed. Engl. 1995, 34,
2287, and references therein.
6. Kitahara, T.; Mori, K. Tetrahedron Lett. 1985, 26, 451.
7. Kitahara, T.; Kurata, H.; Mori, K. Tetrahedron 1988, 44, 4339.
8. Kitahara, T.; Kiyota, H.; Kurata, H.; Mori, K. Tetrahedron
1991, 47, 1649.
9. Akao, H.; Kiyota, H.; Nakajima, T.; Kitahara, T. Tetrahedron
1999, 55, 7757.
10. (a) Watanabe, H.; Watanabe, H.; Kitahara, T. Tetrahedron
Lett. 1998, 39, 8313. (b) Watanabe, H.; Watanabe, H.;
Kitahara, T. Tetrahedron 1999, 55, 9755.
14. Vang, N. C.; Finnegan, R. A. J. Am. Chem. Soc. 1958, 80,
5845.
15. Newton, R. F.; Reynolds, D. P. Tetrahedron Lett. 1979, 20,
3981.
11. Tachihara, T.; Watanabe, H.; Kitahara, T. Heterocycles 2002,
57, 781.
´ ´
12. Concepcion, J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.;
16. Nakamori, K.; Mastuura, H.; Yoshihara, T.; Ichihara, A.;
Koda, Y. Phytochemistry 1994, 35, 835.
´
Salazar, J. A.; Suarez, E. J. Org. Chem. 1986, 51, 402.
17. (a) Sakamura, S.; Ito, J.; Sakai, R. Agric. Biol. Chem. 1970, 34,
153. (b) Sakamura, S.; Ito, J.; Sakai, R. Agric. Biol. Chem.
1971, 35, 105.
13. For the recent synthesis of compound 14 (a) Barros, M. T.;
Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin Trans. 1
2001, 166. (b) Barros, M. T.; Maycock, C. D.; Ventura, M. R.
Tetrahedron Lett. 1999, 40, 557. (c) Audia, J. E.; Boisvert, L.;
18. Muhlenfeld, A.; Achenbach, H. Phytochemistry 1988, 27,
3853.