Synthesis and absolute configuration of (-)-3-butyl-7-hydroxyphthalide, a cytotoxic metabolite of Penicillium vulpinum.

Article abstract of DOI:10.1271/bbb.67.2240

Both the enantiomers as well as the racemate of 3-butyl-7-hydroxyphthalide (1) were synthesized, and the absolute configuration of the naturally occurring (-)-1 (a weakly cytotoxic metabolite of Penicillium vulpinum) was identified as S.

Full text of DOI:10.1271/bbb.67.2240

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Synthesis and Absolute Configuration of (-)-3-
Butyl-7-hydroxyphthalide, a Cytotoxic Metabolite of
Penicillium vulpinum*
Tomoya OHZEKIa & Kenji MORIb
a Department of Chemistry, Graduate School of Science, Science University of
TokyoKagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan
b Glycosphingolipid Synthesis Group, Laboratory for Immune Regulation, RIKEN
Research Center for Allergy and Immunology c/o Seikagaku CorporationTateno 3-1253,
Higashiyamato City, Tokyo 207-0021, Japan
Published online: 22 May 2014.
To cite this article: Tomoya OHZEKI & Kenji MORI (2003) Synthesis and Absolute Configuration of (-)-3-Butyl-7-
hydroxyphthalide, a Cytotoxic Metabolite of Penicillium vulpinum*, Bioscience, Biotechnology, and Biochemistry, 67:10,
2240-2244, DOI: 10.1271/bbb.67.2240
To link to this article: http://dx.doi.org/10.1271/bbb.67.2240
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Biosci. Biotechnol. Biochem., 67 (10), 2240–2244, 2003
－
Synthesis and Absolute Conˆguration of ( )-3-Butyl-7-hydroxyphthalide,
*
a Cytotoxic Metabolite of Penicillium vulpinum
1
2,
†
Tomoya OHZEKI and Kenji MORI
1Department of Chemistry, Graduate School of Science, Science University of Tokyo, Kagurazaka 1-3,
Shinjuku-ku, Tokyo 162-8601, Japan
2Glycosphingolipid Synthesis Group, Laboratory for Immune Regulation, RIKEN Research Center for Allergy
and Immunology c o Seikagaku Corporation, Tateno 3-1253, Higashiyamato City, Tokyo 207-0021, Japan
W
Received June 11, 2003; Accepted July 7, 2003
Both the enantiomers as well as the racemate of 3-
butyl-7-hydroxyphthalide (1) were synthesized, and the
absolute conˆguration of the naturally occurring (
－
)-1
(a weakly cytotoxic metabolite of Penicillium vulpinum
was identiˆed as S.
)
Key words: asymmetric dihydroxylation; cytotoxic
compound;
phthalide
Penicillium
vulpinum;
Lactones are known to show diverse biological
activities as hormones, pheromones, and antibiotics.
In continuation of our work to synthesize bioactive
lactones of microbial origin,1) we became interested
in synthesizing 3-butyl-7-hydroxyphthalide (1,
Scheme 1), the (
－
)-enantiomer of which was isolated
Scheme 1. Synthesis of (
Reagents: (a) sec-BuLi, TMEDA, THF; then CH3(CH2)3-
CHO. (b) 48 HBr, AcOH, re‰ux (68 , 2 steps).
±
)-3-Butyl-7-hydroxyphthalide (1).
in 1998 as a weakly cytotoxic (against L 1210 leuke-
mic cells) metabolite of the fungus Penicillium vulpi-
z
z
2)
－
num. Since the absolute conˆguration of ( )-1 was
unknown, our synthesis was designed to solve that
problem. This paper reports our conclusion that
－
(
)-1 is the (
S
)-isomer.
were in good agreement with those reported for
(
－
)-1.2) The structure 1 proposed by Fujimoto and
co-workers2) was thus veriˆed, and we proceeded to
the next stage, to synthesize both the enantiomers
of 1.
Results and Discussion
Prior to the synthesis of the enantiomers of 1,
±
＋
(
)-1 was prepared as shown in Scheme 1 so as to
Scheme 2 summarizes the synthesis of ( )- and
verify the correctness of the proposed structure.
-Diethylamide 2 was treated with sec-butyllithi-
um in the presence of -tetramethylethyl-
(
－
)-1. Sharpless asymmetric dihydroxylation5) was
N
,
N
used as the key step to introduce the chiral center of
1. Methyl 2,6-dihydroxybenzoate (5)6) was treated
with 1 eq. of benzyl bromide in the presence of potas-
N,N,N?,N?
enediamine (TMEDA) in THF to eŠect ortho lithia-
tion according to Snieckus.3,4) The generated anion
was quenched with pentanal to give a mixture of
sium carbonate and sodium iodide in
formamide (DMF) to give a mixture of the starting
material 5 (25 ), the desired monobenzyl ether 6
(48 ), and dibenzyl ether 7 (24z), which could be
N,N-dimethyl-
±
±
(
)-3 and ( )-4. Treatment of this crude mixture
with hot hydrobromic acid in acetic acid furnished
)-3-butyl-7-hydroxyphthalide (1), mp 59–60 C, in
a 68
yield based on 2. Its 1H- and 13C-NMR spectra
z
z
(
±
9
separated by silica gel chromatography. Hydrogenol-
ysis of 7 over palladium-carbon regenerated the start-
z
*
Synthetic Microbial Chemistry, Part 40. For Part 39, see Mori, K., Bando, M., and Abe, K., Biosci. Biotechnol. Biochem., 66,
1779–1781 (2002). (this paper was erroneously reported as Part 38.)
To whom correspondence should be addressed.
†

Synthesis of 3-Butyl-7-hydroxyphthalide
2241
HPLC analysis on Daicel's Chiralcel} OD. Removal
of the hydroxy group of 10 at C-1 was executed by
Barton's radical deoxygenation via thiocarbonyl
derivative (3 , 1
)-11.9,10) Accordingly, (3
)-11 was treated with tri( -butyl)tin hydride in
the presence of 2,2-azobis(isobutyronitrile) (AIBN)
to give ( )-12 in an 80 yield. At this stage, partial
racemization took place, and the enantiomeric purity
of ( )-12 was 74 e.e. Finally, debenzylation of
)-12 was done by hydrogenolysis over Pearlman's
palladium hydroxide catalyst to furnish the desired
)-1 (41 yield, after recrystallization), mp
47.5–48.5 C, of 99.5 e.e. The overall yield of
)-1 was 14 based on 5 (7 steps). Similarly, asym-
metric dihydroxylation of 9 with AD-mix-
(3 , 1 )-10, which was converted to (
47.5–48.5 C. It should be added that our attempt to
convert (3
?
R
?R
R,
1?R
n
S
z
S
z
(
S
(
S
z
9
À
z
(
S
z
5)
}
b
gave
S
?S
R)-1, mp
9
R
, 1?R )-10 to the corresponding xanthate
ester met with failure, and only the dehydration
product A could be isolated.
Optical rotations of the synthetic enantiomers of 1
25
＋
52 (c 0.96,
were found to be as follows: (
R
)-1, [
a
]
D
25
－
52 (c 0.79, CHCl3). The natur-
CHCl3); (
al 1 was reported as: mp 49–50
CHCl3). The absolute conˆguration of the naturally
S
)-1, [
a
]
D
－
45.5 (c 0.8,
9
C, [
a
]
D
－
occurring ( )-3-butyl-7-hydroxyphthalide (1) was
therefore established as , basing on the well-studied
S
stereochemical outcome of the Sharpless asymmetric
dihydroxylation.5)
Experimental
Melting point (mp) data were measured with a
Yanaco MP-S3 instrument. IR spectra were meas-
ured with a Jasco FT IR-410 spectrometer. 1H-NMR
W
spectra were recorded at 400 MHz with a Jeol JNM-
LA400 spectrometer and at 500 MHz with a Jeol
Scheme 2. Synthesis of
yphthalide (1).
(
R
)- and
(S )-3-Butyl-7-hydrox-
JNM-LA500 spectrometer. The peak for TMS (at
d
0.00) was used for the internal standard. 13C-NMR
were recorded at 100 MHz with a Jeol JNM-LA400
spectrometer and at 126 MHz with a Jeol JNM-
＝
Reagents: (a) BnBr, K2CO3, NaI, DMF (48
and 25 of the recovered 5). (b) H2, Pd„C, EtOAc (98
Tf2O, C5H5N. (d) ( )-CH3(CH2)2CH
K2CO3, THF (99 , 2 steps). (e) AD-mix-
BuOH, H2O (92 ). (f) 1,1-thiocarbonyldiimidazole, DMAP,
CH2Cl2 (quant.). (g) ( -Bu)3SnH, AIBN, toluene (80 ). (h) H2,
Pd(OH)2„C, EtOAc (41 after recrystallization). (i) AD-mix-
, MeSO2NH2, tert-BuOH, H2O (91 ).
z
of 6, 24
z
z
of 7,
). (c)
z
E
z
z
＝
CHB(OH)2, Pd(PPh3)4,
, MeSO2NH2, tert-
b
＝
d
LA500 spectrometer. The peak for CDCl3 (at
77.0) was used for the internal standard. Optical
rotation was measured with Jasco P-1010
n
z
a
z
polarimeter. EI-MS spectra were recorded with a
Jeol JMS-AX505HA spectrometer. Column chro-
matography was done with Merck Kieselgel 60 Art
1.07734. TLC analyses were done with Merck silica
gel plates 60F-254.
a
z
ing material 5, which could be recycled. Treatment of
6 with tri‰ic anhydride (Tf2O) and pyridine gave
tri‰ate 8, which was subjected to Suzuki-Miyaura
±
±
1
(
)-3-Butyl-7-hydroxyphthalide [( )-
] : Under
sec-butyl-
coupling7) with (
E
)-1-penteneboronic acid8) in the
an Ar atmosphere, to a solution of 1.0
M
presence of tetrakis(triphenylphosphine)palladium
(0) to aŠord 9 in a 99 yield based on 6.
Asymmetric dihydroxylation of with AD-
furnished nicely crystalline hydroxylactone
)-10, mp 104–105 C, in a 92 yield, whose
enantiomeric purity was 99 e.e. as checked by
lithium in hexane-cyclohexane (64 ml, 64 mmol) and
TMEDA (9.81 ml, 65.0 mmol) in THF (300 ml) was
added dropwise a solution of 2 (10.4 g, 50.0 mmol) in
z
9
5)
}
－
mix-
b
THF (30 ml) at 78
for 1.5 h. The mixture was warmed to 40
then pentanal (7.35 ml, 70.0 mmol) was added. It
9
C, and the mixture was stirred
－
(3 , 1
R
?
R
9
À
z
9C, and
z

2242
T. OHZEKI and K. MORI
was warmed to room temperature, and stirred for
6 h. After acidiˆcation with 1 HCl aq. (20 ml), the
C22H20O4: C, 75.85; H, 5.79
z.
M
Debenzylation of : Pd on carbon (10z, 1.06 g)
7
solvent was removed in vacuo. The residue was dilut-
ed with EtOAc. The organic solution was successive-
ly washed with water and brine, dried with MgSO4,
and concentrated in vacuo. The residue (3 and 4)
was added to a solution of 7 (1.74 g, 5.00 mmol) in
EtOAc (20 ml), and stirred under H2 for 30 min. The
mixture was ˆltered through Celite and the solvent
was removed in vacuo. The residue was chro-
matographed on silica gel (15 g, eluted with hexane-
was suspended in 48z HBr aq. (30 ml) and AcOH
(20 ml). The mixture was re‰uxed for 8 h, diluted
with water, and extracted with EtOAc. The extract
was successively washed with sat. NaHCO3 aq.,
water and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed on silica
gel (150 g, eluted with hexane-EtOAc) and the solid
fraction was recrystallized from hexane-EtOAc to
z
EtOAc) to give 5 (824 mg, 98 ) as colorless needles.
Methyl 2-(E)-1-Pentenyl-6-benzyloxybenzoate (
Under Ar atmosphere, Tf2O (984 l, 6.00 mmol) was
added to a solution of 6 (1.29 g, 5.00 mmol) in pyri-
dine (5 ml) at 0 C, and the mixture was stirred for
9):
m
9
2 h. The mixture was diluted with EtOAc and succes-
sively washed with water, sat. CuSO4 aq., water, and
brine. The organic layer was dried with MgSO4, and
concentrated in vacuo. The residue 8 was dissolved
in benzene (15 ml) and ethanol (3 ml), and then
give (
needles, mp 59.0–60.0
(m, O„H), 2950 (m), 1730 (s, C O), 1620 (s, Ph).
±
)-1 (7.01 g, 68
z
9
for 2 steps) as colorless
C. IR nmax (KBr) cm－1: 3440
＝
＝
7.0 Hz,
NMR
-H3), 1.33–1.52 (4H, m, 2
m, 1 -H), 1.99–2.06 (1H, m, 1
4.1, 7.8 Hz, 3-H), 6.90 (1H, d,
d
H (400 MHz, CDCl3): 0.92 (3H, t,
-, 3 -H2), 1.74–1.83 (1H,
-H), 5.49 (1H, dd,
J
4?
?
?
(E
)-1-penteneboronic acid8) (798 mg, 7.00 mmol),
?
?
J
＝
K2CO3 (1.38 g, 10.0 mmol), and Pd(PPh3)4 (116 mg,
0.100 mmol) were added. Under an Ar atmosphere,
the mixture was re‰uxed for 14 h. This mixture was
diluted with EtOAc, and successively washed with
＝
J
7.2 Hz, 6-H), 6.93
＝
＝
7.2 Hz,
(1H, d,
J
7.2 Hz, 4-H), 7.54 (1H, t,
J
5-H). NMR dC (126 MHz, CDCl3): 13.9, 22.4, 26.8,
34.3, 83.0, 112.2, 113.1, 115.3, 138.8, 150.4, 156.5,
1
M
NaOH aq., water and brine. The organic layer
was dried with MgSO4 and concentrated in vacuo
The residue was chromatographed on silica gel (35 g,
eluted with hexane-EtOAc) to give 9 (1.55 g, 99 ) as
a colorless oil, n2D5 1.5686. IR nmax (ˆlm) cm－1: 3032
172.2. Anal. Found: C, 69.59; H, 6.80
z
. Calcd. For
.
C12H14O3: C, 69.89; H, 6.84
z
.
z
Methyl 2-Benzyloxy-6-hydroxybenzoate (
6) and
＝
Methyl 2,6-Dibenzyloxybenzoate ( ): To a suspen-
7
(w), 2955 (m), 2870 (w), 1730 (s, C O), 1650 (w),
1600 (m, Ph), 1575 (s, Ph, C C), 1270 (s). NMR dH
(500 MHz, CDCl3): 0.94 (3H, t,
sion of 5 (13.5 g, 80.0 mmol), K2CO3 (11.1 g,
80.0 mmol) and NaI (4.00 g, 26.7 mmol) in DMF
(20 ml) was added benzyl bromide (9.69 ml,
81.6 mmol), and the mixture was stirred for 30 min at
＝
＝
J
7.5 Hz, 5
-H), 2.17 (2H, dt,
-H), 3.90 (3H, s, „OMe), 5.10 (2H, s,
?-H),
＝
J
＝
?
1.48 (2H, tq,
7.1, 7.5 Hz, 3
PhC 2), 6.21 (1H, dt,
(1H, d, 15.9 Hz, 1
3-H or 5-H), 7.11 (1H, d,
J
7.5, 7.5 Hz, 4
?
＝
0
9
C and for 4 h at room temperature. The mixture
H
J
15.9, 7.1 Hz, 2
?
＝
-H), 6.34
8.0 Hz,
8.0 Hz, 3-H or 5-H),
was acidiˆed with 6 HCl aq., and extracted with
M
J
＝
?
-H), 6.78 (1H, d, J
＝
J
EtOAc. The organic layer was successively washed
with water and brine, dried with MgSO4, and concen-
trated in vacuo. The residue was chromatographed
on silica gel (600 g, eluted with hexane-EtOAc) and
the solid fractions were recrystallized from hexane to
＝ ＝
8.0 Hz, Ph„H), 7.28 (1H, t, J
7.23 (1H, t,
J
10.0 Hz, Ph„H), 7.34–7.39 (4H, m, 4-H, Ph„H).
NMR dC (126 MHz, CDCl3): 13.6 (q), 22.3 (t), 35.2
(t), 52.2 (q), 70.4 (t), 110.8 (d), 118.1 (d), 122.8 (s),
×
×
give 6 (9.82 g, 48
z
) and 7 (6.56 g, 24
z
) each as
126.2 (d), 126.8 (d 2), 127.7 (d), 128.5 (d 2), 130.2
colorless needles, and then the recovered starting
(d), 134.5 (d), 136.8 (s), 136.8 (s), 155.5 (s), 168.7 (s).
material 5 (3.38 g, 25
z
). 6: Mp 69.0–70.5
9
C. IR nmax
Anal. Found: C, 77.32; H, 7.31
C20H22O3: C, 77.39; H, 7.15
z
. Calcd. For
(KBr) cm－ : 2950 (w), 1665 (s, C O), 1610 (s, Ph),
z.
1
＝
1580 (s, Ph). NMR dH (400 MHz, CDCl3): 3.94 (3H,
＝
8.3,
s, „OCH3), 5.12 (2H, s, PhC
H
2), 6.48 (1H, dd,
J
(3R, 1
lide [(3R, 1
and MeSO2NH2 (476 mg, 5.00 mmol) in tert
BuOH (20 ml) and water (20 ml) was stirred for
30 min at 0 C. Alkene 9 (1.55 g, 5.00 mmol) was
added to the mixture, and the mixture was stirred for
87 h at 4 C. Then Na2SO3 (7.56 g, 60 mmol) was
?
R)-3-(1
?
-Hydroxybutyl)-7-benzyloxyphtha-
＝
8.3, 1.0 Hz, 3-H or 5-H), 6.62 (1H, dd,
J
?
R)-10
]
: A solution of AD-mix- (7.0 g)
b
1.0 Hz, 3-H or 5-H), 7.30–7.49 (6H, m, Ar„H,
4-H), 11.51 (1H, s, „OH). NMR dC (100 MHz,
CDCl3): 52.3, 70.7, 103.7, 110.4, 126.8, 127.8, 128.4,
135.1, 136.7, 159.9, 163.6, 171.6. Anal. Found: C,
-
9
69.77; H, 5.50
z
. Calcd for C15H14O4: C, 69.76; H,
9
1
5.46 . 7: Mp 74.5–75.5
z
9
C. IR
n
max (KBr) 3035 cm－
:
added, and the mixture was stirred for 1 h at room
temperature. This was diluted with EtOAc and
successively washed with water and brine, dried with
MgSO4, and concentrated in vacuo. The residue was
chromatographed on silica gel (50 g; hexane-EtOAc)
＝
(w), 2950 (w), 1725 (s, C O), 1595 (s, Ph), 1255 (s),
1090 (s). NMR dH (400 MHz, CDCl3): 3.88 (3H, s,
×
＝
J
×
„OCH3), 5.09 (4H, s, PhCH2 2), 6.56 (2H, d,
9.0 Hz, 3-H, 5-H), 7.16–7.39 (11H, m, Ar„H 2,
4-H). Anal. Found: C, 76.08; H, 5.88 . Calcd. For
z
z
to give (3R, 1?R )-10 (1.44 g, 92 ), which was puri-

Synthesis of 3-Butyl-7-hydroxyphthalide
2243
ˆed by recrystallization from hexane-EtOAc to give
(3 , 1 )-10. The enantiomeric purity of the result-
ing (3 , 1 )-10 was shown to be 99 e.e. by
HPLC analysis. HPLC [column: Daicel Chiralcel
OD (0.46 cm 25 cm), eluent: hexane EtOH 9 1,
‰ow rate: 0.5 ml min, temperature: 10
matographed on silica gel (10 g, eluted with hexane-
R
?
R
R
EtOAc) to give (3
R
, 1
?
R
)-11 (469 mg, quant.) as a
1
＝
?R
À
z
colorless oil. IR nmax (CHCl3) cm－ : 1770 (s, C O),
＝
1605 (m, C C). NMR dH (400 MHz, CDCl3): 1.00
×
＝
(3H, t,
7.4 Hz, 3
5.28 (2H, s, PhC
J
＝
?
7.4 Hz, 4
-H), 1.99 (2H, dt,
2), 5.65 (1H, d,
?
-H), 1.53 (2H, tq,
J
＝
-H),
7.4,
W
9
W
＝
7.4, 7.4 Hz, 2?
C, detection:
, (3 , 1 )-10].
max (KBr) cm－1: 3405 (m, br.,
O„H), 1730 (s, C O), 1620 (s, Ph), 1605 (s, Ph).
NMR H (500 MHz, CDCl3): 0.95 (3H, t, 7.3 Hz,
-H), 1.41–1.49 (1H, m, 3 -H), 1.54–1.70 (3H, m,
J
W
＝
UV (254 nm)]: tR 85.8 min [
Mp 104.0–105.0 C. IR
À
99
z
R
?
R
H
J
2.4 Hz, 3-H),
＝
9
n
6.17 (1H, dt,
J
2.4, 7.4 Hz, 1
?
-H), 6.88–6.94 (2H,
＝
＝
7.6 Hz), 7.26–7.36 (4H, m),
m), 7.00 (1H, d,
J
d
J
＝
7.42–7.50 (3H, m), 8.14 (1H, s). NMR dC (100 MHz,
4
?
?
CDCl3): 13.7 (q), 18.4 (t), 31.9 (t), 70.3 (t), 78.5 (d),
81.2 (d), 113.3 (d), 114.0 (s), 114.1 (d), 117.2 (d),
＝
6.4 Hz, OH), 3.97 (1H,
2
?
-H, 3
?
-H), 1.97 (1H, d,
J
＝
×
×
dt,
(1H, d,
4-H), 7.04 (d,
J
3.5, 9.0 Hz, 1
?
-H), 5.29 (2H, s, PhC
H
2), 5.31
＝
8.0 Hz,
126.5 (d 2), 127.8 (d), 128.5 (d 2), 130.8 (d), 135.6
＝
J
3.4 Hz, 3-H), 6.92 (1H, d,
7.6 Hz, 6-H), 7.29 (dd,
J
J
(s), 136.3 (d), 137.0 (d), 147.8 (s), 157.5 (s), 167.1 (s),
J
＝
＝
7.4, 7.4
7.4, 7.4 Hz, 2H,
7.4 Hz, Ph„H), 7.52 (1H,
7.6, 8.0 Hz, 5-H). NMR dC (126 MHz,
183.3 (s). HRFABMS m z (M
＋
H＋ ): Calcd. for
W
＝
Hz, 1H, Ph„H), 7.37 (1H, dd,
J
C23H23O4N2S, 423.1379; Found, 423.1389.
＝
J
Ph„H), 7.48 (2H, d,
＝
dd,
J
(3S, 1
7-benzyloxyphthalide [(3S, 1
manner as described above (3
5.00 mmol) was converted into 2.23 g (quant.) of (3
)-11. Its IR and NMR spectra were identical to
?
S)-3-(1
?
-Imidazolylthiocarbonyloxybutyl)-
S)-11 : In the same
, 1 )-10 (1.56 g,
CDCl3): 13.8 (q), 18.8 (t), 35.0 (t), 70.4 (t), 72.1 (d),
82.0 (d), 112.8 (d), 114.3 (d), 114.6 (s), 126.7 (d),
?
]
S
?S
127.9 (d), 128.6 (d), 136.01 (s), 136.04 (d), 150.0 (s),
S,
24
－
±
157.6 (s), 168.2 (s). [
a
]
13.4 0.05 (
c
0.98,
1?S
D
＋
＋
those of (3R, 1?R )-11. HRFABMS m z (M H ):
W
CHCl3). Anal. Found: C, 73.15; H, 6.75
For C19 H20O4: C, 73.06; H, 6.45
z
. Calcd.
z.
Calcd. for C23H23O4N2S, 423.1379; Found,
423.1374.
(3S, 1
?
S)-3-(1
?-Hydroxybutyl)-7-benzyloxyphtha-
lide [(3S, 1
?
S)-10
]
: A solution of AD-mix-
a
(14.0 g)
(S)-3-Butyl-7-benzyloxyphthalide [(S)-12
an Ar atmosphere, AIBN (16.4 mg, 0.100 mmol)
was added to a solution of (3 , 1 )-11 (469 mg,
1.00 mmol) and tri( -butyl)tin hydride (1078 l,
]: Under
and MeSO2NH2 (951 mg, 10.0 mmol) in tert-BuOH
(40 ml) and water (40 ml) was stirred for 30 min at
R
?R
0
9
C. Alkene 9 (3.09 g, 10.0 mmol) was added to the
n
m
mixture and the mixture was stirred for 87 h at 4
9
C.
4.00 mmol) in toluene (10 ml), and the mixture was
re‰uxed for 15 min. The mixture was diluted with
EtOAc and successively washed with water and
brine. The organic layer was dried with MgSO4,
and concentrated in vacuo. The residue was chro-
Then Na2SO3 (15.1 g, 120 mmol) was added, and
the mixture was stirred for 1 h at room temperature.
This mixture was diluted with EtOAc and successive-
ly washed with water and brine, dried with MgSO4,
and concentrated in vacuo. The residue was chro-
matographed on silica gel (120 g; hexane-EtOAc) to
×
matographed twice on silica gel (15 g 2, eluted with
hexane-EtOAc) to give ( )-12 (207 mg, 80 ) as a
colorless oil. The enantiomeric purity of the resulting
)-12 was shown to be 73.8 e.e. by HPLC analy-
sis. HPLC [column: Daicel Chiralcel OD (0.46 cm
S
z
give (3
by recrystallization from hexane-EtOAc to give (3
)-10. The enantiomeric purity of the resulting
, 1 )-10 was shown to be 99 e.e. by HPLC
analysis. HPLC [column: Daicel Chiralcel OD
(0.46 cm 25 cm), eluent: hexane EtOH 9 1, ‰ow
rate: 0.5 ml min, temperature: 10
z
S, 1?S )-10 (2.85 g, 91 ), which was puriˆed
S
,
(
S
z
1
?
S
×
＝
25 cm), eluent: hexane EtOH 9 1, ‰ow rate:
W W
(3
S
?S
À
z
0.5 ml min, temperature: 10
9
C, detection: UV
W
×
＝
(254 nm)]: tR 46.5 min [13.1
[86.9 , ( )-12]. (
cm－1: 1760 (s, C
, ( 1)-12] tR 58.1 min
R
z
W
W
9
C, detection: UV
z
S
S
)-12: n2D5 1.5710. IR nmax (ˆlm)
W
(254 nm)]:
t
R 80.3 min [
À
99
z
, (3
S
, 1
?
S
)-10]. Its IR,
＝
O), 1605 (m, Ph), 1040 (s). NMR
1H- and 13C-NMR spectra were identical to those of
d
H (500 MHz, CDCl3): 0.88 (3H, t,
J
7.0 Hz, 4?-H),
＝
24
＋
±
(3
R
, 1?
R
)-10. [
a
]
13.6 0.1 (
c
1.00, CHCl3).
. Calcd. for
1.29–1.49 (4H, m, 2
?
-H, 3
?
-H), 1.66–1.73 (1H, m,
-H), 5.27 (2H, s,
7.9, 4.0 Hz, 3-H), 6.90
D
Anal. Found: C, 73.19; H, 6.31
C19H20O4: C, 73.06; H, 6.45
z
1?-H), 1.95–2.02 (1H, m, 1?
＝
z.
PhC
H
2), 5.33 (1H, dd,
J
＝
＝
(1H, d,
J
8.2 Hz, 6-H), 6.93 (1H, d,
J
7.6 Hz,
＝
4-H), 7.26 (1H, t, J
(3R,1
7-benzyloxyphthalide [(3R, 1
atmosphere, 1,1-thiocarbonyldiimidazole (90
ty, 297 mg, 1.50 mmol) was added to a solution
of (3 , 1 )-10 (312 mg, 1.00 mmol) and DMAP
?
R)-3-(1
?
-Imidazolylthiocarbonyloxybutyl)-
R)-11 : Under an Ar
puri-
7.3 Hz, Ph„H), 7.33 (1H, t,
＝
7.5 Hz, Ph„H), 7.48–7.52 (2H, m, 5-H,
?
]
J
z
Ph„H). NMR dC (126 MHz, CDCl3): 13.6 (q), 22.1
(t), 26.5 (t), 34.2 (t), 70.0 (t), 79.8 (d), 112.2 (d),
×
R
?R
113.5 (d), 113.8 (s), 126.4 (d 2), 127.6 (d), 128.3
×
(12.2 mg, 0.100 mmol) in CH2Cl2 (10 ml). After this
was stirred for 3 h at room temperature, the solvent
was removed in vacuo. The residue was chro-
(d 2), 135.7 (d), 135.9 (s), 152.7 (s), 157.2 (s), 168.1
(s). HREIMS m z (M＋ ): Calcd. for C19 H20O3,
W
296.1412; Found, 296.1419.

2244
T. OHZEKI and K. MORI
(R)-3-Butyl-7-benzyloxyphthalide [(R)-12
same manner as described above ( )-11 (2.23 g,
5.00 mmol) was converted into 960 mg (65 ) of
)-12. ( )-12 was shown to be 94.8 e.e. by HPLC
analysis. HPLC [column: Daicel Chiralcel OD
]
: In the
give pure (
purity of the resulting pure (
99.5 e.e. by HPLC analysis. HPLC [column:
Daicel Chiralcel OJ (0.46 cm 25 cm), eluent:
hexane EtOH 30 1, ‰ow rate: 0.5 ml min, temper-
R
)-1 in a 64
z
yield. The enantiomeric
S
,
S
R
)-1 was shown to be
z
À
z
×
(
R
R
z
＝
W
W
W
×
＝
(0.46 cm 25 cm), eluent: hexane EtOH 9 1, ‰ow
ature: 109C, detection: UV (254 nm)]: tR 41.9 min.
W
W
1
rate: 0.5 ml min, temperature: 10
9
C, detection: UV
(
R
)-1: Mp 47.5–48.5
9
C. Its IR, H- and 13C-NMR
W
25
＋
51.9
(254 nm)]: tR 46.8 min [97.4
[2.6 , ( )-12]. (
)-12: n2D4 1.5698. Its IR, H- and
13C-NMR spectra were identical to those of (
)-12.
HREIMS m z (M＋ ): Calcd. for C H O , 296.1412;
z
, (
R
)-12] tR 62.1 min
spectra were identical to those of (
S
)-1. [
a
]
D
1
±
z
S
R
0.1 (c 0.96, CHCl3). Anal. Found: C, 69.62; H,
S
z z
6.77 . Calcd. for C12H14O3: C, 69.89; H, 6.84 .
W
19
20
3
Found, 296.1414.
References
1) Ohzeki, T., and Mori, K., Synthesis of corollospo-
rine, an antibacterial metabolite of the marine
fungus Corollospora maritima
Biochem., 65, 172–175 (2001).
2) Makino, M., Endoh, T., Ogawa, Y., Watanabe, K.,
and Fujimoto, Y., Studies on the metabolites of
(S)-3-Butyl-7-hydroxyphthalide [(S)-
man's catalyst (184 mg) was added to a solution
of ( )-12 (236 mg, 0.796 mmol) in EtOAc (10 ml),
and the mixture was stirred under H2 for 15 min. The
mixture was ˆltered through Celite and the solvent
was removed in vacuo. The residue was chro-
matographed on silica gel (5 g, eluted with hexane-
1
]
:
Pearl-
. Biosci. Biotechnol.
S
Penicillium vulpinum. Heterocycles, 48, 1931–1934
(1998).
z
EtOAc) to give (S)-1 (160 mg, 97 ) as colorless nee-
dles. It was further puriˆed by recrystallization from
3) Wang, X., de Silva, S. O., Reed, J. N., Billadeau, R.,
GriŠen, E. J., Chan, A., and Snieckus, V., 7-
Methoxyphthalide. Org. Synth. Col. Vol., 9, 559–563
(1998).
hexane-EtOAc to give pure (
S
)-1 in a 41
z
99.5
yield. Its
e.e. by
enantiomeric purity was shown to be
À
z
4) Snieckus, V., Directed ortho metalation. Tertiary
HPLC analysis. HPLC [column: Daicel Chiralcel
amide and
O-carbamate directors in synthetic strate-
×
＝
OJ (0.46 cm 25 cm), eluent: hexane EtOH 30 1,
W
9
W
gies for polysubstituted aromatics. Chem. Rev., 90,
879–993 (1990).
‰ow rate: 0.5 ml min, temperature: 10
C, detection:
R 33.2 min. Mp 47.5–48.5 C. IR nmax
(KBr) cm－1: 3535 (s, O„H), 3420 (s, O„H), 1725 (s,
O), 1600 (s, C
C). (CHCl3) cm－1: 3455 (m,
W
UV (254 nm)]:
t
9
5) Kolb, H. C., VanNieuwenhze, M. S., and Sharpless,
K. B., Catalytic asymmetric dihydroxylation. Chem.
Rev., 94, 2483–2547 (1994).
6) Gennari, C., Molinari, F., Piarulli, U., and
Bartoletti, M., Peptide bond formation using an
C
＝
＝
＝
＝
O„H), 1735 (s, C O), 1625 (m, C C). NMR dH
＝
7.2 Hz, 4?-H),
(400 MHz, CDCl3): 0.92 (3H, t,
1.33–1.51 (4H, m, 2 -H, 3 -H), 1.74–1.83 (1H, m,
-H), 1.99–2.07 (1H, m, 1
7.8, 4.2 Hz, 3-H), 6.90 (1H, d,
J
?
?
?
enzyme mimicking approach. Tetrahedron
7289–7300 (1990).
, 46,
＝
J
1?
-H), 5.49 (1H, dd,
7) Miyaura, N., and Suzuki, A., Palladium-catalyzed
cross-coupling reaction of organoboron compounds.
Chem. Rev., 95, 2457–2487 (1995).
8) Reich, H. J., Eisenhart, E. K., Olson, R. E., and
Kelly, M. J., Silyl ketone chemistry. Preparation and
reactions of silyl allenol ethers. Diels-Alder reaction
of siloxy vinylallenes leading to sesquiterpenes. J.
Am. Chem. Soc., 108, 7791–7800 (1986).
J
＝
8.6 Hz, 6-H), 6.92
＝
＝
8.6,
(1H, d,
8.6 Hz, 5-H), 7.80 (1H, s, OH). NMR dC (126 MHz,
CDCl3): 13.8 (4 -C), 22.4 (3 -C), 26.8 (2 -C), 34.3
(1
J
8.6 Hz, 4-H), 7.55 (1H, dd,
J
?
?
?
?
-C), 82.9 (3-C), 112.2 (7a-C), 113.0 (6-C), 115.3
(4-C), 136.8 (5-C), 150.4 (4a-C), 156.5 (7-C), 172.2
25
－
±
(1-C). [
a
]
51.5 0.1 (
c
0.79, CHCl3). Anal.
D
Found: C, 69.70; H, 6.98
69.89; H, 6.84
z. Calcd. for C12H14O3: C,
9) Hartwig, W., Modern methods for the radical deoxy-
genation of alcohols. Tetrahedron, 39, 2607–2645
(1983).
z
.
10) Crich, D., and Quinters, L., Radical chemistry
(R)-3-Butyl-7-hydroxyphthalide [(R)-
same manner as described above ( )-12 (297 mg,
1.00 mmol) was converted into 202 mg (98 ) of
)- . This was recrystallized from hexane-EtOAc to
1]: In the
associated with the thiocarbonyl group. Chem. Rev.
89, 1413–1437 (1989).
,
S
z
(
R 1