Asymmetric synthesis of methyl (-)-13-oxo-15,16-dinorlabda-8(17),11E-dien- 19-oate, methyl ester of a potent suppressor toward carcinogenic promotor

Article abstract of DOI:10.1248/cpb.54.1333

Asymmetric synthesis of methyl ester (4) of (-)-13-oxo-15,16-dinorlabda- 8(17),11E-dien-19-oic acid (1), which exhibited the most potent activity for the prevention of incipient carcinogenesis among the isolated diterpenes from Thuja standishii and its related plants, was achieved by using methyl (-)-1,4a-dimethyl-5-oxodecahydronaphthalene-1-carboxylate (5) as a strating material, which was easily prepared on gram scale by baker's yeast-catalyzed asymmetric reduction.

Full text of DOI:10.1248/cpb.54.1333

September 2006
Notes
Chem. Pharm. Bull. 54(9) 1333—1337 (2006)
1333
Asymmetric Synthesis of Methyl (ꢀ)-13-Oxo-15,16-dinorlabda-8(17),11E-
dien-19-oate, Methyl Ester of a Potent Suppressor toward Carcinogenic
Promotor
Takahiro KATOH, Shinsuke MIZUMOTO, Masato FUDESAKA, Tetsuya KAJIMOTO, and Manabu NODE*
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University;
1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607–8412, Japan.
Received May 11, 2006; accepted June 9, 2006; published online June 13, 2006
Asymmetric synthesis of methyl ester (4) of (ꢀ)-13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid (1),
which exhibited the most potent activity for the prevention of incipient carcinogenesis among the isolated diter-
penes from Thuja standishii and its related plants, was achieved by using methyl (ꢀ)-1,4a-dimethyl-5-oxodecahy-
dronaphthalene-1-carboxylate (5) as a strating material, which was easily prepared on gram scale by baker’s
yeast-catalyzed asymmetric reduction.
Key words (ꢀ)-13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid; Thuja standishii; synthesis; (ꢀ)-1,4a-dimethyl-5-oxo-
decahydronaphthalene-1-carboxylate
A labdane-type diterpenoid, (ꢀ)-13-oxo-15,16-dinorlabda- methylene and a propane unit by Wittig-type of reactions.
8(17),11E-dien-19-oic acid (1) has been reported by Tanaka
In order to achieve the former strategy (Route A), the pre-
to have potent cancer chemopreventive activity toward papil- cursor 5 was first derived to enol triflate (9) with N-phenyl-
loma-bearing mice.1,2) The acid (1) isolated from the stem bis(trifluoromethanesulfonimide) in the presence of potas-
bark of Thuja standishii (GORD.) CARR. as a minor compo- sium tert-butoxide in good yield (84%) (Chart 2). The suc-
nent had the most potent activity for the prevention of incipi- cessive Heck reaction of 9 with methyl vinyl ketone cat-
ent carcinogenesis among the diterpenoids from the same alyzed by palladium acetate (2 mol%) and triphenylphos-
plant source. Although two other plants, Platycladus orien- phine resulted in a low yield (15%) (Table 1, entry 1). When
taris3) and Juniperus chinensis,4,5) were reported as a natural the reaction was run at higher temperature (Table 1, entries 2,
source of 1, its scarce supply from nature required efficient 3) or in the presence of a larger amount of the catalyst (Table
synthetic routes for further estimation as a cancer chemopre- 1, entry 4), higher chemical yields (up to 78%) were ob-
ventive agent. Recently we published a chemical conversion tained. Moreover, the reaction employing bis(triphenylphos-
from trans-communic acid (2), a major component of T. phine)palladium(II) chloride as a catalyst8) and running at
standishii, to 1 via allyl alcohol 3 (Fig. 1).6) Herein, as a part 100 °C gave the best result (86%) (Table 1, entry 5).
of our studies on chemoenzymatic synthesis of bioactive
Since we were able to obtain the coupled product 10 in
diterpenes, we would like to report an asymmetric total syn- good yield by using the Heck reaction, many efforts to intro-
thesis of methyl ester (4) of 1 via (ꢀ)-1,4a-dimethyl-5-oxo- duce a terminal methylene were made. For example, direct
decahydronaphthalene (5),7) which can be provided on gram conjugate addition of carbanion such as methoxymethyl
scale from s-symmetric 1,3-diketone 6 by using baker’s cuprous magnesium bromide to the C-8 position of methyl
yeast-catalyzed asymmetric reduction as a key step (Chart 1). ketone 10 was attempted in the beginning; however, all the
A synthetic approach was considered on the basis of the trials resulted in failure. Thus, the conjugated methyl ketone
plausibility that decahydronaphthalene-1-carboxylate (5) was
an excellent precursor for the synthesis of 4, and two routes
(Routes A and B) were adopted as attainable strategies
(Chart 1). The first strategy (Chart 1, Route A) was started
with linking vinyl methyl ketone to the carbonyl carbon of 5,
followed by introduction of the terminal methylene to an in-
termediate 7. The second strategy (Chart 1, Route B) passed
through aldehyde 8 (XꢁO), of which the two carbonyl
groups would be utilized to successively introduce a terminal
Fig. 1. Structures of Diterpenoids Related to 1 and trans-Communic Acid
(2)
Chart 1. Synthetic Approach of 4
∗ To whom correspondence should be addressed. e-mail: node@mb.kyoto-phu.ac.jp
© 2006 Pharmaceutical Society of Japan

1334
Vol. 54, No. 9
Chart 2. Synthetic Route of 1 from (ꢀ)-5 using Heck Reaction as a Key Step
Table 1. Heck Reaction of Enol Triflate 9 with Methyl Vinyl Ketone
(Chart 3).
Finally, elongation of the 2-propanone side chain onto the
aldehyde group of 20 was scrutinized (Table 2). Addition of
an enolate prepared from acetone with lithium hexamethyl-
silazide did not give satisfactory results (Table 2, entries 1,
2), while a better result to lead to the target molecule 4 (45%)
was obtained when aldehyde 19 was treated with tri-
phenylphosphine ylide in refluxed toluene (Table 2, entry 4).
All the spectral and physical data of our synthesized 4 com-
pletely coincided with that derived from naturally occurring
1.
Entry
Catalyst (mol%)
Time (h) Temp. (°C) Yield (%)
1
2
3
4
5
PPh3, Pd(OAc)2 (2 mol%)
PPh3, Pd(OAc)2 (2 mol%)
PPh3, Pd(OAc)2 (2 mol%)
PPh3, Pd(OAc)2 (20 mol%)
(PPh3)2PdCl2 (10 mol%)
24
24
24
24
r.t.
85
100
100
100
15
45
51
78
86
It is noteworthy that the production of conjugate aldehyde
21 decreased the chemical yield of 4. Unfortunately, neither
direct saponification of the methyl ester in 4 nor demethyla-
tion with soft nucleophiles proceeded well due to the side re-
1.5
10 was next derived to epoxide 11, which was attempted to actions such as Michael addition to the conjugated ketone
transform diketone 7 (XꢁO) by Lewis acid-catalyzed hy- moiety and migration of the double bond at the terminal
dride shift or was attacked by nucleophiles such as phenyl- olefin. In order to avoid these undesired reactions, the syn-
thiomethyl magnesium bromide and methoxymethyl magne- thetic route was revised so as to follow the same route from
sium bromide. To our disappointment, none of them gave ex- trans-communic acid (2) to 1. Namely, the carbonyl group of
pected products (Chart 2).
the conjugate ketone 4 was reduced to 3 under Luche’s con-
After experiencing the difficulties in the Route A ap- dition11) with cerium chloride and sodium borohydride and
proach, the latter strategy (Chart 1, Route B) was attempted. reoxidized after cleavage of the methyl ester with n-dode-
In order to synthesize the key intermediate 8, introduction of canthiol and n-butyllithium in HMPA12,13) via acid 22 (Chart
a C1 unit at the carbonyl carbon of 5 by a Wittig-type reac- 4).
tion using methoxymethylene phosphonium ylide was tried.
In conclusion, we have succeeded in the formal asymmet-
Surprisingly, the reaction did not afford the methyl enolate at ric synthesis of optically pure (ꢀ)-13-oxo-15,16-dinorlabda-
all while Wittig reaction with methylidene triphenylphospho- 8(17),11E-dien-19-oate (1). This synthetic route was started
rane gave 12 in almost quantitative yield (99%). Encouraged with (ꢀ)-1,4a-dimethyl-5-oxodecahydronaphthalene (5), which
by the excellent result of the conventional Wittig reaction, can be provided on gram scale by using baker’s yeast-cat-
the allylic methylene carbon of 12 was oxidized with sele- alyzed asymmetric reduction. Therefore, our strategy is ap-
nium oxide in the presence of tert-butyl hydroperoxide9) to plicable for the synthesis of many derivatives of 1, which
afford allyl alcohol 13, of which the double bond was sub- could support study on the structure–activity relationship for
jected to hydroboration–oxidation to yield diol 14. Stereo- developing novel anti-tumor agents. Further studies are in
chemistry of the secondary hydroxyl group of 14 was de- progress.
duced on the basis of the spectral data of 2-hydroxydecahy-
Experimental
dro-5,5,8a-trimethyl-1-naphthalenemethanol (15) in the liter-
General Infrared (IR) spectra were recorded on a Shimadzu FTIR-8300
ature.10) Although the oxidation of the two hydroxyl groups
diffraction grating infrared spectrophotometer and 1H-NMR spectra were
obtained on a JEOL JNM-AL300, or a Varian GEMINI 2000/200, or a Var-
could formally afford the ketoaldehyde 8 (XꢁO), the diol 14
was oxidized stepwise to carry out regioselective Wittig reac-
tion for the two carbonyl groups of 8 (XꢁO). Therefore, the
primary hydroxyl group of 14 was selectively protected with
tert-butyldimethylsilyl chloride to afford 16. The remaining
secondary hydroxyl group of 16 was then oxidized by Dess–
Martin oxidation to give ketone 17, which was successively
treated with the Wittig reagent to yield exo-olefin 18. Re-
moval of the silyl protecting group of 18 with tetrabutylam-
monium fluoride led to primary alcohol 19, of which the suc-
cessive oxidation with the Dess–Martin reagent afforded the
ian Unity INOVA-400 spectrometer with tetramethylsilane as an internal
standard. 13C-NMR spectra were obtained on a Varian GEMINI 2000/200,
or a Varian Unity INOVA-400 spectrometer with CDCl3 as an internal stan-
dard. Mass spectra (MS) were determined on a JEOL JMS-SX 102A QQ or
a JEOL JMS-GC-mate mass spectrometer. Specific rotations were recorded
on a Horiba SEPA-200 automatic digital polarimeter. Wakogel C-200 (silica
gel) (100—200 mesh, Wako) was used for open column chromatography.
Flash column chromatography was performed using Silica Gel 60N (Kanto
Chemical Co., Inc.) as a solid support of the immobile phase. Kieselgel 60
F-254 plates (Merck) were used for thin-layer chromatography (TLC). Un-
less purification with silica gel gave a pure enough compound, the com-
pounds were further treated with a recycle HPLC (JAI LC-908) on GPC col-
key intermediate 20, which corresponds to 8 (XꢁCH2) umn (JAIGEL 1H and 2H). In the case it is possible, diastereomeric mix-

September 2006
1335
Chart 3. Synthesis of the Key Intermediate (20) from (ꢀ)-5
Table 2. Introduction of a Propane Unit to the Aldehyde 20
Entry
C3 unit
Base
Solvent
Temp.
Time (h)
Yield (%)
1
2
3
4
5
Acetone
Acetone
(EtO)2P(O)CH2COCH3
Ph3PꢁCHCOCH3
Ph3PꢁCHCOCH3
LHMDS
LHMDS
n-BuLi
THF
THF
THF
Toluene
DMF
ꢀ78 °C—r.t.
ꢀ78 °C—r.t.
0 °C—r.t.
Reflux
18
24
3.5
18
48
14
29
31
45
—
130 °C
(31), 67 (23), 55 (42).
Methyl 1,4a-Dimethyl-5-(3-oxobutenyl)-1,2,3,4,4a,7,8,8a-octahydro-
naphthalene-1-carboxylate (10) Methyl vinyl ketone (199 ml,
2.45 mmol), bis(triphenylphosphine)palladium(II) chloride (17 mg,
0.024 mmol), and triethylamine (569 ml, 4.07 mmol) were added to a solu-
tion of 9 (431 mg, 1.16 mmol) in N,N-dimethylformamide (5 ml) and the
mixture was stirred for 3 h at 75 °C. After the reaction, the organic solvent
was removed in vacuo and the residue was purified by silica gel column
chromatography (hexane : ethyl acetateꢁ6 : 1) to afford 10 (277 mg, 82%) as
1
colorless amorphous. H-NMR (300 MHz, CDCl3) d: 0.92 (3H, s), 1.00—
1.40 (4H, m), 1.23 (3H, s), 1.52—1.58 (2H, m), 1.74—2.34 (5H, m), 2.25
(3H, s), 3.66 (3H, s), 6.04—6.06 (1H, m), 6.28 (1H, d, Jꢁ15.8 Hz), 7.17
(1H, d, Jꢁ15.8 Hz). 13C-NMR (100 MHz, CDCl3) d: 18.4, 19.3, 20.0, 27.4,
Chart 4. Synthesis of 1 from 4
tures were also separated by a recycle HPLC (JAI LC-908) on silica gel col- 28.1, 28.4, 37.3, 37.6, 38.2, 43.8, 51.3, 52.8, 127.5, 128.9, 143.6, 144.5,
umn (Kusano Si-10) after the purification mentioned above.
177.7, 198.5. IR (CHCl3) cmꢀ1: 3009, 2951, 1720, 1666, 1593, 1465, 1362,
Methyl 1,4a-Dimethyl-5-trifluoromethanesulfonyl-1,2,3,4,4a,7,8,8a-oc- 1258, 1238, 1177, 1153. EI-MS m/z: 290.1880 (Calcd for C18H26O3:
tahydronaphthalene-1-carboxylate (9) Potassium tert-butoxide (74 mg,
290.1882). MS (70 eV) m/z: 290 (Mꢂ, 2), 275 (9), 231 (11), 215 (23), 187
0.66 mmol) was added to a solution of (ꢀ)-5 (79 mg, 0.33 mmol) in tetrahy- (21), 159 (22), 121 (100), 108 (82), 91 (29), 55 (21).
drofuran (3 ml) at ꢀ78 °C and the mixture was stirred for 20 min. N-Phenyl-
Methyl 4,7a-Dimethyl-7b-(3-oxobutenyl)-decahydro-1-oxa-cyclopro-
bis(trifluoromethanesulfonimide) (249 mg, 0.66 mmol) was added to the re- pa[a]naphthalene-4-carboxylate (11) A saturated aqueous solution of
action mixture, which was stirred for another 20 min with keeping the tem- sodium bicarbonate (1.5 ml) was added to a solution of 10 (28 mg,
perature. After the reaction, the reaction mixture was poured into a saturated 0.096 mmol) and m-chloroperbenzoic acid (80%) (25 mg, 0.12 mmol) in
aqueous solution of ammonium chloride and extracted with diethyl ether. dichloromethane (2 ml) and the biphasic mixture was stirred vigorously for
The organic layer was washed with a saturated aqueous solution of sodium 2 h at 0 °C. After the reaction, the reaction mixture was extracted with ethyl
chloride, dried over magnesium sulfate, and condensed in vacuo. The
acetate. The organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over, and condensed in vacuo. The residue was puri-
fied by silica gel column chromatography (hexane : ethyl acetateꢁ8 : 1) to af-
residue was purified by silica gel column chromatography (hexane : ethyl ace-
1
tateꢁ5 : 1) to afford 9 (103 mg, 84%) as colorless oil. H-NMR (300 MHz,
CDCl3) d: 0.92—1.13 (1H, m), 0.96 (3H, s), 1.18—1.38 (2H, m), 1.23 (3H, ford two diastereomers of 11 (11a, b) (19 mg, 66%) as colorless crystals,
s), 1.46 (2H, m), 1.75—1.87 (2H, m), 2.00—2.28 (4H, m), 3.66 (3H, s), which were separated by HPLC on silica gel column.
5.62—5.64 (1H, m). 13C-NMR (100 MHz, CDCl3) d: 17.0, 18.7, 19.7, 24.9,
28.2, 34.6, 37.4, 39.6, 43.4, 51.4, 52.6, 115.5, 128.0, 156.1, 177.1. IR
(CHCl3) cmꢀ1: 2951, 2361, 2341, 1720, 1408, 1238, 1207, 1142. EI-MS m/z
370.1051 (Calcd for C15H21F3O5S: 370.1061). MS (70 eV) m/z: 370 (Mꢂ, 2),
11a: H-NMR (400 MHz, CDCl3) d: 0.86 (3H, s), 1.00—1.14 (2H, m),
1.17 (3H, s), 1.47 (6H, m), 1.84—1.97 (1H, m), 2.17—2.28 (2H, m), 2.24
(3H, s), 2.97 (1H, s), 3.63 (3H, s), 6.28 (1H, d, Jꢁ15.4 Hz), 7.12 (1H, d,
Jꢁ15.4 Hz). 13C-NMR (100 MHz, CDCl3) d: 14.8, 17.7, 19.9, 28.3, 28.4,
1
295 (15), 237 (28), 205 (18), 177 (30), 161 (100), 145 (38), 105 (46), 91 28.7, 37.9, 38.2, 39.0, 44.0, 51.6, 53.6, 64.8, 66.4, 129.3, 144.4, 177.7,

1336
Vol. 54, No. 9
198.3. IR (CHCl3) cmꢀ1: 3036, 3009, 2980, 2949, 2853, 1719, 1676, 1624,
1468, 1437, 1360, 1290, 1238, 1155. EI-MS m/z: 306.1826 (Calcd for
C18H26O4: 306.1831). MS (70 eV) m/z: 306 (Mꢂ, 2), 288 (2), 263 (3), 213
(2), 181 (4), 175 (8), 148 (100), 135 (60), 121(60), 109 (27), 105 (30), 91
(35), 67 (27), 55 (51).
(7H, m), 2.16—2.20 (1H, m), 3.65 (3H, s), 3.83—3.87 (1H, m), 3.95—4.00
(1H, m), 4.27 (1H, br s). 13C-NMR (100 MHz, CDCl3) d: 18.3, 19.1, 20.5,
28.7, 34.8, 38.1, 38.2, 39.8, 44.2, 51.3, 55.0, 74.8, 111.1, 159.3, 177.9. IR
(CHCl3) cmꢀ1: 3618, 3487, 3435, 3028, 2999, 2951, 2937, 1717, 1468,
1450, 1435. EI-MS m/z: 270.1831 (Calcd for C15H26O4: 270.1829). MS
(70 eV) m/z: 270 (Mꢂ, 1), 252 (5), 238 (18), 222 (14), 193 (20), 175 (37),
161 (24), 147 (20), 121 (100), 109 (58), 93 (55), 81 (76), 67 (57), 55 (83).
[a]D25ꢁꢂ35.6° (cꢁ2.15, CHCl3). Anal. Calcd for C15H26O4: C, 66.64; H,
9.69. Found: C, 66.61; H, 9.60.
(ꢁ)-Methyl 5-(tert-Butyldimethylsilyloxymethyl)-6-hydroxy-1,4a-di-
methyldecahydronaphthalene-1-carboxylate (16) tert-Butyldimethylsilyl
chloride (100 mg, 0.64 mmol) and triethylamine (167 ml, 1.20 mmol) were
added to a solution of 14 (108 mg, 0.40 mmol) in dichloromethane (5 ml)
and the mixture was stirred for 18 h at room temperature. After the reac-
tion, the mixture was poured into a saturated aqueous solution of ammonium
chloride and extracted with ethyl acetate. The organic layer was washed with
a saturated aqueous solution of sodium chloride, dried over magnesium sul-
fate, and condensed in vacuo. The residue was purified by silica gel column
chromatography (hexane : ethyl acetateꢁ5 : 1) to afford 16 (135 mg, 88%) as
a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 0.076 (3H, s), 0.079 (3H, s),
0.89 (9H, s), 0.94—1.12 (3H, m), 0.99 (3H, s), 1.19 (3H, s), 1.23—1.35
(2H, m), 1.40—1.48 (2H, m), 1.73—2.00 (4H, m), 2.06—2.20 (2H, m), 3.64
(3H, s), 3.80 (1H, dd, Jꢁ10.4, 4.2 Hz), 4.03 (1H, dd, Jꢁ10.4, 4.9 Hz),
4.22—4.23 (1H, m). 13C-NMR (100 MHz, CDCl3) d: ꢀ5.7, ꢀ5.6, 15.6,
18.0, 18.6, 18.8, 25.8 (3), 28.7, 34.8, 37.8, 38.2, 40.0, 43.6, 51.2, 54.1, 56.7,
62.8, 69.8, 178.0. IR (CHCl3) cmꢀ1: 3672, 3468, 3024, 3001, 2953, 2932,
1715, 1472, 1450, 1436. CI-MS m/z: 385.2774 (Calcd for C21H41O4Si:
385.2775). MS m/z: 385 (MꢂꢂH, 3), 367 (8), 327 (3), 251 (4), 235 (100),
175 (85), 119 (8), 105 (11), 75 (17), 57 (72). [a]D25ꢁꢂ43.1° (cꢁ0.74,
CHCl3).
1
11b: H-NMR (400 MHz, CDCl3) d: 1.00—1.10 (1H, m), 1.04 (3H, s),
1.17 (3H, s), 1.37—1.56 (3H, m), 1.60—1.96 (5H, m), 2.02—2.11 (1H, m),
2.13—2.21 (1H, m), 2.24 (3H, s), 2.93 (1H, d, Jꢁ4.8 Hz), 3.66 (3H, s), 6.29
(1H, d, Jꢁ15.4 Hz), 7.12 (1H, d, Jꢁ15.4 Hz). 13C-NMR (100 MHz, CDCl3)
d: 16.2, 18.2, 24.1, 28.3, 28.8, 35.9, 36.9, 37.5, 43.4, 45.6, 51.3, 63.8, 67.2,
130.0, 143.2, 177.8, 197.9. IR (CHCl3) cmꢀ1: 3036, 3007, 2980, 2951, 2880,
1719, 1674, 1626, 1565, 1435, 1360, 1263, 1240, 1150. EI-MS m/z:
306.1828 (Calcd for C18H26O4: 306.1831). MS (70 eV) m/z: 306 (Mꢂ, 2),
288 (2), 263 (3), 213 (3), 175 (8), 148 (100), 135 (57), 121(47), 109 (25),
105 (31), 91 (34), 55 (39).
(ꢀ)-Methyl 1,4a-Dimethyl-5-methylenedecahydronaphthalene-1-car-
boxylate (12) Potassium tert-butoxide (814 mg, 7.25 mmol) was added to
a suspension of methyltriphenylphosphonium bromide (2.59 g, 7.25 mmol)
in terahydrofuran (25 ml) and the mixture was stirred for 5 min at room tem-
perature. And then, (ꢀ)-5 (576 mg, 2.42 mmol) was added to the mixture,
which was stirred for 30 min at 60 °C. After the reaction, the reaction mix-
ture was poured into a saturated aqueous solution of ammonium chloride
and extracted with diethyl ether. The organic layer was successively washed
with a saturated aqueous solution of sodium chloride and distilled water,
dried over magnesium sulfate, and condensed in vacuo. The residue was pu-
rified by silica gel column chromatography (hexane : ethyl acetateꢁ8 : 1) to
1
afford 12 (564 mg, 99%) as a colorless oil. H-NMR (400 MHz, CDCl3) d:
0.88 (3H, s), 1.04 (1H, dt, Jꢁ13.5, 4.0 Hz), 1.15—1.27 (2H, m), 1.16 (3H,
s), 1.46—1.60 (2H, m), 1.66—1.71 (1H, m), 1.85—1.96 (4H, m), 2.09—
2.21 (2H, m), 2.26—2.34 (1H, m), 3.66 (3H, s), 4.57 (1H, m), 4.58 (1H, m).
13C-NMR (100 MHz, CDCl3) d: 18.5, 19.6, 23.9, 28.8, 29.1, 33.5, 37.5,
38.3, 40.2, 44.4, 51.2, 55.2, 104.3, 159.2, 177.9. IR (CHCl3) cmꢀ1: 2939,
2854, 1717, 1632, 1447, 1337. EI-MS m/z: 238.1776 (Calcd for C15H24O2:
236.1775). MS (70 eV) m/z: 236 (Mꢂ, 99), 204 (37), 176 (95), 161 (55), 121
(100), 107 (97), 95 (96), 81 (53), 67 (53), 55 (52). [a]D25ꢁꢀ51.5° (cꢁ0.56,
CHCl3). Anal. Calcd for C15H24O2: C, 76.23; H, 10.24. Found: C, 75.96; H,
10.27.
(ꢀ)-Methyl 5-(tert-Butyldimethylsilyloxymethyl)-6-oxo-1,4a-dimethyl-
decahydronaphthalene-1-carboxylate (17) Dess–Martin periodinane
(1.69 g, 3.97 mmol) was added to a solution of 16 (953 mg, 2.48 mmol) in
dichloromethane (35 ml) at 0 °C and the mixture was stirred for 5 h at room
temperature. After the reaction, the reaction mixture was poured into a satu-
rated aqueous solution of sodium thiosulfate and extracted with diethyl
ether. The organic layer was successively washed with a saturated aqueous
solution of sodium bicarbonate and sodium chloride, dried over magnesium
sulfate and condensed in vacuo. The residue was purified by silica gel col-
umn chromatography (hexane : ethyl acetateꢁ5 : 1) to afford 17 (915 mg,
97%) as a colorless oil. 1H-NMR (200 MHz, CDCl3) d: 0.034 (3H, s), 0.054
(3H, s), 0.55 (3H, s), 0.86 (9H, s), 1.12 (1H, dt, Jꢁ13.2, 3.9 Hz), 1.27 (3H,
s), 1.34—1.56 (2H, m), 1.67—1.90 (3H, m), 2.09—2.42 (6H, m), 3.58 (1H,
dd, Jꢁ10.4, 4.0 Hz), 3.63 (3H, s), 4.04 (1H, dd, Jꢁ10.4, 6.6 Hz). 13C-NMR
(50 MHz, CDCl3) d: ꢀ5.4, ꢀ5.2, 13.8, 18.3, 19.7, 25.8, 26.0 (3), 28.9, 38.1,
(ꢀ)-Methyl 6-Hydroxy-1,4a-dimethyl-5-methylenedecahydronaphtha-
lene-1-carboxylate (13) Selenium oxide (139 mg, 1.26 mmol) and tert-
butyl hydroperoxide (70 wt% in water, 700 ml, 5.03 mmol) were added to a
solution of 12 (634 mg, 2.51 mmol) in dichloromethane (15 ml) and the mix-
ture was stirred for 24 h at room temperature. After the reaction, the reaction
mixture was poured into a saturated aqueous solution of sodium thiosulfate
and extracted with chloroform. The organic layer was dried over magnesium
sulfate and condensed in vacuo. The residue was purified by silica gel col-
umn chromatography (hexane : ethyl acetateꢁ10 : 1→2 : 1) to afford 12
(259 mg, 44% rec.) and 13 [326 mg, 51% (conversion yield: 91%)] as color-
39.7, 43.0, 44.3, 51.4, 54.9, 57.1, 65.5, 177.0, 210.3. IR (CHCl3) cmꢀ1
:
3690, 3030, 2993, 2952, 2931, 1715, 1653, 1603, 1472, 1435. EI-MS m/z:
382.2539 (Calcd for C21H38O4Si: 382.2540). MS (70 eV) m/z: 382 (Mꢂ, 1),
325 (32), 293 (7), 265 (9), 233 (7), 213 (7), 181 (9), 173 (53), 157 (100),
121 (92), 105 (20), 91 (26), 75 (55), 55 (21). [a]D25ꢁꢀ15.8° (cꢁ0.53,
CHCl3).
1
less needles. mp. 103—104 °C (hexane/ethyl acetate). H-NMR (400 MHz,
CDCl3) d: 1.02 (1H, dt, Jꢁ13.5, 4.1 Hz), 1.08 (3H, s), 1.16—1.21 (1H, m),
1.19 (3H, s), 1.40—1.58 (4H, m), 1.76—1.82 (2H, m), 1.88—2.06 (2H, m),
2.18—2.28 (2H, m), 3.67 (3H, s), 4.35 (1H, t, Jꢁ2.9 Hz), 4.86 (1H, d,
Jꢁ1.1 Hz), 4.91 (1H, d, Jꢁ1.1 Hz). 13C-NMR (100 MHz, CDCl3) d: 18.3,
19.1, 20.5, 28.7, 34.8, 38.1, 38.2, 39.8, 44.2, 51.3, 55.0, 74.8, 111.1, 159.3,
177.9. IR (CHCl3) cmꢀ1: 3009, 2991, 2939, 2856, 1717, 1466, 1437, 1236.
EI-MS m/z: 252.1725 (Calcd for C15H24O3: 252.1726). MS (70 eV) m/z: 252
(Mꢂ, 6), 237 (12), 192 (13), 175 (95), 159 (27), 145 (19), 123 (100), 109
(48), 105 (63), 91 (54), 67 (46), 55 (74). [a]D25ꢁꢀ1.30° (cꢁ0.61, CHCl3).
Anal. Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.27; H, 9.79.
(ꢁ)-Methyl 6-Hydroxy-5-hydroxymethyl-1,4a-dimethyldecahydro-
naphthalene-1-carboxylate (14) A borane dimethyl sulfide complex
(2.0 M solution in tetrahydrofuran, 436 ml, 0.87 mmol) was added to a solu-
tion of 13 (220 mg, 0.87 mmol) in tetrahydrofuran (5 ml) and the mixture
was stirred for 2 h at room temperature. And then, hydrogen peroxide (30
wt% solution in water, 1 ml) and an aqueous solution of sodium hydroxide
(1.0 M, 1 ml) were added to the reaction mixture, which was stirred for
15 min. After the reaction, the mixture was poured into saturated aqueous
solution of ammonium chloride and extracted with ethyl acetate. The or-
ganic layer was washed with a saturated aqueous solution of sodium chlo-
ride, dried over magnesium sulfate, and condensed in vacuo. The residue
was purified by silica gel column chromatography (hexane : ethyl
acetateꢁ1 : 1) to afford 13 (16 mg, 7% rec.) and 14 [199 mg, 85% (conver-
sion yield: 91%)] as colorless crystals. mp. 116—118 °C (hexane/ethyl ac-
(ꢁ)-Methyl 5-(tert-Butyldimethylsilyloxymethyl)-6-methylene-1,4a-di-
methyldecahydronaphthalene-1-carboxylate (18) n-Butyllitium (2.60 M
solution in n-hexane, 1.9 ml, 4.93 mmol) was added to a suspension of
methyltriphenylphosphonium bromide (2.11 g, 5.92 mmol) in tetrahydrofu-
ran (30 ml) at 0 °C and the mixture was stirred for 30 min at room tempera-
ture. And then, a solution of 17 (755 mg, 1.97 mmol) in tetrahydrofuran
(10 ml) was added to the reaction mixture, which was stirred for another 5 h.
After the reaction, the mixture was poured into a saturated aqueous solution
of ammonium chloride and extracted with ethyl acetate. The organic layer
was washed with a saturated aqueous solution of sodium chloride, dried over
magnesium sulfate, and condensed in vacuo. The residue was purified by sil-
ica gel column chromatography (hexane : diethyl etherꢁ50 : 1) to afford 18
(612 mg, 82%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 0.034 (6H,
s), 0.57 (3H, s), 0.87 (9H, s), 1.06 (1H, dt, Jꢁ13.3, 4.2 Hz), 1.18 (3H, s),
1.21—1.34 (2H, m), 1.48—1.54 (1H, m), 1.71—1.86 (4H, m), 1.93—2.00
(2H, m), 2.14—2.20 (1H, m), 2.36—2.41 (1H, m), 3.62 (3H, s), 3.75 (1H,
dd, Jꢁ10.4, 7.4 Hz), 3.84 (1H, dd, Jꢁ10.4, 3.8 Hz), 4.64 (1H, m), 4.85 (1H,
m). 13C-NMR (100 MHz, CDCl3) d: ꢀ5.4, ꢀ5.3, 13.5, 18.2, 19.9, 25.8, 25.9
(3), 28.9, 38.2, 38.4, 39.4, 39.5, 44.1, 51.2, 56.2, 57.6, 59.8, 107.2, 147.2,
177.8. IR (CHCl3) cmꢀ1: 3690, 3036, 2991, 2932, 1717, 1645, 1603, 1472,
1450. EI-MS m/z: 380.2747 (Calcd for C22H40O3Si: 380.2738). MS (20 eV)
m/z: 380 (Mꢂ, 1), 365 (1), 323 (100), 291 (7), 281 (4), 263 (7), 207 (11),
189 (48), 159 (12), 147 (10), 133 (8), 105 (7), 75 (16). [a]D25ꢁꢂ30.3°
1
etate). H-NMR (400 MHz, CDCl3) d: 0.93 (3H, s), 1.03 (1H, dt, Jꢁ13.4,
4.0 Hz), 1.11—1.20 (2H, m), 1.20 (3H, s), 1.41—1.57 (2H, m), 1.75—2.13

September 2006
1337
NMR (400 MHz, CDCl3) d: 0.60 (1.5H, s), 0.62 (1.5H, s), 1.01—1.09 (2H,
m), 1.20 (3H, s), 1.27 (1.5H, d, Jꢁ6.4 Hz), 1.28 (1.5H, d, Jꢁ6.4 Hz), 1.31—
1.32 (1H, m), 1.44—1.58 (3H, m), 1.74—1.85 (2H, m), 1.93—2.04 (2H, m),
2.14—2.19 (1H, m), 2.28—2.30 (1H, m), 2.41—2.46 (1H, m), 3.63 (1.5H,
s), 3.63 (1.5H, s), 4.33 (1H, quint., Jꢁ6.4 Hz), 4.46 (0.5H, d, Jꢁ1.7 Hz),
4.51 (0.5H, d, Jꢁ1.1 Hz), 4.75—4.77 (1H, m), 5.51 (0.5H, dd, Jꢁ15.4,
6.5 Hz), 5.52 (0.5H, dd, Jꢁ15.4, 6.5 Hz), 5.68 (1H, dd, Jꢁ15.4, 9.7 Hz). IR
(CHCl3) cmꢀ1: 2947, 2850, 1717, 1450, 1381, 1246, 1157. EI-MS m/z:
306.2196 (Calcd for C19H30O3: 306.2195). MS (70 eV) m/z: 306 (Mꢂ, 1),
288 (6), 246 (8), 213(9), 188 (13), 159 (15), 121 (100), 105 (23), 93 (32), 79
(22), 67 (15), 55 (20).
(cꢁ0.85, CHCl3).
(ꢁ)-Methyl 5-Hydroxymethyl-6-methylene-1,4a-dimethyldecahydro-
naphthalene-1-carboxylate (19) Tetra-n-butylammonium fluoride (1.0 M
solution in tetrahydrofuran, 2.3 ml, 2.26 mmol) was added to a solution of 18
(574 mg, 1.51 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred
for 14 h at room temperature. After the reaction, the mixture was extracted
with ethyl acetate. The organic layer was washed with a saturated aqueous
solution of sodium chloride, dried over magnesium sulfate, and condensed
in vacuo. The residue was purified by silica gel column chromatography
(hexane : diethyl etherꢁ3 : 1) to afford 19 (382 mg, 95%) as colorless nee-
1
dles. mp. 93—94 °C (hexane/ethyl acetate). H-NMR (400 MHz, CDCl3) d:
13-Hydroxy-15,16-dinorlabda-8(17),11E-dien-19-oic Acid (22) n-
Butyllithium (2.46 M solution in n-hexane, 104 ml, 0.28 mmol) was added to
a solution of 1-dodecanethiol (66 ml, 0.28 mmol) in hexamethylphospho-
ramide and the mixture was stirred for 30 min at room temperature. The allyl
alcohol 3 (9 mg, 0.028 mmol) was added to the reaction mixture, which was
stirred for 30 min. After the reaction, the mixture was poured into a satu-
rated aqueous solution of ammonium chloride and extracted with diethyl
ether. The organic layer was washed with distilled water, dried over magne-
sium sulfate, and condensed in vacuo. The residue was purified by silica gel
column chromatography (hexane : ethyl acetateꢁ4 : 1) to afford a mixture of
0.54 (3H, s), 1.07 (1H, dt, Jꢁ13.4, 4.0 Hz), 1.19 (3H, s), 1.23—1.33 (1H,
m), 1.35—1.36 (1H, m), 1.42—1.43 (1H, m), 1.50—1.56 (1H, m), 1.73—
1.89 (3H, m), 1.93—2.00 (3H, m), 2.16—2.21 (1H, m), 2.43—2.48 (1H, m),
3.62 (3H, s), 3.73—3.88 (2H, m), 4.65 (1H, d, Jꢁ1.1 Hz), 4.97 (1H, dd,
Jꢁ2.6, 1.1 Hz). 13C-NMR (100 MHz, CDCl3) d: 13.5, 19.8, 26.0, 28.8, 38.1,
38.3, 39.1, 39.5, 44.1, 51.2, 56.0, 58.5, 58.7, 106.3, 147.4, 177.6. IR
(CHCl3) cmꢀ1: 3692, 3593, 3036, 2993, 2949, 2907, 1717, 1643, 1603,
1468, 1450. EI-MS m/z: 266.1887 (Calcd for C16H26O3: 266.1882). MS
(70 eV) m/z: 266 (Mꢂ, 5), 248 (2), 206 (4), 188 (15), 173 (8), 147 (7), 121
(100), 107 (25), 93 (21), 81 (25), 69 (22), 55 (36). [a]D25ꢁꢂ40.5° (cꢁ0.64,
CHCl3).
1
diastereomers of 22 (8 mg, quantitative) as colorless amorphous. H-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, Jꢁ6.5 Hz), 1.28 (1.5H, d,
Jꢁ6.5 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 (0.5H, t of quint., Jꢁ6.4,
1.1 Hz), 4.46 (0.5H, d, Jꢁ1.1 Hz), 4.51 (0.5H, d, Jꢁ1.1 Hz), 4.75—4.77
(1H, m), 5.52 (0.5H, dd, Jꢁ15.4, 6.5 Hz), 5.52 (0.5H, dd, Jꢁ15.4, 6.5 Hz),
5.68 (1H, dd, Jꢁ15.4, 9.7 Hz). IR (CHCl3) cmꢀ1: 3028, 2936, 2851, 1693,
1230. FAB-MS m/z: 315.1942 (Calcd for C18H28O3Na: 315.1936). MS
(FAB) m/z: 315 (MꢂNaꢂ, 100).
(ꢀ)-13-Oxo-15,16-dinorlabda-8(17),11E-dien-19-oic Acid (1) Pyri-
dinium dichromate (26 mg, 0.07 mmol) and Celite® (26 mg) were added to a
solution of 22 (8 mg, mmol) in N,N-dimethylformamide (1 ml) and the mix-
ture was stirred for 7 h at room temperature. After the reaction, the organic
solvent was removed in vacuo and purified by silica gel column chromatog-
raphy (hexane : ethyl acetateꢁ3 : 1) to afford 1 (8 mg, 99%) as colorless
crystals. The 1H-NMR spectrum of our synthesized 1 coincided with that of
naturally occurring 1.6)
(ꢀ)-Methyl 5-Formylmethyl-6-methylene-1,4a-dimethyldecahydro-
naphthalene-1-carboxylate (20) Dess–Martin periodinane (167 mg,
0.39 mmol) was added to
a solution of 19 (35 mg, 0.13 mmol) in
dichloromethane (5 ml) at 0 °C and the mixture was stirred for 4 h at room
temperature. After the reaction, the reaction mixture was poured into a satu-
rated aqueous solution of sodium thiosulfate and extracted with diethyl
ether. The organic layer was successively washed with a saturated aqueous
solution of sodium bicarbonate and sodium chloride, dried over magnesium
sulfate and condensed in vacuo. The residue was purified by silica gel col-
umn chromatography (hexane : ethyl acetateꢁ5 : 1) to afford 20 (34 mg,
98%) as colorless needles. mp. 102—104 °C (hexane/ethyl acetate). 1H-
NMR (400 MHz, CDCl3) d: 0.97 (3H, s), 1.08 (1H, dt, Jꢁ13.4, 4.0 Hz), 1.20
(3H, s), 1.20—1.30 (2H, m), 1.47—1.64 (2H, m), 1.80—1.94 (2H, m),
1.97—2.07 (2H, m), 2.19—2.24 (1H, m), 2.42—2.47 (2H, m), 3.66 (3H, s),
4.51 (1H, m), 4.94 (1H, m), 9.87 (1H, d, Jꢁ4.9 Hz). 13C-NMR (100 MHz,
CDCl3) d: 14.3, 19.4, 24.8, 28.7, 37.3, 38.0, 39.3, 40.0, 43.9, 51.4, 55.0,
67.1, 109.3, 144.6, 177.4, 205.1. IR (CHCl3) cmꢀ1: 3690, 3035, 3008.7,
2993, 2910, 1717, 1645, 1602, 1466, 1450, 1441. EI-MS m/z: 264.1725
(Calcd for C16H24O3: 264.1732). MS (70 eV) m/z: 264 (Mꢂ, 25), 249 (5),
232 (9), 220 (8), 204 (37), 189 (19), 181 (10), 161 (16), 149 (20)135 (17),
121 (100), 109 (30), 95 (25), 81 (22), 67 (15), 55 (21). [a]D25ꢁꢀ34.3°
(cꢁ0.50, CHCl3). Anal. Calcd for C16H24O3: C, 72.69; H, 9.15. Found: C,
72.72; H, 9.03.
Acknowledgements This research was financially supported in part by
Frontier Research Program and the 21st Century Center of Excellence Pro-
gram “Development of Drug Discovery Frontier Integrated from Tradition
to Proteome” of the Ministry of Education, Culture, Sport, Science and
Technology of Japan.
(ꢀ)-Methyl 13-Oxo-15,16-dinorlabda-8(17),11E-dien-19-oate (4) 1-
Triphenylphosphoranylidene-2-propanone (63 mg, 0.20 mmol) was added to
a solution of 20 (17 mg, 0.065 mmol) in toluene (2 ml) and the mixture was
stirred for 24 h at refluxing temperature. After the reaction, the organic sol-
vent was removed in vacuo and the residue was purified by silica gel column
chromatography (hexane : ethyl acetateꢁ5 : 1) to afford 4 (9 mg, 45%) as a
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1
colorless oil. H-NMR (400 MHz, CDCl3) d: 0.71 (3H, s), 1.02—1.14 (2H,
m), 1.21 (3H, s), 1.32 (1H, dd, Jꢁ12.5, 2.8 Hz), 1.42—1.50 (2H, m), 1.73—
1.89 (2H, m), 1.97—2.07 (2H, m), 2.17—2.23 (1H, m), 2.27 (3H, s), 2.43—
2.49 (2H, m), 3.65 (3H, s), 4.42 (1H, dd, Jꢁ3.0, 1.5 Hz), 4.81 (1H, dd,
Jꢁ3.0, 1.5 Hz), 6.07 (1H, d, Jꢁ15.9 Hz), 6.85 (1H, dd, Jꢁ15.9, 10.3 Hz).
13C-NMR (100 MHz, CDCl3) d: 13.5, 19.6, 25.0, 27.3, 28.7, 37.1, 38.2,
39.7, 40.9, 44.2, 51.3, 55.4, 60.0, 108.3, 133.7, 146.0, 148.1, 177.5, 198.0.
IR (CHCl3) cmꢀ1: 3690, 3038, 3001, 1719, 1670, 1645, 1624, 1603, 1545,
1533, 1466, 1434. EI-MS m/z: 304.2038 (Calcd for C19H28O3: 304.2043).
MS (70 eV) m/z: 304 (Mꢂ, 4), 289 (2), 261 (3), 244 (6), 201 (10), 161 (13),
137 (31), 121 (100), 109 (52), 93 (39), 81 (99), 77 (28), 55 (53).
[a]D25ꢁꢀ1.61° (cꢁ0.16, CHCl3).
Methyl 13-Hydroxy-15,16-dinorlabda-8(17),11E-dien-19-oate (3) So-
dium borohydride (2 mg, 0.056 mmol) was added to a solution of cerium
chloride (14 mg, 0.056 mmol) in methanol (1 ml), to which 4 (6 mg,
0.018 mmol) was added and the mixture was stirred for 1 h at 0 °C. After the
reaction, the mixture was poured into a saturated aqueous solution of ammo-
nium chloride and extracted with ethyl acetate. The organic layer was
washed with a saturated aqueous solution of sodium chloride, dried over
magnesium sulfate, and condensed in vacuo. The residue was purified by sil-
ica gel column chromatography (hexane : ethyl acetateꢁ3 : 1) to afford a
mixture of diastereomers of 3 (6 mg, 99%) as colorless amorphous. 1H-
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