Synthesis of novel antifungal phthalides produced by a wheat rhizosphere fungus

Article abstract of DOI:10.1016/j.tet.2008.07.023

Two antifungal phthalides produced by a wheat rhizosphere fungus have been synthesized using the?Alder-Rickert reaction to construct their common isobenzofuranone core structure. The absolute configuration of one of the two phthalides has been determined

Full text of DOI:10.1016/j.tet.2008.07.023

Tetrahedron 64 (2008) 9073–9077
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Synthesis of novel antifungal phthalides produced by a wheat
rhizosphere fungus
*
Naoto Katoh, Takashi Nakahata, Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2008
Received in revised form 5 July 2008
Accepted 8 July 2008
Available online 12 July 2008
Two antifungal phthalides produced by a wheat rhizosphere fungus have been synthesized using
the Alder–Rickert reaction to construct their common isobenzofuranone core structure. The absolute
configuration of one of the two phthalides has been determined to be S by synthesizing its (S)- and
(R)-enantiomer and comparing their optical rotations with that of the natural product.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Phthalide
Take-all
Total synthesis
Alder–Rickert reaction
1. Introduction
HO2C
O
HO2C
O
O
O
Take-all, one of the most serious diseases of wheat, is caused by
infection with the wheat take-all fungus, Gaeumannomyces grami-
nis var. tritici.1 This disease, which damages the roots of wheat,
occurs in continuously cropped wheat fields, causing massive re-
ductions in wheat production.2 However, the disease does not oc-
cur in some wheat fields, even when they are cropped continuously
over long periods. Narita and Suzuki isolated an unidentified fun-
gus from the healthy roots of wheat grown in a continuously
cropped field, and provisionally named it ‘Sterile Dark.’3 They found
that when Sterile Dark was applied to wheat seeds, it colonized the
roots and suppressed the growth of the pathogenic take-all fungus
on the roots.3 This finding led Takahashi and co-workers to assume
that some antifungal substance was produced by Sterile Dark that
inhibited the growth of the take-all fungus. Based on this as-
sumption, they screened the culture broth of Sterile Dark for anti-
fungal substances directed against the take-all fungus and isolated
two novel phthalides, 1 and 2 (Fig. 1).4 Compound 1 exhibited an-
tifungal activity against G. graminis var. tritici and Cladosporium
O
O
OH
OH
1
2
Figure 1. Antifungal phthalides produced by Sterile Dark.
unambiguously determine the absolute configuration of the natural
enantiomer of 2 as S.
2. Results and discussion
Our retrosynthetic analysis of 1 and the enantiomers of 2 is
shown in Scheme 1. The target molecules, 1 and 2, would be ob-
tainable by O-alkylation of hydroxy phthalide A with halides B and
C, respectively. To construct the tetra-substituted phthalide core A,
we planned to utilize the Alder–Rickert reaction of cyclohexadiene
E with dimethyl acetylenedicarboxylate (DMAD) to form aromatic
diester D. Selective reduction of the ester functionality meta to both
of the two alkoxy groups of D would afford the phthalide core A.
The alkylating agent B (X¼Br, R2¼Me) is a known compound, and
both enantiomers of C would readily be obtained by Evans’ asym-
metric alkylation using chiral oxazolidinone auxiliaries.
The synthesis of the key intermediate A (10 in Scheme 2) began
with a two-step preparation of 5 from 2-methyl-1,3-cyclohexa-
nedione (4) according to procedures in the literature.5–7 The enone
5 was converted into unstable TES-enol ether 6,8 which was then
subjected without purification to the Alder–Rickert reaction with
herbarum, whereas compound
2 had activity only against
C. herbarum.4 The agriculturally important biological activities of
1 and 2, and the undefined absolute configuration of 2, prompted
us to synthesize these phthalides. We herein describe the first
synthesis of 1 and both enantiomers of 2, which allowed us to
* Corresponding author. Tel./fax: þ81 22 717 8783.
E-mail address: skuwahar@biochem.tohoku.ac.jp (S. Kuwahara).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.023

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N. Katoh et al. / Tetrahedron 64 (2008) 9073–9077
by observing the NOE and HMBC correlations, as shown in
Scheme 2.12
The phthalide core 10 was treated with bromo ester 1213 in
acetone in the presence of K2CO3 to give alkylation product 13,
which was then exposed to MgI2 in ether/toluene to deprotect the
methoxy moiety (Scheme 3).14,15 The demethylation product 14,
obtained in a moderate yield of 60%, was hydrolyzed with aqueous
LiOH in MeOH to produce the antifungal phthalide 1 in quantitative
yield. The 1H and 13C NMR spectra of the synthetic material were
identical with those of the natural product.
R2O2C
X
X
HO2C
HO2C
O
B
O
O
OH
HO
1
O-alkylation
O
OR1
A
O
O
*
O
R2O2C
*
C
O
OH
+
2
selective
reduction
MeO2C
Br
HO
MeO2C
O
12
Alder-Rickert
CO2Me
CO2Me
O
O
R3O
R3O
CO2Me
CO2Me
K2CO3
(99%)
reaction
O
O
OMe
OMe
10
13
MgI2
(60%)
OR1
E
OR1
D
Scheme 1. Retrosynthetic analysis of 1 and 2.
HO2C
O
MeO2C
O
aq. LiOH
(quant.)
O
O
O
1) K2CO3
LDA
TESCl
O
O
TESO
Me2SO4
DMAD
xylene
O
OH
OH
1
14
2) LDA
MeI
Scheme 3. Synthesis of 1.
O
4
OMe
5
OMe
6
(88%, 2 steps)
Having completed the synthesis of the achiral phthalide 1, we
next turned our attention to the synthesis of both enantiomers of 2,
which contain one stereogenic center. O-Protected iodides (S)-17
and (R)-17 to alkylate the phthalide core 10 were prepared by the
reaction sequence shown in Scheme 4. Known olefinic compound
15, prepared via Evans’ asymmetric alkylation protocol,16 was
subjected to ozonolysis conditions to give alcohol 16 after reductive
workup with NaBH4. The alcohol 16 was then converted into the
corresponding iodide (S)-17 by treatment with I2, Ph3P, and imid-
azole in THF. The (R)-enantiomer of 17 [(R)-17] was obtained from
ent-15 by the same two-step sequence of reactions.16,17
TESO
CO2Me
TESO
CO2Me reflux
CO2Me
TBAF
(71% from 5)
CO2Me
MeO
OMe
8
7
HO
CO2Me
CO2Me
HO
1) aq.NaOH
O
2) Zn,aq.HCl
AcOH
(53%, 2 steps)
O
OMe
9
OMe
10
O3
then
NaBH4
(81%)
I2, Ph3P
imidazole
(76%)
OH
TBSO
TBSO
TBSO
NOE
HMBC
HO
O
O
15
16
HO
O
O
I
I
TBSO
ent-15
OMe
11
OMe
10
(S)-17
(R)-17
Scheme 2. Preparation of phthalide core 10.
Scheme 4. Preparation of both enantiomers of alkylating agent 17.
With both enantiomers of 17 in hand, we moved on to the final
stage of the synthesis of (S)- and (R)-2 (Scheme 5). O-Alkylation of
10 with (S)-17 in acetone in the presence of K2CO3 proceeded
cleanly to give 18. Deprotections of the methyl- and TBS-protected
hydroxy groups of 18 to form 19 were conducted in a single oper-
ation by treatment of 18 with MgI2 followed by exposure of the
resulting demethylated intermediate to aq HCl to remove the TBS
group. Oxidation of alcohol 19 into carboxylic acid (S)-2 was per-
formed in two steps by first converting 19 into an aldehyde in-
DMDA in m-xylene.9,10 The cycloaddition of DMDA to 6 to form
bicyclic intermediate 7 and subsequent elimination of ethylene from
the adduct proceeded smoothly to yield aromatic diester 8. The
TES-protected diester 8, obtained unfortunately as an inseparable
mixture with DMDA employed in excess, was treated with TBAF to
produce, after chromatographic purification, phenolic diester 9 in
71% overall yield from 5. Selective reduction of the ester group meta
to both the hydroxy and methoxy functionalities of 9 was achieved
in two steps according to Patterson’s protocol:9,11 (1) hydrolysis of
the diester to the corresponding dicarboxylic acid intermediate;
and (2) reductive treatment of the intermediate with Zn in 12 M
HCl/AcOH to form lactone 10 via an acid anhydride intermediate,
which is in equilibrium with the dicarboxylic acid under these
reaction conditions.9 Fortunately, this reduction proceeded highly
regioselectively to produce 10 and its isomer 11 in a ratio of >20:1,
and the undesired minor isomer 11 was readily removed by
SiO2 column chromatography. The structure of 10 was confirmed
18
termediate with TEMPO/PhI(OAc)2 and then subjecting the
aldehyde to Pinnick oxidation conditions.19–21 By the same four-
step sequence of reactions, (R)-17 was transformed into (R)-2. The
1H and 13C NMR spectra of (S)-2 and (R)-2 were identical with those
of the natural product, which allowed us to confirm the proposed
gross structure of the antifungal phthalide 2. Comparison of the
22
22
specific rotations of (S)-2 ([
a
]
þ6.8) and (R)-2 ([
a
]
ꢀ7.5) with
D
D
that of the natural compound ([
solute configuration of the chiral phthalide to be S.
a
]
þ6.2)4 clearly showed the ab-
D

N. Katoh et al. / Tetrahedron 64 (2008) 9073–9077
9075
OTBS
was successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
(hexane/EtOAc¼10:1) to give 10.8 g (88%) of 5 as a colorless solid,
recrystallization of which from hexane afforded colorless prisms:
O
HO
OH
MgI2
then
aq. HCl
(88%)
(S)-17
K2CO3
(90%)
O
O
O
O
mp 46.0–46.5 ꢁC; IR
n
2932 (m),1616 (vs),1377 (s),1355 (s),1247 (s),
OMe
OMe
10
1105 (s); 1H NMR (300 MHz)
d
1.14 (3H, d, J¼6.9 Hz), 1.64–1.74 (1H,
18
m), 1.69 (3H, t, J¼1.6 Hz), 2.08 (1H, dq, J¼13.2, 4.5 Hz), 2.27 (1H,
ddq, J¼11.3, 4.5, 6.9 Hz), 2.46–2.59 (1H, m), 2.59–2.70 (1H, m), 3.81
1)TEMPO
PhI(OAc)2
2) NaClO2
(77%, 2 steps)
O
HO2C
O
(3H, s); 13C NMR (75 MHz)
d 7.4, 15.5, 23.8, 28.6, 39.2, 54.9, 114.0,
O
O
170.6, 201.2; HRMS (FAB) m/z calcd for C9H15O2 ([MþH]þ) 155.1072,
found 155.1080.
O
O
OH
OH
(S)-2
19
[α]D+6.8
4.1.2. Dimethyl 4-hydroxy-6-methoxy-3,5-dimethyl-1,2-benzene-
dicarboxylate (9)
(lit.+6.2)
HO2C
O
To a stirred solution of LDA, prepared by treating a solution of
diisopropylamine (3.00 ml, 21.4 mmol) in THF (20 ml) with n-BuLi
(1.6 M in hexane, 13.4 ml, 21.4 mmol) at ꢀ10 ꢁC, were successively
added TESCl (2.74 ml, 21.4 mmol) and a solution of 5 (3.00 g,
19.5 mmol) in THF (10 ml) at ꢀ78 ꢁC. After 1 h, the reaction mixture
was quenched with ice-cold satd NaHCO3 aq and extracted with
hexane. The extract was washed with brine, dried (K2CO3), and
concentrated in vacuo to give 6, which was then dissolved in
m-xylene (20 ml). To the solution was added DMAD (4.78 ml,
38.9 mmol) at ꢀ50 ꢁC while stirring and the mixture was gradually
warmed to 70 ꢁC. After being stirred for 4 h at 70 ꢁC, the mixture
was refluxed for 4 h and then concentrated in vacuo. The residue
was chromatographed over SiO2 (hexane/EtOAc¼5:1) to give an
inseparable mixture of 8 and DMAD. The mixture was dissolved in
THF (20 ml) and cooled to 0 ꢁC. To the stirred solution was added
dropwise a solution of TBAF (1.0 M in THF, 29.2 ml, 0.292 mmol).
After being stirred overnight at room temperature, the mixture was
quenched with satd NH4Cl aq and extracted with EtOAc. The extract
was successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over
SiO2 (hexane/EtOAc¼3:1) to give 3.68 g (71%) of 9 as a white solid,
recrystallization of which from H2O/MeOH afforded colorless nee-
10 + (R)-17
O
O
OH
(R)-2
[α]D–7.5
Scheme 5. Synthesis of both enantiomers of 2.
3. Conclusion
The synthesis of antifungal substance 1 was achieved in 20%
overall yield from 4 via the alkylation of phthalide intermediate 10
with allylic bromide 12; the intermediate 10 in turn was prepared
via the Alder–Rickert reaction between cyclohexadiene derivative
6 and DMAD. Alkylation of 10 with (S)- and (R)-17, prepared
using Evans’ asymmetric alkylation methodology, and subsequent
deprotection and oxidation afforded both enantiomers of chiral
phthalide 2 in 20% overall yield from 4. Comparison of the specific
rotations of (S)- and (R)-2 with that of the natural product led to the
unambiguous conclusion that the absolute configuration of the
natural phthalide (2) is S.
dles: mp 118.0–118.5 ꢁC; IR
(s), 1113 (m); 1H NMR (500 MHz)
(3H, s), 3.86 (3H, s), 3.87 (3H, s), 5.08 (1H, br s, OH); 13C NMR
(125 MHz) 9.1, 12.6, 52.40, 52.42, 62.2, 118.0, 118.3, 119.8, 131.7,
n
3450 (br m), 1713 (vs), 1303 (m), 1197
2.21 (3H, s), 2.23 (3H, s), 3.79
4. Experimental
4.1. General
d
d
155.6, 155.7, 167.1, 168.5; HRMS (FAB) m/z calcd for C13H17O6
([MþH]þ) 269.1025, found 269.1024.
IR spectra were recorded by a Jasco FR/IR-4100 spectrometer.
NMR spectra were recorded with TMS as an internal standard in
CDCl3 by a Varian Gemini 2000 spectrometer (300 MHz for 1H and
75 MHz for 13C), a Varian UNITY plus-500 spectrometer (500 MHz
for 1H and 125 MHz for 13C), or a Varian UNITY plus-600 spec-
trometer (600 MHz for 1H and 150 MHz for 13C) unless otherwise
stated. Optical rotation values were measured with a Jasco DIP-371
polarimeter, and mass spectra were obtained with a Jeol JMS-700
spectrometer. Merck silica gel 60 (70–230 mesh) was used for silica
gel column chromatography.
4.1.3. 5-Hydroxy-7-methoxy-4,6-dimethyl-1(3H)-
isobenzofuranone (10)
To a stirred solution of 9 (0.580 g, 2.16 mmol) in MeOH (4.3 ml)
was added a solution of NaOH (0.520 g, 13.0 mmol) in H2O (7 ml) at
room temperature, and the reaction mixture was warmed to 50 ꢁC.
After 6 h, the mixture was cooled to room temperature, diluted
with water, and extracted with Et2O. The aqueous layer was acid-
ified with 6 M HCl aq and extracted with EtOAc. The EtOAc solution
was washed with brine, dried (MgSO4), and concentrated in vacuo.
The residue was diluted with a mixture of 12 M HCl aq and AcOH
(1:4, 3.3 ml), and the mixture was warmed to 70 ꢁC with stirring.
The mixture was treated with Zn dust for 6 h (1 g/h, 6 g in total),
before being quenched with water and extracted with EtOAc. The
extract was successively washed with satd NaHCO3 aq and brine,
dried (MgSO4), and concentrated in vacuo. The residue was chro-
matographed over SiO2 (CHCl3/MeOH¼50:1) to give 241 mg (54%)
of 10 as a white solid, recrystallization of which from H2O/EtOH
4.1.1. 3-Methoxy-2,6-dimethyl-2-cyclohexen-1-one (5)
To a stirred solution of 4 (10.0 g, 79.3 mmol) in acetone (80 ml)
were successively added K2CO3 (12.1 g, 87.2 mmol) and Me2SO4
(8.27 ml, 87.2 mmol) at room temperature. After being stirred
overnight at reflux, the mixture was filtered, and the filtrate was
concentrated in vacuo to give crude 3-methoxy-2-methyl-2-
cyclohexen-1-one. The enone was dissolved in THF (20 ml) and
added dropwise to a stirred solution of LDA [prepared by treating
a solution of diisopropylamine (12.6 ml, 89.9 mmol) in THF (60 ml)
with n-BuLi (1.6 M in hexane, 56.2 ml, 89.9 mmol) at ꢀ10 ꢁC] at
ꢀ78 ꢁC. After 30 min, MeI (4.94 ml, 79.3 mmol) and HMPA (15.2 ml,
87.4 mmol) were added. The reaction mixture was gradually
warmed to room temperature and stirred overnight before being
quenched with satd NH4Cl aq and extracted with EtOAc. The extract
afforded colorless needles: mp 207.0–208.0 ꢁC; IR
1715 (s), 1592 (m), 1487 (m), 1321 (m); 1H NMR (300 MHz)
(3H, s), 2.21 (3H, s), 4.04 (3H, s), 5.14 (2H, s), 5.24 (1H, br s, OH); 13
NMR (150 MHz, acetone-d6) 9.1, 11.2, 62.0, 68.6, 109.1, 113.6, 118.6,
n
3230 (br m),
2.14
d
C
d
147.7, 156.9, 160.3, 169.4; HRMS (FAB) m/z calcd for C11H13O4
([MþH]þ) 209.0814, found 209.0816.

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N. Katoh et al. / Tetrahedron 64 (2008) 9073–9077
4.1.4. Methyl (E)-4-[(1,3-dihydro-7-methoxy-4,6-dimethyl-1-oxo-
5-isobenzofuranyl)oxy]-2-methyl-2-butenoate (13)
(6H, s), 0.90 (3H, d, J¼6.9 Hz), 0.91 (9H, s), 1.49–1.67 (2H, m), 1.71–
1.84 (1H, m), 2.81 (1H, br s, OH), 3.43 (1H, dd, J¼9.9, 7.1 Hz), 3.54
(1H, dd, J¼9.9, 4.7 Hz), 3.63 (1H, ddd, J¼11.0, 7.1, 5.5 Hz), 3.72 (1H,
To a stirred mixture of 10 (14.0 mg, 67.2 mmol) and K2CO3
(20.8 mg, 0.154 mmol) in acetone (2 ml) was added dropwise 12
(47.1 mg, 0.244 mmol) at room temperature. The mixture was
refluxed for 1 h, and then concentrated in vacuo. The residue was
chromatographed over SiO2 (hexane/EtOAc¼5:1) to give 21.4 mg
(99%) of 13 as a white solid, a portion of which was recrystallized
from CHCl3/MeOH to afford colorless prisms: mp 109.0–109.5 ꢁC; IR
dt, J¼11.0, 5.6 Hz); 13C NMR (75 MHz)
d
ꢀ5.7, ꢀ5.6, 17.2, 18.2, 25.8
(3C), 33.8, 37.9, 61.1, 68.7; HRMS (FAB) m/z calcd for C11H27O2Si
([MþH]þ) 219.1780, found 219.1783.
4.1.8. (S)-1-tert-Butyldimethylsiloxy-4-iodo-2-methylbutane
[(S)-17]
n
1758 (vs), 1715 (vs), 1250 (m), 1131 (m), 1105 (m); 1H NMR
(500 MHz)
1.87 (3H, d, J¼1.0 Hz), 2.18 (3H, s), 2.25 (3H, s), 3.80
To a stirred solution of 16 (128 mg, 0.586 mmol) and Ph3P
(0.385 g, 1.47 mmol) in THF (2 ml) were successively added imid-
azole (99.8 mg, 1.47 mmol) and I2 (297 mg, 1.17 mmol) at 0 ꢁC in the
dark. The mixture was warmed to room temperature, stirred for
3 h, and quenched with satd Na2S2O3 aq. The mixture was extracted
with EtOAc, and the extract was washed with brine, dried (Na2SO4),
d
(3H, s), 4.05 (3H, s), 4.54 (2H, d, J¼6.0 Hz), 5.14 (2H, s), 7.03 (1H, tq,
J¼6.0, 1.0 Hz); 13C NMR (125 MHz)
d 9.6, 11.6, 12.9, 52.1, 62.2, 68.2,
69.5, 112.7, 120.0, 125.3, 129.9, 135.9, 146.1, 156.6, 161.4, 167.6, 168.3;
HRMS (FAB) m/z calcd for C17H21O6 ([MþH]þ) 321.1338, found
321.1347.
and concentrated in vacuo. The residue was chromatographed over
26
SiO2 (hexane) to give 147 mg (76%) of (S)-17 as a colorless oil. [a]
D
27
4.1.5. Methyl (E)-4-[(1,3-dihydro-7-hydroxy-4,6-dimethyl-1-oxo-5-
isobenzofuranyl)oxy]-2-methyl-2-butenoate (14)
ꢀ10.5 (c 2.35, CHCl3), lit.22
[
a
]
D
ꢀ10.5 (c 2.35, CHCl3); IR
n
1256 (m),
d 0.04 (6H, s), 0.88 (3H d,
1094 (m), 838 (m); 1H NMR (500 MHz)
To a stirred suspension of MgI2 in Et2O/toluene, prepared from
Mg (6.5 mg, 0.27 mmol) and I2 (68 mg, 0.27 mmol) in Et2O/toluene
(1:2, 0.8 ml), was added a solution of 13 (72.1 mg, 0.225 mmol) in
Et2O/toluene (1:2, 3 ml) at room temperature. The mixture was
refluxed for 2.5 h, and then quenched with ice-cold 1 M HCl aq.
The mixture was extracted with EtOAc and the extract was suc-
cessively washed with satd NaHCO3 aq and brine, dried (MgSO4),
and concentrated in vacuo. The residue was chromatographed
over SiO2 (hexane/EtOAc¼5:1) to give 41.3 mg (60%) of 14 as
a white solid, recrystallization of which from H2O/MeOH afforded
J¼6.5 Hz), 0.89 (9H, s), 1.61–1.69 (1H, m), 1.70–1.79 (1H, m), 1.97–
2.05 (1H, m), 3.21 (1H, dt, J¼9.5, 7.5 Hz), 3.28 (1H, ddd, J¼9.5, 8.0,
6.0 Hz), 3.43 (1H, dd, J¼10.0, 6.0 Hz), 3.47 (1H, dd, J¼10.0, 6.0 Hz);
13C NMR (125 MHz)
d
ꢀ5.43, ꢀ5.42, 5.3, 15.9, 18.3, 25.9 (3C), 36.6,
37.6, 67.3; HRMS (EI) m/z calcd for C7H16IOSi ([Mꢀ(t-Bu)]þ)
271.0015, found 271.0014.
4.1.9. Preparation of ent-16 and (R)-17
These compounds were obtained from ent-15 in the same
manners as those described for 16 and (S)-17. The IR and NMR
colorless needles: mp 142.0–143.0 ꢁC; IR
1627 (m), 1316 (m), 1274 (m), 1154 (m), 1074 (m); 1H NMR
(300 MHz) 1.87 (3H, s), 2.15 (3H, s), 2.21 (3H, s), 3.80 (3H, s),
4.55 (2H, d, J¼6.0 Hz), 5.21 (2H, s), 7.03 (1H, dq, J¼6.0, 1.2 Hz), 7.70
(1H, br s, OH); 13C NMR (75 MHz)
8.7, 11.5, 12.8, 52.0, 69.6, 70.0,
106.4, 116.6, 118.6, 130.0, 136.0, 143.6, 153.9, 162.5, 167.8, 173.0;
HRMS (FAB) m/z calcd for C16H19O6 ([MþH]þ) 307.1182, found
307.1185.
n
3419 (m), 1719 (s),
spectra of ent-16 and (R)-17 were identical with those of 16 and (S)-
24
17, respectively. Compound ent-16: [
a
]
þ7.67 (c 0.920, CHCl3),
D
24
d
lit.23
[
a
]
þ8.07 (c 1.05, CHCl3); HRMS (FAB) m/z calcd for
D
C
a
11H27O2Si ([MþH]þ) 219.1780, found 219.1789. Compound (R)-17:
24
25
d
[
]
þ9.32 (c 1.11, CHCl3), lit.23
[a
]
þ10.6 (c 1.11, CHCl3); HRMS (EI)
D
D
m/z calcd for C7H16IOSi ([Mꢀ(t-Bu)]þ) 271.0015, found 271.0016.
4.1.10. 5-[(S)-4-tert-Butyldimethylsiloxy-3-methylbutoxy]-7-
methoxy-4,6-dimethyl1(3H)-isobenzofuranone (18)
4.1.6. (E)-4-[(1,3-Dihydro-7-hydroxy-4,6-dimethyl-1-oxo-5-
isobenzofuranyl)oxy]-2-methyl-2-butenoic acid (1)
To a stirred mixture of 10 (235 mg, 1.13 mmol) and K2CO3
(562 mg, 4.06 mmol) in acetone (30 ml) was added a solution of
(S)-17 (373 mg, 1.14 mmol) in acetone (5 ml) at room temperature,
and the mixture was refluxed overnight in the dark. After being
cooled, the mixture was filtered, and the filtrate was concentrated
in vacuo. The residue was diluted with water and extracted with
EtOAc. The extract was washed with brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
To a stirred solution of 14 (28.5 mg, 93.0 mmol) in a mixture
of water and MeOH (1:2, 3 ml) was added LiOH$H2O (16.6 mg,
0.396 mmol) at room temperature. After 6 h, the mixture was
extracted with Et2O, and the aqueous layer was acidified with 6 M
HCl aq. The aqueous layer was extracted with EtOAc, and the extract
was washed with brine, dried (MgSO4), and concentrated in vacuo
to give 26.9 mg (99%) of 1 as a white solid, recrystallization of which
from H2O/MeOH afforded colorless needles: mp 180.5–181.5 ꢁC; IR
(hexane/EtOAc¼10:1) to give 416 mg (90%) of 18 as a colorless oil.
28
[a
]
ꢀ1.4 (c 0.900, CHCl3); IR
n 1761 (s),1602 (m),1138 (m),1102 (s),
D
n
3433 (m), 1729 (s), 1685 (s), 1261 (m), 1146 (s), 1072 (m); 1H NMR
836 (s); 1H NMR (500 MHz)
d 0.04 (6H, S), 0.89 (9H, s), 0.97 (3H, d,
(500 MHz)
d
1.88 (3H, s), 2.16 (3H, s), 2.22 (3H, s), 4.58 (2H, d,
J¼6.3 Hz), 1.58–1.65 (1H, m), 1.84–1.93 (1H, m), 1.98–2.05 (1H, m),
2.16 (3H, s), 2.22 (3H, s), 3.47 (1H, dd, J¼9.8, 5.9 Hz), 3.51 (1H, dd,
J¼9.8, 5.9 Hz), 3.82–3.89 (2H, m), 4.02 (3H, s), 5.12 (2H, s); 13C NMR
J¼5.9 Hz), 5.22 (2H, s), 7.16 (1H, t, J¼5.9 Hz), 7.72 (1H, br s, OH); 13
C
NMR (75 MHz)
d 8.8, 11.6, 12.5, 69.6, 70.0, 106.5, 116.6, 118.7, 129.3,
138.5, 143.6, 154.0, 162.5, 171.9, 173.1; HRMS (FAB) m/z calcd for
(125 MHz)
d
ꢀ5.43, ꢀ5.41, 9.6, 11.6, 16.8, 18.3, 25.9 (3C), 32.8, 33.8,
C
15H17O6 ([MþH]þ) 293.1025, found 293.1027.
62.2, 68.1, 68.3, 71.7, 112.2, 120.0, 125.4, 146.0, 156.6, 162.3, 169.1;
HRMS (FAB) m/z calcd for C22H37O5Si ([MþH]þ) 409.2410, found
409.2412.
4.1.7. (S)-4-tert-Butyldimethylsilyloxy-3-methyl-1-butanol (16)
Ozone was bubbled into a stirred solution of 15 (0.156 g,
0.728 mmol; [
24
20
a
]
ꢀ1.1 (c 1.01, CHCl3), lit.16
[
a
]
ꢀ1.0 (c 1.0, CHCl3))
4.1.11. 5-[(S)-4-Hydroxy-3-methylbutoxy]-7-hydroxy-4,6-
dimethyl-1(3H)isobenzofuranone (19)
D
D
in MeOH (5 ml) for 10 min at ꢀ78 ꢁC. After the addition of NaBH4
(0.138 g, 3.65 mmol), the mixture was stirred for 30 min at ꢀ78 ꢁC,
and then quenched with satd NH4Cl aq. The mixture was extracted
with EtOAc, and the extract was washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was chromatographed over
SiO2 (hexane/EtOAc¼5:1) to give 0.129 g (81%) of 16 as a colorless
To a stirred suspension of MgI2 in Et2O/toluene, prepared from
Mg (5.8 mg, 0.24 mmol) and I2 (30 mg, 0.12 mmol) in Et2O/toluene
(1:2, 3 ml), was added a solution of 18 (81.5 mg, 0.199 mmol) in
Et2O/toluene (1:2, 3 ml) at room temperature, and the mixture was
refluxed for 2.5 h in the dark. To the mixture was added a solution
of 12 M HCl aq (0.18 ml) in MeOH (1.5 ml) at room temperature, and
the resulting mixture was stirred for 1 h before being quenched
27
24
oil. [
a
]
D
ꢀ6.73 (c 6.50, CHCl3), lit.22
[a
]
ꢀ6.96 (c 4.80, CHCl3); IR
n
D
3365 (br m), 1254 (m), 1092 (s), 835 (s); 1H NMR (300 MHz)
d
0.07

N. Katoh et al. / Tetrahedron 64 (2008) 9073–9077
9077
25
with NaHCO3 aq and extracted with EtOAc. The extract was suc-
cessively washed with water and brine, dried (Na2SO4), and con-
centrated in vacuo. The residue was chromatographed over SiO2
(hexane/EtOAc¼2:1) to give 49.4 mg (88%) of 19 as a white solid,
19, and (S)-2, respectively. Compound ent-18: [
a]
þ2.0 (c 0.940,
D
CHCl3); HRMS (FAB) m/z calcd for C22H37O5Si ([MþH]þ) 409.2410,
25
found 409.2414. Compound ent-19: [
a
]
þ7.43 (c 0.740, CHCl3);
D
HRMS (FAB) m/z calcd for C15H21O5 ([MþH]þ) 281.1389, found
24
recrystallization of which from hexane/EtOAc afforded colorless
281.1388. Compound (R)-2: [
a
]
ꢀ7.5 (c 0.23, MeOH); HRMS (FAB)
D
28
needles: mp 88.5–89.5 ꢁC; [
a
]
D
ꢀ7.34 (c 0.730, CHCl3); IR
n
3430 (br
m/z calcd for C15H19O6 ([MþH]þ) 295.1182, found 295.1188.
m), 1731 (s), 1623 (m), 1325 (m), 1152 (m), 1104 (m); 1H NMR
(500 MHz)
d
1.04 (3H, d, J¼6.8 Hz), 1.62 (1H, br s, OH), 1.66–1.73
Acknowledgements
(1H, m), 1.93–2.07 (2H, m), 2.14 (3H, s), 2.20 (3H, s), 3.58 (1H, dd,
J¼10.7, 5.9 Hz), 3.60 (1H, dd, J¼10.7, 5.9 Hz), 3.88 (2H, t, J¼6.6 Hz),
We thank Ms. Yamada (Tohoku University) for measuring NMR
and MS spectra. This work was supported, in part, by a Grant-in-Aid
for Scientific Research (B) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (No. 19380065).
5.20 (2H, s), 7.69 (1H, br s, OH); 13C NMR (125 MHz)
d 8.7, 11.5, 16.7,
33.0, 33.9, 68.0, 70.0, 71.3, 105.9, 116.5, 118.5, 143.4, 153.6, 162.8,
173.0; HRMS (FAB) m/z calcd for C15H21O5 ([MþH]þ) 281.1389,
found 281.1396.
References and notes
4.1.12. (S)-4-[(1,3-Dihydro-7-hydroxy-4,6-dimethyl-1-oxo-5-
isobenzofuranyl)oxy]-2-methylbutanoic acid [(S)-2]
1. Thomashow, L. S.; Weller, D. M. J. Bacteriol. 1988, 170, 3499–3508.
2. Cook, R. J.; Thomashow, L. S.; Weller, D. M.; Fujimoto, D.; Mazzola, M.; Bangera,
G.; Kim, D.-S. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 4197–4201.
3. Narita, Y.; Suzuki, T. Ann. Phytopath. Soc. Jpn. 1991, 57, 301–305.
4. Takahashi, K.; Koshino, H.; Narita, Y.; Yoshihara, T. Biosci. Biotechnol. Biochem.
2005, 69, 1018–1020.
5. Holton, R. A.; Williams, A. D.; Kennedy, R. M. J. Org. Chem. 1986, 51, 5482–5484.
6. Delpech, B.; Calvo, D.; Lett, R. Tetrahedron Lett. 1996, 37, 1015–1018.
7. Miyaura, N.; Satoh, Y.; Hara, S.; Suzuki, A. Bull. Chem. Soc. Jpn. 1986, 59, 2029–
2031.
8. Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495–498.
9. Patterson, J. W. Tetrahedron 1993, 49, 4789–4798.
10. Patterson, J. W. J. Org. Chem. 1995, 60, 560–563.
11. Birch, A. J.; Wright, J. J. Aust. J. Chem. 1969, 22, 2635–2644.
12. The phtalide 10 has previously been isolated from the culture broths of
Aspergillus duricaulis and Lachnum papyraceum. (a) Achenbach, H.; Mu¨hlenfeld,
A.; Brillinger, G. U. Liebigs Ann. Chem. 1985, 1596–1628; (b) Shan, R.; Stadler, M.;
Anke, H.; Sterner, O. J. Nat. Prod. 1997, 60, 804–805.
To a stirred solution of 19 (13.9 mg, 49.5
mmol) in CH2Cl2 (0.5 ml)
were successively added TEMPO (1.5 mg, 9.6
mmol) and PhI(OAc)2
(39.8 mg, 0.124 mmol) at room temperature. After being stirred for
1.5 h, the mixture was poured into water and extracted with
CH2Cl2. The extract was successively washed with water and brine,
dried (Na2SO4), and concentrated in vacuo. The residue was passed
through a short column of SiO2 using hexane/EtOAc (3:1) as the
eluant, and the eluted solution was concentrated in vacuo to give an
aldehyde (13.5 mg) as a pale yellow oil, which was then mixed with
t-BuOH (1.8 ml), 20% NaH2PO4 aq (0.13 ml), and 2-methyl-2-butene
(2 ml). To the mixture was added NaClO2 (30.7 mg, 0.339 mmol) at
room temperature, and the resulting mixture was stirred for 1.5 h
in the dark. The mixture was poured into water and extracted with
EtOAc. The extract was washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
(CHCl3/MeOH¼50:1) to give 11.2 mg (77%) of (S)-2 as a white solid,
recrystallization of which from H2O/MeOH afforded colorless
13. Wolff, M.; Seemann, M.; Grosdemange-Billiard, C.; Tritsch, D.; Campos, N.;
´
´
Rodorıguez-Concepcion, M.; Boronat, A.; Rohmer, M. Tetrahedron Lett. 2002, 43,
2555–2559.
14. Yamaguchi, S.; Sugiura, K.; Fukuoka, R.; Okazaki, K.; Takeuchi, M.; Kawase, Y.
Bull. Chem. Soc. Jpn. 1984, 57, 3607–3608.
15. Ward, R. A.; Procter, G. Tetrahedron 1995, 51, 12301–12318.
16. Schinzer, D.; Bauer, A.; Schieber, J. Chem.dEur. J. 1999, 5, 2492–2500.
17. Hansen, D. B.; Starr, M.-L.; Tolstoy, N.; Joullie´, M. M. Tetrahedron: Asymmetry
2005, 16, 3623–3627.
27
24
prisms: mp 101.0–101.5 ꢁC; [
þ6.2 (c 0.36, MeOH); IR
1077 (s),1040 (m); 1H NMR (600 MHz)
a
]
þ6.8 (c 0.45, MeOH), lit.4
[a]
D
D
n
3231 (br m), 1739 (vs), 1331 (m), 1153 (m),
d
1.32 (3H, d, J¼7.0 Hz),1.92–
18. Mico, A. D.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974–6977.
1.98 (1H, m), 2.12 (3H, s), 2.17 (3H, s), 2.22–2.28 (1H, m), 2.83–2.89
(1H, m), 3.85 (2H, t, J¼6.3 Hz), 5.19 (2H, s); 13C NMR (150 MHz)
d 8.7,
19. Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175–1176.
20. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
21. Direct conversion of 19 into (S)-2 by exposing 19 to the Jones reagent in
acetone or to TEMPO/PhI(OAc)2 in H2O/CH3CN or H2O/CH2Cl2 was unsuccessful,
resulting only in the formation of complex mixtures. (a) Epp, J. B.; Widlanski, T.
S. J. Org. Chem. 1999, 64, 293–295; (b) Van den Bos, L. J.; Code´e, J. D. C.; Van der
Toorn, J. C.; Boltje, T. J.; Van Boom, J. H.; Overkleeft, H. S.; Van der Marel, G. A.
Org. Lett. 2004, 6, 2165–2168.
11.5, 17.4, 33.8, 36.1, 70.1, 70.5, 106.1, 116.5, 118.6, 143.5, 153.8,
162.6, 173.0, 180.9; HRMS (FAB) m/z calcd for C15H19O6 ([MþH]þ)
295.1182, found 295.1189.
4.1.13. Synthesis of ent-18, ent-19, and (R)-2
These compounds were obtained from (R)-17 in the same
manners as those described for 18, 19, and (S)-2. The IR and NMR
spectra of ent-18, ent-19, and (R)-2 were identical with those of 18,
22. Eguchi, T.; Arakawa, K.; Terachi, T.; Kakinuma, K. J. Org. Chem. 1997, 62, 1924–
1933.
23. Nakamura, Y.; Mori, K. Biosci. Biotechnol. Biochem. 2000, 64, 1713–1721.