Acid-catalyzed reactions of sarcophytoxide, a marine cembranoid: An apparently enantio-directive reaction, unusual products and stereochemical reconsideration of epoxide-ketone rearrangement

Article abstract of DOI:10.1246/bcsj.81.562

Perchloric acid treatment of sarcophytoxide, a marine cembranoid possessing an epoxide, brought about epoxide ketone rearrangement affording ketones. When the reaction time was long (22 h), a minor ketone that was antipodal to the ketone obtained in a short-time (l0min) reaction was formed. These puzzling findings, considering that the starting epoxide had three asymmetric carbons, were interpreted by surveying the structures of other ketonic products. The stereochemistry of a major ketone, which had been wrongly assigned, was corrected by extensive analyses of NMR spectra. The correct stereochemistry indicated that the epoxide-ketone rearrangement took a course via a cationic intermediate.

Full text of DOI:10.1246/bcsj.81.562

562 Bull. Chem. Soc. Jpn. Vol. 81, No. 5, 562–573 (2008)
ꢀ 2008 The Chemical Society of Japan
BCSJ Award Article
Acid-Catalyzed Reactions of Sarcophytoxide, a Marine Cembranoid:
An Apparently Enantio-Directive Reaction, Unusual Products and
Stereochemical Reconsideration of Epoxide–Ketone Rearrangement
Keiji Nii,1 Keiko Tagami,1 Masaru Kijima,1 Tatsuo Munakata,2
ꢀ1
Takashi Ooi,1 and Takenori Kusumi
1Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima 770-8505
2Department of Pharmaceutical Sciences, International University of Health and Welfare,
2600-1 Kitakanemaru, Ohtawara 324-8501
Received December 25, 2007; E-mail: tkusumi@ph.tokushima-u.ac.jp
Perchloric acid treatment of sarcophytoxide, a marine cembranoid possessing an epoxide, brought about epoxide–
ketone rearrangement affording ketones. When the reaction time was long (22 h), a minor ketone that was antipodal to
the ketone obtained in a short-time (10 min) reaction was formed. These puzzling findings, considering that the starting
epoxide had three asymmetric carbons, were interpreted by surveying the structures of other ketonic products. The ster-
eochemistry of a major ketone, which had been wrongly assigned, was corrected by extensive analyses of NMR spectra.
The correct stereochemistry indicated that the epoxide–ketone rearrangement took a course via a cationic intermediate.
18
In the course of our study on pharmaceutically active ma-
rine natural products, we found that a hexane extract of the soft
17
R
O
O
coral Sarcophyton glaucum, collected off Ishigaki Island, de-
posited a large amount of crystalline material (ca. 13 g from
240 g of dry body). By analyzing the physical properties, the
material was identified as sarcophytoxide [(+)-1] (Figure 1),1
a marine cembranoid. The structure of (+)-1 has been estab-
lished by X-ray crystallography and its absolute configuration
has been determined by chemical conversion of (+)-1 to sar-
cophine (2)2 and sarcophytonine.3 The chiroptical property
of our sample, ½ꢀꢁD ¼ þ153ꢂ (c 1.0, methanol), is the same
as that reported in the literature,1b ½ꢀꢁD ¼ þ157ꢂ (c 1.0, meth-
anol).
3
7
2
19
H
16
8
11
14
15
20
R = H : sarcophytoxide [(+)-1]
R = O : sarcophine[(+)-2]
2
Figure 1. The structure of sarcophytoxide [(+)-1] and sar-
cophine [(+)-2].
Not much has been reported on pharmaceutical activity of
sarcophytoxide; it has algacidal activity,4 antifeedant activity
against a mollusk,5 and inhibitory effect of the KCl-induced
contraction of vascular smooth muscles.1b In the present study,
no activity was observed for (+)-1 against lung cancer cells
and pathogenic fungi, although it shows moderate activity
(2 ppm) in a brine shrimp assay. This finding reinforces the
supposition that sarcophytoxide may serve as a self-defense
substance to protect the nude body of the soft coral from pred-
ators such as fish and mollusks.5
Considering the large content of (+)-1 that can be a useful
resource for a drug we intended to convert (+)-1 chemically to
compounds having stronger pharmaceutical activities. Similar
studies6 have been carried out starting from sarcophine (2), a
cembranolide abundant in soft corals.
Three kinds of chemically active functional groups are in-
cluded in (+)-1: (i) an epoxide, (ii) a dihydrofuran whose ether
oxygen is footed on a doubly allylic carbon (C-2), and (iii)
three olefin bonds, two of which are included in the 14-mem-
bered ring, and one in the dihydrofuran ring. They are all acid-
susceptible groups, and, therefore, (+)-1 was treated with sev-
eral Brønsted acids, and this paper deals with the structural
investigation of the unique products as well as formation of
enantiomeric ketones depending on the reaction conditions,
and critical reconsideration of the stereochemistry of the com-
monly known epoxide–ketone rearrangement.
Results and Discussion
Formation of Enantiomeric Ketones (+)-5 and (À)-5. It
would be better to start with the puzzling experimental results
Published on the web May 14, 2008; doi:10.1246/bcsj.81.562

K. Nii et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008)
563
2
2
2
O
O
O
3
3
3
7
7
7
HClO
8
8
8
4
HO
(+)-1
+
O
+
O
OH
10 min
[α] = +75°
D
(+)-3 (34%)
(+)-4 (42%)
(+)-5 (4%)
X-ray
enantiomers!
O
HClO
22 h
4
(+)-1
(+)-3 (32%)
+
(+)-4 (7%)
+
O
[α] = −67°
18
D
3
(−)-5 (8%)
X-ray
O
O
2
7
O
O
+
+
8
(−)-6 (8%)
(+)-7 (7%)
X-ray
Scheme 1. The compounds produced (%; isolation yield) by treatment of sarcophytoxide [(+)-1] with 25% perchloric acid in THF
for 10 min (above) and 22 h (below). The 22 h reaction afforded other minor products (+)-23–(+)-25 in Scheme 10 in 1–5%
yields.
obtained in the earliest stage of this study. An acid-catalyzed
reaction of sarcophytoxide [(+)-1] had been reported.7 Ac-
cording to the reference conditions, sarcophytoxide was treat-
ed with aqueous 25% perchloric acid (HClO4) in tetrahydro-
furan (THF). After 10 min, the spot of the starting material dis-
appeared in thin-layer chromatography (TLC), and new spots
appeared. The reaction was stopped, and the products were
separated (Scheme 1 [above]). Besides a reported diol and a
ketone7 [structure: vide infra (v.i.)], a new minor ketone,
(+)-5 (½ꢀꢁD ¼ þ75ꢂ), was isolated in 4% yield. The NMR
properties [a secondary methyl (Me) group, two trisubstituted
E-olefins, a dihydrofuran] indicated that this product must be a
diastereomer of the major ketone. When the reaction time was
extended to 22 h (Scheme 1 [below]), the ‘‘identical’’ product
was separated in 8% yield from a rather complex reaction mix-
ture. The NMR (1H and 13C) properties and chromatographic
behaviors [TLC and high-performance liquid chromatography
(HPLC)] were identical with those of the former minor ketone
(10 min). Surprisingly, this minor ketone (22 h), (ꢃ)-5, showed
the inverse sign of the specific rotation, ½ꢀꢁD ¼ ꢃ67ꢂ. The cir-
cular dichroism (CD) spectra of the enantiomers were antipo-
dal to each other. It was curious enough that the respective
enantiomers were produced from (+)-1, possessing three
asymmetric carbons, depending on the reaction time.
is enantiomerically impure [enantiomeric excess (ee) of (ꢃ)-5:
79% based on the ½ꢀꢁD value of (+)-5]. Probably the racemate
tends to form a good crystal. The 1H NMR spectra of the crys-
talline part and the oily residue were identical. At this stage,
however, the reason why (+)-1 having three asymmetric car-
bons affords enantiomeric ketones remained unclear.
Another annoying fact is that, in the literature,7 the structure
of the ketone produced by the perchloric acid reaction had
been assigned as 5. The physical data of the present minor ke-
tone (+)-5, however, were different from those reported for the
major ketone 5. The authors of reference 7 deduced the stereo-
chemistry of the major ketone from the mechanism of epox-
ide–ketone rearrangement. The present result of X-ray analysis
necessitates correction of the structure 5 of the major ketone to
(+)-4 (or its enantiomer), which is a diastereomer of 5.
Structural Determination of the Products. Among the
products depicted in Scheme 1, diol (+)-3 and major ketone
(+)-4 (corrected structure) are known. The stereochemistry
of (+)-3 had been deduced from the reaction mechanism.7 In
the present study, the absolute stereochemistry of (+)-3 was
confirmed by X-ray data obtained for cyclic sulfinate 12b
(v.i.).
As mentioned above, the relative stereochemistry of (+)-4
deduced based on the X-ray structure of (ꢃ)-5 was still cir-
cumstantial. The major ketone, (+)-4, was reduced with so-
dium tetrahydroborate (NaBH4) in methanol (MeOH) to give
Structure Correction of the Major Ketone. Fortunately,
the minor ketone (ꢃ)-5 was crystallized and the crystal was
subjected to X-ray analysis, determining the structure to be 5
(relative).8 The X-ray crystallography also revealed that the
crystal applied to the analysis was racemic, that is, a racemate
crystallized out from (ꢃ)-5. The smaller ½ꢀꢁD absolute value
(67) of (ꢃ)-5 than that of (+)-5 (75) suggests that this material
1
a separable mixture of 7ꢀ- and 7ꢁ-alcohols (4:3 by H NMR)
8 in a quantitative yield (Scheme 2). Of the epimeric alcohols,
1
7ꢀ-alcohol 8 gives the H NMR spectrum (C6D6) with excel-
lent signal separation, and the relative stereochemistry was
firmly established by the NOESY spectrum and analysis of

564 Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008) BCSJ AWARD ARTICLE
-0.02
-0.05
-0.02
0
O
-0.02
-0.08
+0.01
+0.05
2 O
0
0
7
a
b
OMTPA
(+)-4
OH
+0.11
8
+0.03
+0.02
0
+0.05
+0.04
+0.02
0
+0.02
+0.03
0
8 (7α : 7β = 4 : 3)
9
a: NaBH4 in MeOH, rt (100%), b: 7α-alcohol, (R)- and (S)-MTPACl in pyridine, rt (50 − 60%)
H
H
H
H
H
H
O
H
H
O
Me
Me
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
7α-8
Scheme 2. Absolute configuration determination of (+)-4 by the modified Mosher’s method9 performed on (7ꢀ-OH)-8. The ꢀꢂ val-
ues [ꢂ(S)-MTPA ꢃ ꢂ(R)-MTPA] depicted in 9 were obtained for a CDCl3 solution. The stereochemistry of 7ꢀ-8 was established by the
NOESY spectrum and analysis of the coupling constants.
the coupling constants, which eventually verified structure 4.
The secondary alcohol was treated with (R)- and (S)-ꢀ-meth-
oxy-ꢀ-(trifluoromethyl)phenylacetyl chloride (MTPA-Cl) to
give the (S)- and (R)-MTPA esters 9, respectively. The ꢀꢂ val-
ues [ꢀꢂ ¼ ꢂ(S)-MTPA ester ꢃ ꢂ(R)-MTPA ester] of all the protons
were obtained for 9, and, based on the distribution pattern of
the positive and negative values,9 the 2S,7S,8R-configuration
of 8 (7ꢀ-OH), and thus, 2S,8R-configuration of (+)-4 was un-
ambiguously determined (Scheme 2).
Treatment of (+)-4 with sodium hydroxide in MeOH for 5 d
at room temperature (rt) gave rise to a 1:2 mixture of two ke-
tones. These were separated and identified with starting (+)-4
and (+)-5, respectively. Therefore, the absolute stereochemis-
try of (+)-5, and therefore of (ꢃ)-5, was determined as shown
in Scheme 1.
roptical property greatly helped us to presume the absolute
configuration of the products.
Reaction Mechanism. Formation of diol (+)-3 is inter-
pretable as the SN2-type attack of the water molecule on C-8
of (+)-1, which gives 7S,8R-diol (+)-3. In both of the 10-
min and 22-h reactions, the yield of the diol is practically
the same.
In the 10-min reaction, ketones (+)-4 (42%) and (+)-5 (4%)
must be directly formed from (+)-1 by the epoxide–ketone re-
arrangement. Treatment of (+)-1 with DClO4/D2O in THF-d8
gave (+)-4 and (+)-5, in which no deuterium was incorporated
(1H NMR; doublets due to C-8 Me’s) thus confirming that no
epimerization at the C-8 position occurred in the ketones.
In the 22-h reaction, the yield of the ketone (+)-4 greatly
decreases (7%), and, at the same time, the enantiomer (ꢃ)-5
(8%) and 3Z isomers (ꢃ)-6 (8%) and (+)-7 (7%) are formed.
This suggests that the latter three are produced from the major
ketone (+)-4. As mentioned above, treatment of (+)-4 with
DClO4 for 22 h afforded non-deuterated (ꢃ)-6 and (+)-7
together with (ꢃ)-5.
When the reaction time was extended to 22 h, two new ke-
tones, (ꢃ)-6 and (+)-7, were produced besides (+)-3, (+)-4,
and (ꢃ)-5 (Scheme 1 [below]). The structure of (+)-7 was de-
termined by X-ray crystallography. The NMR properties of the
isomer (ꢃ)-6 revealed that one of the two trisubstituted E-ole-
1
fins of (+)-1 changed to a Z-olefin [13C: ꢂ 22.8 (C-18), H:
Production of these compounds from (+)-4 is understanda-
ble by assuming the cationic intermediates 4a and 4c
(Scheme 3), which result from acid-assisted cleavage of the
doubly allylic ether linkage at C-2 of (+)-4. The cation 4a is
stabilized by resonance with several cations such as 4b, which
can be isomerized to 3Z-isomer 4c. Recombination of the ether
linkage at C-2 of 4a and 4c will give (+)-4, (ꢃ)-5 and (ꢃ)-6,
(+)-7, respectively.
NOE between H-3 and H-18], and because other features are
similar to those of (+)-7, structure 6 was assigned to this iso-
mer. The absolute configurations of (ꢃ)-6 and (+)-7 were con-
firmed by converting (+)-4 to the respective compounds by
treatment with DClO4 for 22 h. Note that 8-protons of both ke-
tones were not replaced with deuterium, which confirmed that
the 8R-configuration of (+)-4 was retained in them.
It should be noteworthy that the compounds with the S-con-
figuration at C-2 such as (+)-1, (+)-3, (+)-4, (+)-5, and (+)-7
show positive ½ꢀꢁD values, and those with the R-configuration
at C-2 [(ꢃ)-5 and (ꢃ)-6] have negative ½ꢀꢁD values. This chi-
The minor ketone (+)-5 initially formed from (+)-1 will
follow the same fate as (+)-4. The yield of (+)-5 is, however,
so low (4% after 10 min) that the supposed products [(ꢃ)-4,
(+)-6, and (ꢃ)-7] may serve as the components that result

K. Nii et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008)
565
3
OH
HO
3
OH
3
2
7
2
2
O
O
O
8
4a
4c
4b
(+)-4 and (−)-5
(−)-6 and (+)-7
Scheme 3. A mechanism to produce isomeric ketones (+)-4, (ꢃ)-5, (ꢃ)-6, and (+)-7 from double allylic cations 4a and 4c formed
by acid-cleavage of the ether linkage at C-2 of (+)-4.
H
H
acid
H
H
δ+
O
O
[X]
A = acid
[Y]
[Z]
δ+
H
O
A
δ-
A
Scheme 4. A commonly granted mechanism of the rearrangement of epoxide [X] to ketone [Y]. The configuration of the migrated
hydrogen is retained because the reaction is supposed to proceed concertedly via an intermediate [Z].
in lowering the enantiomeric excess of the respective enan-
tiomers.
and 1c or to search for the transition state 1bz and 1cz at the
AM1. All energies were calculated using the AM1 geometries
ꢀ
Reconsideration of the Epoxide–Ketone Rearrangement.
It is well known that an epoxide can give a ketone when it is
treated with acid. With respect to the stereochemistry of the
epoxide–ketone rearrangement, the process has been consid-
ered, in many cases, a concerted reaction, in which a substitu-
ent such as hydrogen migrates from the backside of the cleav-
ing C–O bond ([X]) via the transition state ([Z]), giving the
product [Y] (Scheme 4).10 On the basis of this reaction mech-
anism, the stereochemistry of the major ketone had been erro-
neously proposed as 5, in which the hydrogen at C-7 of (+)-1
shifts from the ꢁ-side of C-8.
at the B3LYP/6-31G level, which indicated ꢀGz and
1b
ꢀGz to be 12.1 and 31.9 kJ molꢃ1 respectively [Scheme 5,
1c
left bottom: The conformations of pre-(+)-4 and pre-(+)-5
were presumed to be the same as those of 1b and 1c in the cal-
culation of the activation energies.]. These results agree with
the experimental results.
A similar discussion about the cation intermediate of an ep-
oxide–ketone rearrangement has been made,12 and the critical
role of activation energy in the products ratio in the chemical
reactions of sarcophine (2) has been recently discussed.6b
Inverted-Sarcophytoxide. In order to further investigate
the stereochemical course of the epoxide–ketone rearrange-
ment, (+)-10 (inv-sarcophytoxide),3 the 7R,8R diastereomer
of (+)-1, was synthesized from diol (+)-3, and it was subject-
ed to the HClO4 reaction (Scheme 6). The acid-reaction was a
little slower than the case of sarcophytoxide; it took 2 h until
the starting inv-epoxide disappeared (TLC) when diol (+)-
11, ketone (+)-5, and ketone (+)-4 were obtained in 27, 20,
and 3% yields, respectively. The stereochemistry of (+)-11
was determined by converting it to (+)-1. Noteworthy is the
fact that ketones, (+)-4 and (+)-5, were afforded in 1:7 ratio;
that is, H-7 appears to have migrated to C-8 from the same
side of the leaving oxygen in the major ketone, (+)-5. This
‘‘invalid’’ hydrogen shift is also interpretable by assuming the
intermediacy of the C-8 cation that is a diastereomer (7R) of 1a
in Scheme 5.
So, why is (+)-4 obtained as a major ketone in the epoxide–
ketone rearrangement? The rearrangement cannot proceed in a
concerted manner, because, to give (+)-4, H-7 of (+)-1 must
migrate from the same side of the cleaving C–O bond at C-
8. We here propose the presence of a cation as a ‘‘distinct’’ in-
termediate; that is, this rearrangement proceeds in an SN1 man-
ner (Scheme 5). Cleavage of the epoxide C–O bond at C-8 of
(+)-1 gives a tertiary cation 1a. The lifetime of the cation may
be long enough to change its conformation into 1b and 1c, in
each of which the sp3 orbital of (C-7)–H is parallel with the
vacant 2p-orbital at C-8. It is the difference between the acti-
vation energies, ꢀGz [from 1b to pre-(+)-4] and ꢀGz
1b
1c
[from 1c to pre-(+)-5] (not the energy difference between 1b
and 1c, which is 9.1 kJ molꢃ1), that determines the ratio of
the products (Curtin–Hammett principle),11 and, thus, ꢀGz
1c
would be larger than ꢀGz in the present case. The activation
During the synthesis of (+)-10, we encountered a strange
product: Reaction of (+)-3 with methanesulfonyl chloride
(MsCl) followed by potassium carbonate treatment gave (+)-
10 (77%) together with a minute amount (2%) of 1:1 mixture
1b
energies were calculated: All geometries were initially con-
structed on the basis of the most stable conformation of (+)-
1 and then subjected to optimization for the intermediates 1b

566 Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008) BCSJ AWARD ARTICLE
H
6
H
6
HO
H
7
O
6
O
7
6
7
7
OH
H
Me
8
8
9
9
19
9
19
8 OH
Me
9
Me
H
19
19
(+)-1
1c‡
1a
1b
1c
∆G‡
∆G‡
1b
1c
H
O
1b‡
6
∆G‡
1c = 31.9
7
O
H
Me
H
H
∆G‡
1b = 12.1
104.2
7
6
1b
∆G0 = 9.1
8
8
1c
Me
9
9
60.7
pre-(+)-4
pre-(+)-5
energy: kJ mol-1
pre-(+)-5
(+)-4 (major)
(+)-5 (minor)
∆G‡1c >∆G‡
1b
pre-(+)-4
Scheme 5. An SN1-type mechanism of the epoxide–ketone rearrangement via a distinct cation. Acid-catalyzed cleavage of the
epoxide ring of (+)-1 produces the C-8 cation. Three conformations of the cation, 1a–1c, are shown. Hydrogen (H-7) shift via
1b and 1c gives (+)-4 (major) and (+)-5 (minor), respectively. ꢀGz and ꢀGz are the activation energy of the hydrogen shift.
1b
1c
ꢀ
The left bottom illustrates a calculated (B3LYP/6-31G ) energy diagram of the hydrogen shifts in cations 1b and 1c (Figure 5)
to give ketones, pre-(+)-4 and pre-(+)-5, respectively (see text).
O
O
O
O
b
8
a
c
H
7
OH
+
O
(+)-3
8
HO
a
(+)-1
(+)-4: R = 8β-Me (3%)
(+)-5: R = 8α-Me (20%)
(+)-10 (77%)
(+)-11 (27%)
-
O
S
O
O
+
O
H
7
8
12b
12a: (R)-S (20%)
12b: (S)-S (20%)
a: MsCl, triethylamine in CH2Cl2, then K2CO3 in MeOH. b: HClO4 in THF, 2 h, c: SOCl 2, triethylamine in CH2Cl2, rt.
Scheme 6. Synthesis of inv-sarcophytoxide [(+)-10] and the products, (+)-11, (+)-4, and (+)-5, obtained by perchloric acid
treatment. Other products were too polar (TLC) to be isolated. Stereochemistry of (+)-11 was confirmed by conversion to
(+)-1. Cyclic sulfinates 12a and 12b were produced in reaction a. An ORTEP drawing of structure 12b is shown.
of diastereomers 12a and 12b (Scheme 6) that were separable
by HPLC. One of them crystallized and the crystal was sub-
jected to X-ray analysis, revealing that it was a cyclic sulfinate
12b. This compound cannot be produced by the action of
MsCl, but possibly formed by reaction with thionyl chloride
that might have been present as a minor contaminant of the
commercial MsCl. Actually, treatment of (+)-3 with thionyl
chloride afforded a diastereomeric mixture of 12a and 12b
(1:1). The important thing is that, thanks to sulfur as a heavy
atom, the absolute configuration of 12b, thus (+)-3, has been
established by the X-ray analysis.
Rearrangement of Limonene Oxides. As the reference
experiments, the acid-catalyzed reactions were worked for
(+)-trans-(13) and (+)-cis-limonene 1,2-epoxides (14)
(Scheme 7). The reaction using HClO4 was sluggish. Treat-
ment of both epoxides with trifluoromethanesulfonic acid

K. Nii et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008)
567
is different from the case of (+)-1: Because of the flexibility of
the 14-memberd ring, the cation formed from (+)-1 can take
two conformations, 1b and 1c (Scheme 5), which can bring
about hydrogen shift.
Another evidence of the cation-intermediate mechanism
was obtained in the HClO4 reaction of (ꢃ)-dihydrocaryophyl-
lene oxide (17),14 giving a ketone 18 as a minor (2%) but a sole
ketonic product (Scheme 8). The stereochemistry of 18 was
confirmed by X-ray crystallography. The S-configuration of
the newly formed secondary methyl group indicates that this
reaction proceeded via a cation intermediate 17a rather than
a concerted hydride shift. The detail of this reaction will be
published elsewhere.
Treatment of (+)-1 with TfOH, Hydrochloric Acid, and
Hydrobromic Acid. Treatment of (+)-1 with TfOH (0.01
molar amount) in dry THF for 1 h afforded (+)-4 and (+)-5
in 80% and 8% yields, respectively. The ratio of the two ke-
tones is the same as that obtained in the reaction with HClO4.
Naturally, diol, (+)-3, was not obtained under this anhydrous
reaction condition.
2
2
H
H
1
1
O
O
13
14
Me
Me
a
a
H
Me
HO
R
R
R
HO
H
H
Me
HO
R
Me
Me
HO
H
13a
14a
[conformational changes]
Me
H
HO
2
1
2
HO
Me
R
R
1
H
13b
14b
When (+)-1 was allowed to react with hydrochloric acid
and hydrobromic acid in THF, no ketonic products were ob-
tained, and, instead, isomeric chlorohydrines, (+)-19 and
(+)-20, and bromohydrines, (+)-21 and (+)-22, were afforded,
respectively (Scheme 9). Surprisingly, chlorohydrine (+)-19
was changed into (+)-4 by just letting its solutions to stand
in MeOH/H2O (2:1) at room temperature for 22 h. Bromohy-
drine (+)-21 more smoothly gave (+)-4 after 1 h under the
same conditions. In these reactions, the hydrides apparently
shift from the opposite side of the leaving halogen. In such a
polar solvent, however, the C–X bond may have a tendency
to be cleaved spontaneously, giving a stable tertiary cation at
C-8, onto which H-7 migrates. When polarity of the solvent
was decreased (MeOH), the halohydrines remained unchanged
and production of (+)-4 was not detected even after 48 h.
It should be noted that the spectral data (1H and 13C) of
chlorohydrine (+)-19 are completely identical with those of
a natural product, the structure of which was reported as a
7-diastereomer of diol (+)-3.7 The authors of reference 7 ob-
tained ‘‘isodiol’’ [actually (+)-19], which they thought to be
a diastereomer of diol (+)-3, from the same soft coral. They
found that isodiol was not cleaved with sodium periodate but
it produced a ketone by treatment with HClO4 in MeOH–
H2O. The latter result seemed to them as a pinacol rearrange-
ment, which made them erroneously conclude that the com-
pound had a 1,2-diol moiety.
O
O
16
(90%)
15
Me
Me
(80%)
a: TfOH, THF, 10 min, rt
Scheme 7. Acid-catalyzed reactions worked for (+)-trans-
limonene 1,2-epoxide (13) and (+)-cis-limonene 1,2-ep-
oxide (14) affording rearranged ketones 15 and 16, respec-
tively. Possible conformations of the cations, 13a, 13b,
14a, and 14b, are shown.
(TfOH) (0.1 molar amount) in THF for 10 min at room temper-
ature gave good yields of ketones, 15 and 16.13 It appears that
the rearrangements took place in a concerted way; that is, the
hydrogen (H-2) shifts from the opposite side of the leaving
oxygen at C-1. However, we rather propose that, even in these
well-known cases, the reaction proceeds in an SN1 manner via
cationic intermediate such as 13a and 13b or 14a and 14b. In
the case of 13, initially formed cation 13a is conformationally
changed into 13b, in which the (C-2)–(H-2) orbital is parallel
with the vacant p-orbital of C-1. There are no alternatives of
13b, owing to rigidity of the 6-membered ring. This situation
14
15
H
H
H
4
11
4
R
1
H
1
HClO4
S
O
O
OH
13
H
R
9
9
5
10
H
H
H
X-ray
18 (2%)
other products
12
17
17a
+
Scheme 8. Reaction of (ꢃ)-dihydrocaryophyllene oxide (17) with HClO4 producing a ketone 18 as a sole ketonic compound (2%)
besides other products. The major product (65%) of this reaction was an allyl alcohol. The detailed features of the reaction will be
published elsewhere. Presence of a cationic intermediate 17a is assumed in this epoxide–ketone rearrangement.

568 Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008) BCSJ AWARD ARTICLE
O
O
O
7
7
8
8
7H
+
a
X
OH
X
HO
8
b
(quant)
(+)-1
c
(+)-19: X = Cl (76%)
(+)-21: X = Br (68%)
(+)-20: X = Cl (9%)
(+)-22: X = Br (17%)
b
7
O
(+)-1
8
(+)-4 (78%)
(quant)
a: 35% HClaq in THF or 48% HBraq in THF at rt, 10 min, b: K2CO3 in MeOH, c: MeOH/H2O (2 : 1), rt, 22 h
Scheme 9. Halohydrines, (+)-19/(+)-20, and (+)-21/(+)-22, obtained by the reaction of (+)-1 and hydrochloric acid and hydro-
bromic acid, respectively, and chemical transformations to elucidate their stereochemistry. Halohydrines, (+)-19 and (+)-21,
afford the ketone (+)-4.
O
3
O
O
7
7
3
HO
O
OH
OH
8
1
H
8
(+)-23
(+)-24
(+)-25
Scheme 10. Compounds obtained as the minor products of the acid treatments of (+)-1.
Minor Products Obtained by Acid Treatments of (+)-1.
phytoxide [(+)-10] and (ꢃ)-dihydrocaryophyllene oxide (17)
gave ketone (+)-5 and 18, respectively, whose stereochemistry
was different from that deduced by a concerted mechanism.
Based on these findings, we have proved that the acid-cata-
lyzed epoxide–ketone rearrangement takes an SN1-like path-
way through cationic intermediates such as 1c in Scheme 5.
Depending on the reaction times of the acid treatment, enan-
tiomers (+)-5 and (ꢃ)-5 were formed as minor products. This
curious phenomenon was interpreted by assuming the epimeri-
zation of the doubly allylic C–O linkage at C-2 of (+)-1.
In the aforementioned reactions, minor compounds depicted
in Scheme 10 were isolated from the reaction mixtures in
1%–5% yields; (+)-237 [HClO4 (22 h), TfOH], (+)-24 [HClO4
(22 h)], (+)-25 [HClO4 (22 h)]. The absolute stereochemistry
of (+)-25 was determined by chemical conversion and exciton
chirality method (see Experimental Section).
Pharmaceutical Activities of the Synthetic Compounds.
Activities of all the compounds against MRSA and lung cancer
cells were tested. Sarcophytoxide [(+)-1], the major ketone
[(+)-4], and the chlorohydrine [(+)-20] are weakly active
against MRSA (Inhibitory zones of ꢃ 12–14 mm sizes were
observed on agar dishes after 24 h, when the 33 mM solutions
of (+)-20 in dimethyl sulfoxide were applied to ꢃ 6 mm filter
papers.). Cytotoxicity against lung cancer cells (A549) (IC50
mg mLꢃ1) is as follows: (+)-4 (16), (+)-5 (14), (ꢃ)-5 (14),
(ꢃ)-6 (15), and (+)-7 (16). Other compounds were inactive.
Experimental
General. Melting points were determined on a Buchi 535
¨
melting point apparatus and are uncorrected. Optical rotations
were determined in CHCl3 on a JASCO P-1010 digital polarime-
ter. Circular dichroism (CD) spectra were measured on a JASCO
J600 CD spectrometer. Infrared (IR) absorption spectra were re-
corded on a JASCO FT-IR420 spectrometer. MS spectra were
measured on Waters LCT Premier XE and JEOL JMS-SX102A
mass spectrometers. NMR spectra were recorded in CDCl3 or
C6D6 solution on a JEOL JNM AL400 spectrometer at 400 MHz
(1H), on a JEOL JNM AL300 spectrometer at 75 MHz (13C),
and on a Bruker ARX400 spectrometer (2D NMR) at 400 MHz
(1H)/100 MHz (13C). X-ray crystallography was performed on a
Rigaku R-AXIS RAPID X-ray diffractometer. Chromatography
was done by flash column chromatography using silica gel (Merck
silica gel 60, 0.040–0.063 mm, 230–400 mesh ASTM). Prepara-
tive TLC purification was done using silica gel plate (15 PLC
Conclusion
Perchloric acid treatment of sarcophytoxide (+)-1, a marine
cembranoid abundant in a soft coral Sarcophyton glaucum,
gave ketone (+)-4, whose stereochemistry had been wrongly
reported. The correct stereochemistry indicates that the acid-
catalyzed epoxide–ketone rearrangement of (+)-1 proceeds
in a different way from that deduced by a ‘‘concerted mecha-
nism’’ that would give 8(S)-Me [as in (+)-5] instead of the ac-
tual 8(R)-Me [(+)-4]. Similarly, acid treatment of inv-sarco-

K. Nii et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008)
569
plates 20 ꢄ 20 cm silica gel 60 F254, 1 mm). Recycle-HPLC was
carried out using a JAI LC-908 apparatus and normal phase HPLC
column (Merck Hibar RT250-25 LiChrosorb si 60, 7 mm). TLC
was done using silica gel plate (25 TLC plates 20 ꢄ 20 cm silica
gel 60 F254). (ꢃ)-Caryophyllene oxide was purchased from
Aldrich Chemical Company Inc.
Crystallographic Data. Crystallographic data have been de-
posited with Cambridge Crystallographic Data Centre: Deposition
numbers CCDC-675018 for 3, CCDC-675019 for 5, CCDC-
675020 for 12b, and CCDC-675021 for 18. Copies of the data
can be obtained free of charge via http://www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK; Fax:
+44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
Sarcophytoxide (1). Sarcophyton glaucum was collected at
the Ishigaki Island, Okinawa Prefecture, Japan in 1997 and the
whole body was freeze-dried. The freeze-dried soft coral (240 g)
was extracted successively with hexane, CH2Cl2, and EtOAc. Af-
ter the hexane extract was concentrated, it was stored in a refrig-
erator overnight, when massive crystals deposited in the oily hex-
ane extract. About a half of the crystals was collected by filtration
with the aid of hexane. The weight of this crystalline material was
6.5 g. By analyzing the physical data, this substance was identified
as (2S,7S,8S)-sarcophytoxide [(+)-1].1
2.01 (overlap, 3H, H-6, 9, 8), 1.93 (m, 1H, H-13), 1.86 (m, 1H,
H-13), 1.77–1.74 (overlap, 2H, H-5, 10), 1.61 (s, 3H, H-18),
1.54 (s, 3H, H-20), 1.43 (s, 3H, H-15), 1.29 (ddd, 1H, J ¼ 11:6,
6.7, 3.42 Hz, H-9), 0.87 (d, 3H, J ¼ 6:6 Hz, H-19); 13C NMR
(75 MHz, C6D6) ꢂ 210.1 (s, C-7), 136.5 (s, C-4), 135.9 (s, C-
12), 134.8 (s, C-1), 128.9 (d, C-3), 127.7 (s, C-16), 123.6 (d, C-
11), 84.5 (d, C-2), 78.8 (t, C-17), 46.7 (d, C-8), 38.2 (t, C-6),
36.7 (t, C-13), 33.3 (t, C-5), 32.6 (t, C-9), 27.0 (t, C-10), 24.5
(t, C-14), 18.9 (q, C-19), 15.8 (q, C-20), 15.6 (q, C-18), 10.0
(q, C-15).
Perchloric Acid Treatment of Sarcophytoxide [(+)-1] (22 h).
A solution of (+)-1 (1.00 g, 3.3 mmol) in THF (100 mL) was treat-
ed with 25% perchloric acid (12 mL) for 22 h at room temperature.
The reaction mixture was added to a saturated NaHCO3 solution
(50 mL), and the mixture was extracted with ether (3 ꢄ 60 mL).
The ether layer was washed with water (100 mL), brine
(100 mL), and dried over Na2SO4. After concentration, the residue
(1.17 g) was applied to a silica gel column. The column was eluted
with hexane–EtOAc (30–100%). Compound (+)-24 (14 mg,
0.05 mmol) was obtained in the first fraction. A mixture of (+)-
4, (ꢃ)-5, (ꢃ)-6, and (+)-7 (520 mg) was eluted with hexane–
EtOAc = 7:3. Compound (+)-232 (48 mg, 0.16 mmol) was eluted
with the same solvent. Compound (+)-25 (4.0 mg, 0.01 mmol)
was eluted with hexane–EtOAc = 1:1 and purified by HPLC.
Compounds (+)-3 was eluted with hexane–EtOAc = 3:7
(397 mg, 1.2 mmol). The mixture of the ketones (350 mg) was sep-
arated by recycle-HPLC using four columns connected in series
(flow rate 10 mL minꢃ1) with hexane–isopropyl alcohol = 95:5.
(+)-4 (56 mg, 0.19 mmol), (ꢃ)-5 (72 mg, 0.24 mmol), (ꢃ)-6
(61 mg, 0.20 mmol), and (+)-7 (57 mg, 0.19 mmol) were eluted
at Rt ¼ 60, 63, 54, and 58 min, respectively. (ꢃ)-5: a yellow oil
Perchloric Acid Treatment of Sarcophytoxide [(+)-1]
A solution of (+)-1 (500 mg, 1.7 mmol) in THF
(10 min).
(50 mL) was treated with 25% perchloric acid (6.0 mL) for
10 min at room temperature. The reaction mixture was added to
a saturated NaHCO3 solution (25 mL), and the mixture was ex-
tracted with ether (3 ꢄ 30 mL). The ether layer was washed with
water (50 mL), brine (50 mL), and dried over Na2SO4. After the
ether was evaporated, the residue (490 mg) was applied to a silica
gel column. The column was eluted with hexane–EtOAc (30–
100%). Compounds (+)-4 and (+)-5 were eluted with hexane–
EtOAc (7:3) as a mixture (252 mg) (TLC: Rf ¼ 0:6, hexane–
EtOAc = 1:1). Compound (+)-232 was eluted with the same
eluting solvent (10 mg, Rf ¼ 0:5, 0.03 mmol). Compound (+)-37
was eluted with hexane–EtOAc = 3:7 (172 mg, Rf ¼ 0:18, 0.54
mmol). The mixture of (+)-4 and (+)-5 was separated by recy-
cle-HPLC (flow rate 10 mL minꢃ1) with hexane–isopropyl alco-
hol = 95:5. (+)-4 (217 mg, 0.72 mmol) was eluted at Rt ¼ 62 min
and (+)-5 (20 mg, 0.07 mmol), Rt ¼ 65 min. (+)-4: a colorless oil;
25
that gives colorless crystals (mp 85–87 ꢂC); ½ꢀꢁD ¼ ꢃ67:0ꢂ (c
0.58, CHCl3). Other physical properties were the same with those
27
of (+)-5. (ꢃ)-6: a colorless oil; ½ꢀꢁD ¼ ꢃ68:5ꢂ (c 0.98, CHCl3);
HR-EI-MS m=z 302.2220 (calcd for C20H30O2, 302.2246);
1H NMR (400 MHz, C6D6) ꢂ 5.80 (m, 1H, H-2), 5.35 (d, 1H,
J ¼ 8:4 Hz, H-3), 5.05 (t, 1H, J ¼ 7:2 Hz, H-11), 4.62 (dd, 1H,
J ¼ 12:0, 5.6 Hz, H-17), 4.50 (dd, 1H, J ¼ 12:0, 0.8 Hz, H-17),
2.70 (ddd, 1H, J ¼ 13:6, 11.4, 4.0 Hz, H-5), 2.42–2.40 (overlap,
2H, H-8, 6), 2.32–2.28 (overlap, 2H, H-6, 14), 2.15–2.13 (overlap,
2H, H-5, 10), 2.05 (m, 1H, H-13), 1.92–1.88 (overlap, 2H, H-13,
9), 1.70 (m, 1H, H-14), 1.60 (s, 3H, H-18), 1.56 (overlap, 2H, H-9,
9), 1.48 (s, 3H, H-20), 1.41 (s, 3H, H-15), 0.88 (d, 3H, J ¼ 7:3 Hz,
H-19); 13C NMR (75 MHz, C6D6) ꢂ 212.4 (s, C-7), 136.8 (s, C-4),
136.7 (s, C-12), 134.1 (s, C-1), 128.0 (d, C-3), 127.8 (s, C-16),
124.6 (d, C-11), 84.9 (d, C-2), 78.3 (t, C-17), 46.8 (d, C-8),
38.7 (t, C-13), 38.4 (t, C-6), 34.1 (t, C-9), 26.5 (t, C-5), 26.0
(t, C-10), 23.1 (q, C-18), 22.7 (t, C-14), 17.6 (q, C-19), 15.6
(q, C-20), 9.7 (q, C-15). (+)-7: colorless needles, mp 89–91 ꢂC;
25
½ꢀꢁD ¼ þ135:8ꢂ (c 0.92, CHCl3); HR-EI-MS m=z 302.2278
(calcd for C20H30O2, 302.2246); 1H NMR (400 MHz, C6D6)
ꢂ 5.65 (m, 1H, H-2), 5.42 (d, 1H, J ¼ 9:8 Hz, H-3), 4.93 (t, 1H,
J ¼ 6:0 Hz, H-11), 4.59 (ABX, 2H, JAB ¼ 11:5, JAX{BX
¼
4:6 Hz, H-17), 2.35 (m, 1H, H-6), 2.29–2.27 (overlap, 2H, H-5,
14), 2.20–2.18 (overlap, 3H, H-5, 6, 8), 2.09 (m, 1H, H-10),
2.00 (m, 1H, H-13), 1.96–1.94 (overlap, 4H, H-9, 10, 13, 14),
1.87 (s, 3H, H-18), 1.53 (s, 3H, H-20), 1.44 (s, 3H, H-15),
1.33 (m, 1H, H-9), 0.86 (d, 3H, J ¼ 6:7 Hz, H-19); 13C NMR
(75 MHz, C6D6) ꢂ 212.0 (s, C-7), 139.7 (s, C-4), 136.4 (s, C-
12), 134.6 (s, C-1), 128.3 (s, C-16), 127.3 (d, C-3), 123.5 (d, C-
11), 84.8 (d, C-2), 78.5 (t, C-17), 46.6 (d, C-8), 39.7 (t, C-6),
37.1 (t, C-13), 32.8 (t, C-5), 32.4 (t, C-9), 26.6 (t, C-10), 24.4
(t, C-14), 19.0 (q, C-19), 17.9 (q, C-18), 15.9 (q, C-20), 10.1 (q,
26
½ꢀꢁD ¼ þ49:2ꢂ (c 0.40, CHCl3); HR-EI-MS m=z 302.2247 (calcd
1
for C20H30O2, 302.2246); H NMR (400 MHz, C6D6) ꢂ 5.77 (m,
1H, H-2), 5.38 (d, 1H, J ¼ 8:5 Hz, H-3), 4.98 (dd, 1H, J ¼ 8:0,
1.9 Hz, H-11), 4.64 (dd, 1H, J ¼ 11:7, 5.1 Hz, H-17), 4.51 (d,
1H, J ¼ 11:7 Hz, H-17), 2.90 (td, 1H, J ¼ 13:2, 2.4 Hz, H-5),
2.48 (ddd, 1H, J ¼ 18:5, 12.2, 5.6 Hz, H-6), 2.36 (m, 1H, H-
14), 2.24 (ddd, 1H, J ¼ 18:5, 12.7, 2.9 Hz, H-6), 2.15–2.06 (over-
lap, 2H, H-9, 8), 2.02–1.97 (overlap, 3H, H-5, 13, 10), 1.86 (m,
1H, H-13), 1.59 (m, 1H, H-14), 1.56 (s, 3H, H-18), 1.49 (s, 3H,
H-20), 1.39 (s, 3H, H-15), 1.33 (m, 1H, H-9), 0.93 (d, 3H,
J ¼ 6:8 Hz, H-19); 13C NMR (75 MHz, C6D6) ꢂ 212.6 (s, C-7),
136.3 (s, C-12), 136.0 (s, C-4), 133.4 (s, C-1), 128.5 (s, C-16),
128.3 (d, C-3), 124.5 (d, C-11), 84.9 (d, C-2), 78.4 (t, C-17),
27
C-15). (+)-5: white powder; ½ꢀꢁD ¼ þ74:6ꢂ (c 0.99, CHCl3);
HR-EI-MS m=z 302.2239 (calcd for C20H30O2, 302.2246);
1H NMR (400 MHz, C6D6) ꢂ 5.74 (d, 1H, J ¼ 10:3 Hz, H-3),
5.70 (m, 1H, H-2), 4.89 (t, 1H, J ¼ 7:6 Hz, H-11), 4.60 (m, 2H,
H-17), 2.81 (dd, 1H, J ¼ 11:2, 2.2 Hz, H-5), 2.34–2.33 (overlap,
2H, H-14, 6), 2.22 (m, 1H, H-10), 2.13 (m, 1H, H-14), 2.03–

570 Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008) BCSJ AWARD ARTICLE
45.9 (d, C-8), 42.1 (t, C-6), 38.2 (t, C-13), 33.6 (t, C-9), 26.8 (t, C-
10), 26.2 (t, C-5), 23.0 (q, C-18), 23.0 (t, C-14), 18.8 (q, C-19),
3.4, 2.2 Hz, H-9), 1.58 (overlap, 1H, H-8), 1.58 (s, 3H, H-18),
1.57 (s, 3H, H-20), 1.51 (tdd, 1H, J ¼ 14:0, 4.1, 2.2 Hz, H-6),
1.45 (s, 3H, H-15), 1.23 (dtd, 1H, J ¼ 14:1, 8.3, 3.4 Hz, H-9),
1.07 (ddt, 1H, J ¼ 13:9, 10.8, 4.0 Hz, H-6), 0.83 (d, 3H,
J ¼ 7:1 Hz, H-19); 13C NMR (100 MHz, C6D6) ꢂ 137.7 (s, C-4),
134.4 (s, C-1), 134.2 (s, C-12), 128.3 (d, C-3), 128.1 (s, C-16),
125.9 (d, C-11), 84.3 (d, C-2), 78.7 (t, C-17), 70.2 (d, C-7),
40.7 (d, C-8), 37.0 (t, C-13), 36.1 (t, C-5), 31.3 (t, C-9), 28.2 (t,
C-6), 26.5 (t, C-10), 24.4 (t, C-14), 15.7 (q, C-20), 15.3 (q, C-
18), 15.2 (q, C-19), 10.1 (q, C-15). 7ꢁ-8: a colorless oil. Because
the 1H NMR signals were heavily overlapped in ꢂ 1.35–2.30
region, further characterization was not carried out.
(R)-MTPA Ester 9. A solution of 7ꢀ-8 (3.0 mg, 0.01 mmol)
in pyridine (50 mL) was treated with (S)-MTPACl (10 mL,
0.045 mmol) for 5 h at room temperature. The reaction was
quenched by N,N-dimethyl-1,3-propanediamine (12 mL, 0.10
mmol). The mixture was concentrated and the residue was sub-
jected to a silica gel short column eluted with CH2Cl2. Separation
by TLC (Rf ¼ 0:48, hexane–isopropyl alcohol = 95:5) gave (R)-
MTPA ester 9 (1.8 mg, 0.003 mmol): a colorless oil; 1H NMR
(400 MHz, CDCl3) ꢂ 7.50 (d, 2H, J ¼ 6:8 Hz, H-MTPA), 7.36
(overlap, 3H, H-MTPA), 5.53 (m, 1H, H-2), 5.27 (d, 1H,
J ¼ 8:4 Hz, H-7), 4.96 (d, 1H, J ¼ 5:6 Hz, H-11), 4.91 (d, 1H,
J ¼ 10:4 Hz, H-3), 4.49 (s, 2H, H-17), 3.50 (s, 3H, H-MTPA),
2.53 (dt, 1H, J ¼ 10:4, 8.6 Hz, H-14), 2.16 (overlap, 2H, H-10),
2.11 (m, 1H, H-5), 2.00 (overlap, 1H, H-13), 1.97 (overlap, 1H,
H-5), 1.94 (overlap, 1H, H-8), 1.87 (overlap, 1H, H-13), 1.86
(overlap, 1H, H-14), 1.81 (s, 3H, H-18), 1.72 (overlap, 1H, H-
6), 1.69 (s, 3H, H-20), 1.64 (overlap, 1H, H-6), 1.64 (s, 3H, H-
15), 1.45 (m, 1H, H-9), 1.28 (m, 1H, H-9), 0.73 (d, 3H, J ¼
6:4 Hz, H-19).
25
15.2 (q, C-20), 9.2 (q, C-15). (+)-24: a yellow oil; ½ꢀꢁD
¼
þ70:2ꢂ (c 1.36, CHCl3); HR-EI-MS m=z 300.2064 (calcd for
C20H28O2, 300.2090); 1H NMR (400 MHz, CDCl3) ꢂ 7.01 (s,
1H, H-17), 5.65 (s, 1H, H-3), 4.90 (t, 1H, J ¼ 6:4 Hz, H-11),
2.72 (ddd, 1H, J ¼ 15:1, 9.0, 2.2 Hz, H-6), 2.60 (dd, 1H, J ¼
13:4, 7.1 Hz, H-8), 2.47–2.45 (overlap, 2H, H-5, 14), 2.38–2.35
(overlap, 2H, H-6, 14), 2.29 (m, 1H, H-5), 2.13 (m, 1H, H-13),
2.03 (m, 1H, H-10), 1.95 (overlap, 1H, H-13), 1.93 (s, 3H, H-
18), 1.86 (s, 3H, H-15), 1.85 (overlap, 1H, H-10), 1.71 (m, 1H,
H-9), 1.19 (s, 3H, H-20), 1.16 (m, 1H, H-9), 1.03 (d, 3H,
J ¼ 7:3 Hz, H-19); 13C NMR (100 MHz, CDCl3) ꢂ 214.0 (s, C-
7), 149.6 (s, C-2), 137.4 (d, C-17), 136.6 (s, C-12), 133.7 (s, C-
4), 125.6 (d, C-11), 122.0 (s, C-1), 120.5 (s, C-16), 112.1 (d, C-
3), 43.3 (d, C-8), 38.3 (t, C-13), 38.2 (t, C-6), 35.2 (t, C-5),
30.9 (t, C-9), 24.5 (t, C-10), 24.3 (t, C-14), 18.4 (q, C-18), 17.8
(q, C-19), 17.7 (q, C-20), 8.1 (q, C-15). (+)-25: a colorless oil;
25
½ꢀꢁD ¼ þ206:1ꢂ (c 0.28, CHCl3); HR-EI-MS m=z 320.2336
1
(calcd for C20H32O3, 320.2352); H NMR (400 MHz, C6D6 con-
taining 2 mL of CD3OD/0.4 mL) ꢂ 5.87 (d, 1H, J ¼ 9:5 Hz,
H-2), 5.20 (dd, 1H, J ¼ 10:5, 4.0 Hz, H-11), 5.15 (s, 1H, H-15),
5.02 (s, 1H, H-15), 4.10 (d, 1H, J ¼ 9:7 Hz, H-3), 3.88 (dd, 1H,
J ¼ 8:6, 6.0 Hz, H-7), 2.51–2.48 (overlap, 2H, H-10, 14), 2.32–
2.23 (overlap, 3H, H-14, 13, 5), 2.05 (dd, 1H, J ¼ 13:6, 8.6 Hz,
H-13), 1.92 (m, 1H, H-10), 1.87 (s, 3H, H-17), 1.85–1.82 (overlap,
2H, H-9, 6), 1.71–1.70 (overlap, 2H, H-5, 6), 1.67 (s, 3H, H-20),
1.41 (dd, 1H, J ¼ 14:1, 9.1 Hz, H-9), 1.33 (s, 3H, H-18), 1.06
(s, 3H, H-19); 13C NMR (100 MHz, C6D6 containing 2 mL of
CD3OD/0.4 mL) ꢂ 144.5 (s, C-16), 143.8 (s, C-1), 130.7 (s, C-
12), 129.5 (d, C-11), 127.2 (d, C-2), 113.6 (t, C-15), 84.3 (s, C-
4), 79.8 (d, C-7), 73.2 (s, C-8), 71.1 (d, C-3), 39.4 (t, C-9), 37.6
(t, C-5), 37.5 (t, C-13), 26.3 (t, C-6), 25.3 (t, C-14), 23.2 (q, C-
19), 22.0 (t, C-10), 21.7 (q, C-17), 20.1 (q, C-18), 17.0 (q, C-20).
(S)-MTPA Ester (9). A solution of 7ꢀ-8 (0.5 mg, 0.0016
mmol) was treated with (R)-MTPACl in the same manner as
described above. (S)-MTPA ester 9 (0.3 mg, 0.0006 mmol) was
1
Benzoylation of (+)-25.
A solution of (+)-25 (0.5 mg,
obtained: a colorless oil; H NMR (400 MHz, CDCl3) ꢂ 7.50 (d,
0.0016 mmol) in pyridine (50 mL) was treated with benzoyl chlo-
ride (4.4 mL, 0.04 mmol) for 20 h at room temperature. The reac-
tion was quenched by N,N-dimethyl-1,3-propanediamine (5 mL,
0.04 mmol). The solvent was evaporated and the residue was sub-
jected to a silica gel short column eluted with CH2Cl2. The ben-
zoyl ester of (+)-25 (0.5 mg, 0.0016 mmol) was obtained by pre-
parative TLC (Rf ¼ 0:75, hexane–EtOAc = 1:1). CD (0.12 mM,
2H, J ¼ 7:2 Hz, H-MTPA), 7.35 (overlap, 3H, H-MTPA), 5.53
(m, 1H, H-2), 5.28 (d, 1H, J ¼ 10:4 Hz, H-7), 4.96 (m, 1H, H-
11), 4.86 (d, 1H, J ¼ 10:0 Hz, H-3), 4.49 (s, 2H, H-17), 3.52 (s,
3H, H-MTPA), 2.58 (dt, 1H, J ¼ 10:4, 8.6 Hz, H-14), 2.18 (over-
lap, 2H, H-10), 2.03 (m, 1H, H-5), 2.00 (overlap, 1H, H-13), 1.99
(overlap, 1H, H-8), 1.90 (overlap, 1H, H-14), 1.88 (overlap, 1H,
H-5), 1.86 (overlap, 1H, H-13), 1.78 (s, 3H, H-18), 1.70 (overlap,
1H, H-6), 1.69 (s, 3H, H-20), 1.66 (s, 3H, H-15), 1.64 (overlap,
1H, H-6), 1.47 (m, 1H, H-9), 1.29 (m, 1H, H-9), 0.84 (d, 3H,
J ¼ 6:4 Hz, H-19).
EtOH) ꢀ"ꢄ +20.0 (241 nm), ꢃ12:5 (223 nm).
max
Sodium Tetrahydroborate Reduction of (+)-4. A solution
of (+)-4 (27.4 mg, 0.09 mmol) in MeOH (3.0 mL) was treated
with NaBH4 (26 mg, 0.7 mmol) for 30 min at room temperature.
The reaction mixture was concentrated, water was added, and
the mixture was extracted with ether. The ether layer was dried
over Na2SO4. The mixture of two diastereomeric alcohols 8
(28.0 mg, 0.09 mmol) was obtained (TLC; Rf ¼ 0:5, hexane–
EtOAc = 1:1). The mixture was separated by recycle-HPLC (flow
rate 10 mL minꢃ1) with hexane–isopropyl alcohol = 95:5. 7ꢀ-Al-
cohol 8 (8.9 mg, 0.03 mmol, Rt ¼ 44 min, two cycles) and 7ꢁ-al-
cohol 8 (12.4 mg, 0.04 mmol, Rt ¼ 48 min, two cycles) were ob-
tained. 7ꢀ-8: a colorless oil; HR-EI-MS m=z 304.2393 (calcd
Sodium Hydroxide Treatment of (+)-4 (MeOH). A solution
of (+)-4 (3.6 mg, 0.012 mmol) in MeOH (0.5 mL) was treated
with 2 drops of a NaOH solution, made of MeOH (1.0 mL) and
NaOH (100 mg), for 5 days at room temperature. The mixture
was added to water and extracted with EtOAc. The organic layer
was washed with water and brine, and dried over Na2SO4. The
crude material was separated by recycle-HPLC with hexane–
isopropyl alcohol = 95:5, giving (+)-4 [2.9 mg, 0.01 mmol,
25
½ꢀꢁD ¼ þ135:0ꢂ (c 0.29, CHCl3), Rt ¼ 72 min, six cycles] and
25
(+)-5 [5.7 mg, 0.02 mmol, ½ꢀꢁD ¼ þ75:0ꢂ (c 0.57, CHCl3),
1
for C20H32O2, 304.2402); H NMR (750 MHz, C6D6) ꢂ 5.73 (m,
Rt ¼ 78 min, six cycles].
1H, H-2), 5.38 (dt, 1H, J ¼ 10:0, 1.3 Hz, H-3), 5.13 (ddd, 1H,
J ¼ 7:8, 6.7, 1.3 Hz, H-11), 4.63 (br s, 2H, H-17), 3.65 (ddd,
1H, J ¼ 10:5, 6.0, 1.5 Hz, H-7), 2.38 (ddd, 1H, J ¼ 19:6, 9.7,
3.2 Hz, H-14), 2.36 (dd, 1H, J ¼ 13:2, 9.2 Hz, H-5), 2.12 (m,
2H, H-10), 2.01 (dd, 1H, J ¼ 14:7, 8.5 Hz, H-5), 1.99 (overlap,
2H, H-13), 1.92 (m, 1H, H-14), 1.71 (dddd, 1H, J ¼ 14:2, 8.2,
Deuterated Perchloric Acid Treatment of (+)-1 in THF-d8.
A solution of (+)-1 (5.1 mg, 0.017 mmol) in THF-d8 (0.5 mL) was
treated with 25% DClO4 (22 mL) (in D2O) at room temperature.
The reaction was followed by 1H NMR spectra. After 20 min,
the signals of (+)-1 disappeared and the signals due to diol
[(+)-3] and ketones (+)-4 and (+)-5 appeared. The methyl signals

K. Nii et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008)
571
at C-8 of the two ketones were observed as doublets indicating no
incorporation of deuterium at C-8.
H-14), 1.83 (s, 3H, H-18), 1.70–1.67 (overlap, 2H, H-6, 9),
1.56–1.54 (overlap, 2H, H-6, 9), 1.54 (s, 3H, H-20), 1.44 (s, 3H,
H-15), 1.16 (s, 3H, H-19); 13C NMR (100 MHz, C6D6) ꢂ 140.6
(s, C-4), 135.9 (s, C-12), 134.7 (s, C-1), 128.3 (s, C-16), 126.4
(d, C-3), 125.8 (d, C-11), 85.7 (d, C-2), 78.6 (t, C-17), 75.1 (s,
C-8), 74.0 (d, C-7), 38.7 (t, C-9), 37.9 (t, C-13), 36.8 (t, C-5),
30.4 (t, C-6), 24.8 (q, C-19), 24.0 (t, C-14), 23.1 (t, C-10), 17.6
(q, C-18), 16.0 (q, C-20), 10.4 (q, C-15).
Sulfuric Acid Treatment of (+)-1. A solution (+)-1 (1.52 g,
5.0 mmol) in THF (150 mL) was treated with 50% H2SO4
(5.4 mL) for 15 min at room temperature. After workup, the crude
product was applied to silica gel flash chromatography. The col-
umn was eluted with hexane–EtOAc = 4:6. Compound (+)-3
18
[1.36 g, 4.2 mmol, ½ꢀꢁD ¼ þ112:5ꢂ (c 0.91, CHCl3)] was ob-
tained as a powdery solid. Recrystallization from ether afforded
very fine needles, mp 112–115 ꢂC (lit. 93–95 ꢂC).7
Treatment of (+)-3 with Thionyl Chloride. A solution of
diol (+)-3 (31.0 mg, 0.1 mmol) in CH2Cl2 (1.4 mL) was treated
with thionyl chloride (28 mL, 0.4 mmol) and triethylamine
(70 mL, 0.5 mmol) at room temperature for 25 min. The reaction
mixture was added to water (2 mL), and the mixture was extracted
with CH2Cl2 (3 ꢄ 3 mL). The CH2Cl2 layer was washed with
brine (2 mL) and dried over Na2SO4. After concentration, the
residue (33.2 mg) was separated by recycle-HPLC (flow rate
30 mL minꢃ1) with hexane–isopropyl alcohol = 95:5 to produce
12b (6.4 mg, 0.02 mmol, Rt ¼ 16 min, three cycles) and 12a
(6.0 mg, 0.02 mmol, Rt ¼ 17 min, three cycles). 12a: a colorless
Inv-Sarcophytoxide (+)-10. To a solution of (+)-3 (150 mg,
0.47 mmol) and triethylamine (170 mL, 1.2 mmol) in CH2Cl2
(2.5 mL) cooled at 0 ꢂC was added methanesulfonyl chloride
(55 mL, 0.70 mmol), and the mixture was stirred for 30 min. The
mixture was warmed to room temperature and triethylamine
(100 mL, 0.7 mmol) was added. After stirring for 30 min, a solution
of K2CO3 (295 mg, 2.1 mmol) in MeOH (8.8 mL) was added, and
the mixture was allowed to stand at room temperature for 20 h. Af-
ter filtration, the filtrate was extracted with EtOAc, and the organ-
ic phase was washed with brine and dried over Na2SO4. Inv-sar-
cophytoxide (+)-10 (108 mg, 0.36 mmol) was obtained by flash
column chromatography (hexane–EtOAc = 1:1) of the crude
30
oil; ½ꢀꢁD ¼ þ60:7ꢂ (c 0.60, CHCl3); HR-ESI-MS m=z 389.1761
(calcd for C20H30O4NaS, 389.1763); 1H NMR (400 MHz, C6D6)
ꢂ 5.56 (m, 1H, H-2), 5.31 (d, 1H, J ¼ 10:3 Hz, H-3), 4.60 (m,
1H, H-11), 4.57 (brs, 2H, H-17), 4.44 (dd, 1H, J ¼ 9:8, 3.2 Hz,
H-7), 2.24 (overlap, 2H, H-5, 14), 1.92 (td, 1H, J ¼ 11:5,
2.9 Hz, H-13), 1.85 (overlap, 1H, H-10), 1.82 (overlap, 1H, H-
5), 1.79–1.78 (overlap, 2H, H-10, 13), 1.64 (t, 2H, J ¼ 5:3 Hz,
H-9), 1.60 (overlap, 1H, H-14), 1.58 (s, 3H, H-18), 1.56 (s, 3H,
H-19), 1.45 (s, 3H, H-15), 1.32 (s, 3H, H-20), 1.30 (m, 2H, H-
6); 13C NMR (100 MHz, C6D6) ꢂ 137.7 (s, C-4), 137.6 (s, C-
12), 133.7 (s, C-1), 128.9 (s, C-16), 127.8 (d, C-3), 122.6 (d, C-
11), 91.9 (s, C-8), 88.2 (d, C-7), 84.6 (d, C-2), 78.7 (t, C-17),
37.4 (t, C-13), 35.1 (t, C-5), 33.1 (t, C-9), 29.1 (t, C-6), 25.4
20
product: (+)-10: a colorless oil; ½ꢀꢁD ¼ þ82:5ꢂ (c 0.86, CHCl3);
HR-ESI-MS m=z 325.2100 (calcd for C20H30O2Na, 325.2144);
1H NMR (400 MHz, C6D6) ꢂ 5.54 (m, 1H, H-2), 5.42 (d, 1H,
J ¼ 9:5 Hz, H-3), 5.13 (t, 1H, J ¼ 7:3 Hz, H-11), 4.62 (dd, 1H,
J ¼ 11:3, 5.0 Hz, H-17), 4.53 (dd, 1H, J ¼ 11:9, 3.4 Hz, H-17),
2.75 (t, 1H, J ¼ 5:5 Hz, H-7), 2.24–2.22 (overlap, 2H, H-13,
14), 2.14–2.12 (overlap, 2H, H-5, 10), 2.06 (m, 1H, H-5), 1.99–
1.95 (overlap, 2H, H-9, 13), 1.85 (m, 1H, H-10), 1.71 (m, 1H,
H-6), 1.69 (s, 3H, H-18), 1.65 (overlap, 1H, H-14), 1.56 (m, 1H,
H-6), 1.47 (s, 3H, H-20), 1.44 (s, 3H, H-15), 1.23 (td, 1H,
J ¼ 12:8, 3.5 Hz, H-9), 1.15 (s, 3H, H-19); 13C NMR (75 MHz,
C6D6) ꢂ 139.2 (s, C-4), 135.5 (s, C-12), 134.6 (s, C-1), 128.5 (s,
C-16), 126.6 (d, C-3), 124.1 (d, C-11), 85.8 (d, C-2), 78.5 (t, C-
17), 61.8 (d, C-7), 59.2 (s, C-8), 39.3 (t, C-9), 38.8 (t, C-13),
35.3 (t, C-5), 28.0 (t, C-6), 23.9 (t, C-14), 23.5 (t, C-10), 17.6
(q, C-18), 16.6 (q, C-19), 15.4 (q, C-20), 10.3 (q, C-15). From
the less polar fraction eluted with the same solvent, 12b (1 mg,
0.003 mmol) was obtained as a crystal, which was subjected to
X-ray analysis. In the 1H NMR spectrum of the crude reaction
mixture, the signals due to 12a and 12b were found as very small
ones. Characterization of 12a and 12b was performed on the syn-
thetic products (v.i.).
(t, C-14), 25.1 (q, C-19), 22.6 (t, C-10), 16.6 (q, C-18), 15.0
30
(q, C-20), 10.2 (q, C-15). 12b: colorless needles; ½ꢀꢁD
¼
ꢃ37:1ꢂ (c 0.64, CHCl3); HR-ESI-MS m=z 389.1782 (calcd for
C20H30O4NaS, 389.1763); 1H NMR (400 MHz, C6D6) ꢂ 5.57
(brs, 1H, H-2), 5.31 (d, 1H, J ¼ 10:3 Hz, H-3), 4.63 (dd, 1H,
J ¼ 8:6, 5.8 Hz, H-11), 4.54 (s, 2H, H-17), 4.10 (d, 1H,
J ¼ 11:4 Hz, H-7), 2.46 (overlap, 1H, H-5), 2.44 (overlap, 1H,
H-6), 2.28 (overlap, 1H, H-14), 2.11 (overlap, 1H, H-5), 1.96
(overlap, 1H, H-9), 1.88 (overlap, 1H, H-13), 1.83 (overlap, 1H,
H-9), 1.80 (overlap, 2H, H-10), 1.72 (overlap, 1H, H-13), 1.58
(s, 3H, H-18), 1.57 (overlap, 1H, H-6), 1.51 (overlap, 1H, H-
14), 1.42 (s, 3H, H-15), 1.32 (s, 3H, H-20), 1.02 (s, 3H, H-19);
13C NMR (100 MHz, C6D6) ꢂ 138.4 (s, C-4), 137.9 (s, C-12),
133.4 (s, C-1), 128.8 (s, C-16), 127.4 (d, C-3), 122.2 (d, C-11),
93.5 (s, C-8), 86.1 (d, C-7), 84.5 (d, C-2), 78.6 (t, C-17), 37.1
(t, C-13), 35.5 (t, C-5), 32.8 (t, C-9), 29.9 (t, C-6), 26.0 (t,
C-14), 23.8 (q, C-19), 23.0 (t, C-10), 16.4 (q, C-18), 14.8 (q,
C-20), 10.2 (q, C-15).
Perchloric Acid Treatment of (+)-10. A solution of (+)-10
(29.6 mg, 0.1 mmol) in THF (3.0 mL) was treated with 25% per-
chloric acid (0.36 mL) for 120 min at room temperature. The reac-
tion mixture was treated with a saturated NaHCO3 solution and
the mixture was extracted with ether. The ether layer was washed
with water and brine and dried over Na2SO4. Evaporation of the
solvent gave a crude product (35.5 mg). Compound (+)-11
(7.9 mg, 0.025 mmol) was obtained by preparative TLC of the
crude product. Compounds (+)-4 (0.8 mg, 0.003 mmol) and (+)-
5 (6.0 mg, 0.02 mmol) were separated by recycle HPLC (flow rate
10 mL minꢃ1, hexane–isopropyl alcohol = 95:5) of the less polar
Trifluoromethanesulfonic Acid Treatment of 13. A solution
of 13 (4.0 mg, 0.03 mmol) in THF (0.5 mL) was treated with TfOH
(0.3 mL, 0.003 mmol) for 10 min at room temperature. The reac-
tion mixture was treated with a saturated NaHCO3 solution and
the mixture was extracted with ether. The ether layer was washed
with water and brine and dried over Na2SO4. Evaporation of the
solvent gave a crude product, from which 1513 (3.2 mg, 0.02
mmol) was obtained by preparative TLC.
24
TLC fraction. (+)-11: a colorless oil; ½ꢀꢁD ¼ þ98:1ꢂ (c 0.78,
CHCl3); HR-ESI-MS m=z 343.2268 (calcd for C20H32O3Na,
343.2249); 1H NMR (400 MHz, C6D6) ꢂ 5.58 (m, 1H, H-2),
5.46 (d, 1H, J ¼ 9:8 Hz, H-3), 5.20 (t, 1H, J ¼ 7:3 Hz, H-11),
4.63 (dd, 1H, J ¼ 11:9, 4.5 Hz, H-17), 4.52 (d, 1H, J ¼ 12:0 Hz,
H-17), 3.39 (t, 1H, J ¼ 7:5 Hz, H-7), 2.20–2.12 (overlap, 4H, H-
5, 10, 13, 14), 2.04–2.00 (overlap, 2H, H-10, 13), 1.85 (m, 1H,
Trifluoromethanesulfonic Acid Treatment of 14.
Com-
pound 14 (4.0 mg, 0.03 mmol) was treated with TfOH (0.3 mL,
0.003 mmol) in the same manner as described above, giving
1613 (3.6 mg, 0.02 mmol).

572 Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008) BCSJ AWARD ARTICLE
(À)-Dihydrocaryophyllene Oxide (17). A mixture of (ꢃ)-
caryophyllene oxide (1000 mg, 4.5 mmol) and palladium–charcoal
(10%) (1000 mg) in MeOH (200 mL) was stirred under an atmo-
spheric pressure of hydrogen at room temperature for 3 h. The cat-
alyst was removed by filtration through a pad of Celite and the fil-
trate was concentrated to give a residue (1120 mg). The residue
was applied to a silica gel column. The column was eluted with
hexane–EtOAc = 9:1. The eluted crude product (924 mg) was
separated by recycle-HPLC using four columns connected in se-
ries (flow rate 30 mL minꢃ1) with hexane–EtOAc = 95:5 to give
compound 17 (716 mg, 3.2 mmol, Rt ¼ 77 min, 3 cycles). 17: col-
ed at Rt ¼ 35 min (two cycles) and (+)-20 (10.1 mg, 0.03 mmol)
29
at Rt ¼ 31 min (two cycles). (+)-19: a colorless oil; ½ꢀꢁD
¼
þ115:9ꢂ (c 0.97, CHCl3); HR-ESI-MS m=z 361.1904, 363.1903
(calcd for C20H31O235ClNa, 361.1910, C20H31O237ClNa,
363.1881); 1H NMR (400 MHz, C6D6) ꢂ 5.68 (m, 1H, H-2),
5.39 (d, 1H, J ¼ 10:0 Hz, H-3), 5.07 (t, 1H, J ¼ 7:2 Hz, H-11),
4.58 (m, 2H, H-17), 3.76 (dd, 1H, J ¼ 11:4, 8.5 Hz, H-7), 2.33–
2.27 (overlap, 3H, H-5, 10, 14), 2.21 (m, 1H, H-9), 2.08 (m,
1H, H-10), 1.99–1.84 (overlap, 5H, H-5, 6, 13, 13, 14), 1.79
(ddd, 1H, J ¼ 14:1, 7.9, 3.4 Hz, H-9), 1.63 (s, 3H, H-18), 1.52
(s, 3H, H-20), 1.51 (s, 3H, H-19), 1.43 (s, 3H, H-15), 1.32 (m,
1H, H-6), 1.05 (m, 1H, OH); 13C NMR (75 MHz, C6D6) ꢂ 137.4
(s, C-4), 135.7 (s, C-12), 134.2 (s, C-1), 128.5 (d, C-3), 128.0
(s, C-16), 123.3 (d, C-11), 84.4 (d, C-2), 78.7 (t, C-17),
78.4 (s, C-8), 72.3 (d, C-7), 39.4 (t, C-9), 36.5 (t, C-13),
35.8 (t, C-5), 28.0 (t, C-6), 26.6 (q, C-19), 25.2 (t, C-10), 24.3
(t, C-14), 16.0 (q, C-20), 15.3 (q, C-18), 10.1 (q, C-15). (+)-20:
26
orless needles; mp 68.2 ꢂC (lit.14 mp 66–67 ꢂC); ½ꢀꢁD ¼ ꢃ51:7ꢂ
(c 0.59, CHCl3); HR-ESI-MS m=z 245.1903 (calcd for C15H26-
O2Na, 245.1881); 1H NMR (400 MHz, C6D6) ꢂ 2.76 (dd, 1H,
J ¼ 10:8, 4.0 Hz, H-5), 2.04 (m, 1H, H-6), 1.97 (dddd, 1H,
J ¼ 12:6, 4.4, 2.8, 1.2 Hz, H-3), 1.89 (tdd, 1H, J ¼ 10:0, 8.0,
4.8 Hz, H-9), 1.59 (t, 1H, J ¼ 9:8 Hz, H-1), 1.52 (overlap, 1H,
H-8), 1.47–1.46 (overlap, 3H, H-2, 7, 10), 1.22 (t, 1H, J ¼ 10:4
Hz, H-10), 1.17 (overlap, 1H, H-6), 1.17 (s, 3H, H-15), 1.14 (over-
lap, 1H, H-2), 1.13 (overlap, 1H, H-7), 0.98 (td, 1H, J ¼ 14:0,
5.2 Hz, H-3), 0.94 (s, 3H, H-14), 0.93 (s, 3H, H-13), 0.78 (d,
3H, J ¼ 6:8 Hz, H-12); 13C NMR (100 MHz, C6D6) ꢂ 64.2 (d,
C-5), 59.1 (s, C-4), 47.0 (d, C-9), 45.9 (d, C-1), 39.3 (t, C-3),
35.0 (t, C-10), 34.1 (d, C-8), 33.5 (s, C-11), 30.0 (q, C-14), 28.8
(t, C-6), 27.8 (t, C-2), 27.6 (t, C-7), 21.6 (q, C-13), 19.7 (q,
C-12), 17.5 (q, C-15).
30
a colorless oil; ½ꢀꢁD ¼ þ106:5ꢂ (c 1.05, CHCl3); HR-ESI-MS
m=z 361.1937, 363.1893 (calcd for C20H31O235ClNa, 361.1910,
C20H31O237ClNa, 363.1881); H NMR (400 MHz, C6D6) ꢂ 5.51–
1
5.48 (overlap, 2H, H-2, 3), 5.25 (m, 1H, H-11), 4.64 (dd, 1H,
J ¼ 11:4, 3.9 Hz, H-17), 4.45 (d, 1H, J ¼ 11:7 Hz, H-17), 3.94
(dd, 1H, J ¼ 9:5, 1.7 Hz, H-7), 2.33–2.26 (overlap, 3H, H-5, 6,
10), 2.16–2.12 (overlap, 2H, H-5, 13), 2.07–2.02 (overlap, 5H,
H-9, 10, 13, 14, 14), 1.76 (m, 1H, H-6), 1.74 (overlap, 4H, H-
18, OH), 1.61 (t, 1H, J ¼ 10:7 Hz, H-9), 1.54 (s, 3H, H-20),
1.43 (s, 3H, H-15), 1.26 (s, 3H, H-19); 13C NMR (75 MHz, C6D6)
ꢂ 137.9 (s, C-4), 136.9 (s, C-12), 134.2 (s, C-1), 129.1 (s, C-16),
125.7 (d, C-3), 124.9 (d, C-11), 85.5 (d, C-2), 78.4 (t, C-17), 75.8
(s, C-8), 66.9 (d, C-7), 38.5 (t, C-9), 38.0 (t, C-13), 35.6 (t, C-5),
30.4 (t, C-6), 23.9 (q, C-19), 23.6 (t, C-10), 23.4 (t, C-14), 18.1 (q,
C-18), 16.0 (q, C-20), 10.4 (q, C-15).
Conversion of (+)-19 to (+)-1. To a solution of (+)-19
(2.6 mg, 0.01 mmol) in MeOH (300 mL) was added K2CO3
(41.5 mg, 0.3 mmol) and the mixture was allowed to stand at room
temperature overnight. The crude product was applied to silica
gel column chromatography eluted with CH2Cl2 to give (+)-1
(2.8 mg, 0.01 mmol).
Conversion of (+)-20 to (+)-1. To a solution of (+)-20
(1.0 mg, 0.003 mmol) in MeOH (60 mL) was added K2CO3
(22.3 mg, 0.16 mmol) and the mixture was allowed to stand
overnight. The crude product was applied to silica gel column
chromatography eluted with CH2Cl2 to give (+)-1 (1.0 mg,
0.003 mmol).
Conversion of (+)-19 to (+)-4. A solution of (+)-19 (3.0 mg,
0.01 mmol) in CD3OD/D2O (2:1, 0.6 mL) was allowed to stand
for 22 h at room temperature. The 1H NMR spectrum of the prod-
uct mainly consisted of the signals due to (+)-4. The yield of (+)-
4 was deduced to be >70% by integration of the signals in the
1H NMR spectrum.
Perchloric Acid Treatment of 17. A solution of 17 (300 mg,
1.4 mmol) in CH2Cl2 (30 mL) was treated with 25% perchloric
acid (3.6 mL) for 30 min at room temperature. The reaction mix-
ture was added to a saturated NaHCO3 solution (30 mL), and
the mixture was extracted with ether (3 ꢄ 30 mL). The ether layer
was washed with water (50 mL) and brine (50 mL) and dried over
Na2SO4. After the ether was evaporated, the residue (345 mg) was
applied to a silica gel column. The column was eluted with hex-
ane–EtOAc = 8:2. The eluted crude product (65.9 mg) was puri-
fied by recycle-HPLC (flow rate 30 mL minꢃ1) with hexane–iso-
propyl alcohol = 95:5 to give compound 18 (5.3 mg, 0.02 mmol,
Rt ¼ 11 min, 3 cycles). 18: colorless needles; mp 56–57 ꢂC;
24
½ꢀꢁD ¼ þ13:9ꢂ (c 0.27, CHCl3); HR-ESI-MS m=z 277.2141
[calcd for C16H30O2Na (Mþ + Na + MeOH), 277.2144];
1H NMR (400 MHz, acetone-d6) ꢂ 2.64 (dd, 1H, J ¼ 11:2,
15.4 Hz, H-6), 2.60 (sext, 1H, J ¼ 6:3 Hz, H-4), 2.12 (ddd, 1H,
J ¼ 15:4, 9.8, 1.4 Hz, H-6), 1.96 (br t, 1H, J ¼ 13:3 Hz, H-7),
1.91 (qd, 1H, J ¼ 9:8, 2.5 Hz, H-9), 1.78 (overlap, 2H, H-3),
1.64 (overlap, 1H, H-8), 1.57 (overlap, 2H, H-1, 7), 1.42 (dd,
1H, J ¼ 9:8, 8.4 Hz, H-10), 1.33 (m, 1H, H-2), 1.22 (t, 1H,
J ¼ 10:5 Hz, H-10), 1.18 (m, 1H, H-2), 0.96 (d, 3H, J ¼ 6:3 Hz,
H-15), 0.90 (d, 3H, J ¼ 7:0 Hz, H-12), 0.89 (s, 3H, H-14), 0.88
(s, 3H, H-13); 13C NMR (100 MHz, acetone-d6) ꢂ 213.8 (s,
C-5), 47.9 (d, C-4), 46.4 (d, C-1), 40.7 (d, C-9), 37.2 (t, C-10),
37.2 (t, C-6), 35.7 (d, C-8), 34.1 (s, C-11), 31.7 (t, C-3), 30.2
(t, C-7), 29.5 (q, C-14), 25.0 (t, C-2), 22.4 (q, C-13), 16.1 (q,
C-15), 16.0 (q, C-12).
Hydrobromic Acid Treatment of (+)-1. A solution of (+)-1
(30 mg, 0.1 mmol) in THF (3 mL) was treated with 48% hydrobro-
mic acid (108 mL) for 10 min at room temperature. The reaction
mixture was added to a saturated NaHCO3 solution (1.5 mL),
and the mixture was extracted with ether (3 ꢄ 2 mL). The
combined ether layer was washed with water (3 mL), brine
(3 mL), and dried over Na2SO4. After concentration, the residue
Hydrochloric Acid Treatment of (+)-1. A solution of (+)-1
(100 mg, 0.3 mmol) in THF (10 mL) was treated with 35% hydro-
chloric acid (0.28 mL) for 10 min at room temperature. The reac-
tion mixture was added to a saturated NaHCO3 solution (5 mL),
and the mixture was extracted with ether (3 ꢄ 6 mL). The ether
layer was washed with water (10 mL), brine (10 mL), and dried
over Na2SO4. The crude product (150 mg) was separated by recy-
cle-HPLC (flow rate 10 mL minꢃ1) with hexane–isopropyl alco-
hol = 95:5. Chlorohydrine (+)-19 (84.5 mg, 0.25 mmol) was elut-
(45 mg) was separated by recycle-HPLC (flow rate 10 mL minꢃ1
)
with hexane–isopropyl alcohol = 93:7. (+)-21 (25.3 mg, 0.07
mmol) was eluted at Rt ¼ 47 min (three cycles) and (+)-22
(4.9 mg, 0.01 mmol) at Rt ¼ 126 min (9 cycles). (+)-21: a color-
31
less oil; ½ꢀꢁD ¼ þ105:2ꢂ (c 0.42, CHCl3); HR-ESI-MS m=z

K. Nii et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 5 (2008)
573
405.1388, 407.1385 (calcd for C20H31O279BrNa, 405.1405,
C20H31O281BrNa, 407.1385); 1H NMR (400 MHz, C6D6) ꢂ 5.69
(m, 1H, H-2), 5.40 (d, 1H, J ¼ 10:1 Hz, H-3), 5.00 (t, 1H,
J ¼ 6:8 Hz, H-11), 4.58 (m, 2H, H-17), 3.57 (t, 1H, J ¼ 9:8
Hz, H-7), 2.33 (m, 1H, H-5), 2.26–2.23 (overlap, 3H, H-9,
10, 14), 2.11 (m, 1H, H-10), 2.02 (m, 1H, H-6), 1.96–1.85
(overlap, 4H, H-5, 9, 13, 13), 1.82 (m, 1H, H-14), 1.71 (s,
3H, H-19), 1.64 (s, 3H, H-18), 1.50 (s, 3H, H-20) 1.41 (s,
3H, H-15), 1.35 (m, 1H, H-6), 0.95 (m, 1H, OH); 13C NMR
(75 MHz, C6D6) ꢂ 137.4 (s, C-4), 135.9 (s, C-12), 134.1 (s, C-
1), 128.5 (d, C-3), 128.1 (s, C-16), 123.1 (d, C-11), 84.4 (d, C-
2), 79.1 (s, C-8), 78.7 (t, C-17), 72.8 (d, C-7), 40.6 (t, C-9),
36.6 (t, C-13), 35.9 (t, C-5), 29.5 (t, C-6), 28.1 (q, C-19),
26.4 (t, C-10), 24.3 (t, C-14), 15.9 (q, C-20), 15.4 (q, C-18),
10.1 (q, C-15). The chemical shifts of C-3 and C-16 (overlapped
with C6D6 signals) were determined by HMBC. (+)-22: a color-
structures of (+)-3, (ꢃ)-5, 12b, and 18. This material is available
free of charge on the web at: http://www.csj.jp/journals/bcsj/.
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29
less oil; ½ꢀꢁD ¼ þ78:6ꢂ (c 0.10, CHCl3); HR-ESI-MS m=z
405.1407, 407.1396 (calcd for C20H31O279BrNa, 405.1405,
C20H31O281BrNa, 407.1385); 1H NMR (400 MHz, C6D6) ꢂ 5.50
(overlap, 2H, H-2, 3), 5.26 (m, 1H, H-11), 4.64 (d, 1H, J ¼
10:8 Hz, H-17), 4.43 (d, 1H, J ¼ 11:6 Hz, H-17), 4.01 (dd, 1H,
J ¼ 10:6, 2.4 Hz, H-7), 2.43–2.41 (overlap, 2H, H-6, 10), 2.25
(m, 1H, H-5), 2.17–2.11 (overlap, 3H, H-5, 9, 13), 2.03–
2.01 (overlap, 4H, H-10, 13, 14, 14), 1.87 (dddd, 1H, J ¼ 19:1,
9.8, 6.4, 2.9 Hz, H-6), 1.80 (s, 1H, OH), 1.71 (s, 3H, H-18),
1.66 (ddd, 1H, J ¼ 14:9, 10.9, 3.9 Hz, H-9), 1.54 (s, 3H, H-20),
1.41 (s, 3H, H-15), 1.32 (s, 3H, H-19); 13C NMR (100 MHz,
C6D6) ꢂ 137.5 (s, C-12), 137.3 (s, C-4), 134.1 (s, C-1), 129.4 (s,
C-16), 127.8 (d, C-3), 124.9 (d, C-11), 85.5 (d, C-2), 78.4 (t, C-
17), 75.8 (s, C-8), 62.3 (d, C-7), 39.2 (t, C-9), 38.1 (t, C-13),
36.0 (t, C-5), 30.9 (t, C-6), 24.5 (q, C-19), 23.7 (t, C-10), 23.3
(t, C-14), 18.2 (q, C-18), 16.0 (q, C-20), 10.4 (q, C-15).
5
6
Mar. Drugs 2004, 2, 1. b) I. Katsuyama, H. Fahmy, J. K.
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Conversion of (+)-21 to (+)-4. A solution of (+)-21 (1.8 mg,
0.005 mmol) in CD3OD/D2O (2:1, 0.36 mL) was allowed to
1
stand for 1 h at room temperature. The H NMR spectrum of the
product showed exclusively the signals of (+)-4. The yield of
(+)-4 was deduced to be >80% from the integration of the
1H NMR signals.
Professor Keisuke Suzuki (Graduate School of Science
and Engineering, Tokyo Institute of Technology) is gratefully
acknowledged for giving us a suggestion about Curtin–
Hammett principle.
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Supporting Information
1H NMR and 13C NMR data for all new compounds, CD spec-
tra of (+)-5, (ꢃ)-5, and the benzoyl ester of (+)-25, and crystal
14 A. V. Tkachev, J. Org. Chem. USSR 1990, 26, 1706.