Syntheses of β-resorcylic acid derivatives, novel potato micro-tuber inducing substances isolated from Lasiodiplodia theobromae

Article abstract of DOI:10.1016/S0040-4020(01)00455-0

The syntheses of β-resorcylic acid derivatives 1 and 2, isolated from fungus Lasiodiplodia theobromae, and their dimethyl ethers were accomplished. (R)-(-)-1,3-Butanediol was used as a chiral source of the side chain C₆-synthon. The dianion of the benzoic acid moiety was alkylated with C₆-bromide to give the desired skeleton. Several β-resorcylic acid derivatives including 1 and 2 were synthesized via hydrogenation, lactonization, demethylation and esterification. The (R)-configuration of the stereogenic center in the side chain was proved by this synthesis. It is confirmed that two phenolic hydroxy groups are required for 1 and 2 to exhibit potato micro-tuber inducing activity.

Full text of DOI:10.1016/S0040-4020(01)00455-0

TETRAHEDRON
Pergamon
Tetrahedron 57 &2001) 5377±5384
Syntheses of b-resorcylic acid derivatives, novel potato micro-
tuber inducing substances isolated from Lasiodiplodia theobromae
Qing Yang, Hiroaki Toshima and Teruhiko Yoshiharap
Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
Received 21 March 2001; accepted 27 April 2001
AbstractÐThe syntheses of b-resorcylic acid derivatives 1 and 2, isolated from fungus Lasiodiplodia theobromae, and their dimethyl ethers
were accomplished. &R)-&2)-1,3-Butanediol was used as a chiral source of the side chain C6-synthon. The dianion of the benzoic acid moiety
was alkylated with C6-bromide to give the desired skeleton. Several b-resorcylic acid derivatives including 1 and 2 were synthesized via
hydrogenation, lactonization, demethylation and esteri®cation. The &R)-con®guration of the stereogenic center in the side chain was proved
by this synthesis. It is con®rmed that two phenolic hydroxy groups are required for 1 and 2 to exhibit potato micro-tuber inducing activity.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
In our ongoing screening program for potato micro-tuber
inducing substances from fungus Lasiodiplodia theobromae
IFO 31059, novel b-resorcylic acid derivatives 1 and 2 were
isolated in addition to lasiodiplodin 7 and others &Fig. 1).1±3
The isolation and the structural elucidation of 1 and 2 have
been previously reported,4 in which the absolute con®gu-
ration of the sole stereogenic center in the side chain was
determined to be R by the advanced Mosher method.5 While
both 1 and 2 possessing a 6-hydroxyheptyl side chain at the
C6-position occur as the ester structure, lasiodiplodins
possessing a corresponding 8-hydroxynonyl side chain
occur as the 12-membered macrolactone structure.6 There
is a possibility that both 1 and 2 might be artifacts derived
from the corresponding hydroxy acid 3. In order to con®rm
the absolute con®guration of C-60 and investigate the struc-
ture±activity relationship of such b-resorcylic acid deriva-
tives, 1±6 &Fig. 1) were synthesized.
2.1. Synthesis of chiral bromide 16
Selective protection of the secondary hydroxy group of
&R)-&2)-1,3-butanediol 11 &99.4% e.e.) was achieved via
acetalization and subsequent regioselective reduction.
Treatment of 11 with benzaldehyde dimethyl acetal and
p-toluenesulfonic acid in re¯uxing dichloromethane gave
p-methoxybenzylidene acetal 12 in 98% yield. DIBAL-H
reduction of 12 in toluene alone gave primary alcohol 13
in 91% yield because 12 was regioselectively reduced from
the less-hindered site. Swern oxidation of 13 and subsequent
Wittig reaction with &methoxycarbonylmethylene)triphenyl-
phosphorane in one-pot gave &E)-unsaturated ester 14 in
77% yield. DIBAL-H reduction of 14 gave alcohol 15 in
98% yield. Treatment of 15 with carbon tetrabromide and
triphenylphosphine in dichloromethane gave bromide 16 in
93% yield. After coupling 8 and 16, both benzyl group and
In our approach to 1 and 2, the corresponding dimethyl
ethers 4±6 were supposed and retrosynthesized as shown
in Fig. 2, because several successful syntheses of lasio-
diplodin using an analogous route had been reported.7
Alkylation of a stabilized dianion 8 derived from the
known carboxylic acid 10 with a C6-chiral halide 9 or its
equivalent would provide the desired carbon skeleton.7
&R)-&2)-1,3-Butanediol was selected as the chiral starting
material to introduce the requisite stereogenic center.7
Keywords: b-resorcylic acid derivatives; micro-tuber inducing substance;
demethylation; structure±activity relationship.
p
Corresponding author. Tel.: 181-11-706-3349; fax: 181-11-706-2505;
e-mail: yoshihara@chem.agr.hokudai.ac.jp
Figure 1. Structures of b-resorcylic acid derivatives &1±6) and lasio-
diplodin &7).
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020&01)00455-0

5378
Q. Yang et al. / Tetrahedron 57 02001) 5377±5384
Figure 2. Retrosynthetic analysis of b-resorcylic acid derivatives 1±6.
ole®n originated from 16 would be reduced at the same time
under the conventional catalytic hydrogenolysis or hydro-
genation conditions. Thus, the synthesis of C6-chiral
bromide 16 corresponding to 9 in the retrosynthesis was
completed &Scheme 1).
were employed.8 Treatment of 4 with boron tribromide in
dichloromethane at 2788C resulted in only one methyl ether
cleaved, accompanying substitution of the hydroxyl group
in the side chain by bromine, giving ethyl 2-&6-bromo-
heptyl)-6-hydroxy-4-methoxybenzoate &HR-MS: calcd. for
C17H25O479Br &M1) m/z 372.0937, found 372.0945) as a
major product. The modi®cations of reaction condition
did not affect the result.9 When hydrobromic acid10 was
used for 6, demethylation and decarboxylation occurred
together to give 1-&6-bromoheptyl)-3,5-dihydroxybenzene.
Pyridine hydrochloride11 did not cleave the methyl ether,
but removed the carboxyl group of 6 to give 1-&6-chloro-
heptyl)-3,5-dimethoxybenzene &HR-MS: calcd. for
C15H23O235Cl &M1) m/z 270.1388, found 270.1424). The
reaction using iodotrimethylsilane12 failed to cleave the
methyl ethers even if excess reagent was used for prolonged
time. Aluminum chloride/ethanethiol system13 completely
cleaved the methyl ethers of 6, but substitution of hydroxyl
group with ethylsulfanyl group was not avoided. The
product was con®rmed to be 2,4-dihydroxy-6-&6-ethylsulfa-
nylheptyl)benzoic acid &HR-MS: calcd. for C16H24O4S &M1)
m/z 312.1396, found 312.1364).
2.2. Synthesis of dimethyl ether derivatives of 4, 5 and 6
Carboxylic acid 10 was treated with LDA in THF to give
dianion 8, which was alkylated with 16. After chromato-
graphic puri®cation with silica gel column, the desired
product 17 was obtained in 52% yield without the contami-
nation of unreacted 10. Hydrogenolysis of 17 was carried
out in the presence of palladium hydroxide on carbon at the
atmospheric pressure to give hydroxy acid 6 in 90% yield.
As we expected, deprotection of the benzyl group and
hydrogenation of ole®n proceeded smoothly in one step.
Esteri®cation of 6 with iodoethane and potassium carbonate
gave ethyl ester 4 in 75% yield, and with isobutyl bromide
gave 5 in 71% yield &Scheme 2). The optical purity of 4 was
determined to be .99% e.e. as judged by integration of the
1H NMR signals of the corresponding &R)-MTPA ester. The
optical purity of 5 would be same as that of 4.
Therefore, a suitable protection of the hydroxy group may
be required fundamentally to prevent substitution for our
substrates under the conventional deprotection conditions
of phenolic methyl ethers. Lactonization corresponds to
intramolecular protection by the own acyl group and
might ®ll our objectives preventing not only substitution,
but also decarboxylation, because demethylation in some
successful syntheses of lasiodiplodins was conducted
2.3. Synthesis of 1, 2 and 3
Out of our expectation, the resulting dimethyl ethers 4, 5
and 6 could not be demethylated without substitution of the
hydroxy group in the side chain or decarboxylation. We
failed in all our attempts to deprotect directly the methyl
ethers in 4, 5 and 6, though a lot of ether cleavage reagents
Scheme 1. &a) Benzaldehyde dimethyl acetal p-toluenesulfonic acid/CH2Cl2, 98%; &b) DIBAL-H/CH2Cl2, 91%; &c) Swerm oxid. then Ph3PyCHCOOMe,
77%; &d) DIBAL-H/THF, 98%; &e) CBr4, Ph3P/CH2Cl2, 93%.

Q. Yang et al. / Tetrahedron 57 02001) 5377±5384
5379
Scheme 2. &a) LDA/THF, then 16, 52%; &b) H2, Pd&OH)2/EtOH, 90%; &c) EtI, K2CO3/acetone, 75%; &d) ICH2CH&CH3)2, K2CO3/DMF, 70%.
smoothly in this way.14 Treatment of 6 with di-&2-pyridyl)
disul®de and triphenylphosphine gave the corresponding
2-pyridylthiol ester which was then treated with silver
perchlorate.15 The desired lactone 18, which corresponds
to the C2-shortened homologue of lasiodiplodin, was
obtained in 50% yield. Demethylation of 18 was achieved
with excess boron tribromide at room temperature to yield
phenolic lactone 19 in 25% yield.14 Although the yield is not
high, our experimental hypothesis has been proved by this
improvement. Optimization of this reaction is in progress
&Scheme 3).
ester 23 in 95% yield. Hydrogenolysis of 22 and 23 was
carried out in the presence of palladium hydroxide on
carbon at the atmospheric pressure to give 1 in 87% yield
and 2 in 75% yield, respectively. Synthetic 1 was methyl-
1
ated then converted into &R)-MTPA ester. The H NMR
spectrum of the corresponding &R)-MTPA ester showed
the existence of a single diastereomer. Thus. the optical
purity of synthetic 1 was con®rmed to be .99% e.e. The
optical purity of 2 would be same as that of 1.
The spectral data &1H , 13C NMR, IR, MS) of synthetic 1 and
2 were completely identical with those of natural 1 and 2.
The sign of the speci®c rotation of synthetic 1 and 2 was
similar to that of natural 1 and 2. From this result,
the absolute con®guration of C-60 in 1 and 2 was unambigu-
ously determined as R.
Anyway, the alkaline hydrolysis of 19 cleaved the lactone
ring but in that case decarboxylation also occurred to give
1,3-dihydroxy-5-&6-hydroxyheptyl)benzene. The IR spec-
trum of the product showed no absorption for carboxyl
group. Therefore, the two phenolic functions of 19 were
protected again by benzyl group to give 20 in 88% yield.
Under strong alkaline conditions, 20 was successfully
hydrolyzed to give carboxylic acid 21 in 65% yield.16
Hydrogenolysis of 21 gave hydroxy acid 3, the probable
precursor of 1 and 2 in 90% yield. Esteri®cation of 21
with iodoethane and potassium carbonate gave ethyl ester
22 in 87% yield, and with isobutyl bromide gave isobutyl
3. Conclusion
The asymmetric total syntheses of 1 and 2 were accom-
plished and con®rmed the absolute con®guration of stereo-
genic center in the side chain to be R. The crucial step,
demethylation could be overcame via lactonization
Scheme 3. &a) &1) Pyr2S2, Ph3P, PhH, &2) AgClO4, CH3CN, 50%; &b) BBr3/CH2Cl2, 25%, &c) BnCl, K2CO3/DMSO, 88%; &d) NaOH/H2O/DMSO, 65%;
&e) H2, Pd/EtOH, 90%; &f) EtI, K2CO3/DMF, 87%; &g) ICH2CH&CH3)2, K2CO3/DMF, 95%; &h) H2, Pd&OH)2/EtOH, 87% for 1, 75% for 2.

5380
Q. Yang et al. / Tetrahedron 57 02001) 5377±5384
corresponding to intramolecular protection. The syntheses
of 1±6 made it possible to examine the biological activity of
such b-resorcylic acid derivatives.
concentrated under reduced pressure. The residue was puri-
®ed by column chromatography &silica gel 60 g, hexane:
EtOAcˆ3:1) to give 13 &1.67 g, 91%) as a colorless oil:
[a]D25248.18&c 8.3, CHCl3); IR &®lm) 3398, 3031, 2969,
2932, 1719, 1496, 1453, 1375, 1277, 1206, 737 and
Using bioassay of potato single-node stem segment cultures,
methyl ether derivatives 4, 5 and 6 did not show potato
micro-tuber inducing activity at the same concentration
&1024 M) as that of natural 1 and 2. Dimethyl ether 4
exhibited weak activity at 1023 M. This result implied that
the phenolic group is required for the potato micro-tuber
inducing activity of b-resorcylic acid derivatives. The
bioassay of 3 and other lasiodiplodin related compounds is
in progress.
1
698 cm21; H NMR &270 MHz, CDCl3) d1.16 &3H, d, Jˆ
6.1 Hz), 1.68 &2H, m), 2.28 &1H, br s, OH), 3.71 &3H, m),
4.39 &1H, d, Jˆ11.5 Hz), 4.54 &1H, d, Jˆ11.5 Hz), 7.25 &5H,
m); 13C NMR &67.8 MHz, CDCl3): 19.3, 38.7, 60.9, 70.4,
74.6, 127.6, 127.7, 128.3, 138.4; EI±MS m/z 180 &M1,
0.27), 162 &2.3), 161 &1.4), 145 &0.25), 123 &0.61), 105
&13.4), 91 &100), 77 &44), 51 &43), 43 &90); HR-MS calcd.
for C11H16O2 &M1) m/z 180.1151, found 180.1179.
4.1.3. Methyl +2E,5R)-5-benzyloxy-2-hexenoate +14). To
a stirred solution of oxalyl chloride &1.10 ml, 12.5 mmol) in
CH2Cl2 &50 ml) was added dropwise dimethyl sulfoxide
&1.20 ml, 16.6 mmol) at 2788C under argon atomsphere.
After 5 min, to this solution was added dropwise a solution
of 13 &1.50 g, 8.33 mmol) in dry CH2Cl2 &15 ml) at 2788C.
The mixture was stirred for 30 min at the same temperature.
After the addition of triethylamine &5.80 ml, 41.5 mmol),
the temperature was gradually allowed to warm to room
temperature to give a crude aldehyde which was used for
the next Wittig reaction in one-pot. To the mixture con-
taining a crude aldehyde was added &methoxycarbonyl-
methylene)triphenylphosphorane &13.8 g, 41.5 mmol) at
room temperature and the mixture was stirred overnight.
Hexane &60 ml) was added to the reaction mixture and the
resulting insoluble materials were ®ltered off. The ®ltrate
was diluted with EtOAc &100 ml), washed with 1 M HCl
&50 ml) and brine &50 ml), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was
puri®ed by column chromatography &silica gel 100 g,
hexane:EtOAcˆ15:1) to give 14 &1.50 g, 77%) as a color-
less oil: [a]D2524.18&c 6.1, CHCl3); IR &®lm) 2972, 1724,
1658, 1436, 1322, 1272, 1174, 1091, 980, 737 and
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded with a JEOL JNM-
EX-270 spectrometer &1H: 270 MHz, 13C: 67.8 MHz). IR
spectra were measured with a Perkin Elmer System 2000
FT±IR spectrometer. Mass spectra were recorded with a
JEOL JMS-AX500 spectrometer or a JEOL JMS-SX102A
spectrometer. Melting point values were obtained with a
Yanaco micro-melting point apparatus MP-30 and are
uncorrected. Speci®c rotation values were recorded with a
JASCO DIP-370 digital polarimeter. Column chroma-
tography was carried out with Silica gel 60 &spherical,
70±140 mesh ASTM, Kanto Chemicals). Silica gel 60
F254 precoated plates were used for analytical TLC &catalog
no. 5715, Merck). &R)-&2)-1,3-Butanediol &99.4% e.e.) was
purchased from Wako Pure Chemical Industries Ltd.
4.1.1. +2S,4R)-4-Methyl-2-phenyl-1,3-dioxane +12). A
mixture of 11 &1.00 g, 11.1 mmol), benzaldehyde dimethyl
acetal &2.50 ml, 16.7 mmol) and p-toluenesulfonic acid
&94.6 mg, 0.55 mmol) in CH2Cl2 &23 ml) was re¯uxed for
3 h. After addition of NaHCO3 &46.2 mg, 0.55 mmol), the
reaction mixture was concentrated under reduced pressure.
The residue was puri®ed by column chromatography &silica
gel 60 g, hexane: EtOAcˆ20:1) to give 12 &1.93 g, 98%) as
a pale yellow oil. [a]D2512.08&c 7.1, CHCl3); IR &®lm) 2973,
2853, 1454, 1375, 1311, 1247, 1166, 1110, 1061, 1026, 968,
853, 820 and 664 cm21; 1H NMR &270 MHz, CDCl3) d 1.30
&3H, d, Jˆ6.2 Hz), 1.54 &1H, br. d, Jˆ12.5 Hz), 1.78 &1H,
dq, Jˆ12.5, 5.3 Hz), 3.98 &2H, m), 4.24 &1H, br. dd, Jˆ12.5,
5.3 Hz), 5.50 &1H, s), 7.30±7.50 &5H, m); 13C NMR
&67.8 MHz, CDCl3): 21.8, 33.0, 67.1, 73.4, 101.3, 126.1,
128.2, 128.7, 138.7; EI-MS m/z 178 &M1, 15), 177 &M12
H, 25), 105 &100), 91 &21), 77 &54), 55 &38); HR-MS calcd.
for C11H14O2 &M1) m/z 178.0994, found 178.0966.
697 cm21 1H NMR &270 MHz, CDCl3) d1.14 &3H, d,
;
Jˆ6.3 Hz), 2.35 &2H, m), 3.61 &1H, m), 3.64 &3H, s), 4.42
&1H, d, Jˆ11.7 Hz), 4.44 &1H, d, Jˆ11.7 Hz), 5.80 &1H, dt,
Jˆ15.7, 1.5 Hz), 6.90 &1H, dt, Jˆ15.7, 7.4 Hz), 7.25 &5H,
m); 13C NMR &67.8 MHz, CDCl3): 19.7, 39.3, 51.4, 70.5,
73.5, 123.0, 127.5, 127.6, 128.4, 138.5, 145.6, 166.8; EI-MS
m/z 234 &M1, 0.11), 216 &0.12), 190 &0.39), 174 &0.78), 158
&0.84), 135 &5.8), 128 &3.5), 105 &1.2), 91 &100); HR-MS
calcd. for C14H18O3 &M1) m/z 234.1256, found 234.1237.
4.1.4. +2E,5R)-5-Benzyloxy-2-hexen-1-ol +15). To a solu-
tion of 14 &1.50 g, 6.41 mmol) in dry THF &40 ml) was
added dropwise DIBAL-H &20.0 ml, 19.2 mmol, 0.96 M
solution in hexane) at 2788C under argon atmosphere.
The mixture was gradually allowed to warm to room
temperature and stirring was continued overnight. To the
reaction mixture cooled to 08C was added sat. aq. Rochelle
salt &15 ml) in three portion. After being stirred for 2 h at
room temperature, the mixture was ®ltered through a Celite
pad. The ®ltrate was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The resi-
due was puri®ed by column chromatography &silica gel
60 g, hexane:EtOAcˆ3:1) to give 15 &1.30 g, 98%) as a
colorless oil: [a]D25212.08&c 2.4, CHCl3); IR &®lm) 3389,
3031, 2970, 2866, 1670, 1496, 1454, 1375, 1342, 1206,
4.1.2. +R)-3-Benzyloxy-butan-1-ol +13). To a solution of 12
&1.82 g, 10.2 mmol) in dry CH2Cl2 &50 ml) was added drop-
wise DIBAL-H &31.9 ml, 30.6 mmol, 0.96 M solution in
hexane) at 2788C under argon atmosphere. The mixture
was gradually allowed to warm to room temperature and
stirring was continued overnight. To the reaction mixture
cooled to 08C was added sat. aq. Rochelle salt &15 ml) in
three portions. After being stirred for 1 h at room tempera-
ture, the mixture was ®ltered through a Celite pad. The
®ltrate was dried over anhydrous magnesium sulfate and
1
1090, 972, 923, 737 and 697 cm21; H NMR &270 MHz,

Q. Yang et al. / Tetrahedron 57 02001) 5377±5384
5381
CDCl3) d1.13 &3H, d, Jˆ6.1 Hz), 1.68 &1H, br. s, OH), 2.24
&2H, m), 3.50 &1H, m), 4.03 &2H, br. s), 4.44 &1H, d,
Jˆ11.8 Hz), 4.46 &1H, d, Jˆ11.8 Hz), 5.64 &2H, m), 7.27
&5H, m); 13C NMR &67.8 MHz, CDCl3): 19.5, 39.1, 63.7,
70.3, 74.4, 127.4, 127.6, 128.3, 129.0, 131.4, 138.8; EI-
MS m/z 206 &M1, 1.2), 188 &1.7), 135 &20.4), 91 &100);
HR-MS calcd. for C13H18O2 &M1) m/z 206.1307, found
206.1344.
0.45), 383 &M12H, 0.45), 366 &M1218, 0.99), 252 &14),
236 &8.9), 219 &7.1), 178 &7.6), 105 &18), 91 &35), 77 &23.5);
HR-MS calcd. for C23H28O5 &M1) m/z 384.1937, found
384.1937.
4.1.7. +R)-2,4-Dimethoxy-6-+6-hydroxyheptyl)benzoic acid
+6). A mixture of 17 &224 mg, 0.58 mmol) and palladium
hydroxide on carbon &71.6 mg) in ethanol &6.0 ml) was
stirred under hydrogen atmosphere for 3 h at room tempera-
ture. The reaction mixture was ®ltered through a Celite pad,
and the ®ltrate was concentrated under reduced pressure.
Puri®cation of the crude product with column chroma-
tography &silica gel 50 g, CHCl3: EtOAc:AcOHˆ1:1:0.01)
gave 6 &155 mg, 90%) as a colorless oil: [a]D2526.88&c 4.5,
CHCl3); IR &®lm) 3400±2600 &br.), 2935, 1699, 1604, 1463,
1423, 1324, 1203, 1162, 1114, 1047, 945, 833, 758 and
4.1.5. +2E,5R)-5-Benzyloxy-1-bromo-2-hexene +16). To a
stirred solution of 15 &1.25 g, 6.10 mmol) in CH2Cl2 &40 ml)
was added triphenylphosphine &2.40 g, 9.15 mmol) and
carbon tetrabromide &3.03 g, 9.15 mmol) at 48C. After
being stirred for 30 min at room temperature, the reaction
mixture was concentrated under reduced pressure. The
residue was puri®ed by column chromatography &silica gel
50 g, hexane:EtOAcˆ30:1) to give 16 &1.53 g, 93%) as a
colorless oil: [a]D2528.78&c 9.8, CHCl3); IR &®lm) 2969,
1
601 cm21; H NMR &270 MHz, CDCl3) d 1.16 &3H, d,
Jˆ6.1 Hz), 1.40 &6H, m), 1.60 &2H, m), 2.87 &2H, t, Jˆ
7.8 Hz), 3.57 &1H, br. s, OH), 3.77 &1H, m), 3.82 &3H, s),
3.88 &3H, s), 6.35 &1H, d, Jˆ2.2 Hz), 6.40 &1H, d, Jˆ
1
1453, 1375, 1203, 1092, 966, 772, 735 and 697 cm21; H
NMR &270 MHz, CDCl3) d1.10 &3H, d, Jˆ6.1 Hz), 2.24
&2H, m), 3.50 &1H, m), 3.85 &2H, d, Jˆ6.1 Hz), 4.44 &1H,
d, Jˆ11.7 Hz), 4.46 &1H, d, Jˆ11.7 Hz), 5.69 &2H, m), 7.26
&5H, m); 13C NMR &67.8 MHz, CDCl3): 19.5, 33.2, 39.1,
70.4, 74.2, 127.5, 127.6, 128.3, 128.6, 132.5, 138.7; FD±
MS m/z 270 &M1 for 81Br, 0.90), 268 &M1 for 79Br, 0.94);
EI-MS m/z 189 &M12Br, 3.8), 172 &1.7), 145 &2.6), 135
&16.2), 91 &100); HR-MS calcd. for C13H17O &M12Br) m/
z 189.1280, found 189.1298.
1
2.2 Hz), the H signal of COOH could not be observed
clearly due to broadening; 13C NMR &67.8 MHz, CDCl3):
23.3, 25.0, 29.2, 31.1, 34.6, 38.9, 55.4, 56.3, 68.3, 96.4,
107.6, 113.3, 146.9, 159, 162.0, 168.7; EI-MS m/z 296
&M1, 34.6), 278 &M1218, 14.8), 263 &26.5), 261 &12.2),
233 &5.2), 207 &30.2), 196 &100), 191 &41.4), 152 &54.1),
151 &20.0), 137 &14.8), 120 &14.2), 91 &9.1), 77 &8.6), 45
&16.4), 44 &15.2); HR-MS calcd. for C16H24O5 &M1) m/z
296.1624, found 296.1613.
4.1.6. +30E,60R)-2,4-Dimethoxy-6-+60-benzyloxy-hept-30-
enyl)benzoic acid +17). To a solution of diisopropylamine
&2.97 ml, 21.0 mmol) in dry THF &25 ml) was added drop-
wise n-butyllithium &14.0 ml, 21.0 mmol, 1.50 M solution
in hexane) at 2788C under argon atmosphere. The reaction
mixture was slowly warmed up to 08C and stirred for 30 min
to give a LDA solution &0.50 M). To a solution of 10 &1.12 g,
5.69 mmol) in dry THF &15 ml) was added dropwise the
above LDA solution &23.8 ml, 11.9 mmol) at 2788C under
argon atmosphere. The reaction mixture was stirred in the
range from 215 to 2108C for 3 h then cooled to 2308C. To
the resulting dianion solution, bromide 16 &1.53 g,
5.69 mmol) in 10 ml THF was added. The stirring was
continued for 12 h and the temperature was gradually
increased from 230 to 208C. The reaction mixture was
poured into saturated aq. NH4Cl solution &100 ml) and
subsequently acidi®ed by 2 M HCl to pH 2. After evapo-
ration of the organic solvent, the aq. layer was extracted
with EtOAc &100 ml£3). The combined EtOAc layers
were concentrated, and the residue was subjected to column
chromatography &silica gel 50 g, CHCl3: EtOAc:AcOHˆ
12:1:0.02) to give 17 &1.14 g, 52%) as a colorless oil:
[a]D2527.38&c 3.3, CHCl3); IR &®lm) 3400±2600 &br.),
4.1.8. Ethyl +R)-2,4-dimethoxy-6-+6-hydroxyheptyl)ben-
zoate +4). A mixture of 6 &20.0 mg, 0.07 mmol), dry K2CO3
&28.2 mg, 0.20 mmol) and iodoethane &21.8 ml, 0.27 mmol)
in dry acetone &1.0 ml) was stirred at room temperature
overnight. The reaction mixture was concentrated and
subjected to column chromatography &silica gel 5 g, hexane:
EtOAcˆ3:2) to give 4 &16.5 mg, 75%) as a colorless oil:
[a]D2526.28&c 1.5, CHCl3); IR &®lm) 3419, 2934, 1723,
1
1605, 1436, 1268, 1203, 1159 and 1097 cm21; H NMR
&270 MHz, CDCl3) d 1.15 &3H, d, Jˆ6.2 Hz), 1.32 &3H, t,
Jˆ7.1 Hz), 1.24±1.44 &7H, m), 1.58 &2H, m), 2.54 &2H, t,
Jˆ7.6 Hz), 3.70 &1H, m), 3.77 &3H, s), 3.78 &3H, s), 4.34
&2H, q, Jˆ7.3 Hz), 6.30 &2H, s); 13C NMR &67.8 MHz,
CD3COCD3): 14.5, 24.0, 26.3, 29.2, 32.1, 34.3, 40.1, 55.2,
56.4, 67.1, 67.8, 97.0, 106.9, 117.8, 143.1, 158.8, 162.2,
168.4; EI-MS m/z 324 &M1, 48.7), 279 &32), 263 &33.4), 251
&23.7), 224 &100), 211 &27.1), 191 &46), 165 &13), 151 &50.9),
91 &9), 77 &8.3), 45 &23.9), 43 &8.6); HR-MS calcd. for
C18H28O5 &M1) m/z 324.1937, found 324.1950.
4.1.9. Isobutyl +R)-2,4-dimethoxy-6-+6-hydroxyheptyl)-
benzoate +5). A mixture of 6 &10.0 mg, 0.03 mmol), dry
K2CO3 &14.0 mg, 0.10 mmol) and isobutyl iodide &3.90 ml,
0.03 mmol) in DMF &1.0 ml) was stirred at room tempera-
ture overnight. The reaction mixture was partitioned
between water &10 ml) and EtOAc &3 ml) and the aqueous
layer was further extracted with EtOAc &5 ml£2). The
combined extracts were washed with water and brine,
dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was puri®ed by column chro-
matography &silica gel 5 g, hexane:EtOAcˆ2:1) to give 5
&8.40 mg, 70%) as a colorless oil: [a]D25215.98&c 1.0,
CHCl3); IR &®lm) 3429, 2931, 2857, 1722, 1604, 1463,
2934, 1715, 1603, 1455, 1277, 1203, 1161 and 772 cm21
;
1H NMR &270 MHz, CDCl3) d 1.05 &3H, d, Jˆ6.1 Hz), 2.08
&2H, m), 2.25 &2H, m), 2.88 &2H, t, Jˆ7.6 Hz), 3.43 &1H, m),
3.74 &3H, s), 3.80 &3H, s), 4.43 &1H, d, Jˆ12.2 Hz), 4.45
&1H, d, Jˆ12.2 Hz), 5.30 &1H, dt, Jˆ15.2, 8.3 Hz), 5.45 &1H,
dt, Jˆ15.2, 8.3 Hz), 6.26 &1H, d, Jˆ2.2 Hz), 6.34 &1H, d,
Jˆ2.2 Hz), 7.25 &5H, m), the 1H signal of COOH could not
be observed clearly due to broadening; 13C NMR &67.8
MHz, CDCl3): 19.2, 34.4, 34.8, 39.5, 55.4, 56.3, 70.1,
74.5, 96.6, 108.1, 113.2, 127.1, 127.4, 127.6, 128.2, 131.9,
138.7, 146.6, 158.9, 162.1, 167.9; EI-MS m/z 384 &M1,

5382
Q. Yang et al. / Tetrahedron 57 02001) 5377±5384
1422, 1374, 1265, 1203, 1159, 1098, 1048, 946 and
71 &14.3), 57 &19.1), 55 &13.7), 43 &13.1); HR-MS calcd. for
C14H18O4 &M1) m/z 250.1205, found 250.1189.
1
831 cm21; H NMR &270 MHz, CDCl3) d 0.97 &6H, d, Jˆ
6.6 Hz), 1.15 &3H, d, Jˆ6.3 Hz), 1.32±1.41 &7H, m), 1.55
&2H, m), 2.03 &1H, m), 2.55 &2H, t, Jˆ7.6 Hz), 3.75 &1H, m),
3.77 &3H, s), 3.78 &3H, s), 4.05 &2H, d, Jˆ6.6 Hz), 6.30 &2H,
s); 13C NMR &67.8 MHz, CDCl3): 19.2, 23.5, 25.5, 27.8,
29.7, 31.2, 33.8, 39.2, 55.3, 55.9, 68.1, 71.3, 96.1, 105.7,
116.8, 142.7, 158.0, 161.2, 168.6; EI-MS m/z 352 &M1,
66.4), 279 &76), 252 &100), 251 &52), 196 &61.4), 191
&55.7), 152 &63), 151 &38.6), 99 &14.5), 91 &9.6), 85 &18),
77 &6.8), 57 &62), 43 &37.7); HR-MS calcd. for C20H32O5
&M1) m/z 352.2251, found 352.2267.
4.1.12. +R)-2,4-Dibenzyloxy-7-methyl-7,8,9,10,11,12-hexa-
hydro-6-oxa-benzocyclodecen-5-one +20). A mixture of
19 &33.0 mg, 0.13 mmol), benzyl chloride &52.0 ml,
0.45 mmol) and anhydrous potassium carbonate &82.0 mg,
0.59 mmol) in dimethyl sulfoxide &4.0 ml) was stirred at
1008C for 2 h. The reaction mixture was cooled to room
temperature, diluted with water &2 ml), and extracted three
times with CHCl3. The combined organic layers were
washed with brine, dried over anhydrous magnesium sul-
fate, and concentrated under reduced pressure. The residue
was puri®ed with column chromatography &silica gel 40 g,
hexane:EtOAc:AcOHˆ10:1:0.01) to give 20 &49.9 mg,
88%) as an oil. Crystallization from ether/hexane gave
pure 20 as a white powder: [a]D2518.68&c 1.0, CHCl3);
mp 118±1198C; IR &®lm) 2933, 1717, 1653, 1603, 1498,
4.1.10. +R)-2,4-Dimethoxy-7-methyl-7,8,9,10,11,12-hexa-
hydro-6-oxa-benzocyclodecen-5-one +18). To a solution
of 6 &92.0 mg, 0.31 mmol) in benzene &2.8 ml) was added
di-&2-pyridyl) disul®de &97.0 mg, 0.44 mmol) and triphenyl-
phosphine &115 mg, 0.44 mmol). After stirring for 1 h, dry
acetonitrile &25 ml) was added. The resulting yellow solu-
tion was added with an automatic syringe over 5 h to a
boiling solution of silver perchlorate &322 mg, 1.55 mmol)
in acetonitrile &28 ml). After heating the mixture at 1608C
for 30 min, the solvent was evaporated. The residue was
dissolved in EtOAc, and the insoluble materials were
®ltered off. The ®ltrate was concentrated, and the residue
was subjected to column chromatography &silica gel 75 g,
hexane:EtOAcˆ10:1) to give 18 &43.2 mg, 50%) as color-
less crystals: [a]D25138.78&c 2.3, CHCl3); mp 138±1408C;
IR &®lm) 2930, 1719, 1605, 1465, 1330, 1261, 1204, 1159,
1
1456, 1375, 1266, 1159, 1041, 736, 696 and 669 cm21; H
NMR &270 MHz, CDCl3) d 1.30 &3H, d, Jˆ6.2 Hz), 1.42
&3H, m), 1.53 &1H, m), 1.72 &4H, m), 2.60 &2H, m), 5.00 &2H,
s), 5.05 &2H, s), 5.25 &1H, m), 6.42 &2H, s), 7.36±7.37 &10H,
m); 13C NMR &67.8 MHz, CDCl3): 20.8, 21.9, 26.2, 29.1,
30.4, 34.3, 70.1, 70.3, 73.9, 98.5, 107.9, 118.7, 126.8, 127.5,
127.7, 128.1, 128.4, 128.6, 136.6, 136.8, 143.0, 156.4,
160.3, 168.2; EI-MS m/z 430 &M1, 23.1), 386 &1.9), 355
&3.59), 321 &3.89), 279 &2.35), 253 &1.37), 221 &3.25), 181
&14.1), 149 &11.3), 147 &2.77), 91 &100), 57 &6.38), 43 &4.17);
HR-MS calcd. for C28H30O4 &M1) m/z 430.2145, found
430.2156.
1
1095, 1046, 962, 843 and 730 cm21; H NMR &270 MHz,
CDCl3) d 1.32 &3H, d, Jˆ6.5 Hz), 1.42 &4H, m), 1.60±1.77
&4H, m), 2.54 &2H, t, Jˆ7.2 Hz), 3.79 &3H, s), 3.80 &3H, s),
5.17 &1H, m), 6.31 &2H, s); 13C NMR &67.8 MHz, CDCl3):
20.7, 21.8, 28.8, 30.7, 34.1, 34.9, 55.3, 55.8, 74.0, 96.2,
106.3, 117.2, 143.4, 152.0, 157.7, 161.3; EI-MS m/z 278
&M1, 76.1), 250 &14.8), 234 &14.6), 205 &23.6), 191 &75.2),
165 &32.1), 152 &100), 151 &28.6), 127 &12.8), 99 &15.3), 91
&17), 83 &23.2), 77 &13.1), 57 &50), 40 &51.1); HR-MS calcd.
for C16H22O4 &M1) m/z 278.1518, found 278.1489.
4.1.13. +R)-2,4-Dibenzyloxy-6-+6-hydroxyheptyl)benzoic
acid +21). A solution of 20 &15.2 mg, 0.04 mmol) in 40%
sodium hydroxide &1.0 ml) and dimethyl sulfoxide &3.0 ml)
was heated at re¯ux overnight. The cooled solution was
acidi®ed with concentrated HCl. After the addition of
water &3 ml), the mixture was extracted with EtOAc
&10 ml£3). The combined extracts were washed with
water, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. Puri®cation of the
crude product with preparative TLC &hexane:EtOAc:
AcOHˆ15:10:0.1, double development) provided 21 as a
white solid &10.3 mg, 65%). [a]D2518.78&c 1.2, CHCl3);
mp 130±1318;C IR &®lm) 3421 &br.), 2927, 1699, 1602,
4.1.11. +R)-2,4-Dihydroxy-7-methyl-7,8,9,10,11,12-hexa-
hydro-6-oxa-benzocyclodecen-5-one +19). To a solution
of 18 &156 mg, 0.56 mmol) in methylene chloride &10 ml)
under argon atmosphere at 08C, was added a cooled 1.26 M
solution of BBr3 in methylene chloride &7.40 ml,
8.40 mmol). The reaction mixture was stirred for 30 min
between 08C and room temperature. After addition of satu-
rated aqueous NaHCO3 &10 ml), the mixture was acidi®ed
with 3 M HCl, and then extracted with CHCl3. The
combined extracts were dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was
puri®ed with column chromatography &silica gel 100 g,
hexane:EtOAc:AcOHˆ7:1:0.02) to give 19 &35.0 mg,
25%) as a white powder: [a]D25152.08&c 1.0, CHCl3); mp
94±968C; IR &®lm) 3357, 2938, 1653, 1457, 1362, 1312,
1
1541, 1457, 1376, 1312, 1162, 1028, and 802 cm21; H
NMR &270 MHz, CDCl3) d 1.15 &3H, d, Jˆ6.0 Hz), 1.24±
1.41 &6H, m), 1.57±1.62 &2H, m), 2.81 &2H, t, Jˆ7.2 Hz),
3.79 &1H, m), 4.20 &1H, br. s, OH), 5.02 &2H, s), 5.11 &2H, s),
6.48 &2H, br. s), 7.30±7.67 &10H, m), the 1H signal of COOH
could not be observed clearly due to broadening; 13C NMR
&67.8 MHz, CDCl3): 23.5, 25.1, 29.3, 31.1, 34.8, 38.9, 68.2,
70.2, 71.6, 98.7, 109.5, 113.2, 127.4, 127.5, 128.3, 128.5,
128.7, 128.8, 135.7, 136.5, 147.8, 158.3, 161.1, 167.5; EI-
MS m/z 448 &M1, 3.7), 430 &M1218, 1.05), 415 &1.52), 404
&0.93), 357 &0.77), 339 &21.03), 321 &6.88), 258 &4.09), 251
&1.88), 181 &6.79), 180 &3.02), 149 &1.90), 91 &100), 44
&2.91); HR-MS calcd. for C28H32O5 &M1) m/z 448.2251,
found 448.2296.
;
1261, 1156, 1005, 772 and 669 cm21 1H NMR
&270 MHz, CDCl3) d 1.36 &3H, d, Jˆ6.2 Hz), 1.43 &3H,
m), 1.64±1.84 &5H, m), 2.30 &1H, m), 3.30 &1H, t, Jˆ
9.9 Hz), 5.07 &1H, s, OH), 5.28 &1H, m), 6.21 &1H, d, Jˆ
2.3 Hz), 6.24 &1H, d, Jˆ2.3 Hz), 11.5 &1H, s, OH); 13C NMR
&67.8 MHz, CDCl3): 19.4, 19.8, 28.0, 29.0, 32.7, 34.8, 71.7,
101.3, 105.8, 110.8, 149.5, 160.1, 165.2, 170.5; EI-MS m/z
250 &M1, 26.4), 232 &7.0), 203 &5.1), 182 &10.8), 168 &59.4),
4.1.14. +R)-2,4-Dihydroxy-6-+6-hydroxyheptyl)benzoic
acid +3). A mixture of 21 &10.0 mg, 0.02 mmol) and 5%
palladium on carbon &11.5 mg) in ethanol &2.0 ml) was
vigorously stirred for 4 h at room temperature under

Q. Yang et al. / Tetrahedron 57 02001) 5377±5384
5383
hydrogen atmosphere. The catalyst was ®ltered through a
Celite pad and the ®ltrate was concentrated under reduced
pressure. The residue was puri®ed with column chroma-
tography &silica gel 5 g, hexane:EtOAc:AcOHˆ1:1:0.02)
to give 3 &5.10 mg, 90%) as a powder. [a]D252103.68&c
1.0, MeOH); mp 98±1018C; IR &®lm) 3400±2600 &br.),
CDCl3): 19.2, 23.5, 25.5, 27.8, 29.4, 31.1, 33.7, 39.2,
68.0, 70.1, 70.4, 71.3, 98.4, 107.3, 117.6, 127.1, 127.5,
127.8, 128.1, 128.4, 128.6, 136.6, 136.7, 142.7, 157.0,
160.3, 168.5; EI-MS m/z 504 &M1, 7.44), 431 &4.41), 413
&4.71), 339 &26.88), 321 &5.90), 181 &12.02), 180 &6.69), 91
&100); HR-MS calcd. for C32H40O5 &M1) m/z 504.2877,
found 504.2898.
2925, 2854, 1732, 1601, 1464, 1260, 1091 and 802 cm21
;
1H NMR &270 MHz, CD3OD) d 1.04 &3H, d, Jˆ6.1 Hz),
1.20±1.40 &6H, m), 1.40±1.60 &2H, m), 2.87 &2H, t, Jˆ
7.2 Hz), 3.55 &1H, m), 6.03 &2H, d, Jˆ6.1 Hz); 13C NMR
&67.8 MHz, CD3OD): 23.4, 26.8, 31.0, 33.1, 37.0, 40.2,
68.6, 101.4, 110.9 129.8, 133.8, 149.8, 151.5, 161.9; FD±
MS m/z 269 &M11 H, 28.1), 291 &M1 1 Na, 92.6); FAB m/z
267 &M12H), 291 &M11Na), 313 &M112Na); FAB±HR-
MS calcd. for C14H19O5 &M12H) m/z 267.1233, found
267.1223.
4.1.17. Ethyl +R)-2,4-dihydroxy-6-+6-hydroxyheptyl)-
benzoate +1). A mixture of 22 &10.0 mg, 0.02 mmol) and
palladium hydroxide on carbon &2.60 mg) in ethanol
&2.0 ml) was vigorous stirred for 3 h at room temperature
under hydrogen atmosphere. The catalyst was ®ltered
through a Celite pad and the ®ltrate was concentrated
under reduced pressure. The residue was puri®ed with
column chromatography &silica gel 5 g, MeOH:CHCl3ˆ
25
4:96) to give 1 &5.50 mg, 87%) as a colorless oil. [a]D
210.38&c 1.6, MeOH), lit.4 [a]D2529.18&c 0.9, MeOH); EI-
MS m/z 296 &M1, 47.6), 249 &14.2), 232 &32.2), 203 &9.9),
196 &100), 168 &52.6), 150 &80.7), 123 &18.6), 121 &11.9), 81
&5.9), 69 &14.4), 45 &14.8); HR-MS calcd. for C16H24O5 &M1)
m/z 296.1624, found 296.1583. Other spectral data were
completely identical with those of natural 1.
4.1.15. Ethyl +R)-2,4-dibenzyloxy-6-+6-hydroxyheptyl)-
benzoate +22). A mixture of 21 &14.8 mg, 0.03 mmol), dry
K2CO3 &13.8 mg, 0.10 mmol) and iodoethane &2.70 ml,
0.03 mmol) in DMF &1.0 ml) was stirred at room tempera-
ture overnight. The reaction mixture was partitioned
between water &10 ml) and EtOAc &3 ml), and the aqueous
layer was further extracted with EtOAc &5 ml£3). The
combined organic layers were washed with water and
brine, dried over anhydrous magnesium sulfate, and concen-
trated under reduced pressure. The residue was subjected to
column chromatography &silica gel 5 g, hexane:EtOAcˆ
2:1) to give 22 &13.8 mg, 87%) as a colorless oil:
[a]D25115.08&c 2.3, CHCl3); IR &®lm) 3418, 2930, 2858,
1722, 1603, 1498, 1455, 1263, 1161, 1096, 1028, 804, 736
4.1.18. Isobutyl +R)-2,4-dihydroxy-6-+6-hydroxyheptyl)-
benzoate +2). A mixture of 23 &14.0 mg, 0.02 mmol) and
palladium hydroxide on carbon &3.40 mg) in ethanol
&3.0 ml) was vigorous stirred for 5 h at room temperature
under hydrogen atmosphere. The catalyst was ®ltered
through a Celite pad and the ®ltrate was concentrated
under reduced pressure. The residue was puri®ed with
column chromatography &silica gel 5 g, MeOH:CHCl3ˆ
4:96) to give 2 &6.81 mg, 75%) as a colorless oil.
[a]D25222.08&c 1.0, CHCl3), lit.4 [a]D25215.58&c 0.6,
CHCl3); EI-MS m/z 324 &M1, 35.7), 250 &13.9), 224
&50.7), 211 &28.2), 177 &10.0), 168 &100), 150 &52.3), 124
&11.4), 69 &8.8), 57 &14.9), 41 &14.2); HR-MS calcd. for
C18H28O5 &M1) m/z 324.1937, found 324.1914. Other spec-
tral data were completely identical with those of natural 2.
1
and 697 cm21; H NMR &270 MHz, CDCl3) d 1.15 &3H, d,
Jˆ6.1 Hz), 1.27 &3H, t, Jˆ7.2 Hz), 1.25±1.40 &5H, m),
1.52±1.58 &4H, m), 2.60 &2H, t, Jˆ7.4 Hz), 3.76 &1H, m),
4.30 &2H, q, Jˆ7.1 Hz), 5.01 &4H, s), 6.41 &2H, d, Jˆ
1.8 Hz), 7.27±7.37 &10H, m); 13C NMR &67.8 MHz,
CDCl3): 14.2, 23.5, 25.5, 29.4, 31.0, 33.7, 39.2, 61.0,
68.1, 70.1, 70.4, 98.4, 107.3, 117.4, 127.1, 127.5, 127.8,
128.1, 128.4, 128.6, 136.6, 136.7, 142.8, 157.0, 160.3,
168.3; EI-MS m/z 476 &M1, 7.40), 431 &2.79), 385 &4.77),
339 &17.67), 321 &6.11), 286 &2.75), 181 &13.41), 180 &6.94),
91 &100); HR-MS calcd. for C30H36O5 &M1) m/z 476.2564,
found 476.2519.
Acknowledgements
We are grateful to Mr K. Watanabe and Dr E. Fukushi in our
faculty for measuring the MS spectra.
4.1.16. Isobutyl +R)-2,4-dibenzyloxy-6-+6-hydroxyheptyl)-
benzoate +23). A mixture of 21 &14.8 mg, 0.03 mmol), dry
K2CO3 &13.8 mg, 0.10 mmol) and isobutyl iodide &3.80 ml,
0.03 mmol) in DMF &1.5 ml) was stirred at room tempera-
ture overnight. The reaction mixture was partitioned
between water &10 ml) and EtOAc &3 ml) and the aqueous
layer was further extracted with EtOAc &5 ml£3). The
combined organic layers were washed with water and
brine, dried over anhydrous magnesium sulfate, and concen-
trated under reduced pressure. The residue was subjected to
column chromatography &silica gel 5 g, hexane:EtOAcˆ
3:1) to give 23 &15.8 mg, 95%) as a colorless oil:
[a]D25110.48&c 2.0, CHCl3); IR &®lm) 3384, 2928, 1723,
1603, 1455, 1376, 1262, 1160, 1038, 803, 736 and
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