First syntheses of 1,13- and 1,15-dihydroxyherbertenes, and herbertenolide by applying intramolecular Heck reaction for the construction of adjacent quaternary centers

Article abstract of DOI:10.1016/S0040-4020(01)00932-2

1,13- and 1,15-Dihydroxyherbertenes and hebertenolide, typical herbertane-type sesquiterpenes with an oxidized methyl group, were synthesized by using intramolecular Heck reaction for the construction of adjacent quaternary centers.

Full text of DOI:10.1016/S0040-4020(01)00932-2

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 9299±9307
First syntheses of 1,13- and 1,15-dihydroxyherbertenes,
and herbertenolide by applying intramolecular Heck reaction
for the construction of adjacent quaternary centers
Yoshiyasu Fukuyama,p Hiroaki Yuasa, Yasutoshi Tonoi, Kenichi Harada, Mitsumasa Wada,
Yoshinori Asakawa and Toshinori Hashimoto
Faculty of Pharmaceutical Sciences, Institute of Pharmacognosy, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 22 August 2001;accepted 21 September 2001
AbstractÐ1,13- and 1,15-Dihydroxyherbertenes and hebertenolide, typical herbertane-type sesquiterpenes with an oxidized methyl group,
were synthesized by using intramolecular Heck reaction for the construction of adjacent quaternary centers. q 2001 Elsevier Science Ltd.
All rights reserved.
1.Introduction
typical number of herbertenols in which one of three methyl
groups on a cyclopentane ring is oxidized.
Cuparane and herbertane are sesquiterpenes which differ in
the substitution pattern of the aromatic ring. Both series of
compounds contain two contiguous quaternary carbon
centers on a cyclopentane ring. A number of herbertane-
type sesquiterpenes have been found in a wide variety of
liverworts1 since 42)-herbertene was ®rst isolated from the
liverwort Herberta adunca2 4Fig. 1).
Our basic plan for the preparation of 3 and 5 and 6 involves
two-steps procedure consisting of intramolcular Heck
reaction used for the construction of the quaternary carbon
centers and interconversion of the ester group to the corre-
sponding methyl and/or hydroxyl groups 4Scheme 1).
2.Results and discussion
Recently, we reported the isolation of 1,13-, 1,14- and 1,15-
dihydroxyherbertenes 46, 2 and 3) and hebertenolide 45).3
The herbetanes such as herbertenediol 41)2 and its dimer
mastigophorenes A and B4 exhibit signi®cant biological
activity, e.g. antifungal,5 antilipidoxidation6 and neuro-
trophic activities.7 The interesting biological properties of
the herbertanes and their unique carbon framework have
stimulated extensive synthetic efforts from many research
groups.8 In recent years we have developed an enantio-
selective general approach to the synthesis of herbertane-
type sesquiterpenes. This approach, based on intramolecular
Heck reaction used for the construction of quaternary
carbon centers followed by elaboration of the geminal
methyl groups, has been successfully used for the prepa-
ration of 42)-herbertenediol 41),6 42)-1,14-dihydroxy-
2.1. Synthesis of 1,15-dihydroxyherbertene &3) and
herbertenolide &5)
The C-15 methyl group among three methyls attached on
the cyclopentane ring is oxidized in herbertenol 3 and
herbertene 42),9 mastigophorenes
A
and B,9 and
42)-laurequinone.10 In connection with this related project,
we describe the ®rst and ef®cient syntheses of 1,13- and
1,15-dihydroxyherbetene 46 and 3) and herbertenolide 45),
Keywords: 1,13-dihydroxyherbertene;1,15-dihydroxyherbertene;herberte-
nolide;herbertane-type sesquiterpene;Heck reaction;palladium.
p
Corresponding author. Tel.: 181-88-622-9611;fax: 181-88-655-3051;
e-mail: fukuyama@ph.bunri-u.ac.jp
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00932-2

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Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
Scheme 1.
herbertenolide 5. We have envisioned that an allyl group is
suitable for later conversion to a hydroxymethyl group after
two-steps process involving intramolecular Heck reaction
and conversion of the ester group to the C-14 methyl group.
employed under the established condititon6,9 such as
10 mol% Pd4OAc)2, 20 mol% 4o-tol)3P and n-Bu3N in
DMF, followed by hydrogenation, giving rise to a d-lactone
17 in 95% yield. Reduction of 17 with LiAlH4 gave a diol,
the phenolic hydroxyl group of which was selectively
methylated under the standard basic conditions to afford
18 in 79% yield. Swern oxidation of the primary alcohol
in 18 yielded the aldehyde 19, which was subjected to
Huang±Minlon reduction giving rise to 20 in 58% yield
over two steps. Subsequent acid treatment of 20 afforded
the methyl ketone 21. The remaining elaboration seems to
be simple conversion of the methyl ketone to a primary
alcohol by Baeyer±Villiger oxidation. Baeyer±Villiger
oxidation of 21, however, under standard mCPBA and
The readily prepared 12 was converted to 13 according to
the previously reported procedure.6,9 The methyl ester in 13
was hydrolyzed to the carboxylic acid, which was coupled
with 2-iodo-p-cresol under DCC conditons giving rise to an
ester 7 in 69% yield. The allyl group in 7 must be trans-
formed to some unreactive functional group before Heck
reaction. Thus, Wacker reaction11 of 7 afforded a methyl
ketone, which was protected as an ethylene acetal to give
16 in 56% yield. Intramolecular Heck reaction of 16 was
Scheme 2. Reagents, conditions and yields: 4a) MeMgI, ether, 4b) P2O5, benzene, 69% over two steps, 4c) NaOH, MeOH±H2O 41:1), 92%, 4d) 2-iodo-p-cresol,
DCC, DMAP, 65%, 4e) PdCl2, CuI, O2, DMF±H2O 47:1), 56%, 4f) ethylene glycol, p-TsOH, benzene, 100%, 4g) 10 mol% Pd4OAc)2, 20 mol% tris-
42-methylphenyl)phosphine, n-Bu3N, DMF, 1208C, 4h) 10% Pd/C, H2, EtOH, 95% over two steps. 4i) LiAlH4, THF, 08C, 4j) MeI, K2CO3, acetone, 79% over
two steps, 4k) DMSO, 4COCl)2, Et3N, CH2Cl2, 2788C and then 08C, 96%, 4l) NH2NH2´H2O, NaOH, diethylene glycol, 1508C, 59%, 4m) 2.5 M HCl, THF, 100%.

Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
9301
Scheme 3. Reagents, conditions and yields: 4a) 60% NaH, PhCH2OCH2Cl, toluene, 49%, 4b) MeMgI, ether, 4c) P2O5, benzene, and then NaOH, MeOH±H2O
41:1), 66% over three steps, 4d) 2-iodo-p-cresol, DCC, DMAP, CH2Cl2, 87%, 4e) 10 mol% Pd4OAc)2, 20 mol% dppf, 2 equiv. n-Bu3N, DMF, 1208C, and then
10% Pd/C, H2, EtOH, 71%, 4f) CH3OCH2Cl, Et3N, CH2Cl2, 97%, 4g) LiAlH4, THF, 08C, 4h) MeI, K2CO3, acetone, 89% over two steps, 4i) DMSO, 4COCl)2,
Et3N, CH2Cl2, 2788C and then 08C, 74%, 4j) NH2NH2´H2O, NaOH, diethylene glycol, 1508C, 76%, 4k) 40% HBr, MeOH, 87%, 4l) Jones reagent, acetone,
64%, 4m) BBr3, CH2Cl2, rt, 46%, 4n) LiAlH4, THF, 08C, 83%.
oxone12 conditions gave no acetate 22, but totally the
recovery presumably due to the hindered neopentyl position
of the corresponding methylene 4Scheme 2).
converted the aldehyde function to the corresponding
methyl group giving rise to 29 in 76% yield. Deprotection
of the MOM group with 45% HBr, followed by Jones oxi-
dation, afforded the carboxylic acid 31. Finally, treatment of
31 with BBr3 gave herbertenolide 45) in 46% yield, whereas
5 was reduced with LiAlH4 to give rise to 1,15-dihydroxy-
herbetene 43). The synthesized compounds are identical in
We have decided that the hydoxymethyl group should be
introduced before intramolecular Heck reaction. Alkylation
of methyl 2-cyclopentanonecarboxylate with allyl bromide
using NaH as base in THF as solvent gave the C-alkylated
product 12 quantitatively, whereas alkylation using benzyl-
oxymethyl chloride as an electrophile under the same basic
conditions gave exclusively an O-alkylated product.13 After
several attempts, toluene was found to be only solvent for
effecting the C-alkylation. Thus, the requisite 23a 449%)
was obtained along with the O-alkylated product 23b
441%) from the reaction of methyl 2-cyclopentanonecarb-
oxylate with NaH in toluene followed by adding benzyl-
oxymethyl chloride. With 23a in hand, similar procedures
used for 12 were applied to the synthesis of 3. At ®rst, 23a
was converted to the carboxylic acid 24 in 66% yield over
three steps, and then 24 was coupled with 2-iodo-p-cresol by
DCC method to give 7a in 78% yield. Intramolecular Heck
reaction of 7a, followed by hydrogenation, smoothly
proceeded to afford the lactone 25 in 71% yield. The
liberated hydroxyl group was protected again as a MOM
ether and then the LiAlH4 reduction of 26 gave the diol,
selective methylation of which afforded 27 in 89% yield.
Swern oxidation of the primary alcohol in 27 yield the
aldehyde 28, and then subsequent Huang±Minlon reduction
1
the H and 13C NMR spectra with those of natural ones
4Scheme 3).
2.2. Synthesis of 1,13-dihydroxyherbertene &6)
Our intramolecuar Heck reactions were successfully
employed through an ester linkage for the construction of
the adjacent quaternary carbon centers composed by a
benzene ring and three methyl groups. The methyl group
attached on the C-7 quaternary center with a benzene
moiety, however, had to be converted from the ester linkage
by three-steps elaboration. On the other hand, synthesis of
1,13-hydroxyherbetrene 46) only requires the introduction
of one of the dimethyl groups on the C-11 position. Thus,
2-methylcyclopentenecarboxylic acid14 was selected as a
partner of intramolecular Heck reaction 4Scheme 4).
The ester 9 prepared from 2-methylcyclopentenecarboxylic
acid and 2-iodo-p-cresol by Yamaguchi method15 was
subjected to Heck reaction under the same conditions
410 mol% Pd4OAc)2, 20 mol% 4o-tol)3P and n-Bu3N in

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Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
I
O
b
c
a
CO2H
O
O
O
O
O
9
10
11
HO
e
d
O
O
OH
32
6
Scheme 4. Reagents, conditions and yields: 4a) 2,4,6-tri-ClBzCl, Et3N, and then 2-iodo-p-cresol, 75%, 4b) 10 mol% Pd4OAc)2, 20 mol% tri-o-tolylphosphine,
DMF, 1208C, 95%, 4c) CH2I2, Zn±Cu, ether, 92%, 4d) PtO2, NaOAc, H2, AcOH, 32%, 4e) LiAlH4, THF, rt, 100%.
DMF). The cyclization reaction was smoothly preceded in a
5-exo-trig manner16 to give rise to a spiro-lactone 10 in 95%
yield. In the next stage, a cyclpropane ring can replace a
requisite methyl group. Thus, a cyclopropane 11 was
obtained in 92% yield by applying Simmons±Smith
reaction17 to 10. Subsequent hydrogenation of the cyclo-
propane ring was troublesome. After several attempts, the
cyclopropane ring of 11 was cleaved over PtO2 in AcOH
containing NaOAc giving rise to the dimethyl lactone 32 in
32% yield. Finally, reduction of 32 with LiAlH4 afforded
1,13-dihydroxyherbertene 46), quantitatively. Its NMR
spectra were superimposed with those of natural ones.
To a suspension of 60% sodium hydride 48.5 g, 0.21 mol)
in THF 4130 mL) was added a solution of methyl 2-cyclo-
pentanonecarboxylate 425 g, 0.18 mol) in THF at 08C, and
the mixture was stirred for 3 h. To this solution was added
allyl bromide 415 mL, 0.18 mol) and then the mixture was
stirred at room temperature for 3 h. The reaction mixture
was quenched by adding water, extracted with ether, washed
with aqueous NaHCO3 solution, water, saturated NaCl
solution, and dried over MgSO4. Evaporation of the solvent
gave a crude mixture 443 g), which was chromatographed
on silica gel 4hexane/EtOAcˆ4:1) to give 12 431 g, 97%) as
1
an oil: IR 4®lm) 1745, 1725 cm21; H NMR 4200 MHz,
CDCl3) d 1.89±2.15 42H, m), 2.19±2.52 45H, m), 2.67
41H, m), 3.71 43H, s), 5.06±5.15 42H, m), 5.68 41H, m);
HREIMS m/z 182.0918 [M1] 4calcd 182.0942 for
C10H14O3).
In conclusion, we have succeeded in applying an intra-
molecular Heck reaction through an ester linkage to syn-
theses of all herbertenols, which have one oxidized methyl
group among three methyl groups vicinally placed on the
cyclopentane ring. Our approach to the contraction of the
adjacent quaternary centers using the intramolecular Heck
reaction provides a suitable way to synthesize a variety of
herbertane-type and cuparane-type sesquiterpenes.
3.2.2. Methyl 1-allyl-2-methyl-2-cyclopentenecarboxyl-
ate &13). To the stirred MeMgI ether solution 4100 mL,
84 mmol) was added a solution of 12 413.6 g, 75 mmol) in
ether 4235 mL) at room temperature and the mixture was
stirred for 10 h. The mixture quenched by the addition of
saturated NH4Cl solution was extracted with ether, washed
with saturated NaHCO3 solution, water and saturated NaCl
solution, dried over MgSO4. Evaporation of ether afforded a
residue 414 g). To a solution of the residue in benzene
4250 mL) was added phosphorus pentaoxide 415 g). The
mixture was stirred at room temperature for 12 h. Water
was added and the mixture was extracted with ether. The
organic layer was washed with saturated NaCl solution, and
dried over MgSO4. Evaporation of solvent gave the residue
49.7 g), which was chromatographed on silica gel 4hexane/
EtOAcˆ4:1) to give 13 49.3 g, 69%) as an oil: IR 4®lm)
3.Experimental
3.1. General
IR spectra were recorded on JASCO 5300 FT IR, Shimadzu
1
UV 300 and JASCO J-500 spectrometer. H and 13C NMR
spectra were taken on a Varian unity-200 or a JEOL GX-400
spectrometer. Chemical shifts are expressed in d units 4ppm
down®eld from Me4Si). Mass spectra 4MS) were recorded
on a JEOL AX-500. Air- and moisture-sensitive reagents
were transferred via syringe or cannula, and reactions
involving these materials were carried out in oven-dried
¯asks under a positive pressure of argon. Silica gel
4Wako, C-300) was used for column chromatography.
Analytical thin-layer chromatography 4TLC) was per-
formed with Merck precoated TLC plates 4Kieselgel 60
F254, 0.25 mm), and spots were visualized with ultraviolet
light, iodide, and 40% CeSO4±H2SO4.
1
2951, 1738, 1641 cm21; H NMR 4200 MHz, CDCl3) d
1.70 43H, brs), 1.87 41H, m), 2.30 44H, m), 2.62 42H, m),
3.68 43H, s), 5.07 42H, m), 5.63 42H, m); 13C NMR
450 MHz, CDCl3) d 13.1, 30.2, 32.9, 39.4, 51.4, 60.5,
117.5, 128.5, 134.3, 140.2, 175.5;EIMS m/z 4rel. int.) 180
[M1] 413), 139 4100), 107 454), 79 476), 44 484);HREIMS
m/z 180.1150 [M1] 4calcd 180.1162 for C11H16O2).
3.2.3. 1-Allyl-2-methyl-2-cyclopentenecarboxylate &14).
To a solution of 13 42.56 g, 14.2 mmol) in a mixture of
methanol±water 41:1, 120 mL) was added NaOH 42.56 g,
64 mmol), and the mixture was stirred for 12 h. This
solution was acidi®ed with 2 M HCl, and then extracted
3.2. Synthesis of 1,15-dihydroxyherbertene and
herbertenolide
3.2.1. Methyl 1-allyl-2-cyclopentanonecarboxylate &12).

Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
9303
with ether. The organic layer was extracted with saturated
NaHCO3 solution. The resulting aqueous layer was acidi®ed
with 2 M HCl, and then extracted with ether. The extract
was washed with water and saturated NaCl solution, dried
over MgSO4, concentrated, and puri®ed by column chroma-
tography 4hexane/EtOAcˆ4:1) to give 14 42.3 g, 92%) as an
oil: IR 4®lm) 2932, 1703 cm21; 1H NMR 4200 MHz, CDCl3)
d 1.73 43H, s), 1.89 41H, m), 2.26 44H, m), 2.60 41H, m),
5.09 42H, m), 5.65 42H, m);HREIMS m/z 166.0994 [M1]
4calcd 166.0994 for C10H14O2).
[M1] 411), 320 421), 289 418), 87 4100);HREIMS m/z
442.0639 [M1] 4calcd for 442.0641 for C19H23O4I).
3.2.7. Heck reaction of 16. To a solution of 16 4100 mg,
0.23 mmol) in DMF 410 mL) was added palladium acetate
45.2 mg, 0.023 mmol), tris42-methylphenyl)phosphine 414
mg, 0.046 mmol) and tri-n-butylamine 40.13 mL, 0.46
mmol). The mixture was heated at 1208C for 18 h. The
cooled mixture was diluted with water and washed with
water and saturated NaCl solution, dried over MgSO4.
Removal of solvent afforded the residue, which was
chromatographed on silica gel 4hexane/EtOAcˆ3:1) to
afford a g-lactone 468 mg), which was hydrogenated in
EtOH 45 mL) containing palladium carbon 4Pd/C, Pd:
10%, 5 mg) under an atmosphere of hydrogen for 10 h.
The reaction mixture was ®ltered, concentrated to afford
17 469 mg, 95%) as an oil: IR 4®lm) 2955, 1755,
3.2.4. 2-Iodo-4-methylphenyl 1-allyl-2-methyl-2-cyclo-
pentenecarboxylate &7). To a solution of 14 43.3 g,
20 mmol) in benzene 4230 mL) was added DCC 48.3 g,
40.2 mmol) and DMAP 42.5 g, 20.1 mmol). To this stirring
mixture was added 2-iodo-p-cresol 47.07 g, 30.2 mmol).
The mixture was stirred at room temperature for 12 h.
After being ®ltered, the ®ltrate was washed with water,
Cu4NO3)2 solution, NaHCO3 solution and saturated NaCl
solution and dried over MgSO4. Evaporation of solvent
gave a crude product 411.6 g), which was chromatographed
on silica gel 4hexane/methylene chlorideˆ1:1) to afford 7
44.97 g, 65%) as an oil: IR 4®lm) 2924, 1750, 1481 cm21; 1H
NMR 4200 MHz, CDCl3) d 1.84 43H, s), 2.01 41H, m), 2.30
43H, s), 2.64 45H, m), 5.15 42H, m), 5.77 42H, m), 6.89 41H,
d, Jˆ8.3 Hz), 7.12 41H, dd, Jˆ8.3, 1.6 Hz), and 7.63 41H, d,
Jˆ1.6 Hz); 13C NMR 450 MHz, CDCl3) d 13.6, 20.1, 30.5,
33.1, 39.4, 60.6, 89.7, 118.0, 122.2, 129.82, 129.88, 134.0,
137.1, 139.4, 139.6, 149.0, 173.1;EIMS m/z 4rel. int.) 382
[M1] 42), 121 4100), 93 435);HREIMS m/z 382.0399 [M1]
4calcd for 382.0430 for C17H19O2I).
1
1494 cm21; H NMR 4200 MHz, CDCl3) d 1.26 43H, s),
1.34 43H, s), 1.63±1.89 45H, m), 2.34 43H, s), 3.00 41H,
m), 3.58 41H, m), 3.71±3.92 43H, m), 6.93 41H, d, Jˆ
8.1 Hz), 7.03 41H, dd, Jˆ8.1, 1.3 Hz), 7.09 41H, d, Jˆ
1.3 Hz);EIMS m/z 4rel. int.) 316 [M1] 416), 87 4100), 83
442);HREIMS m/z 316.1617 [M1] 4calcd for 316.1674 for
C19H24O4).
3.2.8. 1-Hydroxylmethyl-1-&2,2-ethylenedioxypropyl)-2-
methyl-2-&2-methoxy-5-methyl phenyl)cyclopentane &18).
To a solution of 17 4107 mg, 0.34 mmol) in THF 43 mL) was
added LiAlH4 460 mg, 1.6 mmol) at 08C and the mixture
was stirred for 3 h at room temperature. The reaction
mixture was treated with water, and then was extracted
with ether. The ether layer was washed with saturated
NaCl solution, dried over MgSO4. Removal of solvent
gave a diol 488 mg, 81%) as a colorless oil, which was
dissolved in acetone 410 mL). To this solution was added
K2CO3 460 mg) and iodomethane 40.20 mL) and the reac-
tion mixture was re¯uxed for 11 h. The reaction mixture
was diluted with water and extracted with ether. The result-
ing organic layer was washed with saturated NaCl solution,
dried over MgSO4. Evaporation of organic solvent gave the
residue, which was chromatographed on silica gel 4hexane/
EtOAcˆ6:1) to afford 18 4117 mg, 98%) as an oil: IR 4®lm)
3505, 2955, 1499 cm21; 1H NMR 4200 MHz, CDCl3) d 1.38
43H, s), 1.43 43H, s), 1.53±2.04 46H, m), 3.78 43H, s), 3.95
44H, s), 6.77 41H, d, Jˆ8.2 Hz), 6.98 41H, dd, Jˆ8.2,
1.7 Hz), 7.13 41H, d, Jˆ1.7 Hz);EIMS m/z 4rel. int.) 334
[M1] 48), 149 4100);HREIMS m/z 334.2130 [M1] 4Calcd
for 334.2144 for C20H30O4).
3.2.5. Wacker oxidation of 7. A mixture of 7 46 g, 15.7
mmol), palladium4II) chloride 40.85 g, 4.7 mmol), and CuCl
41.57 g, 15.7 mmol) in 100 mL of DMF and water 47:1) was
stirred at room temperature under oxygen atmosphere for
19 h. The reaction mixture was diluted with 2 M HCl and
extracted with ether. The resulting organic solution was
washed with water and saturated NaCl solution, and dried
over MgSO4. The solvent was removed and the residue was
chromatographed on silica gel 4hexane/EtOAcˆ4:1) to
afford 15 43.5 g, 56%) as an oil: IR 4®lm) 2922, 1748,
1715, 1483 cm21 1H NMR 4200 MHz, CDCl3) d 1.80
;
43H, s), 2.19 43H, s), 2.29 43H, s), 2.57 41H, d, Jˆ
17.9 Hz), 3.45 41H, Jˆ17.9 Hz), 5.67 41H, m), 7.02 41H,
d, Jˆ8.4 Hz), 7.12 41H, dd, Jˆ8.4, 1.8 Hz), 7.60 41H, d,
Jˆ1.8 Hz);EIMS m/z 4rel. int.) 398 [M1] 450), 234 458),
137 4100);HREIMS m/z 398.0374 [M1] 4calcd for 398.0379
for C17H19O3I).
3.2.9. 1-Formyl-1-&2,2-ethylenedioxypropyl)-2-methyl-2-
&2-methoxy-5-methylphenyl) cyclopentane &19). To a
solution of dimethyl sulfoxide 40.08 mL, 0.99 mmol) in
CH2Cl2 41 mL) was added oxalyl chloride 40.06 mL,
0.66 mmol) at 2788C, and stirring was continued for
10 min. A solution of 18 4101 mg, 0.3 mmol) in CH2Cl2
42 mL) was added to this solution, and the reaction mixture
was stirred for 1 h at the same temperature and then treated
with Et3N 40.09 mL, 0.65 mmol). After further stirring for
30 min at 08C, the reaction mixture was treated with satu-
rated NH4Cl solution and extracted with ether. The organic
layer was washed with water and saturated NaCl solution,
dried over MgSO4. The solvent was removed in vacuo and
the residue was chromatographed on silica gel 4hexane/
3.2.6. Ethylene acetalization of 15. A solution of 15
4175 mg, 0.44 mmol) in benzene 47 mL) containing
p-toluenesulfonic acid 49.6 mg) was re¯uxed under removal
of the formed water by a Dean±Stark apparatus for 20 h.
The cooled solution was diluted with ether and washed with
saturated NaHCO3 and NaCl solutions, dried over MgSO4.
Removal of solvent gave an acetal 16 4194 mg, 100%) as an
1
oil: IR 4®lm) 2979, 1754, 1483 cm21; H NMR 4200 MHz,
CDCl3) d 1.39 43H, s), 1.84 41H, d, Jˆ14.4 Hz),. 1.86 43H,
d, Jˆ0.7 Hz), 2.01±2.27 42H, m), 2.28 43H, s), 2.50±2.80
42H, m), 2.84 41H, d, Jˆ14.4 Hz), 3.84±4.00 44H, m), 5.62
41H, m), 7.02 41H, d, Jˆ8.3 Hz), 7.12 41H, dd, Jˆ8.3,
1.5 Hz), 7.60 41H, d, Jˆ1.5 Hz);EIMS m/z 4rel. int.) 442

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Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
EtOAcˆ2:1) to afford 19 496 mg, 96%) as an oil: IR 4®lm)
2961, 2890, 1713, 1502 cm21; 1H NMR 4200 MHz, CDCl3)
d 1.29 43H, s), 1.43 43H, s), 2.09 41H, d, Jˆ15.0 Hz), 2.25
43H, s), 2.94 41H, d, Jˆ15.0 Hz), 3.78 43H, s), 6.77 41H, d,
Jˆ8.1 Hz), 7.00 41H, dd, Jˆ8.1, 1.5 Hz), 7.04 41H, dd,
Jˆ1.5 Hz), 9.00 41H, s);EIMS m/z 4rel. int.) 332 [M1]
415), 241 423), 87 4100);HREIMS m/z 332.1978 [M1]
4calcd 332.1988 for C20H28O4).
3.2.13.
carboxylate &24). To
1-Benzyloxymethyl-2-methyl-2-cyclopentene-
solution of 23a 4397 mg,
a
1.51 mmol) in ether 415 mL) was added the MeMgI ether
solution 42.15 mL, 1.81 mmol) at room temperature and the
mixture was stirred for 19 h. The reaction mixture was
quenched by the addition of saturated NH4Cl solution,
extracted with ether, washed with saturated NaHCO3
solution, water and saturated NaCl solution, dried over
MgSO4. Evaporation of ether afforded a residue 4369 mg).
To a solution of this residue in benzene 45 mL) was added
phosphorus pentaoxide 40.43 g). The mixture was stirred at
room temperature for 14 h. Water was added and the
mixture was extracted with ether. The organic layer was
washed with saturated NaCl solution, and dried over
MgSO4. Evaporation of solvent gave the residue, which
was chromatographed on silica gel 4hexane/EtOAcˆ4:1)
to give a methyl ester 4360 mg), which was dissolved in
methanol and water 41:1, 2 mL) and then NaOH 4390 mg)
was added. After being stirred at room temperature for 10 h,
this reaction mixture was acidi®ed with 2 M HCl, and then
extracted with ether. The organic layer was extracted with
saturated NaHCO3 solution. The resulting aqueous layer
was acidi®ed with 2 M HCl, and then extracted with ether.
The combined extracts were washed with water and
saturated NaCl solution, dried over MgSO4, concentrated,
and puri®ed by column chromatography 4hexane/EtOAcˆ
4:1) to give 24 4245 mg, 66%) as an oil: 1H NMR 4200 MHz,
CDCl3) d 1.73 43H, s), 3.52 41H, d, Jˆ8.9 Hz), 3.75 41H, d,
Jˆ8.9 Hz), 4.54 41H, d, Jˆ12.5 Hz), 4.62 41H, d, Jˆ
12.5 Hz), 5.60 41H, m), 7.30±7.40 45H, m);EIMS m/z
4rel. int.) 246 [M1] 42), 123 439), 91 4100);HREIMS m/z
246.1246 [M1] 4calcd 246.1256 for C15H18O3).
3.2.10. 1,2-Dimethyl-1-&2,2-ethylenedioxypropyl)-2-&2-
methoxy-5-methylphenyl) cyclopentane &20). To a solu-
tion of 19 460 mg, 0.18 mmol) in diethylene glycol 48 mL)
was added hydrazine monohydrate 42 mL, 40 mmol). After
being stirred at 1508C for 5 h, NaOH 4100 mg, 1.78 mmol)
was added. The reaction mixture was stirred at 1908C for
additional 7 h. The reaction mixture was extracted with
ether, washed with water, saturated NaCl solution, dried
over MgSO4 and concentrated in vacuo. The residue was
chromatographed on silica gel 4hexane/EtOAcˆ5:1) to
afford 20 434 mg, 59%) as an oil: IR 4®lm) 2954,
1
1497 cm21; H NMR 4200 MHz, CDCl3) d 0.82 43H, s),
1.34 43H, s), 1.39 43H, s), 1.93 41H, d, Jˆ14.8 Hz), 2.28
43H, s), 2.33 41H, d, Jˆ14.8 Hz), 3.75 43H, s), 3.77±4.05
44H, m), 6.76 41H, d, Jˆ8.4 Hz), 6.97 41H, dd, Jˆ8.4,
2.2 Hz), 7.18 41H, d, Jˆ2.2 Hz);EIMS m/z 4rel. int.) 318
[M1] 45), 149 460), 87 4100);HREIMS m/z 318.2202 [M1]
4calcd 318.2194 for C20H30O3).
3.2.11.
1,2-Dimethyl-1-&2-oxopropyl)-2-&2-methoxy-5-
methylphenyl)cyclopentane &21). To a solution of 20
412 mg, 0.037 mmol) in THF 41.5 mL) was added 3.5 mL
of 2.5 M HCl, and the mixture was stirred at room tempera-
ture for 15 min. The reaction mixture was extracted with
ether, washed with saturated NaHCO3 solution and
saturated NaCl solution, and dried over MgSO4. Evapora-
3.2.14. 2-Iodo-4-methylphenyl 1-benzyloxymethyl-2-
methyl-2-cyclopentenecarboxylate &7a). To a solution of
24 4500 mg, 2.03 mmol) in benzene 420 mL) was added
DCC 4639 mg, 3.1 mmol) and DMAP 4250 mg, 2.03
mmol). To this stirring mixture was added 2-iodo-p-cresol
4475 mg, 2.03 mmol). The mixture was stirred at room
temperature for 17 h. After being ®ltered, the ®ltrate was
washed with water, Cu4NO3)2 solution, NaHCO3 solution
and saturated NaCl solution and dried over MgSO4.
Evaporation of the solvent gave a crude product 411.6 g),
which was chromatographed on silica gel 4hexane/EtOAcˆ
9:1) to afford 7a 4821 mg, 87%) as an oil: 1H NMR
4200 MHz, CDCl3) d 1.85 43H, d, Jˆ1.8 Hz), 2.29 43H,
s), 3.72 41H, d, Jˆ8.8 Hz), 3.98 41H, d, Jˆ8.8 Hz), 4.57
41H, d, Jˆ12.5 Hz), 4.65 41H, d, Jˆ12.5 Hz), 5.68 41H,
m), 6.89 41H, d, Jˆ8.1 Hz), 7.11 41H, dd, Jˆ8.1, 1.8 Hz),
7.25±7.40 45H, m) and 7.62 41H, d, Jˆ1.8 Hz);EIMS m/z
4rel. int.) 462 [M1] 45), 234 448), 93 491);HREIMS m/z
462.0665 [M1] 4calcd 462.0692 for C22H23O3I).
1
tion of the solvent afford 21 410.1 mg, 100%) as an oil: H
NMR 4200 MHz, CDCl3) d 0.75 43H, s), 1.35 43H, s), 2.15
43H, s), 2.28 43H, s), 2.67 41H, d, Jˆ14.8 Hz), 3.03 41H, d,
Jˆ14.8 Hz), 3.79 43H, s), 6.77 41H, d, Jˆ8.1 Hz), 7.02 41H,
dd, Jˆ8.1, 1.5 Hz), 7.12 41H, d, Jˆ1.5 Hz); 13C NMR
4200 MHz, CDCl3) d 20.4, 20.8, 22.2, 24.2, 30.0, 38.0,
38.3, 51.3, 52.0, 54.8, 59.2, 111.8, 127.5, 129.2, 129.9,
124.4, 156.5, 208.4.
3.2.12. Methyl 1-benzyloxymethyl-2-cyclopentanone-
carboxylate &23a). To a suspension of 60% sodium hydride
4169 mg, 4.22 mmol) in toluene 410 mL) was added a
solution of methyl 2-cyclopentanonecarboxylate 4500 mg,
3.5 mmol) in toluene at 08C, and the mixture was stirred
for 30 min. To this solution was added benzylchloromethyl-
ether 40.73 mL, 5.3 mmol) and then the mixture was stirred
at room temperature for 16 h. The reaction mixture was
quenched by adding water and extracted with ether, washed
with aqueous NaHCO3 solution, water and saturated NaCl
solution, and dried over MgSO4. Evaporation of the solvent
gave a crude mixture 41.45 g), which was chromatographed
on silica gel 4hexane/EtOAcˆ4:1) to give 23a 4450 mg,
49%) and an O-alkylated product 23b 4376 mg, 41%) as
an oil, respectively. 23a: IR 4®lm) 2955, 1755 and
3.2.15. Heck reaction of 7a. To a solution of 7a 42 g,
4.33 mmol) in DMF 4400 mL) was added palladium acetate
4100 mg, 0.433 mmol), 1,10-bis4diphenylphosphino)ferro-
cene 4480 mg, 0.866 mmol) and tri-n-butylamine 42.1 mL,
8.66 mmol). The mixture was heated at 1208C for 14 h. The
cooled mixture was diluted with water and washed with
water and saturated NaCl solution, dried over MgSO4.
Removal of solvent afforded the residue, which was
chromatographed on silica gel 4hexane/EtOAcˆ9:1)
to afford d-lactone 4860 mg, 4.33 mmol), which was
1728 cm21 1H NMR 4200 MHz, CDCl3) d 1.95±2.58
;
46H, m), 3.69 43H, s), 3.63 41H, d, Jˆ7.9 Hz), 3.86 41H,
d, Jˆ7.9 Hz), 4.46 41H, d, Jˆ12.1 Hz), 4.53 41H, d, Jˆ
12.1 Hz), 7.24±7.39 45H, m).

Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
9305
hydrogenated in EtOH 49 mL) containing palladium carbon
4Pd/C, Pd: 10%, 90 mg) under an atmosphere of hydrogen
for 10 h. The reaction mixture was ®ltered, concentrated to
afford 25 4756 mg, 71%) as an oil: IR 4®lm) 3450, 2966,
1741, 1494 cm21; 1H NMR 4200 MHz, CDCl3) d 1.27 43H,
s), 2.34 43H, s), 3.60 41H, m), 4.03 41H, m), 6.91 41H, d,
Jˆ8.1 Hz), 7.05 41H, dd, Jˆ8.1, 1.5 Hz), 7.11 41H, d,
Jˆ1.5 Hz);EIMS m/z 4rel. int.) 246 [M1] 4100), 201 460),
91 411);HREIMS m/z 246.1265 [M1] 4calcd for 246.1256
for C15H18O3).
with saturated NH4Cl solution and then extracted with ether.
The organic layer was washed with water and saturated
NaCl solution, dried over MgSO4. The solvent was removed
in vacuo and the residue was chromatographed on silica gel
4hexane/EtOAcˆ4:1) to afford 28 4147 mg, 74%) as an oil:
IR 4®lm) 2946, 1720, 1499 cm21 1H NMR 4200 MHz,
;
CDCl3) d 1.38 43H, s), 2.26 43H, s), 3.36 43H, s), 3.71
41H, d, Jˆ9.5 Hz), 3.75 43H, s), 4.46 41H, d, Jˆ9.5 Hz),
4.64 42H, s), 6.73 41H, d, Jˆ8.1 Hz), 7.02 41H, dd, Jˆ8.1,
1.5 Hz), 7.04 41H, d, Jˆ1.5 Hz), 9.17 41H, s); 13C NMR
450 MHz, CDCl3) d 20.7, 21.9, 22.8, 30.7, 40.6, 50.9,
54.4, 55.2, 61.4, 69.6, 96.8, 111.1, 128.3, 128.6, 129.7,
132.4, 155.3, 204.3;EIMS m/z 4rel. int.) 306 [M1] 415),
175 4100), 149 431);HREIMS m/z 306.1832 [M1] 4calcd
306.1831for C18H26O4).
3.2.16. Methoxymethylation of 25. A solution of 25
4346 mg, 1.4 mmol), choromethylmethylether 40.13 mL)
and triethylamine in methylene chloride 410 mL) was stirred
at room temperature for 10 h. The reaction mixture was
diluted with water and extracted with ether. The organic
layer was washed with 2 M HCl and saturated NaCl
solution, dried over MgSO4. Removal of solvent afforded
the residue, which was chromatographed on silica gel
4hexane/EtOAcˆ4:1) to give 26 4396 mg, 97%) as an oil:
3.2.19. 1-Methyl-1-methoxymethyloxymethyl-2-methyl-
2-&2-methoxy-5-methylphenyl) cyclopentane &29). To a
solution of 28 4140 mg, 0.46 mmol) in diethylene glycol
427 mL) was added hydrazine monohydrate 46.8 mL).
After being stirred at 1508C for 5 h, NaOH 4340 mg,
6 mmol) was added. The reaction mixture was stirred at
1908C for additional 7 h. The reaction mixture was extracted
with ether, washed with water and saturated NaCl solution,
dried over MgSO4, and concentrated in vacuo. The residue
was chromatographed on silica gel 4hexane/EtOAcˆ5:1) to
afford 30 4102 mg, 76%) as an oil: IR 4®lm) 2947,
IR 4®lm) 2949, 1747, 1496 cm21 1H NMR 4CDCl3,
;
200 MHz) d 1.38 43H, s), 2.33 43H, s), 3.20 43H, s), 3.69
42H, s), 4.42 41H, d, Jˆ6.8 Hz), 4.45 41H, d, Jˆ6.8 Hz),
6.89 41H, d, Jˆ8.2 Hz), 7.02 41H, dd, Jˆ8.2, 1.5 Hz),
7.09 41H, d, Jˆ1.5 Hz);EIMS m/z 4rel. int.) 290 [M1]
496), 185 466), 45 4100);HREIMS m/z 290.1525 4calcd
for 290.1518 for C17H22O4).
1
1498 cm21; H NMR 4200 MHz, CDCl3) d 0.70 43H, s),
3.2.17. 1-Hydroxymethyl-1-methoxymethyloxymethyl-2-
methyl-2-&2-methoxy-5-methylphenyl)cyclopentane &27).
To a solution of 26 4479 mg, 1.65 mmol) in THF 416 mL)
was added LiAlH4 4479 mg, 12.8 mmol) at 08C, and stirring
was continued at room temperature for 3 h. After being
cooled down to 08C, EtOAc 48 mL) and water were succes-
sively added to the reaction mixture. After being ®ltered, the
®lterate was condensed in vacuo to give diol 4396 mg),
which was dissolved in acetone 420 mL). To this solution
was added iodomethane 40.15 mL, 2.48 mmol) and K2CO3
4342 mg, 2.48 mmol), and the mixture was re¯uxed for 12 h.
After being cooled, the reaction mixture was extracted with
ether, washed with water and saturated NaCl solution, dried
over MgSO4. Evaporation of solvent afforded the residue,
which was chromatographed on silica gel 4hexane/
EtOAcˆ3:1) to give 27 4452 mg, 89%) as an oil: IR 4®lm)
3441, 1498 cm21; 1H NMR 4200 MHz, CDCl3) d 1.35 43H,
s), 2.28 43H, s), 2.70 41H, dd, Jˆ9.9, 2.9 Hz), 3.31 41H, dd,
Jˆ9.9, 2.9 Hz), 3.40 43H, s), 3.66 41H, d, Jˆ8.9 Hz), 3.88
43H, s), 4.32 41H, d, Jˆ8.9 Hz), 4.64 41H, d, Jˆ6.4 Hz),
4.69 41H, d, Jˆ6.4 Hz), 6.78 41H, d, Jˆ8.1 Hz), 7.01 41H,
dd, Jˆ8.1, 1.5 Hz), 7.08 41H, d, Jˆ1.5 Hz);EIMS m/z 4rel.
int.) 308 [M1] 45), 276 473), 149 4100);HREIMS 308.1989
4cacld 308.1988 for C18H28O4).
1.34 43H, s), 2.28 43H, s), 3.38 43H, s), 3.67 41H, d, Jˆ
9.0 Hz), 3.76 43H, s), 3.78 41H, d, Jˆ9.0 Hz), 4.64 41H, d,
Jˆ6.4 Hz), 4.67 41H, d, Jˆ6.4 Hz), 6.75 41H, d, Jˆ8.2 Hz),
6.98 41H, dd, Jˆ8.2, 2.0 Hz), 7.12 41H, d, Jˆ2.0 Hz);EIMS
m/z 4rel. int.) 292 [M1] 47), 83 4100), 78 432);HREIMS m/z
292.2035 [M1] 4calcd 292.2039 for C18H28O3).
3.2.20. 1-Methyl-1-hydroxymethyl-2-methyl-2-&2-meth-
oxy-5-methylphenyl) cyclopentane &30). To a solution of
29 445 mg, 0.16 mmol) in MeOH 46 mL) was added one
drop of 48% HBr. The mixture was re¯uxed for 1 h and
then condensed in vacuo to give the residue, which was
chromatographed on silica gel 4hexane/EtOAcˆ4:1) to
1
afford 30 434 mg, 87%) as an oil: H NMR 4200 MHz,
CDCl3) d 0.71 43H, s), 1.39 43H, s), 2.28 43H, s), 3.48
41H, d, Jˆ11.5 Hz), 3.83 43H, s), 3.93 41H, d, Jˆ
11.5 Hz), 6.80 41H, d, Jˆ8.2 Hz), 7.00 41H, dd, Jˆ8.2,
1.5 Hz), 7.16 41H, d, Jˆ1.5 Hz).
3.2.21. 1-Carboxy-1,2-dimethyl-&2-methoxy-5-methyl-
phenyl)-cyclopentane &31). To a cooled solution of 30
412 mg, 0.048 mmol) in acetone 40.8 mL) was added
Jones reagent 41.3 mL), and the mixture was stirred for
19 h. The reaction mixture was treated with Na2SO3 and
water was added. The solution was extracted with ether,
washed with water and saturated NaCl solution, and dried
over MgSO4. Removal of solvent afforded the residue
412 mg), which was chromatographed on silica gel
3.2.18. 1-Formyl-1-methoxymethyloxymethyl-2-methyl-
2-&2-methoxy-5-methylphenyl) cyclopentane &28). To
solution of dimethyl sulfoxide 40.14 mL, 1.96 mmol) in
CH2Cl2 43.2 mL) was added oxalyl chloride 40.12 mL,
1.31 mmol) at 2788C, and stirring was continued for
10 min. A solution of 27 4200 mg, 0.65 mmol) in CH2Cl2
46 mL) was added to this solution, and the reaction mixture
was stirred for 1 h at the same temperature and then treated
with triethylamine 40.64 mL, 4.58 mmol). After further
stirring for 30 min at 08C, the reaction mixture was treated
4hexane/EtOAcˆ2:1) to give carboxylic acid 31 48.0 mg,
21
64%) as an oil;IR 4®lm) 2960, 1683, 1501, 1464 cm
;
1H NMR 4300 MHz, CDCl3) d 0.87 43H, s), 1.47 43H, s),
2.28 43H, s), 3.68 43H, s), 6.72 41H, d, Jˆ8.2 Hz), 7.02 41H,
dd, Jˆ8.2, 2.0 Hz), 7.04 41H. d, Jˆ2.0 Hz); 13C NMR
475 MHz, CDCl3) d 20.0, 20.8, 22.8, 25.2, 39.7, 39.8,
53.1, 53.6, 53.7, 110.2, 127.5, 128.8, 129.2, 135.2, 155.0,

9306
Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
183.0;EIMS m/z 4rel. int.) 262 [M1] 4100), 161 467), 230
466);HREIMS m/z 262.1560 [M1] 4Calcd 262.1569 for
C16H22O3).
137.1, 139.4, 149.0. 159.8, 163.4;EIMS m/z 4rel. int.) 342
[M1] 44), 234 423), 109 4100);HREIMS m/z 342. 0102
4calcd 342.0117 for C14H15O2I).
3.2.22. Herbertenolide &5). To a solution of 31 411 mg,
0.042 mmol) in methylene chloride 41.5 mL) was added
boron tribromide 40.17 mL, 1.0 M solution in methylene
chloride) at room temperature. After stirring was continued
for 22 h, water was added. The solution was extracted with
ether, washed with water and saturated NaCl solution, dried
over MgSO4. Removal of solvent afforded the residue
412 mg), which was chromatographed on silica gel 4hexane/
3.3.2. Heck reaction of 9. To a solution of 9 4440 mg,
1.29 mmol) in DMF 4130 mL) was added palladium acetate
428.9 mg, 0.13 mmol) and tri-o-tolylphosphine 478.4 mg,
0.26 mmol) and tributylamine 40.62 mL, 2.58 mmol), and
the mixture was stirred at 1208C for 22 h. Water was
added and the solution was extracted with ether. The
organic layer was washed with 2 M HCl, water and
saturated NaCl solution, dried over MgSO4. Evaporation
of solvent afforded the residue 4404 mg), which was
chromatographed on silica gel 4methylene chloride/hexaneˆ
1:1) to give a g-lactone 10 4262 mg, 95%) as an oil: IR 4®lm)
EtOAcˆ5:1) to give herbertenolide 45) 44.4 mg, 46%) as a
21
colorless oil;IR 4®lm) 1775, 1489 cm
;
1H NMR
4300 MHz, CDCl3) d 0.93 43H, s), 1.12 43H, s), 2.33 43H,
s), 6.89 41H, d, Jˆ2.2 Hz), 6.93 41H, d, Jˆ8.0 Hz), 7.02
41H, dd, Jˆ8.0, 2.2 Hz); 13C NMR 475 MHz, CDCl3) d
19.8, 19.9, 20.9, 25.4, 29.0, 29.7, 47.1, 50.8, 115.8, 125.3,
128.0, 133.0, 134.1, 149.6, 173.6;EIMS m/z 4rel. int.) 230
[M1] 4100), 187 478), 215 466);HREIMS m/z 230.1313
[M1] 4calcd 230.1307 for C15H18O2). These spectral data
were identical with those of natural one.
1
1800 cm21; H NMR 4200 MHz, CDCl3) d 2.34 43H, s),
2.63 45.81 41H, m), 6.93 41H, d, Jˆ1.3 Hz), 6.99 41H, d,
Jˆ8.1 Hz), 7.08 41H, dd, Jˆ8.1, 1.3 Hz); 13C NMR
450 MHz, CDCl3) d 13.0, 21.1, 31.4, 37.6, 62.2, 110.2,
123.9, 129.2, 130.8, 131.3, 134.2, 139.4, 151.0, 180.1;
EIMS m/z 4rel. int.) 214 [M1] 4100), 186 482), 171 465);
HREIMS m/z 214.1003 [M1] 4calcd 214.0994 for
C14H12O2).
3.2.23. 1,15-Hydroxyherbertene &3). To a solution of 5
47.2 mg, 0.031 mmol) in THF 41 mL) was added LiAlH4
44.8 mg) at 08C. The reaction mixture was stirred at room
temperature for 28 h. The reaction was terminated by adding
water and EtOAc, and the solution was acidi®ed with 2 M
HCl and was extracted with EtOAc. The organic layer was
washed with water and dried over MgSO4. Removal of
solvent afforded the residue 48 mg), which was chromato-
graphed on silica gel 4hexane/EtOAcˆ2:1) to give 1,15-
3.3.3. Simmons±Smith reaction of 10. To a solution of 10
4260 mg, 1.22 mmol) in ether 410 mL) was added Zn±Cu
couple 4623 mg, 4.86 mmol). The mixture was heated under
gentle re¯uxing. To this mixture was added dropwise
diiodomethane 40.25 mL, 3.0 mmol) and then the reaction
mixture was re¯uxed for 48 h. Water was added and the
mixture was extracted with ether. The organic layer was
washed with 2 M HCl, water and saturated NaHCO3
solution, and dried over MgSO4. Evaporation of solvent
afforded the residue 4296 mg), which was chromatographed
on silica gel 4hexane/methylene chlorideˆ1:1) to give 11
1
dihydroxyherbertene 43) 46 mg, 83%) as a colorless oil; H
NMR data 4200 MHz, CDCl3) d 0.81 43H, s), 1.49 43H, s),
2.27 43H, s), 3.47 41H, d, Jˆ11.0 Hz), 4.91 41H, d,
Jˆ11.0 Hz), 6.75 41H, d, Jˆ8.1 Hz), 6.93 41H, dd, Jˆ8.1,
1.5 Hz), 7.12 41H, d, Jˆ1.5 Hz); 13C NMR data 475 MHz,
CDCl3) d 20.8, 21.0, 21.9, 24.2, 39.5, 42.2, 48.1, 49.3, 69.2,
118.8, 127.9, 128.9 4£2), 132.9, 152.5.
1
4253 mg, 92%) as an oil: IR 4KBr) 2924, 1804 cm21; H
NMR 4200 MHz, CDCl3) d 0.49 41H, dd, Jˆ7.0, 5.3 Hz),
0.86 43H, s), 1.03 41H, dd, Jˆ7.0, 7.0 Hz), 2.37 43H, s), 7.01
41H, dd, Jˆ8.4, 2.3 Hz), 7.04 41H, d, Jˆ8.3 Hz), 7.10 41H,
d, Jˆ2.3 Hz); 13C NMR 450 MHz, CDCl3) d 13.2, 17.4,
21.2, 24.5, 27.9, 33.2, 34.9, 55.6, 110.3, 123.9, 128.8,
131.8, 133.8, 150.3, 180.5;EIMS m/z 4rel. int.) 228 [M1]
452), 213 427), 185 445), 160 4100), 149 472);HREIMS m/z
228.1164 [M1] 4calcd 228.1150 for C15H16O2).
3.3. Synthesis of 1,13-dihydroxyherbertene &6)
3.3.1. 2-Iodo-4-methylphenyl 2-methyl-cyclopentenecar-
boxylate &9). To a solution of 2-methylcyclopentene-
carboxylic acid 4215 mg, 1.71 mmol) was added tri-
ethylamine 40.24 mL, 1.71 mmol) and 2,4,6-trichloro-
benzoyl chloride 40.27 mmol) and the solution was stirred
at room temperature for 4 h. After ®ltering off the precipi-
tate, the ®lterate was condensed in vacuo to leave the
residue, which was dissolved in benzene 415 mL). To this
solution was added 2-iodo-p-cresol 4600 mg, 2.65 mmol)
and 4-dimethylaminopyridine 4418 mg, 3.24 mmol). The
mixture was stirred at room temperature for 13 h. Water
was added and the solution was extracted with ether, washed
with saturated Cu4NO3)2 solution, saturated NaHCO3 solu-
tion and saturated NaCl solution and dried over MgSO4.
Evaporation of solvent gave a crude product 41.3 g),
which was chromatographed on silica gel 4hexane/methyl-
ene chlorideˆ2:1) to afford 9 4441 mg, 75%) as an oil: IR
4®lm) 1732, 1644 cm21; 1H NMR 4200 MHz, CDCl3) d 2.31
43H, s),7.00 41H, d, Jˆ8.1 Hz), 7.15 41H, dd, Jˆ8.1,
2.2 Hz), 7.65 41H, d, Jˆ2.2 Hz); 13C NMR 450 MHz,
CDCl3) d 16.5, 20.2, 21.2, 33.4, 40.9, 90.4, 122.6, 129.9,
3.3.4. Hydrogenation of 32. To a solution of 11 410 mg,
0.044 mmol) in acetic acid 41 mL) was added PtO2 410 mg)
and NaOAc 45 mg). This mixture was stirred under
hydrogen atmosphere at room temperature for 45 min.
After being ®ltered, the ®ltrate was extracted with ether.
The organic layer was washed with saturated NaHCO3
solution, water and saturated NaCl solution, dried over
MgSO4. Removal of solvent afforded the residue, which
was puri®ed by prep. TLC 4hexane/methylene dichlorideˆ
1:1) to give 32 43 mg, 32%) as an oil: 1H NMR 4200 MHz,
CDCl3) d 0.92 43H, s), 1.02 43H, s), 2.36 43H, s), 6.96 41H,
d, Jˆ8.1 Hz), 7.00 41H, d, Jˆ1.0 Hz), 7.08 41H, dd, Jˆ8.1,
1.8 Hz);EIMS m/z 4rel. int.) 230 [M1] 442), 161 4100), 148
417);HREIMS
C15H18O2).
m/z 230.1281 4calcd 230.1306 for
3.3.5. 1,13-Dihydroxyherbertene &6). To a solution of 32
42.6 mg, 0.011 mmol) in THF 41 mL) was added LiAlH4

Y. Fukuyama et al. / Tetrahedron 57 ,2001) 9299±9307
9307
4. Fukuyama, Y.;Toyota, M.;Asakawa, Y. J. Chem. Soc., Chem.
Commun. 1988, 1341±1342.
44.3 mg). The reaction mixture was stirred at room tempera-
ture for 1 h. The reaction was terminated by adding EtOAc
and the solution was acidi®ed with 2 M HCl, and then
extracted with ether. The organic layer was washed with
water and saturated NaCl solution, dried over MgSO4.
Removal of solvent afforded the residue, which was
chromatographed on silica gel 4hexane/EtOAcˆ2:1) to
give 6 42.6 mg, 100%) as an colorless oil: 1H NMR
4200 MHz, CDCl3) d 0.87 43H, s), 1.24 43H, s), 2.27 43H,
s), 3.78 41H, d, Jˆ10.6 Hz), 4.40 41H, d, Jˆ10.6 Hz), 6.69
41H, d, Jˆ8.1 Hz), 6.92 41H, dd, Jˆ8.1, 2.0 Hz), 7.02 41H,
d, Jˆ2.0 Hz);EIMS m/z 4rel. int.) 234 [M1] 434), 216 458),
202 482), 187 4100), 173 464), 159 469), 121 475), 95 456);
HREIMS m/z 234.1588 4calcd 234.1620 for C15H22O2).
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Acknowledgements
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We thank Dr Masami Tanaka and Ms Yasuko Okamoto for
measuring NMR and MS spectra. This work is supported by
a Grant-in Aid for Scienti®c Research 4No. 12480175) from
the Ministry of Education, Sports and Culture, Japan, and
the High Tech Research Center Fund from the Promotion
and Mutual Aid Corporation for Private School, Japan.
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