Syntheses of bioactive bisabolane-type cryptomeria japonica sesquiterpenes

Article abstract of DOI:10.1271/bbb.80671

The first diastereoselective synthesis of (1S,6R)-1- hydroxy-2,7(14),10- bisabolatrien-4-one, an antifeedant against Acusta despesta and Locusta migratoria, was produced from Cryptomeria japonica (commonly known as Japanese cedar), starting from (R)-(-)-carvone via (R)-(-)-cryptomerione. The enantiomer was transformed into (1S,3R,6R)-1-hydroxy-7(14),10-bisaboladien- 4-one, a novel antifeedant against L. migratoria from the same tree, by 1,4-selective reduction of the enone moiety.

Full text of DOI:10.1271/bbb.80671

Biosci. Biotechnol. Biochem., 73 (3), 588–591, 2009
Syntheses of Bioactive Bisabolane-Type Cryptomeria japonica Sesquiterpenes
y
Nobuhiro SHIMIZU and Yasumasa KUWAHARA
Department of Bioscience and Biotechnology, Faculty of Bioenvironmental Science, Kyoto Gakuen University,
1-1 Nanjo, Sogabe, Kameoka 621-8555, Japan
Received September 24, 2008; Accepted October 20, 2008; Online Publication, March 7, 2009
[doi:10.1271/bbb.80671]
The first diastereoselective synthesis of (1S,6R)-1-
hydroxy-2,7(14),10-bisabolatrien-4-one, an antifeedant
against Acusta despesta and Locusta migratoria, was
produced from Cryptomeria japonica (commonly known
as Japanese cedar), starting from (R)-(À)-carvone via
(R)-(À)-cryptomerione. The enantiomer was trans-
formed into (1S,3R,6R)-1-hydroxy-7(14),10-bisabola-
dien-4-one, a novel antifeedant against L. migratoria
from the same tree, by 1,4-selective reduction of the
enone moiety.
Results and Discussion
The synthetic route to 1 and 2 is summarized in
Scheme 1. Bromide 3 was obtained from (R)-(ꢀ)-
carvone by following the reported conditions.5) First,
the carbonyl group of 3 was protected as a dimethyl
ketal or 1,3-dioxolane. Unfortunately, the resulting
ketals did not react with prenylmagnesium bromide in
the presence of a catalytic amount of CuBr. Although
both ketals were deprotected by increasing the dose of
CuBr, the desired (R)-(ꢀ)-cryptomerione could only be
obtained in a low yield. Using 3 equivalents of CuBr and
unprotected bromide 3 as the substrate gave (R)-(ꢀ)-
cryptomerione in a better 58% yield. The two routes
previously reported to prepare (R)-(ꢀ)-cryptomerione
needed 5 steps and the yield of each was 29.8%5) and
ca. 5%.10)
The stereoselective introduction of a hydroxyl group
at the C(5) position of (R)-(ꢀ)-carvone has been
reported by Miyashita et al.11) We presumed that the
methodology would also be efficient for our syntheses of
bisabolane-type sesquiterpenes 1 and 2. Therefore, the
Michael addition of PhSeH to (R)-(ꢀ)-cryptomerione
occurred preferentially from the ꢀ-axial face at C(6),12)
and subsequent protonation at C(1) occurred from the
ꢁ-axial face followed by reduction by LiAlH4, which
resulted in ꢀ-alcohol 4 (70%) and ꢁ-alcohol 5 (19%).
Two dienols, 4 and 5, were easily separated by
chromatography on silica gel. The THP ether of 4 was
oxidized with H2O2 to the corresponding selenoxide,
and benzeneselenenic acid was removed by refluxing
in carbon tetrachloride to give homoallyl alcohol 6, after
deprotecting the THP group with p-TsOH. Minor
alcohol 5 was transformed into epimeric homoallyl
alcohol 8 by the same procedure as that just described.
Furthermore, 8 was effectively converted into desired
alcohol 6 via the Mitsunobu reaction and subsequent
basic hydrolysis with NaOH in a 94% yield. Epoxidation
of 6 with tert-butylhydroperoxide (TBHP) in the
presence of a catalytic amount of VO(acac)2 in benzene
exclusively gave enantiomeric epoxide 7.13) Finally,
oxidation of 7 with Dess-Martin periodinane (DMP) in
CH2Cl2 and subsequent treatment of the resulting ketone
Key words: bisabolane-type sesquiterpene; cryptomer-
ione; antifeedant; diastereoselective synthe-
sis
In 1993, Nagahama and Tazaki isolated and identi-
fied, from Cryptomeria japonica, (+)-1-hydroxy-
2,7(14),10-bisabolatrien-4-one 1 as a novel bisabolane-
type sesquiterpene.1) This compound has various poten-
tial biological uses; for example, as an antifeedant
against Acusta despesta, a species of snail; as a repellent
against Armadillidium vulgare, a pill-bug; and as a
germination inhibitor against Dicotyledoneae and
Monocotyledoneae.2–4) The absolute configuration of 1
was determined by converting natural 1 into (R)-(ꢀ)-
cryptomerione and comparing its specific rotation with
those of both enantiomers of cryptomerione prepared
from (R)-(ꢀ)- and (S)-(+)-carvone.5) In addition to this,
(+)-1-hydroxy-7(14),10-bisaboladien-4-one 2 was iso-
lated and identified as a new compound in the same tree
by Nagahama et al.,6,7) and its antifeeding activity
against L. migratoria was reported by Kim et al.8)
Interestingly, the combination of compounds 1 and 2
resulted in antifeeding activity against L. migratoria,
although each of these compounds alone showed no
antifeeding activity. Therefore, the hypothesis was
proposed that compound 2, with the active site, might
bind directly to the receptors on chemosensory cells of
L. migratoria and that compound 1 might support the
binding by hydrophobic interaction on the surface of
cellulose. The stereochemistry of 2 has recently been
determined by Nakahata et al. through synthesis.9) We
report in this paper a diastereoselective synthesis of
natural enantiomer 1 and the transformation of enone 1
to an another antifeedant 2. Furthermore, we inves-
tigated an effective way to obtain (R)-(ꢀ)-cryptomer-
ione, since the reported syntheses were of multistep and
relatively low yield.5,10)
27
with neutral Al2O3 produced target enone 1 (½ꢁꢁD
20
+133.4 (c 0.8, MeOH), lit. ½ꢁꢁD
+130 (c 1.0,
MeOH)8)) in a 79% yield. The spectral data were in
agreement with those already reported.8)
In order to establish the conditions to transform 1 into
2, we studied the regioselective hydrogenation of 1 by
y
To whom correspondence should be addressed. Tel: +81-771-29-3588; Fax: +81-771-29-3429; E-mail: shimizu@kyotogakuen.ac.jp

Syntheses of Bisabolane-Type Sesquiterpenes
589
O
O
PhSe
OH
PhSe
OH
a
b
+
Br
3
(R )-(-)-cryptomerione
4
5
c
c
g
O
OH
OH
e
OH
d
O
HO
8
1
7
6
f
O
O
+
HO
HO
2
9
Scheme 1.
Reagents and conditions: (a) (CH3)2C=CHCH2MgBr, CuBr, THF, 58%; (b) (i) Ph2Se2, NaBH4, AcOH, EtOH; (ii) LiAlH4, Et2O, 89% (2 steps);
(c) (i) DHP, PPTS, CH2CH2; (ii) 30% H2O2, pyridine, CH2Cl2; (iii) CCl4, reflux; (iv) p-TsOH, MeOH, 56% from 4 and 54% from
.
5 (4 steps); (d) TBHP, cat. VO(acac)2, benzene, 94%; (e) (i) DMP, CH2Cl2; (ii) Al2O3, CH2Cl2, 79% (2 steps); (f) NiCl2 6H2O, NaBH4, MeOH,
H2O, 77%; (g) (i) p-NO2C6H4CO2H, DEAD, PPh3, benzene; (ii) 1 M NaOH, MeOH, 94% (2 steps).
H
6
H
6
O
O
H
H
H
H3C
3
3
OH
OH
H
H
1
1
H
CH3
H
H
H
H
H
H
2
9
Fig. 1. Key NOESY Correlations Observed in 2 and 9.
using a variety of reducing agents. Only the product of
1,2-reduction was obtained when L-Selectride,14,15)
DIBAL-Co(acac)2,16) and Te–NaBH417) were employed.
straightforward, easy and high yielding synthesis for
antifeedants 1 and 2 is essential to advance biological
studies. The efficient synthesis of 2 from 1 or other
intermediates in this manner is in progress.
18)
.
On the other hand, CuF(PPh3)3 2EtOH
and Zn–
KOH19) did not produce any products. Only with the
20)
.
Experimental
use of NiCl2 6H2O–NaBH4, a fair yield of desired
25
ꢁ,ꢀ-saturated ketone 2 (43%, ½ꢁꢁD +39.3 (c 0.14,
All moisture-sensitive reactions were carried out under a nitrogen
atmosphere. Solvents were dried and purified by conventional methods
prior to use. Dichloromethane was freshly distilled from CaH2, and
tetrahydrofuran and diethyl ether from sodium benzophenone kethyl
under a nitrogen atmosphere. All chemicals used were of reagent
grade. Optical rotation data were taken by a SEPA-300 high-sensitive
polarimeter (Horiba), and column chromatography was performed on
silica gel (Wakosil C-200). High-resolution mass spectra were
measured by a JMS SX-102 (Jeol) instrument. 1H-, 13C-NMR and
NOESY spectra were obtained on a Bruker Biospin AC400M NMR
spectrometer with TMS as an internal standard. GC/MS analysis was
carried out with an Agilent Technologies 6890N Network GC System
coupled with a 5975 Inert XL Mass Selective Detector, using an HP-
5MS capillary column (0.25 mm i.d. ꢂ 30 m, 0.25 mm film thickness,
Agilent Technologies Santa Clara, CA, USA). Helium was used as the
carrier gas at a flow rate of 1.00 ml/min in the splitless mode, at 60 ꢃC
for 2 min and increasing to 290 ꢃC at a rate of 10 ꢃC/min, and then held
for 5 min. Signals were acquired with a Chemstation (Hewlett-Packard,
Palo Alto, CA, USA) coupled with an MS database (Wiley 275 library,
Hewlett-Packard).
MeOH)) and epimer 9 (34%) could be obtained. The
1
GC/MS, H- and 13C-NMR spectra of 2 purified by a
silica gel column were identical with those of the natural
product.8) The absolute configuration at the C(3)
position of 2 and 9 was deduced by analyses of the
NOESY data (Fig. 1). The specific rotation of 2 was
considerably different from that of the natural compound
reported by Kim et al. (½ꢁꢁD +15.0 (c 0.1, MeOH)),8)
20
but matched that reported for the synthetic compound
by Nakahata et al. (½ꢁꢁD +37.1 (c 0.29, MeOH)).9)
22
In summary, antifeedant 1 was diastereoselectively
synthesized from brominated (R)-(ꢀ)-carvone 3 in a
21% overall yield. A one-step synthesis of (R)-(ꢀ)-
cryptomerione, an appropriate building block for the
synthesis of 1 and 2, was accomplished in a 58% yield
from 3. Although the yield of an another antifeedant
2 from 1 was only 43%, the development of a

590
N. SHIMIZU and Y. KUWAHARA
(R)-10-Bromo-1(6),8-p-methadien-2-one (3). According to the
procedure previously reported,5) (R)-(ꢀ)-carvone (7.5 g, 50 mmol)
was converted to bromide 3 in a 44% yield.
dihydropyran (336 mg, 4.0 mmol) in CH2Cl2 (10 ml) was stirred at rt
for 3 h. The mixture was diluted with EtOAc and successively washed
with water and brine. After drying over anhydrous Na2SO4, removal of
the solvent gave a residual oil, a crude THP ether, which was dissolved
in CH2Cl2 (20 ml) containing pyridine (320 ml, 4.0 mmol). Then, 30%
H2O2 (2.0 ml, 20 mmol) was added at 0 ꢃC, and the resulting solution
was stirred at rt for 1.5 h. To the solution was added water, and the
solution was extracted with EtOAc. The organic layer was washed with
brine and, after drying over anhydrous Na2SO4, the solvent was
removed in vacuo, leaving an oil which was dissolved in CCl4 (20 ml).
The mixture was refluxed for 30 min, and the solvent was removed
in vacuo. The resulting oil was dissolved in MeOH (5 ml) containing a
catalytic amount of p-TsOH. After stirring at rt for 1 h, the mixture was
diluted with EtOAc and successively washed with water and brine. The
organic layer was dried over anhydrous Na2SO4 and, after removing
the solvent in vacuo, an oil was left that, upon purification in a silica
gel column [7:1 hexane/EtOAc] afforded 6 as a colorless oil (246 mg,
56%). According to the same procedure, C(1) epimer 8 was prepared in
a 54% yield.
(R)-(ꢀ)-Cryptomerione. Magnesium turnings (8.0 g, 328 mmol)
were covered with THF (40 ml), and 1,2-dibromoethane (400 ml,
4.64 mmol) was added in one portion. After stirring the mixture for
1 min at rt, a solution of prenyl bromide (9.30 ml, 80.0 mmol) in THF
(120 ml) was added dropwise for 2 h at ꢀ15 ꢃC. The mixture was
stirred additionally for 2 h at 0 ꢃC, and the resulting solution (0.4–
0.45 M) was ready to use. To the cuprous bromide (5.16 g, 36.0 mmol)
were successively added a freshly prepared Grignard solution (160 ml)
and bromide 3 (2.75 g, 12.0 mmol) in THF (20 ml) at ꢀ15 ꢃC. After
being stirred for 30 min, the reaction mixture was quenched with
saturated NH4Cl and extracted with EtOAc. The organic layer was
washed with brine and dried over anhydrous Na2SO4. Evaporation of
the solvent in vacuo gave an oil which was chromatographed in a silica
gel column [17:1 hexane/EtOAc] to afford (R)-(ꢀ)-cryptomerione as a
25
colorless oil (1.52 g, 58%). ½ꢁꢁD ꢀ17:0 (c 1.0 CHCl3). GC-MS m=z
25
6: ½ꢁꢁD ꢀ120 (c 0.1 CHCl3). GC-MS m=z (%): 220 (Mþ, 6), 202
(%): 218 (Mþ, 11), 203 (4), 175 (24), 148 (54), 135 (41), 121 (23), 109
(63), 69 (100), 41 (54). 1H-NMR (400 MHz, CDCl3) ꢂ: 1.61 (s, 3H,
CH3), 1.65–1.74 (m, 1H, CHAHBCH2), 1.69 (d, J ¼ 1:2 Hz, 3H, CH3),
1.79 (dt, J ¼ 2:4 and 1.2 Hz, 3H, CH3), 2.04–2.13 (m, 3H,
CHAHBCH2), 2.28 (m, 1H, CHCHDCO), 2.35 (dd, J ¼ 16:0 and
13.2 Hz, 1H, CHEHFCH=), 2.46 (m, 1H, CHCHDCO), 2.59 (ddd,
J ¼ 16:0, 4.4 and 1.2 Hz, 1H, CHEHFCH=), 2.68 (m, 1H, CHCH2CO),
4.82 (s, 1H, CHGHH=), 4.85 (s, 1H, CHGHH=), 5.09 (tt, J ¼ 6:8 and
1.2 Hz, 1H, CH=C(CH3)2), 6.75 (ddd, J ¼ 5:6, 2.4 and 1.2 Hz, 1H,
CH2CH=C). 13C-NMR (100 MHz, CDCl3) ꢂ: 199.9, 150.8, 144.7,
135.4, 132.0, 123.7, 109.2, 43.5, 41.2, 34.3, 31.7, 26.6, 25.7, 17.7, 15.7.
(17), 187 (23), 159 (71), 151 (46), 109 (66), 91 (61), 69 (100), 41 (76).
1H-NMR (400 MHz, CDCl3) ꢂ: 1.05 (d, J ¼ 7:6 Hz, 3H, CH3), 1.53–
1.71 (m, 2H, CHCH2CH), 1.61 (s, 3H, CH3), 1.68 (d, J ¼ 1:2 Hz, 3H,
CH3), 2.00–2.17 (m, 4H, C(CH2)2CH), 2.38 (m, 1H, CHCH3), 2.97
(m, 1H, H-5), 3.97 (br.s, 1H, CHOH), 4.81 (s, 2H, CH2=), 5.11
(tq, J ¼ 6:8 and 1.4 Hz, 1H, CH=C(CH3)2), 5.48 (dtd, J ¼ 10:0, 2.4
and 0.8 Hz, 1H, H-4), 5.59 (ddd, J ¼ 10:0, 2.4 and 0.4 Hz, 1H, H-3).
13C-NMR (100 MHz, CDCl3) ꢂ: 152.5, 131.7, 130.3, 129.3, 124.1,
109.6, 68.7, 38.5, 34.9, 34.8, 34.4, 26.7, 25.7, 17.7, 16.0.
25
8: ½ꢁꢁD ꢀ30:5 (c 0.2 CHCl3). GC-MS m=z (%): 220 (Mþ, 4), 202
(9), 187 (14), 159 (31), 151 (37), 109 (71), 91 (49), 69 (100), 41 (66).
1H-NMR (400 MHz, CDCl3) ꢂ: 1.11 (d, J ¼ 7:2 Hz, 3H, CH3), 1.46–
1.77 (m, 2H, CHCH2CH), 1.61 (s, 3H, CH3), 1.69 (d, J ¼ 0:8 Hz, 3H,
CH3), 1.93–2.18 (m, 5H, C(CH2)2CH, CHCH3), 2.94 (m, 1H, H-5),
3.45 (ddd, J ¼ 11:6, 8.4 and 3.2 Hz, 1H, CHOH), 4.78 (dd, J ¼ 2:8 and
1.2 Hz, 1H, CHAHB=), 4.83 (d, J ¼ 0:4 Hz, 1H, CHAHB=), 5.11
(tt, J ¼ 7:2 and 1.4 Hz, 1H, CH=C(CH3)2), 5.46 (m, 2H, CH=CH).
13C-NMR (100 MHz, CDCl3) ꢂ: 152.4, 131.7, 131.5, 129.3, 124.1,
109.0, 74.5, 43.5, 39.3, 38.3, 34.0, 26.7, 25.7, 18.4, 17.7.
(1S,2S,3R,5S)-3-(Phenylseleno)-7(14),10-bisaboladien-1-ol (4) and
its C(1) epimer (5). Sodium borohydride (760 mg, 20.0 mmol) was
added in portions to a mixture of diphenyl diselenide (3.14 g,
10.0 mmol) in ethanol (25 ml) while stirring at rt. The colorless
(or faint yellow) solution of sodium benzeneselenolate obtained was
cooled to 0 ꢃC, and then acetic acid (1.30 ml, 23.0 mmol) was added. A
solution of (R)-(ꢀ)-cryptomerione (1.50 g, 10.0 mmol) in ethanol
(5 ml) was next added and the resulting mixture was stirred at 0 ꢃC for
2 h. The mixture was poured into water and extracted with EtOAc, and
the organic layer was successively washed with water and brine. After
drying over anhydrous Na2SO4, evaporation of the solvent in vacuo
gave an oil which was submitted to subsequent reduction without
purification. LiAlH4 (380 mg, 10.0 mmol) was added to a solution of
the crude selenenyl ketone (3.76 g, 10.0 mmol) in Et2O (70 ml) at
ꢀ10 ꢃC, and the mixture was stirred for 30 min. Excess hydride was
decomposed by adding wet ether, and the mixture was filtered.
Evaporation of the solvent in vacuo gave an oil which was purified in a
silica gel column [10:1–5:1 hexane/EtOAc] to afford 4 (2.65 g, 70%)
and 5 (718 mg, 19%).
(1S,2R,5S)-3,7(14),10-Bisabolatrien-1-ol (6) from (8).
A 40%
solution of DEAD in toluene (540 ml, 1.2 mmol) was added at 0 ꢃC
to a solution of 8 (88 mg, 0.40 mmol) in benzene (5 ml) containing
triphenylphosphine (524 mg, 2.0 mmol) and p-NO2C6H4CO2H
(200 mg, 1.20 mmol). The mixture was stirred at rt for 1 h and diluted
with EtOAc. After successively washing the mixture with water,
saturated NaHCO3 and brine, the organic layer was dried over
anhydrous Na2SO4. The solvent was removed in vacuo, leaving an oil
which was submitted to subsequent hydrolysis without purification. A
mixture of the crude ester and 1 M NaOH (1 ml) in MeOH (5 ml) was
stirred at rt for 1.5 h. The mixture was treated with 2N HCl and
extracted with EtOAc. The organic layer was successively washed with
water, saturated NaHCO3 and brine, and after drying (anhydrous
Na2SO4), the solvent was removed in vacuo, leaving an oil that, upon
purification in a silica gel column [8:1 hexane/EtOAc], afforded 6
(83 mg, 94%).
25
4: ½ꢁꢁD ꢀ172 (c 0.1 CHCl3). 1H-NMR (400 MHz, CDCl3) ꢂ: 1.24
(d, J ¼ 7:2 Hz, 3H, CH3), 1.49 (td, J ¼ 13:6 and 2.8 Hz, 1H, H-6A),
1.61 (s, 3H, CH3), 1.63 (td, J ¼ 13:6 and 3.6 Hz, 1H, H-6B), 1.69
(d, J ¼ 0:8 Hz, 3H, CH3), 1.84–2.16 (m, 7H, CHCH3, H-4,
C(CH2)2CH), 2.82 (tt, J ¼ 12:0 and 2.8 Hz, 1H, CH2CHCH2), 3.54
(q, J ¼ 3:6 Hz, 1H, CHSePh), 3.95 (br.s, 1H, CHOH), 4.74 (s, 1H,
CHCHD=), 4.76 (d, J ¼ 1:2 Hz, 1H, CHCHD=), 5.10 (tt, J ¼ 5:2 and
1.2 Hz, 1H, CH=C(CH3)2), 7.25 (m, 3H, aromatic of PhSe), 7.55
(m, 2H, aromatic of PhSe). 13C-NMR (100 MHz, CDCl3) ꢂ: 153.2,
134.0, 132.1, 131.6, 129.0, 127.1, 124.2, 107.9, 71.6, 49.4, 39.7, 38.6,
38.5, 35.2, 32.2, 26.8, 25.7, 18.0, 17.8.
(1S,2S,3S,4R,5R)-3,4-Epoxy-7(14),10-bisaboladien-1-ol (7). A mix-
ture of 6 (236 mg, 1.07 mmol), TBHP (70% aqueous solution, 284 ml,
2.14 mmol) and a catalytic amount of VO(acac)2 in benzene (10 ml)
was stirred at rt for 3 h. The mixture was diluted with EtOAc and
successively washed with saturated NaHCO3, water and brine. The
organic layer was dried over anhydrous Na2SO4 and, after removing
the solvent in vacuo, left epoxide 7 as an oil (237 mg, 94%) which was
submitted to subsequent oxidation without purification.
25
5: ½ꢁꢁD ꢀ208 (c 0.2 CHCl3). 1H-NMR (400 MHz, CDCl3) ꢂ: 1.23
(d, J ¼ 6:8 Hz, 3H, CH3), 1.62 (s, 3H, CH3), 1.58–1.71 (m, 2H, H-6),
1.69 (d, J ¼ 1:2 Hz, 3H, CH3), 2.00–2.15 (m, 7H, CHCH3, H-4,
C(CH2)2CH), 2.60 (tt, J ¼ 12:2 and 3.0 Hz, 1H, CH2CHCH2), 3.55 (td,
J ¼ 10:4 and 4.0 Hz, 1H, CHOH), 3.65 (q, J ¼ 3:2 Hz, 1H, CHSePh),
4.76 (s, 2H, CH2=), 5.09 (tt, J ¼ 8:8 and 1.6 Hz, 1H, CH=C(CH3)2),
7.25 (m, 3H, aromatic of PhSe), 7.56 (m, 2H, aromatic of PhSe). 13C-
NMR (100 MHz, CDCl3) ꢂ: 152.6, 134.4, 131.7, 130.7, 129.0, 127.3,
124.1, 108.0, 72.9, 52.7, 44.3, 40.9, 38.5, 38.1, 35.0, 26.8, 25.7, 17.8, 17.5.
25
½ꢁꢁD ꢀ25:6 (c 0.5 CHCl3). GC-MS m=z (%): 236 (Mþ, 3), 218
(4), 203 (4), 175 (17), 147 (16), 135 (16), 121 (16), 109 (23), 93 (23),
69 (100), 41 (54). 1H-NMR (400 MHz, CDCl3) ꢂ: 1.22 (d, J ¼ 7:2 Hz,
3H, CH3), 1.61–1.73 (m, 2H, CHCH2CH), 1.62 (s, 3H, CH3), 1.69
(s, 3H, CH3), 2.00–2.22 (m, 4H, C(CH2)2CH), 2.67 (d, J ¼ 11:2 Hz,
1H, CHCH3), 2.85 (dd, J ¼ 12:0 and 6.4 Hz, 1H, H-5), 3.20 (dd, J ¼
4:8 and 0.4 Hz, 1H, H-3), 3.23 (dd, J ¼ 4:8 and 1.2 Hz, 1H, H-4), 3.73
(m, 1H, CHOH), 4.90 (s, 1H, CHAHB=), 4.93 (s, 1H, CHAHB=), 5.11
(1S,2R,5S)-3,7(14),10-Bisabolatrien-1-ol (6) and its C(1) epimer
(8). A mixture of 4 (756 mg, 2.0 mmol), PPTS (51 mg, 0.20 mmol) and

Syntheses of Bisabolane-Type Sesquiterpenes
(m, 1H, CH=C(CH3)2). 13C-NMR (100 MHz, CDCl3) ꢂ: 150.7, 132.1,
591
References
123.6, 110.7, 69.3, 59.5, 57.7, 36.4, 35.5, 35.4, 33.8, 26.4, 25.7, 17.8,
14.8.
1) Nagahama, S., and Tazaki, M., Terpenoids of wood oil of sugi
(Cryptomeria japonica): peculiarities of the Obisugi variety.
Mokuzai Gakkaishi (in Japanese), 39, 1077–1083 (1993).
2) Chen, X. H., Kim, C.-S., Kashiwagi, T., Tebayashi, S., and
Horiike, M., Antifeedants against Acusta despesta from the
Japanese cedar, Cryptomeria japonica II. Biosci. Biotechnol.
Biochem., 65, 1434–1437 (2001).
(1S,6R)-1-Hydroxy-2,7(14),10-bisabolatrien-4-one (1). To a solu-
tion of epoxide 7 (198 mg, 0.83 mmol) in CH2Cl2 (5 ml), Dess-Martin
periodinane (1.06 g, 2.49 mmol) was added at 0 ꢃC. The mixture was
stirred for 30 min and then diluted with EtOAc. After adding saturated
NaHCO3 and saturated Na2S2O3 to the mixture while vigorously
stirring at rt, the resulting solution was extracted with EtOAc, before
the organic layer was successively washed with water and brine, dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue was
dissolved in CH2Cl2 (5 ml) and a moderate amount of neutral alumina
was added. After stirring at rt for 1 h, the mixture was filtered, and the
solvent was concentrated in vacuo. The residual oil was chromato-
graphed in a silica gel column [3:1 hexane/EtOAc] to afford 1 as a
colorless oil (155 mg, 79%).
3) Morisawa, J., Kim, C.-S., Kashiwagi, T., Tebayashi, S., and
Horiike, M., Repellents in the Japanese cedar, Cryptomeria
japonica, against the pill-bug, Armadillidium vulgare. Biosci.
Biotechnol. Biochem., 66, 2424–2428 (2002).
4) Chen, X. H., Kashiwagi, T., Tebayashi, S., and Kim, C.-S.,
Germination inhibitor from the Japanese cedar Cryptomeria
japonica. Z. Naturforsch., 60C, 79–82 (2005).
5) Kim, C.-S., Morisawa, J., Nishiyama, N., Kashiwagi, T.,
Tebayashi, S., and Horiike, M., Determination of the absolute
configuration of (+)-2,7(14),10-bisabolatrien-1-ol-4-one from
Japanese cedar Cryptomeria japonica. Biosci. Biotechnol.
Biochem., 66, 1997–2000 (2002).
27
½ꢁꢁD +133.4 (c 0.8 MeOH). GC-MS m=z (%): 234 (Mþ, 2), 219
(1), 191 (10), 173 (5), 163 (6), 109 (14), 93 (11), 69 (100), 41 (44).
1H-NMR (400 MHz, CDCl3) ꢂ: 1.62 (s, 3H, CH3), 1.69 (d, J ¼ 0:8 Hz,
3H, CH3), 1.80 (t, J ¼ 1:6 Hz, 3H, CH3), 2.07 (dd, J ¼ 9:2 and 5.6 Hz,
2H, CH2C=), 2.17 (q, J ¼ 7:0 Hz, 2H, CH2CH=), 2.36 (dd, J ¼ 16:4
and 14.0 Hz, 1H, CHAHBCO), 2.55 (dd, J ¼ 16:4 and 3.6 Hz, 1H,
CHAHBCO), 2.68 (ddd, J ¼ 14:0, 10.0 and 4.0 Hz, 1H, H-6), 4.50 (ddt,
J ¼ 11:6, 5.6 and 2.0 Hz, 1H, CHOH), 5.04 (s, 2H, CH2=), 5.10
(tt, J ¼ 6:8 and 1.4 Hz, 1H, CH=C(CH3)2), 6.72 (t, J ¼ 1:6 Hz, 1H,
CHCH=C). 13C-NMR (100 MHz, CDCl3) ꢂ: 198.4, 147.4, 147.2,
135.1, 132.6, 123.4, 112.7, 69.2, 52.0, 41.6, 33.3, 26.3, 25.7, 17.8, 15.3.
HR-FABMS m=z (M + H)þ: calcd. 235.1699 for C15H23O2, found
235.1692.
6) Nagahama, S., Tazaki, M., Nomura, H., Mishimura, K.,
Tanjima, M., and Iwashita, Y., Terpenoids of the wood oil
of sugi (Cryptomeria japonica) IV. Mokuzai Gakkaishi (in
Japanese), 429, 1127–1133 (1996).
7) Nagahama, S., Iwaoka, T., and Ashitani, T., Terpenoids of the
wood oil of sugi (Cryptomeria japonica) VI. Mokuzai Gakkaishi
(in Japanese), 46, 225–230 (2000).
8) Kashiwagi, T., Wu, B., Iyota, K., Chen, X. H., Tebayashi, S.,
and Kim, C.-S., Antifeedants against Locusta migratoria from
the Japanese cedar, Cryptomeria japonica. Biosci. Biotechnol.
Biochem., 71, 966–970 (2007).
(1S,3R,6R)-1-Hydroxy-7(14),10-bisaboladien-4-one (2) and its C(3)
epimer (9). To a solution of 1 (23 mg, 98.3 mmol) in MeOH (1.2 ml)
9) Nakahata, T., Satoh, Y., and Kuwahara, S., Synthesis and
stereochemical determination of an antifeeding bisabolanoid
from Japanese cedar. Tetrahedron Lett., 49, 2438–2441
(2008).
.
were added NiCl2 6H2O (1.16 g, 4.9 mmol) and then distilled water
(0.2 ml). NaBH4 (74 mg, 1.97 mmol) was next added, and the reaction
mixture was stirred at rt for 2 h. The mixture was treated with water
and extracted with EtOAc. The organic layer was washed with brine,
and after drying (anhydrous Na2SO4), the solvent was removed
in vacuo, leaving an oil that, upon purification in a silica gel column
[3:1 hexane/EtOAc] afforded 2 as a white crystalline solid (10 mg,
43%) and 9 as an oil (8 mg, 34%).
10) Macaev, F., Vlad, L., and Gudima, A., Selective synthesis of
carvone and cryptomerione from ꢁ-pinene. Chem. Nat. Comp.,
42, 301–303 (2006).
11) Miyashita, M., Suzuki, T., and Yoshikoshi, A., Highly efficient
conversion of (ꢀ)-carvone to (+)-5ꢀ-hydroxycarvone. J. Org.
Chem., 50, 3377–3380 (1985).
25
2: Mp 76.5–77 ꢃC. ½ꢁꢁD +39.3 (c 0.14 MeOH). GC-MS m=z (%):
236 (Mþ, 2), 218 (16), 193 (12), 175 (14), 149 (12), 109 (31), 69 (100),
41 (50). 1H-NMR (400 MHz, CDCl3) ꢂ: 1.06 (d, J ¼ 6:4 Hz, 3H,
CH3), 1.09 (m, 1H, CHCHAHBCH), 1.48 (q, J ¼ 13:0 Hz, 1H,
CHCHAHBCH), 1.62 (s, 3H, CH3), 1.69 (d, J ¼ 0:8 Hz, 3H, CH3),
1.98–2.10 (m, 2H, CH2 CH2C=), 2.17 (q, J ¼ 6:8 Hz, 2H, CH2CH=),
2.32–2.40 (m, 3H, CH2CO, H-6), 2.53 (m, 1H, CHCH3), 4.01 (m, 1H,
CHOH), 5.03 (s, 1H, CHAHB=), 5.04 (t, J ¼ 1:6 Hz, 1H, CHAHB=),
5.11 (tt, J ¼ 6:8 and 1.6 Hz, 1H, CH=C(CH3)2). 13C-NMR (100 MHz,
CDCl3) ꢂ: 210.4, 148.2, 132.6, 123.4, 112.5, 69.7, 53.5, 44.1, 42.3,
41.4, 32.9, 26.2, 25.7, 17.8, 14.2. HR-FABMS m=z (M + H)þ: calcd.
237.1855 for C15H25O2, found 237.1853.
12) Miyashita, M., and Yoshikoshi, A., Facile and highly efficient
conjugate addition of benzeneselenol to ꢁ,ꢀ-unsaturated
carbonyl compounds. Synthesis, 664–666 (1980).
13) Sharpless, K. B., and Michaelson, R. C., High stereo- and
regioselectivities in the transition metal catalyzed epoxidations
of olefinic alcohols by tert-butyl hydroperoxide. J. Am. Chem.
Soc., 95, 6136–6137 (1973).
14) Brown, H. C., and Krishnamurthy, S., Forty years of hydride
reductions. Tetrahedron, 35, 567–607 (1979).
15) Brown, H. C., and Krishnamurthy, S., Boranes for organic
reductions. Aldrichimica Acta, 12, 3–11 (1979).
25
9: ½ꢁꢁD +13.3 (c 0.09 MeOH). GC-MS m=z (%): 236 (Mþ, 3), 218
16) Ikeno, T., Kimura, T., Ohtsuka, Y., and Yamada, T., Selective
1,4-reduction of ꢁ,ꢀ-unsaturated carbonyl compounds by
combined use of bis(1,3-diketonato)cobalt(II) complex and
diisobutylaluminum hydride. Synlett, 96–98 (1999).
17) Yamashita, M., Kato, Y., and Suemitsu, R., Selective reduction
of ꢁ,ꢀ-unsaturated carbonyl compounds by sodium hydro-
telluride. Chem. Lett., 9, 847–848 (1980).
(11), 193 (17), 175 (13), 147 (6), 109 (34), 69 (100), 41 (40). 1H-NMR
(400 MHz, CDCl3) ꢂ: 1.12 (d, J ¼ 6:8 Hz, 3H, CH3), 1.61 (d, J ¼
2:0 Hz, 3H, CH3), 1.69 (d, J ¼ 0:8 Hz, 3H, CH3), 1.91 (m, 2H,
CHCH2CH), 2.05 (m, 2H, CH2C=), 2.14 (m, 2H, CH2CH=), 2.46
(q, J ¼ 8:4 Hz, 1H, H-6), 2.63–2.69 (m, 2H, CH2CO), 2.74 (q, J ¼
7:2 Hz, 1H, CHCH3), 4.17 (br.q, J ¼ ca. 5.0 Hz, 1H, CHOH), 4.88
(s, 1H, CHAHB=), 4.97 (s, 1H, CHAHB=), 5.08 (tt, J ¼ 6:8 and
1.4 Hz, 1H, CH=C(CH3)2). 13C-NMR (100 MHz, CDCl3) ꢂ: 213.0,
149.0, 132.3, 123.5, 112.5, 66.9, 50.7, 40.5, 37.6, 34.6, 26.5, 25.7, 17.8,
15.6. HR-FABMS m=z (M + H)þ: calcd. 237.1855 for C15H25O2,
found 237.1863.
18) Mori, A., Fujita, A., Kajiro, H., Nishihara, Y., and Hiyama, T.,
Conjugate reduction of ꢁ,ꢀ-unsaturated ketones with hydro-
silane mediated by copper(I) salt. Tetrahedron, 55, 4573–4582
(1999).
19) Fairli, J. C., Hodgson, G. L., and Money, T., Synthesis of
(ꢄ)-camphor. J. Chem. Soc., Perkin Trans. 1, 2109–2112
(1973).
Acknowledgments
20) Khurana, J. M., and Sharma, P., Chemoselective reduction of
ꢁ,ꢀ-unsaturated aldehydes, ketones, carboxylic acids, and esters
with nickel boride in methanol-water. Bull. Chem. Soc. Jpn., 77,
549–552 (2004).
This work was supported, in part, by grant-aid for
young scientists (B) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT),
Japan (no. 20780086).