A new synthesis of a potent cancer chemopreventive agent, 13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid from trans-communic acid.

Article abstract of DOI:10.1248/cpb.50.1625

The first synthesis of a labdane diterpenoid, (-)-13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid [(-)-1a], isolated from the stem bark of Thuja standishii (GORD.) CARR., from the major component trans-communic acid (3a) is described.

Full text of DOI:10.1248/cpb.50.1625

December 2002
Notes
Chem. Pharm. Bull. 50(12) 1625—1629 (2002)
1625
A New Synthesis of a Potent Cancer Chemopreventive Agent,
13-Oxo-15,16-dinorlabda-8(17),11E-dien-19-oic Acid from
trans-Communic Acid
Takahiro KATOH,a Reiko TANAKA,b Masatoshi TAKEO,a Kiyoharu NISHIDE,a and Manabu NODE*,a
a Kyoto Pharmaceutical University; Misasagi, Yamashina, Kyoto 607–8414, Japan: and b Osaka University of
Pharmaceutical Sciences; 4–20–1 Nasahara, Takatsuki, Osaka 569–1094, Japan.
Received August 9, 2002; accepted September 20, 2002
The first synthesis of a labdane diterpenoid, (؊)-13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid [(؊)-
1a], isolated from the stem bark of Thuja standishii (GORD.) CARR., from the major component trans-communic
acid (3a) is described.
Key words trans-communic acid; Thuja standishii; chemical conversion; (Ϫ)-13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic
acid
constructing the methyl vinyl ketone moiety from the alde-
hyde using 2-methyl-1,3-dithiane as a methyl ketone equiva-
lent. In a model experiment, the attempted dehydration of the
alcohol 5, derived from 3-phenylpropanal and 2-methyl-1,3-
dithiane, with mesyl chloride in the presence of pyridine
gave the undesired 2-methylene-3-phenethyl-1,4-dithiepane
(6), whereas in the presence of DBU as the base it afforded
2-methyl-3-phenethyl-6,7-dihydro-5H-1,4-dithiepine (7), an
isomerization product of 6, as shown in Chart 3. These re-
sults showed that the migration of sulfur to the carbocation is
much faster than the desired dehydration. Attempted dehy-
drations from 3-hydroxy-5-phenylpenta-2-one or 1-phenyl-
4,4-ethylenedioxy-3-pentanol prepared from 5 were unsuc-
cessful.
A labdane-type diterpenoid, (Ϫ)-13-oxo-15,16-dinorlabda-
8(17),11E-dien-19-oic acid [(Ϫ)-1a], has been revealed by
Tanaka et al. to have potent cancer chemopreventive activity,
i.e., the percentage of papilloma-bearing mice was reduced to
25% by the treatment of (Ϫ)-1a, compared with the control
group (DMBA and TPA only).1) The acid (Ϫ)-1a, isolated
from the chopped stem bark of Thuja standishii (GORD.)
CARR. as a minor component, along with three new and two
known diterpenoids, has the most potent activity among the
isolated diterpenoids for the prevention of incipient carcino-
genesis. In addition to the above plant, three other sources of
the labdane diterpenoid 1a have been reported, the seeds of
Platycladus orientalis,2) the heartwood of Juniperus chinen-
sis3) and the pericarp of Platycladus orientalis.4) Because this
compound is in short supply from these natural sources, an
efficient synthesis of 1a would be highly useful in order to
further evaluate the compound’s potential as a cancer chemo-
preventive agent. A transformation of methyl cis-communate
(2b) into the methyl ester 1b has been reported,5) however the
diene isomerization required a high temperature (200 °C) in a
sealed tube to proceed from the 12,14-diene to the 11,13-
diene and the selective oxidative cleavage of the 13-ene in
the triene via ozone or osmium tetroxide–sodium periodate
resulted in poor yields. Among the diterpenoids in Thuja
standishii (GORD.) CARR., the trans-communic acid (3a) was
isolated as the major component (ca. 10 g) from the stem
bark (ca. 5 kg), and therefore was thought to be appropriate
as the starting material for the preparation of 1a. Herein we
describe the first efficient synthesis of 1a from the major
diterpenoid 3a.
Next, we tested the reductive detriflation of the vinyl tri-
flate 8 derived from 5 using formic acid with the assistance
Chart 1
The chemical conversion of methyl cis-communate (2b)
into the aldehyde 4 having been reported by Barrero et al.,6)
we reasoned that the aldehyde 4 would be an excellent choice
as an intermediate for the synthesis of 1a (Chart 2). Follow-
ing Barrero’s procedure,6) we prepared the aldehyde 4 from
trans-communic acid (3a) using the selective epoxidation
with MCPBA of the 12-ene in methyl ester 3b, which was
obtained by methylation of the acid 3a with diazomethane.
Subsequent cleavage of the resultant epoxide with periodic
acid gave the aldehyde 4 in high yield (3 steps, 63%).
Chart 2
In the transformation of the aldehyde 4 into 1a, a two car-
bon elongation to the aldehyde group and appropriate func-
tional group manipulations were required. Initially, we tried
Chart 3
© 2002 Pharmaceutical Society of Japan
* To whom correspondence should be addressed. e-mail: node@mb.kyoto-phu.ac.jp

1626
Vol. 50, No. 12
Chart 4
Chart 5
of a catalytic palladium(0) species,7) as shown in Chart 4.
The reaction gave the trans-olefin 9 in good yield. Subse-
quent hydrolysis afforded the methyl vinyl ketone 10. The
vinyl triflate 11 derived from 4 was subjected to the above
conditions of reductive detriflation, unfortunately, no forma-
tion of the desired 12 was observed. It seems most likely that
an exo carbon–carbon double bond at the 8,17-positions in
the 13-oxo-15,16-dinorlabdane skeleton must interfere with
the oxidative addition of the palladium(0) species to the car-
bon–oxygen bond of the vinyl triflate 11. Therefore, we de-
cided to undertake a stepwise synthesis of 1 through a one
carbon elongation instead of a two carbon elongation, as
shown in Chart 5.
The Wittig reaction of the aldehyde 4 with (methoxy-
methyl)triphenylphosphonium chloride gave the enol methyl
ether 13 in 94% yield. The palladium(II)-promoted oxida-
tion8) of 13 to 15 resulted in a complex mixture, probably due
to the coordination of the palladium(II) to the exo carbon–
carbon double bond at the 8,17-positions in the 13-oxo-
15,16-dinorlabdane skeleton. Hydrolysis of 13 with 1 N-hy-
drochloric acid or trifluoroacetic acid was likewise unsuc-
cessful because of contamination of the by-product.9) Hy-
drolysis with the milder acid pyridinium p-toluenesulfonate
(PPTS) proved successful and furnished the aldehyde 14 in
61% yield (with 38% of the recovered 13). a-Phenylseleny-
lation of the aldehyde 14 followed by oxidation with hydro-
gen peroxide afforded the a,b-unsaturated aldehyde 15 in an
acceptable yield (71%). The chemoselective attack of the
Grignard reagent on the aldehyde 15 possessing a methyl
ester functionality led to the allyl alcohol 16 (1 : 1 mixture) in
excellent yield (97%). Nucleophilic demethylation of the
methyl ester 16 to 17 was performed in quantitative yield
under odorless conditions by the use of dodecanethiol (Dod-
SH),10) a technique recently developed in our laboratory as an
odorless substitute for malodorous alkanethiols such as
ethanethiol. Oxidation of the allyl alcohol 17 with pyri-
dinium dichromate (PDC) furnished the desired 13-oxo-
15,16-dinorlabda-8(17),11E-dien-19-oic acid (1a) in 38%
overall yield from the trans-communic acid (3a). Spectro-
scopic data and the specific rotation of the synthesized (Ϫ)-
1a from trans-communic acid (3a) which was isolated from
Thuja standishii (GORD.) CARR. by Tanaka, were identical
with those of the isolated authentic sample of (Ϫ)-1a. How-
ever, the specific rotation of 1a isolated from the heartwood
of Juniperus chinensis by Cheng3) had the opposite sign. In
addition, the forms of both our synthesized and isolated au-
thentic samples of (Ϫ)-1a were crystalline, while those re-
ported in the literature were oily.2,3) Although the absolute
configuration of 1a has not been definitively elucidated, we
were able to provide the first synthetic route to (Ϫ)-1a from
the major diterpenoid trans-communic acid (3a) isolated
from Thuja standishii (GORD.) CARR. The synthetic route to
1a described herein is a contribution that should be useful in
further evaluating the physiological activities of the com-

December 2002
1627
sium sulfate, filtered, then concentrated in vacuo. The residue was purified
by silica gel column chromatography (eluent; hexane : ethyl acetateϭ4 : 1) to
give 1-phenyl-4,4-ethylenedioxy-3-pentanol (2.16 g, 75%).
pound.
Experimental
General Melting points were taken with a micro hot-stage apparatus
1-Phenyl-4,4-ethylenedioxy-3-pentanol: Colorless oil; 1H-NMR (300
(Yanagimoto) and are uncorrected. IR spectra were recorded with a Shi- MHz, CDCl3) d: 1.29 (3H, s), 1.71—1.95 (2H, m), 2.20—2.21 (1H, m),
1
madzu FT-IR 8300. H-NMR spectra were obtained with a JEOL JNM-AL 2.62—2.73 (1H, m), 2.88—2.98 (1H, m), 3.51 (1H, dt, Jϭ9.9, 2.9 Hz),
300 and Varian Unity INOVA 400 NMR spectrometer. Signals are given in 3.94—4.00 (4H, m), 7.15—7.30 (5H, m). IR (CHCl3) cmϪ1: 3584, 3009,
ppm using tetramethylsilane as an internal standard. MS spectra were deter- 2889, 2360, 1381, 1242, 1176, 1049. EI-MS m/z: 222.1259 (Calcd for
mined on a JEOL JMS SX-102A QQ and JEOL JMS-GCmate mass spec- C13H18O3: 222.1256). MS (70 eV) m/z: 222 (Mϩ, 1), 204 (1), 91 (16), 87
trometer. Combustion analyses were performed by a Yanaco CHN-corder
MT-3. Silica Gel 60N (KANTO CHEMICAL CO., INC.) was used for flash
(100), 65 (5).
To a chloroform (35 ml) suspension of pyridinium chlorochromate (PCC)
column chromatography. Kieselgel 60 F254 plates (Merck) were used for thin (2.3 g, 10.6 mmol) and Celite® (2.3 g) was added a chloroform (5 ml) solu-
layer chromatography (TLC). If necessary, the compounds were purified by tion of 1-phenyl-4,4-ethylenedioxy-3-pentanol (784 mg, 3.57 mmol). The re-
a recycle HPLC (LC-908, Japan Analytical Industry Co., Ltd.) on GPC action mixture was stirred at room temperature under a nitrogen atmosphere
columns (JAIGEL 1H and 2H) after purification on silica gel.
for 24 h. PCC (1.1 g, 5.3 mmol) and Celite® (1.1 g) were added and the reac-
Materials Diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran were tion mixture was stirred at room temperature for 8 h. Again, PCC (0.8 g,
distilled from sodium benzophenone ketyl under a nitrogen atmosphere be- 3.5 mmol) and Celite® (0.8 g) were added, the reaction mixture was stirred at
fore use. N,N-Dimethylformamide, dichloromethane, pyridine and triethy- room temperature for an additional 3 h, and PCC and Celite® were filtered
lamine were distilled from calcium hydride under a nitrogen atmosphere be- off with silica gel (eluent; ethyl acetate). The residue was purified by silica
fore use.
1-Phenyl-4,4-propylenedithio-3-pentanol (5) To a tetrahydrofuran
(150 ml) solution of 2-methyl-1,3-dithiane (2.32 ml, 19.4 mmol) was added
gel column chromatography (eluent; hexane : ethyl acetateϭ5 : 1) to give 1-
phenyl-4,4-ethylenedioxy-3-pentanone (669 mg, 86%).
1-Phenyl-4,4-ethylenedioxy-3-pentanone: Colorless oil; 1H-NMR (300
MHz, CDCl3) d: 1.42 (3H, s), 2.90 (4H, s), 3.86—4.01 (4H, m), 7.18—7.27
n-butyllithium (2.46 M solution in hexane, 7.28 ml, 17.9 mmol) at 0 °C. The
resulting mixture was stirred at 0 °C for 10 min under a nitrogen atmosphere. (5H, m). IR (CHCl3) cmϪ1: 3008, 2893, 1728, 1454, 1373, 1195, 1037. EI-
3-Phenylpropanal (1.96 ml, 14.9 mmol) was added at Ϫ78 °C. The reaction MS m/z: 220.1099 (Calcd for C13H16O3: 220.1079). MS (20 eV) m/z: 220
mixture was stirred at Ϫ78 °C for 30 min, poured into water (100 ml), then (Mϩ, 1), 87 (100), 58 (8).
extracted with ethyl acetate (200 mlϫ3). The combined organic layer was
To a 1,2-dimethoxyethane (30 ml) solution of 1-phenyl-4,4-ethylenedioxy-
washed with brine (100 ml), dried over anhydrous magnesium sulfate, fil- 3-pentanone (684 mg, 3.11 mmol) was added potassium tert-butoxide (697
tered, and concentrated in vacuo. The residue was purified by silica gel col- mg, 6.21 mmol) at Ϫ78 °C. The reaction mixture was stirred at Ϫ78 °C for
umn chromatography (eluent; hexane : ethyl acetateϭ20 : 1) to give 5 (3.8 g, 20 min under a nitrogen atmosphere. 1,1,1-Trifluoro-N-phenyl-N-[(trifluo-
95%).
romethyl)sulfonyl]methanesulfonamide (2.33 g, 6.21 mmol) was added at
Ϫ78 °C, and the reaction mixture was stirred at Ϫ78 °C for 20 min. The re-
5: Colorless oil; 1H-NMR (300 MHz, CDCl3) d: 1.37 (3H, s), 1.68—1.80
(2H, m), 1.97—2.02 (1H, m), 2.3—2.35 (1H, m), 2.43—2.77 (5H, m), action mixture was poured into a saturated ammonium chloride solution
2.83—2.92 (1H, m), 2.95—3.01 (1H, m), 3.90—3.93 (1H, m), 7.17—7.32
(20 ml), then extracted with diethyl ether (40 mlϫ3). The combined organic
(5H, m). IR (CHCl3) cmϪ1: 3487, 3009, 2931, 1450, 1296, 1277, 1056. Elec- layer was washed with brine (30 ml), dried over anhydrous magnesium sul-
tron ionization (EI)-MS m/z: 268.0958 (Calcd for C14H20OS2: 268.0956).
MS (70 eV) m/z: 268 (Mϩ, 2), 250 (1), 159 (3), 146 (4), 133 (100), 91 (3),
59 (27).
fate, filtered, and finally concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluent; hexane : chloroformϭ2 : 1) to
give 8 (1.04 g, 95%).
2-Methylene-3-phenethyl-1,4-dithiepane (6) To a pyridine (15 ml) so-
8: Colorless oil; 1H-NMR (300 MHz, CDCl3) d: 1.54 (3H, s), 3.53 (2H, d,
lution of 5 (428 mg, 1.59 mmol) was added methanesulfonyl chloride Jϭ7.7 Hz), 3.99—4.03 (4H, m), 5.96 (1H, t, Jϭ7.7 Hz), 7.18—7.34 (5H,
(0.35 ml, 4.78 mmol) at 0 °C. The reaction mixture was stirred at room tem- m). IR (CHCl3) cmϪ1: 3001, 2901, 1412, 1238, 1196, 1137, 1042, 1007,
perature for 2.5 h under a nitrogen atmosphere, then poured into water 945, 907. EI-MS m/z: 352.0599 (Calcd for C14H15O5F3S: 352.0592). MS
(30 ml), and extracted with ethyl acetate (50 mlϫ3). The combined organic (20 eV) m/z: 352 (Mϩ, 7), 337 (10), 219 (17), 157 (6), 115 (4), 87 (100), 73
layer was washed with brine (30 ml), dried over anhydrous magnesium sul- (7).
fate, filtered, then concentrated in vacuo. The residue was purified by silica
2-Methyl-2-(3-phenylpropenyl)-1,3-dioxolane (9) To a N,N-dimethyl-
gel column chromatography (eluent; hexane to hexane : ethyl acetateϭ10 : 1) formamide (7 ml) solution of 8 (247 mg, 0.70 mmol) was added pal-
to give 6 (368 mg, 92%).
ladium(II) acetate (3.1 mg, 0.014 mmol), triphenylphosphine (7.4 mg, 0.028
6: Colorless oil; 1H-NMR (300 MHz, CDCl3) d: 1.99—2.08 (2H, m), mmol), triethylamine (0.29 ml, 2.10 mmol) and formic acid (60 ml, 1.40
2.14—2.26 (2H, m), 2.66—2.75 (3H, m), 2.89—3.07 (3H, m), 3.73 (1H, t, mmol). The resulting mixture was stirred at 60 °C for 1 h. The reaction mix-
Jϭ7.2 Hz), 5.22 (1H, s), 5.46 (1H, s), 7.16—7.31 (5H, m). IR (CHCl3) ture was poured into water (10 ml), then extracted with diethyl ether
cmϪ1: 3001, 2928, 1600, 1497, 1454, 1423, 1308, 1238, 921. EI-MS m/z: (30 mlϫ3). The organic layer was washed with water (10 ml) and brine
250.8450 (Calcd for C14H18S2: 250.0850). MS (70 eV) m/z: 250 (Mϩ, 25),
175 (15), 159 (34), 146 (100), 106 (54), 91 (60), 85 (15), 73 (27), 65 (24),
59 (11).
(10 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo. Purification by silica gel column chromatography (eluent;
hexane : ethyl acetateϭ10 : 1) gave 9 (112 mg, 79%).
2-Methyl-3-phenethyl-6,7-dihydro-5H-1,4-dithiepine (7) To a toluene
9: Colorless oil; 1H-NMR (300 MHz, CDCl3) d: 1.47 (3H, s), 3.38 (2H, d,
(3 ml) solution of 5 (60 mg, 0.22 mmol) was added 1,8-diazabicyclo[5.4.0]- Jϭ6.6 Hz), 3.85—3.98 (4H, m), 5.51 (1H, d, Jϭ15.4 Hz), 5.98 (1H, dt,
undec-7-ene (DBU) (0.16 ml, 1.12 mmol) and methanesulfonyl chloride Jϭ15.4, 6.6 Hz), 7.15—7.31 (5H, m). IR (CHCl3) cmϪ1: 3009, 2990, 2889,
(0.05 ml, 0.67 mmol) at 0 °C. The reaction mixture was refluxed for 18 h 1497, 1450, 1337, 1196, 1042, 976, 860. EI-MS m/z: 204.1144 (Calcd for
under a nitrogen atmosphere, poured into water (10 ml), and finally extracted C13H16O2: 204.1150). MS (20 eV) m/z: 204 (Mϩ, 1), 189 (100), 117 (13), 87
with ethyl acetate (20 mlϫ3). The combined organic layer was washed with (47), 58 (17).
brine (10 ml), dried over anhydrous magnesium sulfate, filtered, then con-
centrated in vacuo. The residue was purified by silica gel column chro-
matography (eluent; hexane : ethyl acetateϭ5 : 1) to give 7 (50 mg, 89%).
5-Phenylpent-3-en-2-one (10) To a tetrahydrofuran (6 ml) solution of 9
(112 mg, 0.55 mmol) was added 1 N hydrochloric acid (3 ml), which was
stirred at room temperature for 9 h. The reaction mixture was poured into a
saturated sodium hydrogencarbonate solution (5 ml), then extracted with di-
1
7: Pale yellow oil; H-NMR (300 MHz, CDCl3) d: 1.77 (3H, s), 2.06—
2.10 (2H, m), 2.45 (2H, t, Jϭ6.6 Hz), 2.82 (2H, t, Jϭ6.6 Hz), 3.19—3.23 ethyl ether (10 mlϫ3). The combined organic layer was washed with brine
(4H, m), 7.18—7.30 (5H, m). IR (CHCl3) cmϪ1: 2928, 1215. EI-MS m/z: (10 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated
250.0855 (Calcd for C14H18S2: 250.0850). MS (70 eV) m/z: 250 (Mϩ, 35),
159 (100), 125 (11), 113 (10), 91 (27), 59 (13).
in vacuo. Purification by silica gel column chromatography (eluent;
hexane : ethyl acetateϭ8 : 1) gave 10 (88 mg, 91%).
1
1-Phenyl-4,4-ethylenedioxy-2-penten-3-yl Trifluoromethanesulfonate
10: Colorless oil; H-NMR (300 MHz, CDCl3) d: 2.24 (3H, s), 3.55 (2H,
(8) To an ethylene glycol (150 ml) solution of 5 (3.5 g, 13.0 mmol) was dd, Jϭ7.0, 1.3 Hz), 6.09 (1H, dt, Jϭ16.0, 1.3 Hz), 6.92 (1H, dt, Jϭ16.0,
added methyl iodide (40.6 ml, excess). The reaction mixture was stirred at 7.0 Hz), 7.16—7.35 (5H, m). IR (CHCl3) cmϪ1: 3009, 1670, 1362, 1258,
room temperature for 3 d under a nitrogen atmosphere, poured into water 980. EI-MS m/z: 160.0896 (Calcd for C11H12O: 160.0888). MS (20 eV) m/z:
(100 ml), and extracted with ethyl acetate (300 mlϫ3). The combined or- 160 (Mϩ, 42), 145 (19), 127 (10), 117 (100), 58 (24).
ganic layer was washed with brine (100 ml), dried over anhydrous magne-
Methyl 12-Trifluoromethanesulfonyloxy-13,13-ethylenedioxy-15,16-di-

1628
Vol. 50, No. 12
norlabda-8(17),11-dien-19-oate (11) To a tetrahydrofuran (40 ml) solu- mers.
tion of 2-methyl-1,3-dithiane (0.64 ml, 5.3 mmol) was added n-butyllithium
(2.46 M solution in hexane, 1.7 ml, 4.9 mmol) at 0 °C. The resulting mixture
1
13: Colorless oil; H-NMR (300 MHz, CDCl3) d: 0.52 (1H, s), 0.53 (2H,
s), 1.04—1.18 (2H, m), 1.18 (3H, s), 1.29—1.34 (1H, m), 1.52—1.56 (1H,
was stirred at 0 °C for 10 min under a nitrogen atmosphere. A tetrahydrofu- m), 1.70—2.41 (7H, m), 3.46 (2H, s), 3.58 (1H, s), 3.61 (3H, s), 4.57 (1H, d,
ran (3 ml) solution of 4 (1.14 g, 4.1 mmol) was added at Ϫ78 °C, and the re-
action mixture was stirred at Ϫ78 °C for 1 h., poured into water (100 ml),
Jϭ7.3 Hz), 4.85 (1H, m), 5.81—5.83 (1H, m), 6.24—6.29 (1H, m).
To an acetone (16 ml) solution of 13 (478 mg, 1.56 mmol) was added pyri-
and then extracted with ethyl acetate (200 mlϫ3). The combined organic dinium p-toluenesulfonate (392 mg, 1.56 mmol). The resultant mixture was
layer was washed with brine (100 ml), dried over anhydrous magnesium stirred at room temperature for 3 h, poured into a saturated sodium hydro-
sulfate, filtered, and concentrated in vacuo. The residue was purified by gencarbonate solution (5 ml), then concentrated in vacuo. The aqueous layer
silica gel column chromatography (eluent; hexane : ethyl acetateϭ10 : 1) to was extracted with ethyl acetate (20 mlϫ3). The combined organic layer was
give methyl 12-hydroxy-13,13-propylenedithio-15,16-dinorlabda-8(17)-en- washed with brine (10 ml), dried over anhydrous magnesium sulfate, filtered,
19-oate (1.25 g, 74%).
and concentrated in vacuo. Purification by silica gel column chromatography
(eluent; hexane : ethyl acetateϭ10 : 1) gave 13 (181 mg, 38%) and (ϩ)-14
Methyl 12-Hydroxy-13,13-propylenedithio-15,16-dinorlabda-8(17)-en-19-
1
oate: Colorless oil; H-NMR (300 MHz, CDCl3) d: 0.53 (3H, s), 1.19 (3H, [276 mg, 61% (conversion: 98%)].
s), 1.29—1.65 (3H, m), 1.45 (3H, s), 1.73—1.88 (4H, m), 1.94—2.10 (4H,
(ϩ)-14: Colorless needles; mp 75—78 °C (ether); 1H-NMR (400 MHz,
m), 2.39—2.52 (1H, m), 2.40—2.67 (3H, m), 2.86—3.02 (2H, m), 3.62 (3H, CDCl3) d: 0.53 (3H, s), 1.01—1.70 (2H, m), 1.18 (3H, s), 1.29—1.33 (1H,
s), 3.89—3.96 (1H, m), 4.82 (1H, s), 4.91 (1H, s).
To an ethylene glycol (5.2 ml) solution of the methyl 12-hydroxy-13,13-
propylenedithio-15,16-dinorlabda-8(17)-en-19-oate (340 mg, 0.82 mmol) was
m), 1.51—1.60 (3H, m), 1.77—2.02 (6H, m), 2.16—2.20 (1H, m), 2.31—
2.43 (2H, m), 2.56—2.64 (1H, m), 3.62 (3H, s), 4.45 (1H, s), 4.87 (1H, d,
Jϭ0.9 Hz), 9.76 (1H, dd, Jϭ1.6, 1.1 Hz). IR (CHCl3) cmϪ1: 2947, 2847,
added methyl iodide (2.6 ml, excess). The reaction mixture was stirred at 2361, 1717, 1450, 1161, 798, 675. EI-MS m/z: 292.2034 (Calcd for
room temperature for 6 d under nitrogen atmosphere, poured into water C18H28O3: 292.2038). MS (70 eV) m/z 292 (Mϩ, 5), 274 (28), 259 (8), 232
(20 ml), then extracted with ethyl acetate (30 mlϫ3). The combined organic (14), 214 (100), 199 (70), 143 (46), 121 (74), 106 (32), 91 (55), 55 (27).
layer was washed with brine (10 ml), dried over anhydrous magnesium sul- [a]D24 ϩ58.0° (cϭ1.2, CHCl3). Anal. Calcd for C18H28O3: C, 73.93; H, 9.65.
fate, filtered, and concentrated in vacuo. The residue was purified by silica Found: C, 73.66; H, 9.38.
gel column chromatography (eluent; hexane : ethyl acetateϭ3 : 1) to give
methyl 12-hydroxy-13,13-ethylenedioxy-15,16-dinorlabda-8(17)-en-19-oate To a tetrahydrofuran (1.5 ml) solution of (ϩ)-14 (35 mg, 0.12 mmol) was
(154 mg, 51%). added phenylselenyl chloride (30 mg, 0.16 mmol) and potassium tert-butox-
Methyl 13-Oxo-14,15,16-trinorlabda-8(17),11E-dien-19-oate [(؉)-15]
Methyl 12-Hydroxy-13,13-ethylenedioxy-15,16-dinorlabda-8(17)-en-19- ide (20 mg, 0.18 mmol) at Ϫ78 °C. The resulting mixture was stirred at
1
oate: Colorless oil; H-NMR (300 MHz, CDCl3) d: 0.51 (2H, s), 0.69 (1H, Ϫ78 °C under a nitrogen atmosphere for 1 h. Potassium tert-butoxide (20
s), 1.02—2.46 (14H, m), 1.19 (2H, s), 1.29 (1H, s), 1.32 (2H, s), 1.33 (1H, mg, 0.18 mmol) was added at Ϫ78 °C, and the reaction mixture was stirred
s), 3.63 (2H, s), 3.65 (1H, s), 3.93—3.99 (4H, m), 4.55 (0.6H, s), 4.72 at Ϫ78 °C for 2 h. Additional potassium tert-butoxide (40 mg, 0.36 mmol)
(0.3H, s), 4.857 (0.6H, s), 4.86 (0.3H, s).
was added at Ϫ78 °C, and the mixture was stirred again at Ϫ78 °C for 2
To a dichloromethane (5 ml) solution of methyl 12-hydroxy-13,13-ethyl- more h. The reaction mixture was poured into a saturated ammonium chlo-
enedioxy-15,16-dinorlabda-8(17)-en-19-oate (104 mg, 0.28 mmol) was ride solution (5 ml), and extracted with ethyl acetate (10 mlϫ3). The com-
added pyridinium chlorochromate (PCC) (184 mg, 0.85 mmol) and Celite®
bined organic layer was washed with brine (10 ml), dried over anhydrous
(184 mg). The reaction mixture was stirred at room temperature under a ni- magnesium sulfate, filtered, and concentrated in vacuo. The residue was pu-
trogen atmosphere for 3 d. PCC and Celite® were then filtered off with silica rified by silica gel column chromatography (eluent; hexane : ethyl ac-
gel (eluent; ethyl acetate). The residue was purified by silica gel column etateϭ10 : 1) to give a selenylated compound as a colorless oil. To a
chromatography (eluent; hexane : ethyl acetateϭ5 : 1) to give the methyl 12-
oxo-13,13-ethylenedioxy-15,16-dinorlabda-8(17)-en-19-oate (71 mg, 69%).
dichloromethane (1 ml) solution of the above selenylated compound was
added a hydrogen peroxide solution (30% solution in water, 18 mg, 0.16
Methyl 12-Oxo-13,13-ethylenedioxy-15,16-dinorlabda-8(17)-en-19-oate: mmol). The resulting mixture was stirred at room temperature for 20 min.
Colorless oil; 1H-NMR (300 MHz, CDCl3) d: 0.56 (3H, s), 1.20 (3H, s), The mixture was filtered off (eluent; chloroform) to remove the phenylsele-
1.42—1.63 (3H, m), 1.46 (3H, s), 1.73—1.89 (2H, m), 1.96—2.22 (4H, m),
2.35—2.58 (3H, m), 2.81—2.95 (1H, m), 3.62 (3H, s), 3.95—4.06 (4H, m),
4.40 (1H, s). 4.73 (1H, s).
nenic acid. The eluate was washed with a saturated sodium hydrogencarbon-
ate solution (5 ml), dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. Purification by silica gel column chromatography
To a 1,2-dimethoxyethane (1.5 ml) solution of the ketone (45 mg, 0.12 (eluent; hexane : ethyl acetateϭ10 : 1) gave (ϩ)-15 (18.6 mg, 71%).
mmol) was added potassium tert-butoxide (28 mg, 0.25 mmol) at Ϫ50 °C.
(ϩ)-15: Pale yellow oil; 1H-NMR (400 MHz, CDCl3) d: 0.73 (3H, s),
The resulting mixture was stirred at Ϫ50 °C under a nitrogen atmosphere 1.03—1.12 (2H, m), 1.22 (3H, s), 1.33—1.36 (1H, m), 1.43—1.50 (2H, m),
for 30 min. 1,1,1-Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methane- 1.79—1.87 (2H, m), 1.99—2.04 (2H, m), 2.18—2.22 (1H, m), 2.46—2.51
sulfonamide (94 mg, 0.25 mmol) was added at Ϫ50 °C. The reaction mixture (1H, m), 2.63 (1H, d, Jϭ10.4 Hz), 3.65 (3H, s), 4.43 (1H, d, Jϭ1.5 Hz), 4.84
was stirred at Ϫ50 °C for 1 h, poured into a saturated ammonium chloride (1H, d, Jϭ1.5 Hz), 6.12 (1H, ddd, Jϭ15.7, 7.9, 0.4 Hz), 6.89 (1H, dd,
solution (10 ml), then extracted with ethyl acetate (20 mlϫ3). The combined Jϭ15.7, 10.4 Hz), 9.57 (1H, d, Jϭ7.9 Hz). IR (CHCl3) cmϪ1: 2951, 2847,
organic layer was washed with brine (10 ml), dried over anhydrous magne- 1717, 1690, 1465, 729. EI-MS m/z: 290.1897 (Calcd for C18H26O3 (Mϩ)
sium sulfate, filtered, and concentrated in vacuo. The residue was purified by 290.1882). MS (70 eV) m/z: 290 (Mϩ, 13), 230 (24), 213 (13), 181 (18), 161
silica gel column chromatography (eluent; hexane : ethyl acetateϭ8 : 1) to (18), 121 (100), 107 (88), 95 (79), 81 (61), 55 (37). [a]D24 ϩ2.42° (cϭ0.6,
give 11 (58 mg, 95%).
CHCl3).
Methyl 13-Hydroxy-15,16-dinorlabda-8(17),11E-dien-19-oate (16) To
1
11: Colorless oil; H-NMR (300 MHz, CDCl3) d: 0.65 (3H, s), 1.21 (3H,
s), 1.28—1.61 (3H, m), 1.59 (3H, s), 1.95—2.06 (3H, m), 1.70—1.87 (3H, a tetrahydrofuran (4 ml) solution of (ϩ)-15 (108 mg, 0.37 mmol) was added
m), 2.18—2.22 (1H, m), 2.41—2.48 (1H, m), 2.76—2.85 (1H, m), 3.64 (3H,
s), 3.99—4.05 (4H, m), 4.38 (1H, d, Jϭ1.2 Hz), 4.78 (1H, d, Jϭ1.5 Hz), 0.44 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 15 min
5.87 (1H, d, Jϭ10.5 Hz). under a nitrogen atmosphere, poured into a saturated ammonium chloride
methyl magnesium bromide (3.0 M solution in tetrahydrofuran, 0.15 ml,
Methyl 13-Oxo-14,15,16-trinorlabda-8(17)-en-19-oate [(؉)-14] To a solution (5 ml), then extracted with ethyl acetate (10 mlϫ3). The combined
diethyl ether (20 ml) suspension of (methoxymethyl)triphenylphosphonium organic layer was washed with brine (10 ml), dried over anhydrous magne-
chloride (2.32 g, 6.78 mmol) was added potassium tert-butoxide (761 mg,
sium sulfate, filtered, and concentrated in vacuo. The residue was purified by
6.78 mmol) at 0 °C. The resulting mixture was stirred at room temperature silica gel column chromatography (eluent; hexane : ethyl acetateϭ3 : 1) to
for 30 min under a nitrogen atmosphere. A diethyl ether (3 ml) solution of 4 gave 16 (109 mg, 97%) as a diasteremeric mixture (1 : 1).
(629 mg, 2.26 mmol) was added, and the reaction mixture was stirred at
16: Colorless oil; 1H-NMR (400 MHz, CDCl3) d: 0.60 (1.5H, s), 0.62
room temperature for 7 h. The mixture was poured into a saturated ammo- (1.5H, s), 1.01—1.09 (2H, m), 1.20 (3H, s), 1.27 (1.5H, d, Jϭ6.4 Hz), 1.28
nium chloride solution (10 ml), then extracted with diethyl ether (20 mlϫ3). (1.5H, d, Jϭ6.4 Hz), 1.31—1.32 (1H, m), 1.44—1.58 (3H, m), 1.74—1.85
The combined organic layer was washed with water (20 ml) and brine (2H, m), 1.93—2.04 (2H, m), 2.14—2.19 (1H, m), 2.28—2.30 (1H, m),
(20 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated 2.41—2.46 (1H, m), 3.63 (1.5H, s), 3.63 (1.5H, s), 4.33 (1H, quint.,
in vacuo. The residue was purified by silica gel column chromatography Jϭ6.4 Hz), 4.46 (0.5H, q, Jϭ1.7 Hz), 4.51 (0.5H, q, Jϭ1.7 Hz), 4.75 (0.5H,
(eluent; hexane : ethyl acetateϭ20 : 1) to give methyl 13-methoxy-14,15,16- q, Jϭ1.7 Hz), 4.76 (0.5H, q, Jϭ1.7 Hz), 5.51 (0.5H, dd, Jϭ15.3, 6.4 Hz),
trinorlabda-8(17),12-dien-19-oate (13) (652 mg, 94%) as a mixture of iso- 5.52 (0.5H, dd, Jϭ15.3, 6.4 Hz), 5.67 (1H, d, Jϭ15.3 Hz). IR (CHCl3) cmϪ1
:

December 2002
1629
1
(Ϫ)-1a: Colorless crystals; mp 155—161 °C (hexane/ethyl acetate); H-
2497, 2850, 1717, 1450, 1381, 1246, 1157, 983, 895. EI-MS m/z: 306.2196
(Calcd for C19H30O3: 306.2195). MS (70 eV) m/z: 306 (Mϩ, 1), 288 (6), 246
(8), 213 (9), 188 (13), 159 (15), 121 (100), 105 (23), 93 (32), 79 (22), 67
(15), 55 (82).
NMR (400 MHz, CDCl3) d: 0.81 (3H, s), 1.04—1.14 (2H, m), 1.27 (3H, s),
1.34—1.37 (1H, m), 1.43—1.50 (2H, m), 1.77—2.07 (4H, m), 2.17—2.20
(1H, m), 2.28 (3H, s), 2.45—2.50 (2H, m), 4.43 (1H, d, Jϭ1.1 Hz), 4.81
(1H, d, Jϭ1.3 Hz), 6.08 (1H, d, Jϭ15.8 Hz), 6.86 (1H, dd, Jϭ15.8, 10.3 Hz).
The proton of carboxylic acid part was not observed. 13C-NMR (75 MHz,
CDCl3) 13.6, 19.5, 24.8, 27.3, 28.9, 37.1, 37.9, 39.9, 40.9, 44.1, 55.4, 60.0,
108.8, 133.8, 146.0, 147.9, 183.4, 198.1. IR (CHCl3) cmϪ1: 3032, 3013,
2939, 1732, 1693, 1670, 1450, 1362, 1258, 1234, 1200, 995, 895. FAB-MS
m/z: 313.1787 (Calcd for C18H26O3Na: 313.1780). MS (FAB) m/z: 313
(MϩϩNa, 23). [a]D24 Ϫ10.4° (cϭ0.6, CHCl3). Anal. Calcd for C18H28O3: C,
74.45; H, 9.02. Found: C, 74.64; H, 9.45.
13-Hydroxy-15,16-dinorlabda-8(17),11E-dien-19-oic Acid (17) To a
hexamethylphosphoramide (0.5 ml) solution of 1-dodecanethiol (76 ml,
0.32 mmol) was added n-butyllithium (2.46 M solution in hexane, 0.13 ml,
17.9 mmol) at 0 °C, and the reaction mixture was stirred at room tempera-
ture for 30 min under nitrogen atmosphere. To a hexamethylphosphoramide
(1 ml) solution of 16 (10 mg, 0.03 mmol) was added the above mercaptide
solution at room temperature. The resulting mixture was stirred at room
temperature for 2.5 h, then poured into 1 N hydrochloric acid (3 ml), and ex-
tracted with diethyl ether (5 mlϫ3). The combined organic layer was washed
with water (5 ml) and brine (5 ml), dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. Purification by silica gel column chro-
matography (eluent; hexane : ethyl acetateϭ5 : 1) gave 17 (10 mg, 100%) as
a diastereomeric mixture (1 : 1).
References and Notes
1) Tanaka R., Ohtsu H., Iwamoto M., Minami T., Tokuda H., Nishino H.,
Matsunaga S., Yoshitake A., Cancer Lett., 161, 165—170 (2000).
2) Inoue M., Hasegawa S., Hirose Y., Phytochemistry, 24, 1602—1604
(1985).
3) Fang J.-M., Chen Y.-C., Wang B.-W., Cheng Y.-S., Phytochemistry, 41,
1361—1365 (1996).
4) Kuo Y.-H., Chen W.-C., J. Chin. Chem. Soc., 46, 819—824 (1999).
5) Barrero A. F., Alvarez-Manzaneda E. J., Altarejos J., Ramos J. M.,
Salido S., Bull. Soc. Chim. Fr., 130, 700—707 (1993).
6) Barrero A. F., Sánchez J. F., Elmerabet J., Jiménez-González D.,
Macías F. A., Simonet A. M., Tetrahedron, 55, 7289—7304 (1999).
7) Cacchi S., Morera E., Orter G., Tetrahedron Lett., 25, 4821—4824
(1984).
8) Takayama H., Koike T., Aimi N., Sakaki S., J. Org. Chem., 57, 2173—
2176 (1992).
9) The cyclohexenol derivative was obtained as a by-product through an
intramolecular ene reaction.
10) Node M., Kumar K., Nishide K., Ohsugi S., Miyamoto T., Tetrahedron
Lett., 42, 9207—9210 (2001).
17: Pale pink amorphous solid; 1H-NMR (400 MHz, CDCl3) d: 0.70
(1.5H, s), 0.71 (1.5H, s), 1.02—1.10 (2H, m), 1.24—1.35 (2H, m), 1.26 (3H,
s), 1.28 (1.5H, d, Jϭ6.5 Hz), 1.28 (1.5H, d, Jϭ6.5 Hz), 1.45—1.59 (2H, m),
1.76—2.04 (4H, m), 2.15—2.19 (1H, m), 2.29—2.31 (1H, m), 2.43—2.47
(1H, m), 4.34 (1H, t of quint., Jϭ6.5, 1.1 Hz), 4.46 (0.5H, d, Jϭ1.1 Hz),
4.51 (0.5H, d, Jϭ1.1 Hz), 4.75—4.77 (1H, m), 5.52 (0.5H, dd, Jϭ15.4,
6.5 Hz), 5.52 (0.5H, dd, Jϭ15.4, 6.5 Hz), 5.68 (1H, dd, Jϭ15.4, 9.7 Hz). IR
(CHCl3) cmϪ1: 3028, 2936, 2851, 1693, 1230. FAB-MS m/z: 315.1942
(Calcd for C18H28O3Na: 315.1936). MS m/z: 315 (MϩϩNa, 100).
13-Oxo-15,16-dinorlabda-8(17),11E-dien-19-oic Acid [(؊)-1a] To a
N,N-dimethylformamide (4 ml) solution of 17 (118 mg, 0.40 mmol) was
added pyridinium dichromate (PDC) (304 mg, 0.81 mmol) and Celite® (304
mg), which was stirred at room temperature for 7 h under a nitrogen atmos-
phere. PDC and Celite® were filtered off with silica gel (eluent; diethyl
ether). The crude material was purified with silica gel column chromatogra-
phy (hexane : ethyl acetateϭ3 : 1) to gave (Ϫ)-1a (110 mg, 94%).