Synthesis of Hyperolactones A and C

Article abstract of DOI:10.1002/jhet.5570380124

Hyperolactones A (1) and C (3) have been synthesized starting from (S)-malic acid by a straightforward route. The unique spirolactone skeleton was efficiently constructed by one-pot reaction as a key step. The absolute stereochemistry of hyperolactones was unambiguously established by this synthesis.

Full text of DOI:10.1002/jhet.5570380124

Jan-Feb 2001
Synthesis of Hyperolactones A and C
165
Toshihiko Ueki [a], Matsumi Doe [a], Rika Tanaka [b], Yoshiki Morimoto [a],
Kazuo Yoshihara [c] and Takamasa Kinoshita* [a]
Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585, Japan
Department of Applied Chemistry, Faculty of Engineering, Osaka City University
Suntory Institute for Bioorganic Research, Shimamoto-cho, Osaka 618-0024, Japan
Received May 22, 2000
Hyperolactones A (1) and C (3) have been synthesized starting from (S)-malic acid by a straightforward
route. The unique spirolactone skeleton was efficiently constructed by one-pot reaction as a key step. The
absolute stereochemistry of hyperolactones was unambiguously established by this synthesis.
J. Heterocyclic Chem., 38, 165 (2001).
(-)-Hyperolactone A (1) was isolated from the leaves
tone skeleton (anti-orientation at the stereogenic center
C-5 in 2 as compared with 1 and 3), and some novel char-
acteristics of the structure are (1) a highly substituted 1,7-
dioxaspiro[4,4]non-2-ene-4,6-dione skeleton; (2) a
strained 2,2,5-trisubstituted 3(2H)furanone ring system.
Owing to their structural uniqueness, compound 1 and
structurally related natural products are good targets for
total synthesis [3]. We now describe herein the synthesis of
1 and 3 in a stereoselective fashion, which enables us to
establish their absolute stereochemistry unambiguously.
and stems of the Chinese plant Hypericum chinense L. by
M. Tada and co-workers in 1989 [1]. Later, two structural
relatives of 1, (+)-hyperolactone B (2) and (-)-hyperolac-
tone C (3), were also isolated from the same plant as minor
components in 1995 [2]. The gross structure of 1 and its
relative stereochemistry were determined by means of
extensive spectroscopic studies and chemical transforma-
tion, and was finally confirmed by X-ray crystallographic
analysis. These compounds possess a common spirolac-
Synthesis of the Side Chain Units 8 and 14.
The requisite aldehyde 8 was synthesized as shown in
Scheme 1. The β-keto ester 6 was obtained by the Collins
oxidation of the β-hydroxy ester 5, which was prepared from
ethyl bromoacetate and benzaldehyde 4 by the Reformatsky
reaction [4]. The keto ester 6 was heated with ethylene glycol
containing a small amount of p-toluenesulfonic acid in ben-
zene to give the ketal 7 in 73% yield. Diisobutylaluminium
hydride reduction of 7 afforded the aldehyde 8 in 78% yield.
Figure 1

166
T. Ueki, M. Doe, R. Tanaka, Y. Morimoto, K. Yoshihara and T. Kinoshita
Vol. 38
Since the X-ray crystallographic analysis of 1 suggests
(Figure 2). Both in 17a and 17b, a NOE was observed
(2'S)-configuration, a synthetic plan for the requisite (4S)-
aldehyde 14 as a coupling partner is shown in Scheme 2.
Reduction of (2S, 3S)-acetoxy-3-methylvaleric acid 9 [5],
prepared from (2S, 3S)-isoleucine, with lithium aluminium
hydride afforded the diol 10 in 83% yield, which was con-
verted [6] into the volatile epoxide 11 in 62% yield. The
lithiation of 1,3-dithiane with n-butyllithium and subse-
quent addition to the epoxide 11 gave the dithiane 12 in
79% yield. p-Methoxybenzyl protection of the hydroxyl
group in 12 and subsequent oxidative cleavage of the dithi-
ane afforded the desired aldehyde 14.
between the 4-methyl group (4-CH ) and a higher-field
hydrogen (5-Ha) of the 5-methylene, but not observed
3
between the 4-CH and a lower-field hydrogen (5-Hb). In
3
17a, a small NOE was observed between the 4-CH and a
3
methylene hydrogen of the methoxymethyloxy group,
whereas a NOE was not observed in 17b. By the
anisotropic effect of the methoxymethyloxy group, the
signals of 4-CH and 5-Ha for 17a appeared in the lower
3
field than the corresponding signals for 17b, and 5-Hb
signal for 17b was observed in the lower field than that
for 17a. These results indicate that the methoxymethy-
loxy group and the 4-CH in 17a were located in the syn
Synthesis of 3 (Scheme 3).
3
relationship. From these considerations, it was found that
the stereochemistry of 17a was (3S,4S)- configuration
and 17b was its 3R-epimer.
The aldol reaction of the lithium enolate of (3S,4S)-3-
methoxymethyloxy-4-methyl-4-vinyl-γ-butyrolactone 15
(Scheme 5, see experimental section) [3b] with the alde-
hyde 8 afforded 16 as an inseparable mixture of four
diastereomers in 83% yield. Although a multitude of iso-
mers is formed, in the light of the subsequent steps this
factor is of minor significance. Successive treatment of 16
with the Jones reagent provided 17 in 92% yield (a:b = 2:3)
as a separable mixture.
Acid-catalyzed hydrolysis of 17a in boiling tetrahydro-
furan containing 3 M hydrochloric acid furnished 3 (93%
yield) consequently via a subsequent ring closure and
dehydration (Scheme 3). The compound 3 was found to be
identical with the natural product [2] by comparing the mp,
1
13
[α] , ms, H and C NMR spectra with those reported,
D
1
The stereochemistries of 17 were confirmed by H
while the physical data of compound 3a derived from 17b
NMR analysis and NOE experiments of 17a and 17b
were all different except the hrms.
Scheme 3

Jan-Feb 2001
Synthesis of Hyperolactones A and C
167
1
13
ms, H and C NMR spectra with those reported [1]. The
β-methoxymethyloxy isomer 20b was treated with bromo-
trimethylsilane to afford a 5R-isomer 1a as a single product in
95% yield.
Thus, we have completed the total synthesis of 1 and 3. This
synthesis discloses that the stereochemistry should be depicted
as (2'S,5S,9S)-2-(2'-butyl)-9-ethenyl-9-methyl-1,7-dioxaspiro-
[4,4]non-2-ene-4,6-dione for (-)-hyperolactone A and (5S,9S)-
configuration for (-)-hyperolactone C, respectively.
Figure 2
Synthesis of 1 (Scheme 4).
The advantages of this strategy are the short and efficient
steps in one-pot direct construction of spirolactone by acid-
catalysis via deprotection, cyclization and elimination.
A similar coupling reaction of 15 with the aldehyde 14
gave an inseparable mixture of four diastereomers of the
hydroxyl compound in 84% yield, which on oxidation with
Dess-Martin periodinane provided 18 in quantitative yield
EXPERIMENTAL
sep-
(a:b = 1:1). The two diastereoisomers 18a and 18b were
1
Melting points were measured with a Yanagimoto MP apparatus
and are uncorrected. Specific rotations were measured with a
JASCO Model DIP-370 polarimeter. Ir spectra were obtained on a
JASCO A-102 infrared spectrophotometer. H and C nmr spectra
were recorded on a JEOL LA-300 (300 MHz) in deuterio chloro-
form solution, unless stated otherwise. Chemical shifts (ppm) are
given downfield of tetramethylsilane. Mass spectra were deter-
mined on a JEOL AX-500 spectrometer. Elemental analyses were
performed with a JMS AX-500 elemental analyzer by the staff at
our Instrumental Measurement Center. Thin-layer chromatography
arated by chromatography. By similar H NMR analysis and
NOE experiments of 18, a 2.2% enhancement was observed
in the signal for the 4-methyl group upon irradiation of the
methylene proton of the methoxymethyloxy group in 18a,
thereby confirming that the desired stereochemistry had been
established. Deprotection of the p-methoxybenzyl group in
the lactone 18a was accomplished using dichlorodicyanoben-
zoquinone in dichloromethane to give the β-hydroxy ketone
19a in 94% yield. The Jones oxidation of 19a under mild con-
dition resulted in enol formation of the diketone 20a, the
structure of which was elucidated by NMR.
An acid-catalyzed reaction of 20a with boiling tetrahydro-
furan in the presence of 3 M hydrochloric acid gave a mixture
of diastereomers of 1 and its 2'-isomer 1b (1:1 by NMR) in
70% yield. Such drastic conditions indeed would be inappro-
priate for the delicate ketone. Finally and much to our relief,
deprotection of 20a was achieved using bromotrimethylsilane
in dichloromethane at -20° to give the spirolactone 1 as a sin-
gle product in 98% yield. The synthetic 1 was found to be
1
13
(TLC) was performed with a glass plate coated Kieselgel 60 GF
254
(Merck). Column chromatography was carried out on silica gel 60
(Merck No. 7734; 63-200 µm). Solvents were dried (drying agent in
parenthesis) and distilled prior to use: tetrahydrofuran and diethyl
ether (sodium/benzophenone ketyl), benzene and dichloromethane
(phosphorous pentoxide), and dimethylsulfoxide (calcium hydride).
Organic solutions were dried over anhydrous sodium sulfate.
Ethyl 3-hydroxy-3-phenylpropanoate (5).
This compound was prepared from benzaldehyde and ethyl
bromoacetate by the Reformatsky reaction in 85% yield as a col-
orless oil; bp 120-123°/2 mm Hg; (lit [4] 105°/0.2 mm Hg).
identical with the natural product by comparing the mp, [α] ,
D

168
T. Ueki, M. Doe, R. Tanaka, Y. Morimoto, K. Yoshihara and T. Kinoshita
Vol. 38
Ethyl 3-Phenyl-3-oxopropanoate (6).
into 25 ml of water. The organic layer was dried and distilled to
give 11 (1.3 g, 62%) as a colorless liquid; bp 95°/760 mm Hg;
This compound was prepared by the Collins oxidation [7] of 5
21
1
[α] +3.8 (c 2.10, ethanol); H nmr: δ 0.92 (d, 3H, J = 6.7 Hz),
in 82% yield as a colorless oil: bp 115°/1 mm Hg; (lit [7] 95°/0.2
D
0.96 (t, 3H, J = 7.3 Hz), 1.15-1.66 (m, 3H), 2.46-2.56 (m, 1H),
-1
1
mm Hg); ir (film) 1725, 1670, 1620 cm ; H nmr: δ 1.25 (t, 3H,
13
2.64-2.78 (m, 2H); C nmr: δ 11.2 (q), 15.1 (q), 27.2 (t), 37.6
J = 7.1 Hz), 3.99 (s, 2H), 4.21 (q, 2H, J = 7.1 Hz), 7.37-7.96 (m,
(d), 45.6 (t), 56.9 (d).
13
5H); C nmr: δ 14.1 (q), 46.0 (t), 61.5 (t), 126.0 (d), 128.5 (d),
128.8 (d), 133.7 (s), 167.5 (s), 192.5 (s). hrms: Calcd. for
(2R,3S)-2-(2-Hydroxy-3-methylpentyl)-1,3-dithiane (12).
+
C H O : (M ) 192.0786. Found: m/z 192.0775.
11 12
3
To a solution of 1,3-dithiane (3.01 g, 25.1 mmoles) in tetra-
hydrofuran (40 ml) was added n-butyllithium (1.6 M in hexane,
14.2 ml, 22.9 mmols) at -40° under nitrogen and the mixture was
stirred for 2 hours. A solution of 11 (2.09 g, 20.9 mmoles) in
tetrahydrofuran (15 ml) was added to the reaction mixture, and
stirred for additional 5 hours at -40°. After standing overnight at
0°, the reaction mixture was quenched with saturated aqueous
ammonium chloride, and extracted with ether (4 x 100 ml). The
combined organic layer was dried and concentrated. The residue
was purified by column chromatography (hexane/ethyl acetate,
Ethyl 3,3-Ethylenedioxy-3-phenylpropanoate (7).
A solution of 6 (10 mmoles), ethyleneglycol (20 mmoles) and p-
toluenesulfonic acid (20 mg) in benzene (50 ml) was refluxed for 15
hours. The cooled mixture was poured onto saturated aqueous
sodium bicarbonate (50 ml), and the organic layer was washed with
water and dried. The solvent was removed and the residue was dis-
tilled to give 7 in 73% yield as a colorless oil; bp 121°/2 mm Hg; ir
-1
1
(film) 1720 cm ; H nmr: δ 1.15 (t, 3H, J = 7.1 Hz), 2.96 (s, 2H),
3.80-3.84 (m, 2H), 4.03-4.11 (m, 2H), 4.07 (q, 2H, J = 7.1 Hz), 7.27-
20
13
5:1) to give 12 (3.63 g, 79%) as a pale yellow oil; [α] +28.3 (c
7.52 (m, 5H); C nmr: δ 14.0 (q), 45.8 (t), 60.4 (t), 64.8 (t), 107.8
D
-1 1
0.91, ethanol); ir (film) 3350 cm ; H nmr: δ 0.89 (d, 3H, J = 6.8
(s), 125.6 (d), 128.1 (d), 128.2 (d), 141.4 (s), 168.5 (s). hrms: Calcd.
+
Hz), 0.92 (t, 3H, J = 7.3 Hz), 1.12-1.21 (m, 1H), 1.44-1.53 (m,
for C H O : (M + H) 237.1129. Found: m/z 237.1127.
13 17
4
2H), 1.80-1.96 (m, 3H), 2.02-2.19 (m, 1H), 2.84-2.94 (m, 4H),
Anal. Calcd for C
H O : C, 66.09; H, 6.83. Found: C, 66.00;
13 16 4
13
3.78-3.90 (m, 1H), 4.28 (dd, 1H, J = 5.5 Hz, J = 8.3 Hz);
C
H, 6.88.
nmr: δ 11.6 (q), 14.4 (q), 24.8 (t), 26.0 (t), 30.0 (t), 30.4 (t), 38.8
3,3-Ethylenedioxy-3-phenylpropanal (8).
+
(d), 40.7 (t), 44.7 (d), 72.0 (d). MS (EI) m/z 220 (M , 60%), 145
+
(100), 119 (75); hrms: Calcd. for C
Found: m/z 220.0982.
H
OS : (M) 220.0956.
To a solution of 7 (1.0 mmol) in toluene (10 ml) was added
diisobutylaluminium hydride (1.5 M in toluene, 1.01 mmoles) at
-78°. After stirring for 10 minutes the reaction mixture was
quenched by addition of water. The precipitate was removed by fil-
tration through celite. The filtrate was washed with water, dried and
distilled to give 8 in 78% yield as white crystals; mp 87°; ir (nujol)
10 20
2
(2R,3S)-2-[2-(4-Methoxybenzyloxy)-3-methylpentyl]-1,3-dithiane
(13).
To a suspension of sodium hydride (158 mg, 3.96 mmoles) in
dimethylformamide (15 ml) was added 12 (581 mg, 2.64
mmoles) in dimethylformamide (3 ml) at room temperature, and
the mixture was stirred for 1 hour. To the mixture was added
p-methoxybenzyl chloride (1.07 ml, 7.90 mmoles), and the mix-
ture was stirred for 21 hours at 50°. The reaction mixture was
quenched with water, and extracted with ether (3 x 30 ml). The
combined organic layer was dried and concentrated in vacuo. The
residue was purified by column chromatography (hexane/ethyl
-1
1
1710 cm ; H nmr: δ 2.90 (d, 2H, J = 2.9 Hz), 3.78-3.90 (m, 2H),
13
4.03-4.14 (m, 2H), 7.29-7.50 (m, 5H), 9.76 (t, 1H, J = 2.9 Hz);
C
nmr: δ 52.7 (t), 64.7 (t), 108.2 (s), 125.3 (d), 128.5 (d x 2), 141.2 (s),
+
199.8 (d). MS (EI) m/z 192 (M , 15%), 149 (90), 115 (100).
Anal. Calcd for C H O : C, 68.74; H, 6.29. Found: C, 68.48;
11 12
3
H, 6.33.
(2S,3S)-3-Methyl-1,2-pentanediol (10).
25
To a stirred suspension of lithium aluminium hydride (4.36 g,
115 mmoles) in tetrahydrofuran (60 ml) was added a solution of
acetate, 10/1) to give 13 (751 mg, 84%) as a colorless oil; [α]
D
1
+43.0 (c 0.56, ethanol); H nmr: δ 0.88 (d, 3H, J = 7.0 Hz), 0.92
(t, 3H, J = 7.3 Hz), 1.10-1.41 (m, 2H), 1.70-1.93 (m, 4H), 2.05-
2.15 (m, 1H), 2.70-2.92 (m, 4H), 3.62-3.68 (m, 1H), 3.81 (s, 3H),
4.13 (dd, 1H, J = 4.2 Hz, J = 10.2 Hz), 4.39 (d, 1H, J = 11.0
Hz), 4.54 (d, 1H, J = 11.0 Hz), 6.88 (d, 2H, J = 8.8 Hz), 7.29 (d,
2H, J = 8.8 Hz); C nmr: δ 12.1 (q), 13.6 (q), 25.8 (t), 26.1 (t),
29.9 (t), 30.5 (t), 35.8 (t), 36.8 (d), 44.5 (d), 55.3 (q), 71.3 (t), 78.5
(2S,3S)-2-acetoxy-3-methylvaleric acid 9 [5] (5.0 g, 28.7 mmoles)
in tetrahydrofuran (30 ml) at 0°. After refluxing for 5 hours a small
amount of water was added dropwise to decompose excess lithium
aluminium hydride, and the precipitate was filtered off through
celite and washed with ethyl acetate. The combined filtrates were
dried and concentrated to give 10 as a colorless oil (2.8 g, 83%); bp
13
24
-1
(d), 113.7 (d), 129.4 (d), 131.2 (s), 159.1 (s). MS (EI) m/z 340
87°/9 mm Hg; [α] +5.9 (c 1.13, methanol); ir (film) 3400 cm ;
D
+
1
(M , 5%), 219 (74), 133 (100). hrms: Calcd. for C
H O S :
H nmr: δ 0.87 (d, 3H, J = 6.7 Hz), 0.91 (t, 3H, J = 7.3 Hz), 1.04-
18 28 2 2
+
(M) 340.1531. Found: m/z 340.1509.
1.24 (m, 1H), 1.50-1.64 (m, 2H), 3.23 (br s, 2H), 3.49 (dd, 2H, J =
13
8.2 Hz, J = 17.1 Hz), 3.64-3.70 (m, 1H); C nmr: δ 11.2 (q), 14.6
(3R,4S)-3-(4-Methoxybenzyloxy)-4-methylhexanal (14).
(q), 25.0 (t), 37.6 (d), 64.2 (t), 76.0 (d).
To a solution of 13 (1.10 g, 3.24 mmoles) in aqueous 80% ace-
tonitrile (30 ml) was added mercury (II) chloride (2.19 g, 8.10
mmoles) and mercury (II) oxide (1.75 g, 8.10 mmoles) at room tem-
perature. The mixture was heated at 60° with stirring for 2 hours.
The cooled mixture was filtered through celite, and the filtrate was
dried and concentrated. The residue was purified by chromatogra-
phy (hexane/ethyl acetate, 10:1) to give 14 (680 mg, 84%) as a col-
(2S,3S)-3-Methyl-1,2-epoxypentane (11).
A mixture of 10 (2.5 g, 21.2 mmoles), benzyltriethylammo-
nium chloride [6] (139 mg, 3 mol%) and 20% aqueous sodium
hydroxide (25 ml) in 25 ml of dichloromethane was heated under
reflux, and a solution of mesyl chloride (3.6g, 31.8 mmoles) in 40
ml of dichloromethane was added in portion. Heating and stirring
was continued until complete consumption of the starting diol.
The mixture was cooled to room temperature, and was poured
23
-1
1
orless oil; [α] +18.5 (c 0.73, ethanol); ir (film) 1724 cm ; H
D
nmr: δ 0.91 (d, 3H, J = 6.8 Hz), 0.94 (t, 3H, J = 7.3 Hz), 1.08-1.23

Jan-Feb 2001
Synthesis of Hyperolactones A and C
169
(m, 1H), 1.34-1.48 (m, 1H), 1.77-1.88 (m, 1H), 2.42 (ddd, 1H, J =
1.7 Hz, J = 3.5 Hz, J = 16.3 Hz), 2.60 (ddd, 1H, J = 2.7 Hz, J =
8.8 Hz, J = 16.3 Hz), 3.80 (s, 3H), 3.85-3.90 (m, 1H), 4.42 (d, 1H, J
= 11.0 Hz), 4.52 (d, 1H, J = 11.0 Hz), 6.88 (d, 2H, J = 8.8 Hz), 7.24
(d, 2H, J = 8.8 Hz), 9.78 (dd, 1H, J = 1.8 Hz, J = 8.8 Hz). C nmr:
δ 11.8 (q), 13.6 (q), 25.6 (t), 36.9 (d), 44.3 (t), 55.2 (q), 70.9 (t), 77.3
cooled and poured into aqueous sodium bicarbonate, and
extracted with ether (3 x 20 ml). The combined extracts were
dried and concentrated. The residue was purified by column
chromatography (hexane/ethyl acetate, 10:1) to give a crystalline
25
13
3 (6 mg, 93%); mp 106°; (lit [2] mp 104°); [α] -390 (c 0.018,
D
1
ethanol) [lit [2] -356 (c 0.018, ethanol)]; H nmr: δ 1.53 (s, 3H),
(d), 113.7 (d), 129.3 (d), 130.3 (s), 159.1 (s), 202.2 (d). hrms: Calcd.
4.11 (d, 1H, J = 8.4 Hz), 4.97 (d, 1H, J = 8.4 Hz), 5.26 (d, 1H,
J = 17.6 Hz), 5.27 (d, 1H, J = 10.8 Hz), 5.98 (s, 1H), 5.99 (dd,
1H, J = 10.8 Hz, J = 17.6 Hz), 7.49-7.54 (m, 2H), 7.58-7.63 (m,
+
for C H O : (M) 250.1569. Found: m/z 250.1545.
15 22
3
(3S,4S) and (3R,4S)-3-[3',3'-(Ethylenedioxy)-3'-phenylpropanoyl]-
3-methoxymethyloxy-4-methyl-4-vinyl-γ-butyrolactone (17a) and
(17b).
13
1H), 7.83-7.86 (m, 2H); C nmr: δ 19.6 (q), 48.9 (s), 74.1 (t),
93.1 (s), 100.3 (d), 119.0 (t), 127.4 (d), 127.7 (s), 129.0 (d), 133.6
(d), 134.3 (d), 168.0 (s), 187.2 (s), 196.6 (s). MS (EI) m/z 270
+
To a solution of lithium diisopropylamide, prepared from diiso-
propylamine (0.12 ml, 0.86 mmol) in tetrahydrofuran (10 ml) and
n-butyllithium (1.6 M in hexane, 0.49 ml, 0.79 mmol), was added a
solution of 15 (123 mg, 0.66 mmol) in tetrahydrofuran (5 ml) at -
78° under nitrogen, and the mixture was stirred for 30 minutes. A
solution of 8 (165 mg, 0.86 mmol) in tetrahydrofuran (5 ml) was
added to the reaction mixture. After stirring for 3.5 hours at -78°,
the mixture was quenched by addition of saturated aqueous ammo-
nium chloride, and extracted with ether (4 x 10 ml). The combined
extracts were dried and concentrated in vacuo. The residue was
purified by column chromatography (hexane/ethyl acetate, 20:1) to
give 16 (207 mg, 83%) as an inseparable mixture of four diastere-
(M , 35%), 252 (8), 225 (15), 211 (23), 197 (4), 187 (100), 173
(11), 147 (15), 105 (5), 129 (9), 102 (56). hrms: Calcd. for
+
C
H
O : (M) 270.0892. Found: m/z 270.0909.
16 14
4
5-Epi-hyperolactone C (3a).
The similar reaction of the β-methoxymethyloxy isomer 17b
(41 mg) as in the synthesis of 3 gave, after chromatography, 3a
20
1
(29.4 mg, 100%) as a wax; [α] +283 (c 0.054, ethanol);
H
D
nmr: δ 1.30 (s, 3H), 4.38 (d, 1H, J = 8.6 Hz), 4.78 (d, 1H, J = 8.6
Hz), 5.34 (d, 1H, J = 17.4 Hz), 5.37 (d, 1H, J = 10.8 Hz), 6.04 (s,
1H), 6.06 (dd, 1H, J = 10.8 Hz, J = 17.4 Hz), 7.48-7.54 (m, 2H),
13
7.58-7.64 (m, 1H), 7.83-7.86 (m, 2H); C nmr: δ 15.4 (q), 48.9
-1
omers; ir (film) 3500, 1765, 1620 cm ; To a solution of 16 (37 mg)
(s), 73.3 (t), 92.3 (s), 100.4 (d), 116.2 (t), 127.4 (s), 127.5 (d),
129.0 (d), 133.6 (d), 136.8 (d), 168.1 (s), 187.4 (s), 196.6 (s). MS
in acetone (30 ml) was added Jones reagent (8 M, 0.04 ml) at 0°.
After stirring for 1.5 hours, the mixture was quenched by addition
of 2-propanol, followed by solid sodium bicarbonate. The mixture
was filtered through celite and the filtrate was concentrated. The
residue was chromatographed on silica gel (hexane/ethyl acetate,
2:1) to give 17a (14 mg, 38%) and 17b (20 mg, 54%) as colorless
+
(EI) m/z 270 (M , 46%), 252 (8), 211 (25), 187 (100), 173 (16),
+
147 (14), 129 (9), 102 (58). hrms: Calcd. for C
270.0892. Found: m/z 270.0880.
H O : (M)
16 14 4
(3S,4S, 3'R, 4'S) and (3R,4S,3'R,4'S)-3-[3'-(4-Methoxy-
benzyloxy)-4'-methylhexanoyl]-3-methoxymethyloxy-4-methyl-
4-vinyl-γ-butyrolactone (18a) and (18b).
23
needles, respectively. 17a: mp 76°; [α] -29.3 (c 0.40, ethanol); ir
D
-1 1
(nujol) 1770, 1715 cm ; H nmr: δ 1.28 (s, 3H), 3.17 (d, 1H, J =
The procedure for 16 was employed with 14 and 15 gave an
alcohol as an inseparable mixture of four diastereomers in 84%
yield. To a solution of the resulting alcohol (269 mg, 0.62 mmol) in
dichloromethane (20 ml) was added Dess-Martin periodinane (915
mg, 2.16 mmoles), and the mixture was stirred for 2 hours at room
temperature. The reaction was quenched by addition of 2-propanol,
and the precipitate was filtered off. The filtrate was washed with
10% sodium thiosulfate solution, and concentrated. The residue
was purified by column chromatography (hexane/ethyl acetate,
20:1) to give 18a (134 mg, 50%) and 18b (134 mg, 50%). 18a (col-
17.2 Hz), 3.39 (s, 3H), 3.48 (d, 1H, J = 17.2 Hz), 3.73-3.85 (m,
2H), 4.00 (d, 1H, J = 8.8 Hz), 4.02-4.12 (m, 2H), 4.19 (d, 1H, J =
8.8 Hz), 4.97 (d, 1H, J = 6.0 Hz), 5.05 (d, 1H, J = 6.0 Hz), 5.12 (d,
1H, J = 17.0 Hz), 5.17 (d, 1H, J = 10.8 Hz), 5.58 (dd, 1H, J =
13
10.8 Hz, J = 17.4 Hz), 7.27-7.37 (m, 3H), 7.48-7.52 (m, 2H);
C
nmr: δ 18.1 (q), 48.7 (t), 50.6 (s), 56.7 (q), 64.8 (t x 2), 73.6 (t),
88.8 (s), 94.6 (t), 108.3 (s), 117.7 (t), 125.8 (d), 128.1 (d), 128.2 (d),
+
135.7 (d), 141.9 (s), 171.6 (s), 203.0 (s). MS m/z 377 [(M + H) ,
5%], 317 (11), 271 (59), 185 (91), 149 (100), 93 (78). hrms: Calcd.
+
for C H O : (M + H) 377.1600. Found: m/z 377.1579.
20 25
7
21
1
orless oil); [α] -0.20 (c 2.7, ethanol); H nmr: δ 0.89 (d, 3H, J =
Anal. Calcd for C
H
O : C, 63.82; H, 6.43. Found: C, 63.75;
20 24
7
D
6.8 Hz), 0.91 (t, 3H, J = 7.3 Hz), 1.03-1.18 (m, 1H), 1.30 (s, 3H),
1.23-1.40 (m, 1H), 1.68-1.80 (m, 1H), 2.59 (dd, 1H, J = 2.7 Hz, J
= 19.0 Hz), 2.99 (dd, 1H, J = 9.0 Hz, J = 19.0 Hz), 3.43 (s, 3H),
3.79 (s, 3H), 3.94-3.97 (m, 1H), 4.00 (d, 1H, J = 8.6 Hz), 4.18 (d,
1H, J = 8.6 Hz), 4.41 (d, 1H, J = 10.8 Hz), 4.48 (d, 1H, J = 10.8
Hz), 4.99 (s, 2H), 5.11 (d, 1H, J = 10.8 Hz), 5.14 (d, 1H, J = 17.4
Hz), 5.75 (dd, 1H, J = 10.8 Hz, J = 17.4 Hz), 6.84 (d, 2H, J = 8.4
H, 6.47.
23
Compound 17b has mp 76°; [α] -30.2 (c 2.0, ethanol); ir
(nujol) 1770, 1715 cm ; H nmr: δ 1.00 (s, 3H), 3.17 (d, 1H, J =
17.3 Hz), 3.35 (s, 3H), 3.37 (d, 1H, J = 17.3 Hz), 3.74-3.82 (m,
2H), 3.83 (d, 1H, J = 8.5 Hz), 3.99-4.13 (m, 2H), 4.29 (d, 1H, J =
8.5 Hz), 4.79 (d, 1H, J = 6.4 Hz), 4.85 (d, 1H, J = 6.4 Hz), 5.17
D
-1 1
(d, 1H, J = 17.6 Hz), 5.33 (d, 1H, J = 11.0 Hz), 6.15 (dd, 1H, J =
11.0 Hz, J = 17.6 Hz), 7.26-7.35 (m, 3H), 7.47-7.52 (m, 2H);
13
13
Hz), 7.22 (d, 2H, J = 8.4 Hz); C nmr: δ 12.0 (q), 13.9 (q), 17.7
C
(q), 25.6 (t), 37.1 (d), 41.6 (t), 50.7 (s), 55.2 (q), 56.6 (q), 71.6 (t),
73.9 (t), 77.3 (d), 88.8 (s), 94.5 (t), 113.5 (d), 117.5 (t), 129.2 (d),
131.1 (s), 135.7 (d), 158.9 (s), 171.8 (s), 206.4 (s). hrms: Calcd. for
nmr: δ 17.7 (q), 48.7 (t), 49.3 (s), 56.5 (q), 64.7 (t), 64.9 (t), 74.6
(t), 87.3 (s), 94.6 (t), 108.1 (s), 117.7 (t), 125.8 (d), 128.0 (d),
128.1 (d), 135.2 (d), 141.9 (s), 170.2 (s), 200.7 (s). hrms: Calcd.
+
+
C H O : (M) 434.2304. Found: m/z 434.2328. 18b (colorless
for C
H
O : (M + H) 377.1600. Found: m/z 377.1583.
24 34
7
20 25
7
22
1
oil); [α] -11.3 (c 3.76, ethanol); H nmr: δ 0.88 (d, 3H, J = 6.8
D
(-)-Hyperolactone C (3).
Hz), 0.91 (t, 3H, J = 7.3 Hz), 1.11 (s, 3H), 1.23-1.41 (m, 2H), 1.70-
1.78 (m, 1H), 2.31 (dd, 1H, J = 2.8 Hz, J = 18.1 Hz), 3.00 (dd, 1H,
J = 9.4 Hz, J = 18.1 Hz), 3.35 (s, 3H), 3.78 (s, 3H), 3.88 (d, 1H, J =
8.4 Hz), 3.96-4.03 (m, 1H), 4.36 (d, 1H, J = 8.4 Hz), 4.41 (d, 1H,
To a solution of 17a (9 mg, 0.024 mmol) in tetrahydrofuran (10
ml) was added a few drops of 3 M hydrochloric acid, and the
mixture was heated at reflux for 11 hours. The mixture was

170
T. Ueki, M. Doe, R. Tanaka, Y. Morimoto, K. Yoshihara and T. Kinoshita
Vol. 38
J = 10.6 Hz), 4.45 (d, 1H, J = 10.6 Hz), 4.77 (d, 1H, J = 6.4 Hz),
4.81 (d, 1H, J = 6.4 Hz), 5.17 (d, 1H, J = 17.8 Hz), 5.34 (d, 1H, J =
11.0 Hz), 6.23 (dd, 1H, J = 11.0 Hz, J = 17.8 Hz), 6.84 (d, 2H, J =
(q), 17.2 (q), 17.9 (q), 27.1 (t), 43.6 (d), 50.7 (s), 56.8 (q), 73.9 (t),
85.8 (s), 94.4 (t), 97.8 (d), 116.3 (t), 136.4 (d), 172.2 (s), 190.8 (s),
+
196.5 (s). hrms: Calcd. for C H O : (M) 312.1573. Found: m/z
16 24
6
13
8.6 Hz), 7.22 (d, 2H, J = 8.6 Hz); C nmr: δ 12.0 (q), 13.9 (q), 18.3
312.1563.
(q), 26.0 (t), 37.0 (d), 41.4 (t), 49.5 (s), 55.2 (q), 56.5 (q), 72.0 (t),
74.9 (t), 77.9 (d), 87.2 (s), 94.7 (t), 113.6 (d), 117.6 (t), 129.5 (d),
130.8 (s), 135.1 (d), 159.0 (s), 170.7 (s), 204.8 (s). hrms: Calcd. for
The β-methoxymethyloxy isomer 19b was treated as in the
synthesis of 20a to give pale yellow crystals 20b (65%); mp 54.5
20
o
1
C; [α] +13.6 (c 0.89, ethanol); H nmr: δ 0.90 (t, 3H, J = 7.5
D
+
C H O : (M) 434.2304. Found: m/z 434.2281.
Hz), 1.15 (d, 3H, J = 6.8 Hz), 1.16 (s, 3H), 1.41-1.55 (m, 1H),
1.59-1.73 (m, 1H), 2.25-2.37 (m, 1H), 3.43 (s, 3H), 3.99 (d, 1H,
J = 8.4 Hz), 4.43 (d, 1H, J = 8.4 Hz), 4.83 (d, 1H, J = 6.2 Hz),
4.92 (d, 1H, J = 6.2 Hz), 5.17 (d, 1H, J = 17.6 Hz), 5.32 (d, 1H,
J = 11.0 Hz), 5.95 (s, 1H), 6.17 (dd, 1H, J = 11.0 Hz, J = 17.6
24 34
7
(3S,4S,3'R,4'S) and (3R,4S,3'R,4'S)-3-(3'-Hydroxy-4'-methyl-
hexanoyl)-3-methoxymethyloxy-4-methyl-4-vinyl-γ-butyrolac-
tone (19a) and (19b).
13
A mixture of 18a (131 mg, 0.3 mmol), dichlorodicyanobenzo-
quinone (DDQ) (177 mg, 0.76 mmol) in dichloromethane (9 ml)
and water (0.5 ml) was stirred at room temperature for 90 minutes.
The mixture was diluted with saturated aqueous sodium bicarbon-
ate solution and extracted with dichloromethane (3 x 30 ml). The
organic layer was dried and concentrated. The residue was chro-
matographed on silica gel (hexane/ethyl acetate, 10:1) to give 19a
Hz); C nmr: δ 11.6 (q), 17.0 (q), 18.9 (q), 27.1 (t), 43.8 (d), 49.9
(s), 56.7 (q), 74.8 (t), 84.9 (s), 94.4 (t), 98.2 (d), 116.9 (t), 135.6
(d), 171.2 (s), 188.2 (s), 197.9 (s).
(2'S,5S,9S)-Isomer (1): (-)-Hyperolactone A.
To a cooled solution of 20a (7.5 mg) in dichloromethane (5 ml)
was added trimethylsilyl bromide (0.03 ml, 0.22 mmol) at -20°, and
the mixture was stirred for 14 hours. The reaction was quenched by
addition of saturated aqueous sodium bicarbonate and the mixture
was extracted with dichloromethane (3 x 10 ml). The combined
extracts were washed with water, dried and concentrated. The
residue was chromatographed on silica gel (hexane/ethyl acetate,
10:1) to give 1 (5.9 mg, 98%) as a single product; mp 57° (recrys-
tallized from ether and n-hexane); [lit [1] mp 57° for natural hyper-
23
(84 mg, 94% yield) as a colorless oil; [α] +1.87 (c 1.65, ethanol);
D
-1
1
ir (film) 3545, 1790, 1710 cm ; H nmr: δ 0.87 (d, 3H, J = 6.6
Hz), 0.90 (t, 3H, J = 7.1 Hz), 1.04-1,26 (m, 1H), 1.34 (s, 3H), 1.43-
1.57 (m, 2H), 2.74 (d, 1H, J = 9.5 Hz), 2.79 (dd, 1H, J = 4.2 Hz,
J = 15.0 Hz), 3.43 (s, 3H), 3.88-3.95 (m, 1H), 4.12 (d, 1H, J = 8.8
Hz), 4.25 (d, 1H, J = 8.8 Hz), 4.96 (s, 2H), 5.23 (d, 1H, J =17.4
Hz), 5.29 (d, 1H, J = 10.8 Hz), 5.78 (dd, 1H, J = 10.8 Hz, J = 17.4
24
24
olactone A]; [α] -265 (c 0.13, methanol); [lit [1] [α] -229 (c
13
D
D
Hz); C nmr: δ 11.4 (q), 14.4 (q), 17.0 (q), 24.8 (t), 39.7 (d), 44.3
1
0.13, methanol)]; H nmr: δ 0.96 (t, 3H, J = 7.5 Hz), 1.25 (d, 3H, J
= 6.8 Hz), 1.41 (s, 3H), 1.59-1.78 (m, 2H), 2.63-2.75 (m, 1H), 4.05
(d, 1H, J = 8.4 Hz), 4.90 (d, 1H, J = 8.4 Hz), 5.24 (d, 1H, J = 17.4
Hz), 5.28 (d, 1H, J = 10.8 Hz), 5.38 (s, 1H), 5.94 (dd, 1H, J = 10.8
(t), 50.6 (s), 56.6 (q), 70.8 (d), 74.0 (t), 87.7 (s), 94.5 (t), 117.7 (t),
135.9 (d), 171.5 (s), 208.8 (s). hrms (FAB): Calcd. for
+
+
C H O Na : (M + Na) 337.1627. Found: m/z 337.1640.
16 26
6
The β-methoxymethyloxy isomer 18b was treated as in the
13
Hz, J = 17.4 Hz). C nmr: δ 11.0 (q), 16.9 (q), 19.3 (q), 27.1 (t),
23
synthesis of 19a to give a colorless oil 19b (94% yield); [α]
D
37.1 (d), 48.4 (s), 74.0 (t), 92.5 (s), 102.1 (d), 118.8 (t), 134.3 (d),
1
-11.1 (c 2.55, ethanol); H nmr: δ 0.87 (d, 3H, J = 6.6 Hz), 0.90
+
168.0 (s), 197.3 (s), 200.2 (s). MS (EI) m/z 250 (M , 31%), 193
(t, 3H, J = 7.3 Hz), 1.14 (s, 3H), 1.10-1.17 (m, 1H), 1.41-1.56
(m, 2H), 2.63-2.77 (m, 2H), 2.92 (d, 1H, J = 3.3 Hz, OH), 3.42
(s, 3H), 3.90 (d, 1H, J = 8.6 Hz), 3.90-3.96 (m, 1H), 4.36 (d,
1H, J = 8.6 Hz), 4.86 (s, 2H), 5.24 (d, 1H, J = 17.6 Hz), 5.38
(d, 1H, J = 10.8 Hz), 6.25 (dd, 1H, J = 10.8 Hz, J = 17.6 Hz);
+
(53), 177 (42), 167 (100). hrms: Calcd. for C
250.1205. Found: m/z 250.1216.
H O : (M)
14 18 4
(2'S,5R,9S)-Isomer (1a).
The β-methoxymethyloxy isomer 20b was treated as in the
synthesis of 1 to give a colorless wax 1a (89% yield) as a single
13
C nmr: δ 11.4 (q), 14.4 (q), 18.2 (q), 24.8 (t), 39.5 (d), 43.6
(t), 49.3 (s), 56.6 (q), 70.6 (d), 74.8 (t), 87.1 (s), 94.6 (t), 118.0
(t), 134.9 (d), 170.2 (s), 207.3 (s). hrms (FAB): Calcd. for
21
1
product; [α] +194 (c 0.20, ethanol); H nmr: δ 0.99 (t, 3H, J =
D
7.3 Hz), 1.23 (s, 3H), 1.27 (d, 3H, J = 7.0 Hz), 1.54-1.68 (m, 1H),
1.67-1.79 (m, 1H), 2.61-2.73 (m, 1H), 4.31 (d, 1H, J = 8.6 Hz),
4.71 (d, 1H, J = 8.6 Hz), 5.27 (d, 1H, J = 17.4 Hz), 5.30 (d, 1H,
J = 10.8 Hz), 5.43 (s, 1H), 5.93 (dd, 1H, J = 10.8 Hz, J = 17.4 Hz);
+
+
C
H O Na : (M + Na) 337.1627. Found: m/z 337.1640.
16 26 6
(3S,4S,4'S) and (3R, 4S, 4'S)-3-(3'-Oxo-4'-methylhexanoyl)-3-
methoxymethyloxy-4-methyl-4-vinyl-γ-butyrolactone (20a) and
(20b).
13
C nmr: δ 11.3 (q), 15.4 (q), 17.2 (q), 27.1 (t), 37.3 (d), 48.4 (s),
73.2 (t), 90.3 (s), 102.2 (d), 116.0 (t), 136.8 (d), 168.0 (s), 197.4
+
To a solution of 19a (28.1 mg, 0.09 mmol) in acetone (5 ml)
was added an excess amount of Jones reagent (8 M solution) at
-20°. After stirring for 2 hours, the reaction mixture was quenched
by addition of 2-propanol and solid sodium bicarbonate. The mix-
ture was filtered through Celite, and the filtrate was concentrated
in vacuo. The residue was purified by chromatography
(hexane/ethyl acetate, 9:1) to give 20a (18.3 mg, 66% yield) as a
(s), 200.5 (s). MS (EI) m/z 250 (M , 23%), 193 (42), 177 (47),
+
167 (100). hrms: Calcd. for C
m/z 250.1215.
H
O : (M) 250.1205. Found:
14 18
4
(2'R,5S,9S)-Isomer (1b).
The α-methoxymethyloxy isomer 20a was treated with boiling
tetrahydrofuran containing 3 M hydrochloric acid to give a mix-
ture of 1 and its 2'-isomer 1b (88% yield), which was separated
by HPLC [Shimadzu LC-3A; column: Cosmosil 5SI; n-hexane-
diethyl ether (95:5); 5 ml/minute]. The first peak (Rt 21.25 min-
utes) gave 1 and second peak (Rt 21.75 minutes) gave 1b as a
21
pale yellow oil; [α] -11.7 (c 0.63, ethanol); ir (film) 2970,
D
-1
1
1790, 1600 cm ; H nmr: δ 0.89 (t, 3H, J = 7.5 Hz), 1.14 (d, 3H,
J = 7.0 Hz), 1.36 (s, 3H), 1.42-1.54 (m, 1H), 1.59-1.73 (m, 1H),
2.22-2.34 (m, 1H), 3.47 (s, 3H), 4.12 (d, 1H, J = 8.6 Hz), 4.33 (d,
1H, J = 8.6 Hz), 4.94 (d, 1H, J = 5.9 Hz), 5.09 (d, 1H, J = 5.9
Hz), 5.13 (d, 1H, J = 17.4 Hz), 5.16 (d, 1H, J = 11.0 Hz), 5.73
1
colorless wax. 1b: H nmr: δ 0.97 (t, 3H, J = 7.3 Hz), 1.25 (d,
3H, J = 7.3 Hz), 1.41 (s, 3H), 1.50-1.62 (m, 1H), 1.62-1.80 (m,
1H), 2.69 (sextet, 1H, J = 7.3 Hz), 4.04 (d, 1H, J = 8.5 Hz), 4.89
13
(dd, 1H, J = 11.0 Hz, J = 17.4 Hz), 5.92 (s, 1H); C nmr: δ 11.6

Jan-Feb 2001
Synthesis of Hyperolactones A and C
171
(d, 1H, J = 8.5 Hz), 5.24 (d, 1H, J = 17.1 Hz), 5.28 (d, 1H, J =
11.0 Hz), 5.37 (s, 1H), 5.93 (dd, 1H, J = 11.0 Hz, J = 17.1 Hz);
C nmr: δ 11.3 (q), 17.3 (q), 19.3 (q), 27.2 (t), 37.3 (d), 48.4 (s),
23.5 (q), 33.8 (t), 42.5 (s), 66.0 (t), 73.1 (t), 74.7 (t), 75.4 (d), 127.9
(d), 128.1 (d), 128.4 (d), 136.7 (s), 176.5 (s). hrms: Calcd. for
+
13
C H O : (M) 250.1205. Found: m/z 250.1219.
14 18
4
74.0 (t), 92.5 (s), 102.2 (d), 118.9 (t), 134.4 (d), 168.0 (s), 197.4
(3S,4S)-4-(2-Benzyloxyethyl)-3-methoxymethyloxy-4-methyl-γ-
butyrolactone (22b).
+
(s), 200.2 (s). hrms: Calcd. for C
Found: m/z 250.1195.
H
O : (M) 250.1205.
14 18
4
To a solution of 22a (730 mg, 2.92 mmoles) and diisopropylethy-
lamine (5.1 ml, 29.0 mmoles) in dichloromethane (50 ml) was
added chloromethoxymethane (1.11 ml, 14.6 mmoles), and the
mixture was heated at reflux for 48 hours. The mixture was cooled,
diluted with water, and extracted with dichloromethane (4 x 20 ml).
The combined extracts were dried and concentrated in vacuo. The
residue was purified by column chromatography (hexane/ethyl
Preparation of the Key Intermediate 15.
(2S,3R)-5-Benzyloxy-3-ethoxycarbonyl-2-hydroxy-3-methyl-
pentanoic acid (21b).
To a solution of lithium diisopropylamide, prepared from diiso-
propylamine (11.3 ml, 80.4 mmoles) and n-butyllithium (1.6 M in
hexane, 45.6 ml, 73.7 mmoles) in tetrahydrofuran (200 ml), was
added a solution of diethyl (2S,3R)-(+)-2-hydroxy-3-methylsucci-
nate [8] (6.8 g, 33.4 mmoles) in tetrahydrofuran (12 ml) at -78° and
the mixture was stirred for 3 hours. To the cooled (-78) solution
was added benzyl 2-iodoethyl ether [9] (13.1 g, 50 mmoles) within
5 minutes and the mixture was stirred for 8 hours, then at 0° for 13
hours. After quenching by addition of a solution of acetic acid (8
ml) in 15 ml of ether, the mixture was poured into water and
extracted with ether (4 x 100 ml). The combined extracts were
washed with aqueous sodium bicarbonate, dried and concentrated
in vacuo. The residue was purified by column chromatography
(hexane/ethyl acetate, 10:1) to give 21a (12.46 g, 67%) as a pale
27
acetate, 3:1) to give 22b (795 mg, 93%) as a pale yellow oil; [α]
-47.7 (c 2.3, ethanol); ir (film) 1770 cm ; H nmr: δ 1.19 (s, 3H),
D
-1 1
1.72-1.95 (m, 2H), 3.41 (s, 3H), 3.57-3.62 (m, 2H), 3.88 (d, 1H, J =
9.0 Hz), 3.99 (s, 1H), 4.39 (d, 1H, J = 9.0 Hz), 4.47 (s, 2H), 4.69 (d,
13
1H, J = 6.8 Hz), 4.99 (d, 1H, J = 6.8 Hz), 7.28-7.35 (m, 5H);
C
nmr: δ 21.1 (q), 31.3 (t), 42.1 (s), 56.0 (q), 66.4 (t), 73.2 (t), 75.1 (t),
78.3 (d), 95.9 (t), 127.6 (d x 2), 128.4 (d), 138.1 (s), 175.0 (s). MS
+
(EI): m/z 249 ([M-CH OCH ] , 40%), 143 (65), 91 (100).
2
3
(3S,4S)-4-(2-Hydroxyethyl)-3-methoxymethyloxy-4-methyl-γ-
butyrolactone (23a).
27
A mixture of 22b (622 mg, 2.11 mmoles) and 10% palladium
on carbon (300 mg) in ethanol (25 ml) was vigorously stirred
under an atmosphere of hydrogen at room temperature for 44
hours. The mixture was filtered and the filtrate was concentrated
in vacuo. The residue was purified by column chromatography
(hexane/ethyl acetate, 1:1) to give 23a (414 mg, 96%) as a color-
-1
yellow oil; [α] +12.9 (c 0.70, ethanol); ir (film) 3490, 1715 cm ;
D
1
H nmr: δ 1.21 (t, 3H, J = 7.1 Hz), 1.22 (s, 3H), 1.27 (t, 3H, J =
7.1 Hz), 1.80-1.99 (m, 1H), 2.10-2.22 (m,1H), 3.55 (t, 2H, J = 6.5
Hz), 3.65 (d, 1H, J = 9.8 Hz, OH), 4.12 (q, 2H, J = 7.1 Hz), 4.24
(q, 2H, J = 7.1 Hz), 4.32 (d, 1H, J = 9.8 Hz), 4.47 (s, 2H), 7.27-
+
7.33 (m, 5H); MS (EI) m/z 338 (M , 15%), 293 (4), 231 (16), 204
22
-1
less oil; [α] -94.6 (c 0.65, ethanol); ir (film) 3425, 1760 cm ;
(23), 157 (35), 131 (30), 91 (100); hrms: Calcd. for C H O :
D
18 26
6
1
H nmr: δ 1.24 (s, 3H), 1.79 (t, 2H, J = 6.6 Hz), 2.21 (br s, 1H,
+
(M) 338.1729. Found: m/z 338.1728. To the resulting diester 21a
(5.11 g) in methanol (40 ml) was added a solution of potassium
hydroxide (2.85 g, 3.4 equivalents) in methanol (30 ml) and water
(2 ml) at -40°, and the mixture was stirred for 1 hour, then at room
temperature for 3 days. The mixture was acidified by addition of 3
M hydrochloric acid to pH-2 and extracted with ether (4 x 100 ml).
The combined extracts were dried and concentrated in vacuo to
OH), 3.44 (s, 3H), 3.70-3.82 (m, 2H), 3.93 (d, 1H, J = 9.0 Hz),
4.05 (s, 1H), 4.35 (d, 1H, J = 9.0 Hz), 4.73 (d, 1H, J = 6.8 Hz),
13
5.01 (d, 1H, J = 6.8 Hz); C nmr: δ 21.1 (q), 34.6 (t), 42.1 (s),
56.0 (q), 58.7 (t), 75.0 (t), 78.3 (d), 96.0 (t), 175.0 (s). MS (EI)
+
m/z ([M-OCH OCH ] , 16%), 129 (11), 113 (43), 99 (100), 91
2
3
+
(11), 85 (27). hrms: Calcd. for C H O : (M - OCH OCH )
7
11
3
2
3
27
143.0708. Found: m/z 143.0722.
give 21b (4.55 g, 97%) as a pale yellow syrup; [α] +8.4 (c 0.71,
D
-1 1
ethanol); ir (film) 3400, 1700 cm ; H nmr: δ 1.21 (t, 3H, J = 7.1
(3S,4S)-3-Methoxymethyloxy-4-methyl-4-[2-(2-nitrophenyl)-
seleno]-γ-butyrolactone (23b).
Hz), 1.25 (s, 3H), 1.99-2.15 (m, 2H), 3.57-3.66 (m, 2H), 4.13 (q,
2H, J = 7.1 Hz), 4.51 (s, 2H), 7.27-7.33 (m, 5H); C nmr: δ 13.9
13
A mixture of 23a (673 mg, 3.3 mmoles), 2-nitrophenylseleno-
cyanate (1.05 g, 4.62 mmoles) and n-tributylphosphine (1.15 ml,
4.62 mmoles) in 30 ml of tetrahydrofuran was stirred at room
temperature for 1 hour. The reaction mixture was diluted with
water and extracted with ether (5 x 20 ml). The combined
extracts were dried and concentrated in vacuo. The residue was
purified by column chromatography (hexane/ethyl acetate, 4/1)
(q), 18.6 (q), 34.8 (t), 49.0 (s), 60.9 (t), 61.4 (t), 66.4 (t), 73.4 (t),
74.4 (d), 128.0 (d), 128.5 (d x 2), 137.0 (s), 174.4 (s), 174.9 (s).
+
hrms: Calcd. for C H O : (M) 310.1416. Found: m/z 310.1429.
16 22
6
(3S,4S)-4-(2-Benzyloxyethyl)-3-hydroxy-4-methyl-γ-butyrolac-
tone (22a).
To a solution of 21b (2.29 g, 7.4 mmoles) in tetrahydrofuran (100
ml) was added lithium triethylborohydride (1.0 M in tetrahydrofu-
ran, 44.3 ml, 44.3 mmoles) at -78°, and the mixture was stirred for 3
hours, then at room temperature for 40 hours. To the reaction mix-
ture was added 17 ml of water at -10°, and the aqueous layer was
extracted with ether (3 x 50 ml). The combined extracts were dried
and concentrated in vacuo. The residue was purified by column
chromatography (hexane/ethyl acetate, 2:1) to give 22a (1.37 g,
27
to give 23b (1.13 g, 88%) as yellow crystals; mp 74-75°; [α]
D
-1
-37.0 (c 0.24, ethanol); ir (nujol) 1770, 1590, 1560, 1510 cm ;
1
H nmr: δ 1.29 (s, 3H), 1.87-2.06 (m, 2H), 2.85-3.00 (m, 2H),
3.46 (s, 3H), 4.01 (d, 1H, J = 9.4 Hz), 4.18 (s, 1H), 4.26 (d, 1H,
J = 9.4 Hz), 4.78 (d, 1H, J = 6.8 Hz), 5.08 (d, 1H, J = 6.8 Hz),
7.30-7.35 (m, 1H), 7.50-7.59 (m, 3H), 8.28 (dd, 1H, J = 1.3 Hz,
13
J = 8.3 Hz). C nmr: δ 20.4 (t), 22.2 (q), 33.3 (t), 44.7 (s), 56.2
27
(q), 74.3 (t), 77.5 (d), 96.2 (t), 125.5 (d), 126.5 (d), 128.9 (d),
74%) as a colorless oil; [α] +6.0 (c 0.80, ethanol); ir (film) 3400,
D
-1 1
132.8 (d), 133.7 (s), 146.7 (s), 174.8 (s). hrms: Calcd. for
1760, 1620 cm ; H nmr: δ 1.26 (s, 3H), 1.58-1.94 (m, 2H), 3.48
+
C
H
NO Se: (M) 389.0377. Found: m/z 389.0399.
(dt, 1H, J = 2.4 Hz, J = 10.1 Hz), 3.57-3.66 (m, 1H), 3.97 (d, 1H, J
= 9.3 Hz), 4.08 (s, 1H), 4.19 (d, 1H, J = 9.3 Hz), 4.31 (d, 1H, J =
15 19
6
Anal. Calcd for C
H NO Se: C, 46.40; H, 4.93; N, 3.61.
15 19 6
13
Found: C, 46.45; H, 4.98; N, 3.61.
11.7 Hz), 4.59 (d, 1H, J = 11.7 Hz), 7.30-7.38 (m, 5H); C nmr: δ

172
T. Ueki, M. Doe, R. Tanaka, Y. Morimoto, K. Yoshihara and T. Kinoshita
Vol. 38
REFERENCES AND NOTES
(3S,4S)-3-Methoxymethyloxy-4-methyl-4-vinyl-γ-butyrolactone
(15).
To a solution of 23b (1.11 g, 2.85 mmoles) in tetrahydrofuran
(40 ml) was added dropwise 30% hydrogen peroxide (1.58 ml,
17.2 mmoles) at 0°, and the mixture was warmed to room tem-
perature. After stirring for 5 hours, the reaction mixture was
diluted with water and extracted with ether (4 x 50 ml). The com-
bined extracts were washed with sodium thiosulfate solution,
dried and concentrated in vacuo. The residue was purified by col-
umn chromatography (hexane/ethyl acetate, 6:1) to give 15 (403
[1] M. Tada, M. Nagai, C. Okumura, Y. Osano and T.
Matsuzaki, Chem. Lett., 683 (1989).
[2] Y. Aramaki, K. Chiba and M. Tada, Phytochemistry, 38,
1419 (1995).
[3a] D. Ichinari, T. Ueki, K. Yoshihara and T. Kinoshita,
Chem. Commun., 1743 (1997); [b] T. Ueki, D. Ichinari, K.
Yoshihara, Y. Morimoto and T. Kinoshita, Tetrahedron Lett., 39,
667 (1998).
[4a] R. L. Shriner, Org. React., 1, 1 (1942); [b] M. W.
Rathke, Org. React., 22, 423 (1975); [c] M. W. Rathke and A.
Lindert, J. Org. Chem., 35, 3966 (1970).
[5] U. Schmidt, M. Kroner and H. Griesser, Synthesis, 832
(1989).
25
mg, 76%) as an oil; [α] -64.7 (c 2.20, ethanol); ir (film) 1780,
D
-1 1
1630 cm ; H nmr: δ 1.32 (s, 3H), 3.43 (s, 3H), 3.98 (d, 1H, J =
9.0 Hz), 4.13 (s, 1H), 4.28 (d, 1H, J = 9.0 Hz), 4.71 (d, 1H, J =
6.8 Hz), 4.98 (d, 1H, J = 7.0 Hz), 5.23 (d, 1H, J = 17.6 Hz), 5.27
(d, 1H, J = 10.8 Hz), 5.97 (dd, 1H, J = 10.8 Hz, J = 17.5 Hz);
13
C nmr: δ 20.4 (q), 45.6 (s), 55.9 (q), 74.1 (t), 78.4 (d), 96.0 (t),
[6] M. Szeja, Synthesis 983 (1985).
115.9 (t), 136.3 (d), 174.2 (s). hrms (CI): Calcd. for C H O : (M
+ H) 187.0934. Found: m/z 187.0954.
[7] A. B. Smith III and P. A. Levenberg, Synthesis, 567
(1981).
9
15 4
+
[8] D. Seebach, J. Aebi and D. Wasmuth, Org. Synth. Coll.
Vol. VII, 153 (1990).
Acknowledgement.
We are grateful to Professor M. Tada (Tokyo University of
Agriculture and Technology) for helpful comments.
[9] R. S. Tipson, M. A. Clapp and L. H. Cretcher, J. Org.
Chem., 12, 133 (1947).