Oxidation of cyclopropane terpenoids with ruthenium tetraoxide.

Article abstract of DOI:10.1248/cpb.51.291

Oxidation products of cyclopropanoid terpenes, (-)-carane (4), (+)-cyclosativene (5), laurinterol methyl ether (6), and thujopsane (7), with ruthenium tetraoxide were investigated.

Full text of DOI:10.1248/cpb.51.291

March 2003
Chem. Pharm. Bull. 51(3) 291—294 (2003)
291
Oxidation of Cyclopropane Terpenoids with Ruthenium Tetraoxide
Takahiro KAWAI, Takashi OOI, and Takenori KUSUMI*
Faculty of Pharmaceutical Sciences, Tokushima University; Tokushima 770–8505, Japan.
Received October 31, 2002; accepted December 18, 2002
Oxidation products of cyclopropanoid terpenes, (؊)-carane (4), (؉)-cyclosativene (5), laurinterol methyl
ether (6), and thujopsane (7), with ruthenium tetraoxide were investigated.
Key words absolute configuration; ruthenium tetraoxide; terpene; cyclopropane
Recently, we have reported the isolation of a new produce unexpected products.
sesquiterpene, cyclosinularane (1) from a soft coral collected
Oxidation of (؉)-Cyclosativene Commercially avail-
off Ishigaki Island.1) The compound is a tetracyclic hydrocar- able (ϩ)-cyclosativene (5) afforded three products, 13 (15%),
bon composed of a cyclopropane ring. Its absolute configura- 14 (7%) and 16 (5%), by the ruthenium oxidation.
tion has been undetermined because it is an oily substance
The major product 13 exhibited a molecular ion at m/z
and no oxygen function necessary for chemical derivatization 220.1835 (C15H24O) and it showed a carbon signal at d 74.5
is present. If a carbonyl group could be introduced on one of (s) due to an oxygenated quaternary carbon in its 13C-NMR
the methylene carbons, the absolute configuration would be spectrum. The cyclosativene framework and the position of
determined by means of the modified Mosher’s method2) the hydroxy group were deduced by the extensive study of
after the carbonyl is reduced to a hydroxy group. This the two dimensional (2D) NMR spectra including the het-
seemed feasible because Hasegawa and co-workers reported eronuclear multiple bond connectivity (HMBC) spectrum.
that ruthenium tetraoxide oxidation of cyclopropyl hydrocar- The correlations observed between protons and carbons are
bons afforded a-ketocyclopropanes as exemplified by reac- illustrated in 13a. The orientation of the hydroxy group was
tion 2 to 3.3) Coudret and co-workers also reported the same supposed to be a, that is C-5(R), by the cross peaks observed
category of the reactions.4)
in the nuclear Overhauser effect spectroscopy (NOESY)
Because of the limited amount of 1, (Ϫ)-carane (4), (ϩ)- spectrum [13b], and the a-orientation was further confirmed
cyclosativene (5), laurinterol methyl ether (6), and thujop- by the titration study using a paramagnetic shift reagent,
sane (7) were chosen as substrates, and they were subjected Eu(fod)3.6) The downfield shift of H-1 is greater (Ddϭ0.46)
to ruthenium tetraoxide oxidation.
than that of H-7 (Ddϭ0.25) when Eu(fod)3/13ϭ0.27 in 54
mM CDCl3 solution of 13.
Results and Discussions
The second product had an unexpected structure. The mol-
The reaction conditions were the same as those reported ecular formula was established by high resolution (HR)-MS
by Hasegawa and co-workers.3) The substrate was treated as C14H21ClO, showing that one carbon was eliminated from
with ruthenium chloride (0.2—0.3 eq) and an excess (3 eq) of cyclosativene (5) and a chlorine atom was incorporated,
sodium periodate in carbon tetrachloride-acetonitrile and a which was verified by appearance of Mϩ2 ion at m/z 242
phosphate buffer solution (pH 7). The reaction was carried (33% intensity of the molecular ion). The IR absorption at
out at room temperature (rt) for 24—26 h.
1748 cmϪ1 and the 13C signal at d 216.8 indicated the pres-
Oxidation of (؊)-Carane and Application of the Modi- ence of a cyclopentanone moiety. Two possible structures, 14
fied Mosher’s Method (Ϫ)-Carane (4) was prepared from and 14Ј, were deducible for this product even after the 2D
commercially available (ϩ)-3-carene by borane reduction. NMR (heteronuclear single quantum coherence (HSQC),
The ruthenium oxide oxidation of 4 for 24 h afforded 5-cara- HMBC, NOESY etc.) studies, because there was an ambigu-
none (8) in 75% yield. The ketone was reduced with di- ity in the assignment of two methine signals at dC 57.1/dH
isobutylaluminum hydride, and the volatile alcohol (9) was, 3.68 (br s) and dC 61.4/dH 2.77 (br s). These signals could be
without purification, converted to (R)- and (S)-methoxy- assigned as C-7 and C-9 of either 14 or 14Ј. Therefore, this
(phenyl)trifluoromethylacetic acid (MTPA) esters (10, 11) by product was transformed into an alcohol (15) by reduction
using 2,4,6-trinitrochlorobenzene as a condensation reagent.5) with sodium borohydride. C-8 of 15 appears at d 80.6, and
The b-configuration of the oxygen function at C-5 was deter- by the HSQC spectrum, H-8 (d 3.81) was assignable. H-8 is
mined by the nuclear Overhauser effects (NOEs) observed coupled with H-9 (d 2.47) (Jϭ3.6 Hz) which was further cor-
between 5a-H and 3a-H as well as 5a-H and 6a-H observed related with a methine (dH 4.25/dC 56.5) assignable as H-7.
for 11. The Dd values [d(S)-MTPAϪd(R)-MTPA] were calculated Structure 15 was eventually confirmed by the NOESY spec-
as shown in 12.2) The absolute configuration predicted on the trum (see 15), and these findings led to the structure of 14 as
basis of these values is identical with the known one.
the oxidation product.
These results indicated that combination of the ruthenium
The third oxidation product (C15H22O4 by HR-MS: m/z
tetroxide oxidation and the modified Mosher’s method would 267.1597 [Mϩ1]) showed two signals of ester carbonyl car-
be useful for the absolute configuration determination of cy- bons at d 167.1 (s) and 168.0 (s). The IR spectrum exhibited
clopropane terpenoids.
a strong absorption band at 1749 cmϪ1, suggesting the pres-
Encouraged by the positive findings, we further advanced ence of strained ester moieties. In the 13C-NMR spectrum an
toward more complex cyclopropanoids, which turned out to acetalic carbon shows a signal at d 110.1 (C-8), to which two
* To whom correspondence should be addressed. e-mail: tkusumi@ph2.tokushima-u.ac.jp
© 2003 Pharmaceutical Society of Japan

292
Vol. 51, No. 3
Fig. 1. A Possible mechanism to Produce the Chloroketone (14) from Cy-
closativene (5)
Here we considered the pathway to produce 13, 14, and
16. Inertness of the methylene group at C-10 of cy-
closativene (5) against oxidation may be ascribed to the steric
hindrance by the surrounding aliphatic moieties, especially
from methyl-11. It has been reported that a hydroxy group is
introduced to a tertiary carbon,7) as in the case of 13, by oxi-
dation with ruthenium tetraoxide, which can oxidize a me-
thine rather than a methylene or methyl because the C–H
bond of the former is more electron-rich than that of the lat-
ter. The oxidation at C-5 took place from the less crowded
side to give the a-hydroxy product (13).
Formation of the chloroketone (14) is quite puzzling. The
chlorine atom apparently originated from ruthenium chlo-
ride. A possible pathway leading to 14 is described in Fig. 1.
Although disfavored, the methyl hydrogens can be neverthe-
less attacked by RuO4.8) Then a chloride anion attacks at C-7
carbon with concomitant C7–C8 bond cleavage. Oxidative
cleavage of the exomethylene group with ruthenium tetraox-
ide affords 14. It is peculiar, however, that the chlorine atom
is introduced from the more hindered side (C-7) rather than
from the less crowded direction (C-9).
Peroxidation of the cyclopropane ring of 5, two methines
at C-7 and 9 giving carboxyl groups and the quaternary car-
bon at C-8 transforming to a ketone (16Ј), produces 16. To
our best knowledge, this type of oxidation of 1,1,2,3-tetra-
substituted cyclopropane may be the unprecedented one.
Oxidation of Laurinterol Methyl Ether Laurinterol
was obtained from the red alga Laurencia intermedia YA-
MADA.9) The phenolic hydroxy group was converted into a
methyl ether (6) to prevent the oxidation of the phenyl group.
Oxidation of 6 under the conditions described above afforded
a product (C16H19BrO2: HR-MS m/z 322.0546) in 32% yield.
This compound showed an intense IR absorption band at
1660 cmϪ1 due to a conjugated enone. Presence of the enone
system was further confirmed by the singlets at d 5.88 (1H)
and 1.65 (3H) ascribable to a-proton of the a,b-unsaturated
1
ketone and the olefinic methyl, respectively, in the H-NMR
spectrum and by the olefinic carbon signals at d 169.4 (s)
and 125.8 (d) and a carbonyl carbon signal at d 198.9 in the
13C-NMR spectrum. Presence of 5-bromo-2-methoxy-4-
methylphenyl group and vicinal two methylene groups were
obvious from the NMR properties, and structure 18 was as-
signed for this oxidation product.
Instead of oxidizing the methylene group (C-5) adjacent to
methyl signals at d 1.59 (s) (H-15) and 1.17 (s) (H-11) the cyclopropyl moiety, ruthenium tetraoxide cleaved, as in
showed correlation peaks in the HMBC spectrum. On the the case of 14, one (C2–C4) of the cyclopropyl bonds to give
basis of these properties as well as other NMR data, structure possibly the hydroxy ketone (17), which afforded 18 by dehy-
16 was assigned to this product.
dration.

March 2003
293
complex (10.5 ml, 110.6 mmol, 4.9 eq) at 0 °C under argon. After the mix-
ture was stirred for 19 h at rt, water was added to the reaction mixture, and
the solution was extracted with dichloromethane (ϫ3). The organic layer
was washed with brine, dried over anhydrous Na2SO4, and concentrated to
give a residue (yellow oil, 4.5 g) which was chromatographed on silica gel to
afford (Ϫ)-carane (4) (660.3 mg, 21%). 4: 1H-NMR (400 MHz, CDCl3) d:
0.40 (1H, t, Jϭ8.0 Hz, 6-H), 0.63 (1H, m, 4-H), 0.67 (1H, td, Jϭ13.2, 4.4
Hz, 2-H), 0.71 (1H, m, 1-H), 0.81 (3H, d, Jϭ6.8 Hz, 10-CH3), 0.94 (3H, s,
8-CH3), 0.97 (3H, s, 9-CH3), 1.16 (1H, m, 3-H), 1.39 (1H, m, 4-H), 1.73
(1H, m, 5-H), 1.80 (1H, m, 5-H), 1.88 (1H, ttd, Jϭ13.2, 4.4, 2.0 Hz, 2-H).
13C-NMR (100 MHz, CDCl3) d: 15.4 (C-8), 17.4 (C-7), 18.1 (C-6), 19.8 (C-
5), 21.0 (C-1), 22.2 (C-10), 28.4 (C-2), 28.7 (C-3), 29.4 (C-9), 31.2 (C-4).
GC-MS m/z 138 (Mϩ). [a]D Ϫ41.7° (cϭ2.99, EtOH) {lit. [a]D Ϫ47.7°
(cϭ3.03, EtOH)12)}.
Oxidation of Thujopsane We were further interested in
the mode of ruthenium tetraoxide oxidation of a cyclo-
propane compound. Thujopsane (7), obtained by reduction of
thujopsene with borane, was chosen as another example and
subjected to the ruthenium oxidation.
The product turned out to be a ketocarboxylic acid (19)
that was isolated as a methyl ester (20) after treatment with
diazomethane. It should be remarkable that the same com-
pound (19) was obtained by oxidation of thujopsene under
the same conditions. Although the latter type of oxidative
cleavage of an olefin is already documented,10,11) the rapture
of the sigma bond adjacent to a cyclopropane ring into a di-
carbonyl moiety must be unique.
Oxidation of (؊)-Carane (4) 4 (100.0 mg, 0.72 mmol) was oxidized for
1
24 h. The reaction afforded a ketone compound (8) (82.5 mg, 75 %). 8: H-
Coudret and co-workers reported the same type of oxida-
tive cleavage in the ruthenium oxide oxidation of cyclo-
propane compounds.4) According to the proposed mecha-
nism, a hydroxy group is at first introduced at C-2 as in the
case of 13, the tertiary alcohol is dehydrate to thujopsene, and
then the oxidative cleavage of the double bond takes place.
NMR (400 MHz, CDCl3) d: 0.92 (3H, d, Jϭ6.4 Hz, 10-CH3), 1.09 (1H, m,
Jϭ13.6, 4.4 Hz, 2b-H), 1.10 (3H, s, 8-CH3), 1.11 (3H, s, 9-CH3), 1.36 (1H,
d, Jϭ7.6 Hz, 6-H), 1.52 (1H, ddd, Jϭ9.4, 8.0, 4.4 Hz, 1-H), 1.57 (1H, dd,
Jϭ16.8, 13.6 Hz, 4b-H), 1.91 (1H, m, 3-H), 2.01 (1H, tdd, Jϭ9.6, 4.8,
2.8 Hz, 2a-H), 2.20 (1H, br d, Jϭ16.8 Hz, 4a-H). 13C-NMR (100 MHz,
CDCl3) d: 16.6 (C-8), 21.1 (C-10), 27.5 (C-2), 27.7 (C-7), 29.1 (C-9), 30.5
(C-1), 34.1 (C-3), 34.5 (C-6), 48.3 (C-4), 209.8 (C-5).
Reduction of 8 To a solution of 8 (39.6 mg, 0.24 mmol) in THF/
dimethoxyethane (1 : 1, 5.2 ml) was added diisobutylaluminum hydride
(0.35 ml of a 1.0 M solution in toluene, 0.35 mmol) at Ϫ60 °C. After stirring
for 5 min at Ϫ60 °C, the reaction was quenched with methanol (18 ml), and
the mixture was diluted with ether. The ethereal solution was washed with
Conclusion
Four cyclopropane terpenoids, (Ϫ)-carane (4), (ϩ)-cy-
closativene (5), laurinterol methyl ether (6), and thujopsane
(7) were subjected to ruthenium tetraoxide oxidation. (Ϫ)- saturated potassium sodium tartrate solution, and dried over Na2SO4. Filtra-
tion and concentration afforded the alcohol (9) as white crystals (42.7 mg).
Carane (4) afforded a ketone (8), the reduction product (9) of
which was subjected to the modified Mosher’s method to
confirm the absolute configuration. In the case of 5 and 6,
carbonyl functions were not introduced at the a-methylenes
9: 1H-NMR (400 MHz, CDCl3) d: 0.87 (3H, d, Jϭ6.4 Hz, 10-CH3), 1.04
(3H, s), 1.15 (3H, s), 4.29 (1H, dt, Jϭ10.8, 7.2 Hz, 5-H).
Condensation of (R)-MTPA with 9 9 (15.0 mg), 37.6 mg of 2,4,6-trini-
trochlorobenzene and 24.7 mg of (R)-MTPA were dissolved in 1.5 ml of
pyridine. After the mixture was stirred for 10.5 h, ether was added, and
organic layer was washed with 0.1 M NaOH, water, saturated aqueous cop-
per(II) sulfate and brine, dried over Na2SO4 and concentrated to yield a
residue (yellow oil, 30.3 mg). The crude product was chromatographed on
silica gel to afford the ester (10) (19.9 mg, 64.2% {two steps}) as a colorless
oil. 10: 1H-NMR (400 MHz, CDCl3) d: 0.83 (1H, m, 2b-H), 0.89 (3H, d,
Jϭ6.8 Hz, 10-CH3), 0.92 (1H, m, 4b-H), 1.00 (1H, m, 6-H), 1.02 (3H, s, 9-
CH3), 1.03 (3H, s, 8-CH3), 1.11 (1H, td, Jϭ9.2, 4.0 Hz, 1-H), 1.42 (1H, m,
3-H), 1.81 (1H, ddt, Jϭ12.6, 7.8, 2.3 Hz, 4a-H), 1.90 (1H, dddd, Jϭ14.5,
9.7, 4.8, 1.9 Hz, 2a-H), 3.56 (3H, q, Jϭ0.8 Hz, –OCH3), 5.71 (1H, dt,
Jϭ10.8, 7.6 Hz, 5-H), 7.39—7.58 (5H, Ph-H). 13C-NMR (100 MHz, CDCl3)
d: 16.3 (C-8), 21.0 (C-7), 21.3 (C-10), 22.6 (C-6), 26.0 (C-1), 27.6 (C-2),
29.7 (C-9), 30.4 (C-3), 36.1 (C-4), 55.2 (–OCH3), 75.9 (C-5), 127.6, 128.3,
129.4, 132.8 (Ph), 166.3 (CϭO). HR-MS (EI) m/z: 370.1764 (Calcd for
C20H25F3O3: 370.1756).
of the cyclopropane rings. (ϩ)-Cyclosativene (5) afforded a
tertiary alcohol 13 as well as a chloroketone 14 and an acetal
diester 16, which resulted from the oxidative degradation of
the cyclopropane ring. The cyclopropane ring of laurinterol
methyl ether (6) was labile under the oxidation conditions,
and the reaction produced a cyclohexenone (18). The ruthe-
nium oxidation of thujopsane (7) resulted in the unusual
cleavage of the sp3–sp3 sigma bond b to the cyclopropane
ring to produce a ketocarboxylic acid (19).
The result obtained for (ϩ)-cyclosativene (5) is informa-
tive for elucidating the absolute configuration of cyclosinu-
larane (1): Formation of 14 from 5 suggests that a similar
chloro ketone might be produced by ruthenium oxide oxida-
tion of 1. The ketone would be transformed to an alcohol
Condensation of (S)-MTPA with 9 Condensation of compound 9
(18.1 mg, containing solvents) with (S)-MTPA in the same manner afforded
analogous to 15, to which the modified Mosher’s method the desired product (11) (19.0 mg, 50% {two steps}) as a colorless oil. 11:
1H-NMR (400 MHz, CDCl3) d: 0.81 (1H, m, Jϭ15.6 Hz, 2b-H), 0.84 (3H, s,
would be applicable. An attempted experiment along this line
is in progress.
8-CH3), 0.90 (3H, d, Jϭ6.8 Hz, 10-CH3), 0.93 (3H, s, 9-CH3), 0.98 (1H, m,
Jϭ7.2 Hz, 4b-H), 1.02 (1H, m, 6-H), 1.06 (1H, m, 1-H), 1.42 (1H, m, 3-H),
1.83 (1H, dt, Jϭ8.0, 2.4 Hz, 4a-H), 1.88 (1H, dddd, Jϭ14.2, 9.4, 5.0,
1.8 Hz, 2a-H), 3.57 (3H, q, Jϭ0.8 Hz, –OCH3), 5.65 (1H, dt, Jϭ10.8,
7.6 Hz, 5-H), 7.39—7.57 (5H, Ph-H). 13C-NMR (100 MHz, CDCl3) d: 16.1
(C-8), 21.0 (C-7), 21.3 (C-10), 22.4 (C-6), 26.1 (C-1), 27.6 (C-2), 29.5 (C-
9), 30.4 (C-3), 36.4 (C-4), 55.4 (–OCH3), 76.1 (C-5), 127.4, 128.3, 129.4,
132.8 (Ph), 166.2 (CϭO). HR-MS (EI) m/z: 370.1751 (Calcd for
C20H25F3O3: 370.1756).
Experimental
1H- and 13C-NMR spectra were measured with JEOL AL-400 and Bruker
ARX-400 spectrometers. IR spectra were measured on an FT/IR-420 spec-
trophotometer. Low resolution (LR)-MS spectra were taken on a JEOL JMS-
DX 303 spectrometer. GC-MS spectra were taken on a HEWLETT
PACKARD 5890 Series II and a JEOL JMS-AM 150. HR-MS spectra were
taken under electron impact (EI) conditions or fast atom bombardment
(FAB) conditions using a JEOL JMS-SX102A spectrometer.
Oxidation of Cyclosativene Cyclosativene (5) (100 mg, 0.49 mmol)
was oxidized for 24 h. After the crude product was purified by preparative
TLC, 13 (16.2 mg, 0.074 mmol, 15%), 14 (8.3 mg, 0.034 mmol, 7%) and 16
(6.5 mg, 0.025 mmol, 5%) were obtained as colorless oils. 13: 1H-NMR
(400 MHz, CDCl3) d: 0.73 (1H, br d, Jϭ5.6 Hz, H-7), 0.77 (3H, s, 11-CH3),
0.87 (1H, m, 9-H), 0.89 (3H, d, Jϭ7.0 Hz, 13-CH3), 0.92 (3H, d, Jϭ7.0 Hz,
14-CH3), 1.00 (3H, s, 15-CH3), 1.03 (1H, br d, Jϭ11.6 Hz, 10a-H), 1.40
(1H, m, 3a-H), 1.44 (1H, m, 4b-H), 1.52 (1H, m, 3b-H), 1.52 (1H, m, 4a-
H), 1.53 (1H, br s, 1-H), 1.68 (1H, br d, Jϭ11.6 Hz, 10b-H), 1.70 (1H, m,
Jϭ7.0 Hz, 12-H), 1.77 (1H, br s, 6-H). 13C-NMR (100 MHz, CDCl3) d: 10.4
(C-15), 16.0 (C-13), 16.4 (C-14), 19.0 (C-11), 20.0 (C-9), 22.0 (C-8), 22.3
(C-7), 29.0 (C-3), 30.9 (C-4), 31.0 (C-10), 35.6 (C-12), 41.3 (C-1), 43.8 (C-
General Procedure of Ruthenium Tetraoxide Oxidation To a sub-
strate in carbon tetrachloride, acetonitrile, and a phosphate buffer (pH 6.86)
(1 : 1 : 1.5) was added sodium periodate (3.0 eq) and ruthenium chloride hy-
drate (0.2—0.3 eq). The mixture was stirred at rt (reaction time varied in
each reaction), diluted with water, and extracted with dichloromethane (ϫ5).
The combined organic layer was washed with a 1 : 1 mixture of saturated
sodium thiosulfate (Na2S2O3) and brine (1 : 1), and dried over anhydrous
sodium sulfate (Na2SO4), and concentrated.
Preparation of (؊)-Carane (4) To a solution of (ϩ)-3-carene (3.1 g,
22.8 mmol) in dry THF (7 ml) was added dropwise dimethyl sulfide borane

294
Vol. 51, No. 3
2), 49.3 (C-6), 74.5 (C-5). HR-MS (EI) m/z: 220.1835 (Calcd for C15H24O:
220.1827). 14: 1H-NMR (400 MHz, CDCl3) d: 0.70 (1H, qd, Jϭ13.6,
3.6 Hz, 4b-H), 0.91 (3H, d, Jϭ6.6 Hz, 13-CH3), 1.00 (3H, s, 11-CH3), 1.03
(3H, d, Jϭ6.6 Hz, 14-CH3), 1.15 (1H, td, Jϭ13.6, 4.4 Hz, 3a-H), 1.19 (1H,
Preparation of Thujopsane (7) To a solution of thujopsene (2.4 g, 11.7
mmol) in dry THF (7 ml) was added dimethyl sulfide borane complex (2.3
ml, 24.2 mmol) at 0 °C under argon. After the mixture was stirred for 15 h at
rt, water was added to the reaction mixture, and the solution was extracted
m, 5-H), 1.47 (1H, septd, Jϭ6.6, 2.2 Hz, 12-H), 1.60 (1H, br d, Jϭ13.6 Hz, with dichloromethane (ϫ3). The organic layer was washed with brine, dried
4a-H), 1.88 (1H, dt, Jϭ13.6, 3.6 Hz, 3b-H), 2.05 (1H, dd, Jϭ11.0, 3.0 Hz, over anhydrous Na2SO4 and concentrated to give a residue (yellow oil, 1.7
10b-H), 2.14 (1H, d, Jϭ11.0 Hz, 10a-H), 2.46 (1H, br d, Jϭ3.0 Hz, 1-H), g), which was chromatographed on silica gel to afford 7 (134.7 mg, 6%) as a
2.76 (1H, br s, 6-H), 2.76 (1H, br s, 9-H), 3.80 (1H, br s, 7-H). 13C-NMR colorless oil. 7: H-NMR (400 MHz, CDCl3) d: 0.012 (1H, t, Jϭ5.2 Hz, 1-
1
(100 MHz, CDCl3) d: 20.7 (C-13), 21.1 (C-14), 22.1 (C-11), 22.7 (C-4),
H), 0.39 (1H, dd, Jϭ10.0, 5.2 Hz, 1-H) 0.51 (3H, s, 8-CH3), 0.80 (1H, dd,
30.7 (C-12), 32.6 (C-10), 33.9 (C-3), 44.1 (C-5), 46.9 (C-2), 48.1 (C-1), 50.2 Jϭ10.0, 5.6 Hz, 1a-H), 0.88 (1H, m, 4b-H), 1.0 (3H, s, 8-CH3), 1.0 (3H, d,
(C-6), 56.7 (C-7), 61.2 (C-9), 219.5 (C-8). 1H-NMR (400 MHz, C6D6) d: Jϭ6.7 Hz, 2-CH3), 1.0 (1H, t, Jϭ12.8 Hz, 3b-H), 1.0 (1H, m, 4a-H), 1.1
0.47 (1H, qd, Jϭ13.4, 3.4 Hz, 4b-H), 0.75 (1H, td, Jϭ13.4, 3.4 Hz, 3a-H), (3H, s, 4a-CH3), 1.1 (1H, d, Jϭ14.2 Hz, 5a-H), 1.2 (1H, dd, Jϭ12.8, 6.0 Hz,
0.76 (3H, d, Jϭ6.4 Hz, 13-CH3), 0.77 (1H, m, 5-H), 0.77 (3H, s, 11-CH3), 3a-H), 1.2 (1H, t, Jϭ14.2 Hz, 7b-H), 1.4 (1H, d, Jϭ14.2 Hz, 7a-H), 1.5
1.00 (3H, d, Jϭ6.4 Hz, 14-CH3), 1.22 (1H, m, 12-H), 1.23 (1H, dd, Jϭ13.4,
3.4 Hz, 4a-H), 1.54 (1H, q, Jϭ1.6 Hz, 1-H), 1.61 (1H, dd, Jϭ11.0, 1.6 Hz,
(1H, d, Jϭ14.2 Hz, 6b-H), 1.5 (1H, m, 2-H), 1.7 (1H, td, Jϭ14.2, 3.2 Hz,
5b-H), 1.8 (1H, tt, Jϭ14.2, 3.2 Hz, 6a-H). 13C-NMR (100 MHz, CDCl3) d:
10b-H), 1.83 (1H, dt, Jϭ13.4, 3.4 Hz, 3b-H), 1.89 (1H, d, Jϭ11.0 Hz, 10a- 13.1 (C-1), 19.0 (C-6), 24.4 (2-CH3), 25.2 (C-1a), 27.1 (8-CH3), 27.5 (C-3),
H), 2.56 (1H, br d, Jϭ3.2 Hz, 6-H), 2.77 (1H, br s, 9-H), 3.68 (1H, br s, 7-H). 29.3 (8-CH3), 29.6 (4a-CH3), 31.1 (C-2), 31.6 (C-4a), 32.4 (C-8a), 33.4 (C-
13C-NMR (100 MHz, C6D6) d: 20.8 (C-13), 21.3 (C-14), 22.2 (C-11), 22.7 8), 36.6 (C-5), 38.6 (C-4), 40.8 (C-7). GC-MS m/z 206 (Mϩ).
(C-4), 30.8 (C-12), 32.7 (C-10), 34.0 (C-3), 44.2 (C-5), 46.6 (C-2), 48.1 (C-
Oxidation of Thujopsane (7) 7 (25.2 mg, 0.12 mmol) was oxidized for
1
1), 50.5 (C-6), 57.1 (C-7), 61.4 (C-9), 216.8 (C-8). GC-MS m/z (rel. int. %): 24 h. The H-NMR spectrum of the crude product (32.1 mg) indicated that
242 (Mϩϩ2, 33), 240 (100). HR-MS (EI) m/z: 240.1284 (Calcd for ca. 30% yield 19 was produced. The crude product was methylated with dia-
1
C14H21ClO: 240.1281). IR (liquid film) 1748 cmϪ1. 16: H-NMR (400 MHz, zomethane in an ether solution. After the solvent was removed, the residue
CDCl3) d: 0.88 (3H, d, Jϭ6.6 Hz, 13-CH3), 1.03 (3H, d, Jϭ6.6 Hz, 14-CH3), was chromatographed on silica gel to afford 20 (5.9 mg, 18% from thujop-
1.17 (3H, s, 11-CH3), 1.17 (1H, m, 4b-H), 1.28 (1H, m, 5-H), 1.47 (1H, m, sane). In another experiment, a small amount of 19 was isolated from an oxi-
12-H), 1.51 (1H, m, Jϭ14.6 Hz, 3a-H), 1.59 (3H, s, 15-CH3), 1.89 (1H, dd, dation product by chromatography on silica gel. 19: 1H-NMR (400 MHz,
Jϭ17.6, 4.0 Hz, 4a-H), 1.96 (1H, dd, Jϭ8.0, 2.6 Hz, 1-H), 2.11 (1H, ddd, CDCl3) d: 0.69 (3H, s, 8-CH3), 0.99 (3H, s, 4a-CH3), 1.16 (1H, dd, Jϭ5.9,
Jϭ14.6, 4.0, 2.0 Hz, 3b-H), 2.55 (1H, d, Jϭ19.8 Hz, 10b-H), 2.93 ( 1H, br s, 4.8 Hz, 1-H), 1.24 (3H, s, 8-CH3), 1.26 (1H, t, Jϭ13.6 Hz, 5b-H), 1.32 (1H,
6-H), 3.11 (1H, dd, Jϭ19.8, 8.0 Hz, 10a-H). 13C-NMR (100 MHz, CDCl3) td, Jϭ13.6, 3.6 Hz, 7a-H), 1.45 (1H, dt, Jϭ13.6, 3.6 Hz, 6a-H), 1.52 (1H,
d: 20.5 (C-13), 21.1 (C-14), 21.3 (C-15), 23.2 (C-11), 24.5 (C-4), 29.4 (C- dq, Jϭ13.6, 3.0 Hz, 7b-H), 1.70 (1H, br s, 1-H), 1.74 (1H, q, Jϭ13.6 Hz,
12), 34.2 (C-2), 34.4 (C-10), 34.9 (C-3), 39.9 (C-1), 47.7 (C-6), 48.5 (C-5), 6b-H), 1.74 (1H, m, 1a-H), 1.94 (1H, dq, Jϭ13.6, 2.8 Hz, 5b-H), 2.04 (1H,
110.1 (C-8), 167.1 (C-9), 168.0 (C-7). HR-MS (FAB): m/z: 267.1597 (Calcd d, Jϭ12.8 Hz, 4-H), 2.35 (3H, s, 2-CH3), 3.05 (1H, d, Jϭ12.8 Hz, 4-H). 13C-
for C15H22O4: 267.1596 [MϩϩH]). IR (liquid film) 1749 cmϪ1
Reduction of 14 Sodium borohydride (5.8 mg) was added to 0.8 mg of CH3), 29.6 (8-CH3), 32.4 (2-CH3), 32.6 (C-1a), 36.0 (C-8), 38.0 (C-4a), 39.9
.
NMR (100 MHz, CDCl3) d: 17.0 (C-1), 18.4 (C-6), 26.8 (4a-CH3), 29.0 (8-
14 in 0.1 ml of MeOH. After the mixture was stirred for 30 min at rt, the re-
(C-5), 40.7 (C-7), 43.5 (C-4), 47.9 (C-8a), 177.0 (C-3), 207.8 (C-2). HR-MS
action mixture was concentrated by applying nitrogen. The residue was di- (EI) m/z: 252.1706 (Calcd for C15H24O3: 252.1725). 20: 1H-NMR (400 MHz,
luted with water, and the mixture was extracted with dichloromethane (ϫ3). CDCl3) d: 0.68 (3H, s, 8-CH3), 0.92 (3H, s, 4a-CH3), 1.14 (1H, dd, Jϭ6.8,
The combined organic layer was washed with brine, dried over anhydrous 4.4 Hz, 1-H), 1.24 (3H, s, 8-CH3), 1.25 (1H, m, 5-H) , 1.31 (1H, td, Jϭ13.2,
1
Na2SO4, and concentrated to yield 1.1 mg (containing solvents) of 15: H- 4.0 Hz, 7-H), 1.44 (1H, dt, Jϭ14.0, 3.6 Hz, 6-H), 1.51 (1H, dbrd, Jϭ13.0,
NMR (400 MHz, CDCl3) d: 0.91 (3H, d, Jϭ7.0 Hz, 13-CH3), 0.94 (3H, s, 2.8 Hz, 7-H), 1.72 (1H, m, 1-H), 1.73 (1H, m, 1a-H), 1.75 (1H, m, 6-H),
11-CH3), 1.03 (3H, d, Jϭ7.0 Hz, 14-CH3), 1.07 (1H, m, 5-H), 1.09 (1H, td, 1.87 (1H, dbrd, Jϭ13.6, 2.0 Hz, 5-H), 2.00 (1H, d, Jϭ12.8 Hz, 4-H), 2.35
Jϭ13.4, 4.0 Hz, 3a-H), 1.32 (1H, qd, Jϭ13.4, 4.0 Hz, 4b-H), 1.55 (1H, br d, (3H, s, 2-CH3), 3.03 (1H, d, Jϭ12.8 Hz, 4-H), 3.59 (3H, s, 3-OCH3). 13C-
Jϭ13.4 Hz, 4a-H), 1.56 (1H, m, 12-H), 1.59 (1H, d, Jϭ10.8 Hz, 10b-H), NMR (100 MHz, CDCl3) d: 17.0 (C-1), 18.5 (C-6), 26.8 (4a-CH3), 29.1 (8-
1.63 (1H, br s, 1-H), 1.65 (1H, br d, Jϭ13.4 Hz, 3b-H), 1.72 (1H, d, CH3), 29.9 (8-CH3), 32.5 (2-CH3), 32.7 (C-1a), 36.0 (C-8), 38.2 (C-4a), 40.0
Jϭ10.8 Hz, 10a-H), 2.47 (1H, m, 9-H), 2.48 (1H, m, 6-H), 3.81 (1H, d, (C-5), 40.8 (C-7), 43.7 (C-4), 48.0 (C-8a), 51.1 (3-OCH3), 172.0 (C-3),
Jϭ3.6 Hz, 8-H), 4.25 (1H, d, Jϭ4.2 Hz, 7-H). 13C-NMR (100 MHz, CDCl3) 207.4 (C-2). HR-MS (EI) m/z: 266.1870 (Calcd for C16H26O3: 266.1882).
d: 20.7 (C-13), 21.3 (C-14), 23.8 (C-4), 30.0 (C-11), 30.9 (C-10), 30.9 (C-
12), 33.0 (C-3), 36.1 (C-2), 43.8 (C-5), 50.6 (C-1), 51.1 (C-6), 54.3 (C-9),
56.5 (C-7), 80.6 (C-8). HR-MS (EI) m/z: 242.1439 (Calcd for C14H23ClO: ment of Applied Physics and Chemistry, The University of Electro-Commu-
242.1437). nication, for his suggestion on the ruthenium oxidation. We are also grateful
Acknowledgments We are indebted to Professor Haruki Niwa, Depart-
Preparation of Laurinterol Methyl Ether (6) A solution of laurinterol to Takasago International Corporation for its kind donation of thujopsene.
(300.0 mg, 1.0 mmol) in dry THF (10 ml) was treated with sodium hydride
(60% dispersion in mineral oil; 79.9 mg, 2.0 mmol) under nitrogen. The mix- References
1) Yasumoto M., Mada K., Ooi T., Kusumi T., J. Nat. Prod., 63, 1534—
1536 (2000).
2) Ohtani I., Kusumi T., Kashman Y., Kakisawa H., J. Am. Chem. Soc.,
113, 4092—4096 (1991).
3) Hasegawa T., Niwa H., Yamada K., Chem. Lett., 1985, 1385—1386.
4) Coudret J. L., Zöllner S., Ravoo B. J., Malara L., Hanisch C., Dörre K.,
de Meijere A., Waegell B., Tetrahedron Lett., 37, 2425—2428 (1996).
5) Takimoto S., Inanaga J., Katsuki T., Yamaguchi M., Bull. Chem. Soc.
Jpn., 54, 1470—1473 (1981).
6) Silverstein R. M., Webster F. X., “Spectrometric Identification of Or-
ganic Compounds,” 6th edition, John Wiley & Sons, New York, 1998,
p. 191.
ture was stirred at rt for 30 min. Then, iodomethane (0.31 ml, 5.0 mmol) was
added to the mixture. After the mixture was stirred for 10 h at rt, water and
ether were added and the organic layer was washed with 1 M NaOH, water
and brine. The organic layer was dried over anhydrous Na2SO4 and concen-
trated to give a residue (292.5 mg) which was chromatographed on silica gel
to afford 6 (229.1 mg, 74%) as white crystals. 6: 1H-NMR (400 MHz,
CDCl3) d: 0.47—0.52 (2H, m, overlap), 1.06 (1H, dt, Jϭ7.6, 4.0 Hz), 1.17
(1H, td, Jϭ12.2, 8.2 Hz), 1.29 (3H, s), 1.35 (3H, s), 1.60 (1H, dd, Jϭ12.4,
8.0 Hz), 1.91 (1H, m), 2.16 (1H, dd, Jϭ13.6, 8.0 Hz), 2.35 (3H, s, benzylic-
CH3), 3.76 (3H, s, –OCH3), 6.72 (1H, s, Ph-H), 7.67 (1H, s, Ph-H).
Oxidation of Laurinterol Methyl Ether (6) Laurinterol methyl ether
(6) (19.6 mg, 0.063 mmol) was oxidized for 26 h. After the crude product
was purified by preparative TLC, 18 (6.5 mg, 0.020 mmol, 32%) was ob-
7) Tenaglia A., Terranova E., Waegell B., J. Org. Chem., 57, 5523—5528
(1992).
1
8) Coudret J.-L., Waegell B., Inorganica Chimica Acta, 222, 115—122
(1994).
9) Irie T., Suzuki M., Kurosawa E., Masamune T., Tetrahedron Lett.,
1966, 1837—1840.
10) Wolfe S., Hasan S. K., Campbell J. R., Chem. Commun., 1970, 1420—
1421.
11) Webster F. X., Rivas-Enterrios J., Silverstein R. M., J. Org. Chem., 52,
tained. 18: H-NMR (400 MHz, CDCl3) d: 1.59 (3H, s, CH3), 1.65 (3H, d,
Jϭ0.8 Hz, allylic-CH3), 1.69 (1H, dt, Jϭ13.6, 4.8 Hz), 2.35 (1H, dt, Jϭ16.8,
4.8 Hz), 2.37 (3H, s, benzylic-CH3), 2.53 (1H, ddd, Jϭ17.4, 12.8, 5.2 Hz),
2.71 (1H, td, Jϭ12.8, 4.8 Hz), 3.72 (3H, s, –OCH3), 5.88 (1H, s, olefin-H),
6.72 (1H, s, Ph-H), 7.34 (1H, s, Ph-H). 13C-NMR (100 MHz, CDCl3) d: 20.9
(q), 22.7 (q), 23.3 (q), 34.6 (t), 35.0 (t), 42.5 (s), 55.0 (q), 113.7 (d), 115.4
(s), 125.8 (d), 131.1 (d), 133.1 (s), 137.6 (s), 156.3 (s), 169.4 (s), 198.9 (s).
MS m/z (rel. int. %): 324 (Mϩϩ2, 99.8), 322 (100). HR-MS (EI) m/z:
689—691 (1987).
12) Cocker W., Shannon P. V. R., Staniland P. A., J. Chem. Soc. (C), 1966,
946—949.
322.0546 (Calcd for C16H19BrO2: 322.0568). IR (liquid film) 1660 cmϪ1
.