A novel synthesis of (?)-callicarpenal

Article abstract of DOI:10.1016/j.tet.2018.08.012

Callicarpenal, isolated from the leaves of American beautyberry (Callicarpa americana) and Japanese beautyberry (Callicarpa japonica), exhibits significant mosquito bite-deterring activity and repellent activity against ticks and fire ants. The mosquito bite-deterring activity level of callicarpenal was reported to be similar to that of N,N-diethyl-m-toluamide. The novel synthesis of (?)-callicarpenal reported herein was accomplished by starting from (+)-pulegone. In our original approach, a novel Prins-type cyclization based on Meyer–Schuster rearrangement was featured as a key step.

Full text of DOI:10.1016/j.tet.2018.08.012

Accepted Manuscript
A novel synthesis of (−)-callicarpenal
Daichi Oguro, Naoki Mori, Hirosato Takikawa, Hidenori Watanabe
PII:
S0040-4020(18)30963-3
10.1016/j.tet.2018.08.012
TET 29732
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 July 2018
Revised Date: 2 August 2018
Accepted Date: 10 August 2018
Please cite this article as: Oguro D, Mori N, Takikawa H, Watanabe H, A novel synthesis of (−)-
callicarpenal, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.012.
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A novel synthesis of (−)-callicarpenal
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Daichi Oguro, Naoki Mori, Hirosato Takikawa, Hidenori Watanabe

1
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Tetrahedron
journal homepage: www.elsevier.com
A novel synthesis of (−)-callicarpenal
a, b
b
b,
b
Daichi Oguro , Naoki Mori , Hirosato Takikawa ∗ , Hidenori Watanabe
a
Technical Research Institute, R&D Center, T. Hasegawa Co., Ltd., 29-7 Kariyado, Nakahara-ku, Kawasaki, Kanagawa 211-0022, Japan
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-
657, Japan
b
8
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Callicarpenal, isolated from the leaves of American beautyberry (Callicarpa americana) and
Japanese beautyberry (Callicarpa japonica), exhibits significant mosquito bite-deterring activity
and repellent activity against ticks and fire ants. The mosquito bite-deterring activity level of
callicarpenal was reported to be similar to that of N,N-diethyl-m-toluamide. The novel synthesis
of (−)-callicarpenal reported herein was accomplished by starting from (+)-pulegone. In our
original approach, a novel Prins-type cyclization based on Meyer–Schuster rearrangement was
featured as a key step.
Available online
Keywords:
Callicarpenal
Prins reaction
2
009 Elsevier Ltd. All rights reserved.
Meyer-Schuster rearrangement
Mosquito repellent
Pulegone
1
. Introduction
Callicarpenal (1) is a tetranorclerodane-type aldehyde isolated
in 2005 from the leaves of American beautyberry (Callicarpa
1
americana) and Japanese beautyberry (Callicarpa japonica).
This aldehyde has been reported to exhibit significant mosquito
bite-deterring activity against Aedes aegypti and Anopheles
1
stephensi, and repellent activity against host-seeking nymphos
2
of ticks (Ixodes scapularis and Amblyomma americanum) and
workers of imported fire ants (Solenopsis invicta Buren,
3
Solenopsis richteri Forel and their hybrid). Since the mosquito
bite-deterring activity level of callicarpenal was reported to be
similar to that of N,N-diethyl-m-toluamide (DEET), the most
commonly used mosquito repellent agent, callicarpenal is
expected to be a naturally occurring DEET alternative. Quite
interestingly, the absolute configuration of the natural
callicarpenal (Scheme 1) was confirmed by an “unintended”
synthesis once (−)-1 has already been reported as an intermediate
in the synthesis of a clerodane diterpenoid before the isolation of
Scheme 1. Structure of (−)-1 and our initial synthetic plan.
2
. Results and Discussion
4
callicarpenal. Besides the serendipitous first synthesis, Ling et
5
al. reported the enantioselective synthesis of (−)-1. It is also
Our initial synthetic plan for (−)-1 is shown in Scheme 1. The
interesting that (+)-1 was also unintentionally synthesized before
the isolation of callicarpenal. Herein, we report a novel approach
for the synthesis of (−)-1 using the readily available (R)-(+)-
pulegone (2) as a chiral starting material.
protected target compound A could be synthesized from B via
ring-closing metathesis (RCM) and reductive deoxygenation. The
key intermediate B would be prepared by the homoallylation of
C. The ketone C would be synthesized by appropriate
manipulations of the allyl side-chain of D, which should be
obtainable through two consecutive alkylations of the starting
material (R)-(+)-pulegone (2).
6
—
——
∗
Corresponding author. Tel.: +81-3-5841-5119; fax: +81-3-5841-8019; e-mail: atakikawa@mail.ecc.u-tokyo.ac.jp

2
Tetrahedron
atePT MAno
We first attempted to synthesize the int
A
erm
C
e
C
di
E
D
E
in
D
a
N
t
U
est
S
im
C
a
R
ted
I
.
P
The oxidative cleavage of a double bond by
T
straightforward manner, as shown in Scheme 2. According to a
previously reported procedure, (R)-(+)-pulegone (2) was
converted to a diastereomeric mixture of 3 (trans:cis = 4:1) in
ozonolysis and subsequent acetalization could convert 10 into 12
in 79% yield. According to a previously reported procedure, the
reductive cleavage of an epoxide group was successfully
achieved by treatment with Mo(CO) to afford 13 in 79% yield.
7
9
moderate yield. However, further allylation of 3 was not
6
successful, and only a trace amount of 4 was obtained, whereas
the undesired regioisomer 5 was the major product. The
undesired regioselectivity could be explained by steric hindrance
to proton abstraction. Therefore, we decided to use pulegone
oxides (6/7) as substrates instead of 2, because base-mediated
alkylations of 6/7 would avoid the problematic γ-proton
abstraction under conventional conditions. Pulegone oxide (6/7),
The deconjugative α-methylation of 13 was then investigated.
Although none of the desired adduct 14 (= C) was obtained using
LDA as a base in THF, a small amount of 14 was observed by
changing the base from LDA to KHMDS. Thus, we eventually
found that the yield of 14 was dramatically improved using DMF
10
as a solvent, and that 14 was obtained as a single diastereomer
in excellent yield. The relative stereochemistry was confirmed by
the observation of NOE between 2- and 6-Me groups. For
synthesizing the RCM precursor, 14 was treated with
homoallyllithium to furnish 15 (= B) as a single diastereomer in
95% yield. Although the orientation of a hydroxy group could
not be determined unambiguously, it should be β based on the
judgment from the knowledge acquired at later stages. The RCM
8
prepared via a known procedure, was methylated by treatment
with LDA and MeI to give a separable mixture of 8 (50%) and 9
(
12%), respectively. The relative stereochemistries of 8 and 9
1
with regard to 5-Me were tentatively assigned based on H NMR
analysis. The major isomer 8 was then treated with KHMDS and
allyl bromide to afford 10 in 92% yield with perfect
stereoselectivity, while the allylation of 9 afforded 11 in a
relatively lower yield with poor selectivity, even under the same
conditions. The relative stereochemistry of 10 was confirmed by
the observation of NOE depicted in Scheme 2, but that of 11 was
nd
11
reaction of 15 was successfully mediated by Grubbs 2 catalyst
to afford 16 in 74% yield. However, disappointingly, all our
attempts to convert 16 into 17 (= A) were unsuccessful in spite of
Scheme 2. Synthetic studies based on the initial plan.

3
ACCEPTED MANUSCRIPT
our efforts. The conversion of 15 into 18 also failed completely.
In all events, a tertiary hydroxy group was adamantly resistant to
derivatization, such as acetylation, phosphorylation and
xanthation. These failures might be due to the massive steric
hindrance around the hydroxy group, which revealed to be quite
difficult to overcome. Thus, we adjusted our initial plan
accordingly to address the aforementioned issues.
By treatment with (ethoxyethynyl)lithium, 14 was converted
to 19 (= F) in excellent yield with perfect stereoselectivity
(Scheme 4). Although the relative stereochemistry of 19 was not
confirmed at this stage, the β-orientation of the hydroxy group
was supported by the formation of 21 in the next step. Then, we
examined the acid-mediated Meyer–Schuster rearrangement.
Although the desired rearranged product was not obtained under
aqueous conditions (aq. H SO4 or aq. AcOH), non-aqueous
2
Scheme 3 illustrates the revised synthetic plan for 1. The
protected target compound A might be synthesized from E by
some means, e.g., by Friedel-Crafts–type reaction. The synthesis
of E should be possible by Meyer–Schuster rearrangement of F.
In this approach, the steric hindrance would not matter at all,
because the tertiary hydroxy group would be removed through β-
elimination. The intermediate F would be then prepared from C
conditions yielded unexpected and surprising results. Treatment
with p-TsOH in dry MeOH afforded 20 (46%) and 21 (36%) as
major products, while the formation of the expected product 22
(
= E) was detected but not estimated quantitatively. As reported
12
by Zhang and Kozmin, this unexpected cyclization might
proceed by Prins-type reaction via a transient ketenium cation
(Scheme 5). However, the timing of transacetalization and β-
(= 14) by addition of an alkynyl group.
elimination is not certain, because these steps should proceed at
any time under the reaction conditions. It was noted that 21 was
obtained as a predominant diastereomer according to its NMR
spectra. The cis-fused 5,6-system of 21 was confirmed by the
observation of NOEs between 10-Hα and 3a-Me and between
1
0-Hα and 6a-Me, but the orientation of 2-OMe could not be
determined via NOE experiments. However, we presume it to be
α-oriented based on thermodynamic stability considerations. The
minor product 21 could then be converted to 20 by BBr3
treatment and subsequent acetalization in moderate yield and not
by a simple acid treatment. We were serendipitously successful
in the construction of the full carbon skeleton of the target
compound 1.
Scheme 3. The revised synthetic plan for 1.
Scheme 4. Synthesis of (−)-1.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 5. Suggested reaction mechanism for the formation of 20/21.
The dienone 20 was reduced under Birch conditions in the
(TLC) was carried out on 0.25 mm Merck silica gel 60 F254 pre-
coated glass plates. Preparative thin layer chromatography
(PTLC) was carried out on 0.5 mm Merck silica gel 60 F254 pre-
coated glass plates. Column chromatography was performed on
Kanto Chemical silica gel 60N (neutral). All melting points
(mps) were uncorrected. Melting points were recorded on a
Yanaco Micro Melting Point Apparatus. Infrared spectra (IR)
presence of t-BuOH as a proton donor to give 24 in 63% yield,
and its relative stereochemistry was determined by the
observation of NOEs between 4-Me and 4a-Me and between 4a-
Me and 8-Me. The conversion of 24 into 25 was successfully
13
executed by Saegusa oxidation in 98% yield, while selenoxide
elimination was less effective for this conversion. The DIBAL
reduction of 25 afforded 26 in quantitative yield but with poor
1
were measured on a Jasco FT/IR-470 plus spectrometer. H NMR
13
diastereoselectivity
diastereoselectivity was improved by Luche reduction to afford
6 as a single isomer in quantitative yield. The α-orientation of a
(α:β
=
76:24).
However,
the
(400 MHz) and C NMR (100 MHz) were recorded on a JEOL
1
4
1
JNM-ECX 400 spectrometer. H NMR (300 MHz) was recorded
2
on a JEOL JNM-AL 300 spectrometer. Chemical shifts (δ) are
1
hydroxy group was estimated by H NMR analysis (J
= < 1
reported in ppm relative to internal chloroform (CHCl at δ 7.26;
H2–H3
3
Hz). Acetylation of 26 (93%) was followed by reductive
deoxygenation under Birch conditions to furnish 17 (= A) in 86%
yield. Finally, deprotection of 17 was performed by treatment
CDCl at δ 77.0). Optical rotations were measured on a Jasco P-
3
1030 polarimeter. HRMS were recorded with a JEOL JMS-
T100LC. GC analyses were carried out with a Shimadzu GC-14B
gas chromatograph (TC-1701 capillary column 30 m, ID 0.53
mm, film 1.0 µm) equipped with a flame ionization detector.
20
with aq. AcOH to afford (−)-1 (91%), [α]
−58.5 (c 0.91,
D
4
20
CHCl ), {lit., [α] −30 (c 0.39, CHCl )}. The spectral data of
3
D
3
our synthesized (−)-1 are in good accordance with those
1,4,5
4.2.
(3R,6R)-
and
(3S,6R)-2,2,6-Trimethyl-1-
previously reported.
Nevertheless, in these previous papers,
oxaspiro[2.5]octan-4-one (pulegone oxide) (6 and 7)
(
(
−)-1 was reported as an oil in contrast to what we obtained, i.e.,
−)-1 as colorless prisms. Notably, to our knowledge, there is
8a
According to the reported procedure, (R)-(+)-pulegone (2,
99.1% ee) was converted to pulegone oxides (6 and 7) in 88%
yield. The ratio of 6:7 was determined by GC analysis to be ca.
2:1. The assignments (3R,6R)-6 and (3S,6R)-7 were confirmed by
only one paper reporting that the naturally occurring (−)-1 was
15
obtained as crystals after extensive purification. These facts
might serve as an evidence for the excellent purity of our
synthetic (−)-1.
8
b
comparing to the reported data. Compound 6 and 7; IR (KBr):
953, 2873, 1715, 1456, 1424, 1376, 1278, 1235, 1119, 879
2
−1
1
cm ; H NMR (400 MHz, CDCl ) δ 1.05* and 1.07 (total 3H,
3
each d, J = 7.2 and 6.0 Hz), 1.20 and 1.22* (total 3H, each s),
3
. Conclusion
1
.39 (3H, s), 1.65–2.06 (4H, m), 2.19* (2/3H, dt, J = 4.3, 13.2
13
We achieved a novel synthesis of (−)-callicarpenal (1) from
Hz), 2.41 (2H, m), 2.60 (1/3H, dt, J = 13.2, 3.1 Hz); C NMR
100 MHz, CDCl ) δ 18.93*, 19.37, 19.60*, 19.72, 19.95*,
(R)-(+)-pulegone (2) in 15 steps with an overall yield of 5%. Two
(
3
sequential diastereoselective alkylations of pulegone oxide (6/7)
and the unexpected Prins-type cyclization based on Meyer–
Schuster rearrangement were featured as the key steps.
22.03, 26.28*, 29.93, 30.19*, 30.70*, 33.02, 33.95, 49.49*,
1.37, 63.20, 63.42*, 70.13*, 70.24, 206.47, 207.53* (The peaks
with * are due to 6.); HRMS (ESI) calcd for C H NaO
2
5
1
0
16
+
[
M+Na] : 191.1048, found 191.1039.
4
.3. (3R,5S,6R)-2,2,5,6-Tetramethyl-1-oxaspiro[2.5]octan-4-
4
. Experimental section
.1. General
All air-sensitive and/or water-sensitive reactions were carried
one (8)
4
To a solution of (i-Pr) NH (1.1 mL, 7.9 mmol) in THF (16
2
mL), n-BuLi (1.60 M in hexane; 4.5 mL, 7.2 mmol) was added
dropwise over 10 min at 0 °C. After stirring for 0.5 h, the
reaction mixture was cooled to −78 °C. To this solution was
added dropwise a solution of pulegone oxides (6 and 7, 1.0 g, 6.0
mmol) in THF (6 mL) over 10 min. After stirring for 1 h at −78
C, MeI (1.1 mL, 18 mmol) was added dropwise. The reaction
mixture was allowed to warm to room temperature with stirring
over 2 h, quenched with sat. aq. NH Cl and extracted with Et O.
The extract was washed with brine, dried (MgSO ) and
concentrated in vacuo. The residue (1.1 g) was chromatographed
on silica gel (45 g). Elution with hexane/EtOAc (30/1–2/1) gave
out under Ar atmosphere in dry solvents. (R)-(+)-Pulegone (2)
was purchased from Nippon Terpene Chemicals, Inc., and
purified by column chromatography and distillation before using.
The enantiomeric excess of
chromatograph using a chiral separation column, CHIRAMIX
2 was determined by gas
®
°
16
(60 m, ID 0.25 mm). THF and Et O were freshly distilled from
2
sodium/benzophenone under Ar. CH Cl was freshly distilled
from P O under Ar. Toluene and MeOH were dried over MS 4Å
and 3Å, respectively. Analytical thin-layer chromatography
4
2
2
2
4
2
5

5
8
(548 mg, 50%) as a pale yellow oil, and a m
A
ixt
C
ur
C
e o
E
f
P
(9
T
, 1
E
2
D
%, MAN
4
U
.6.SCR
(
I
2 3R)-2-(2,2-Dimethoxyethyl)-2,3-dimethyl-6-(1-
P
S,
T
determined by GC analysis) and starting material (6/7 = 2:3,
methylethylidene)cyclohexanone (13)
2
0
2
1
9
4%, determined by GC analysis). Compound 8; [α]D +70.9 (c
A mixture of 12 (54 mg, 0.20 mmol), Mo(CO) (58 mg, 0.22
mmol), pyridine (64 µL, 0.80 mmol) and toluene (2 mL) was
heated under reflux for 1 h. After cooling, the mixture was
diluted with Et O (2 mL), stirred for 15 min and filtered through
Celite pad. The filtrate was concentrated in vacuo. The residue
92 mg) was chromatographed on silica gel (3 g). Elution with
hexane/EtOAc (50/1–20/1) to give a mixture of 13 and polar
impurity (not identified), which was further chromatographed on
silica gel (3 g) and eluted with CHCl /EtOAc (30/1) to give 13
43 mg, 85%) as a colorless oil. [α]D +70.8 (c 0.83, CHCl ); IR
film): 2932, 1681, 1443, 1372, 1284, 1190, 1121, 1074, 1056,
85 cm ; H NMR (400 MHz, CDCl ) δ 0.93 (3H, d, J = 7.2
6
.48, CHCl ); IR (film): 2965, 2930, 1717, 1456, 1378, 1122,
3
−1
1
53, 927, 883, 651 cm ; H NMR (400 MHz, CDCl ) δ 1.07
3
(3H, d, J = 7.0 Hz), 1.10 (3H, d, J = 7.0 Hz), 1.22 (3H, s), 1.40
2
(3H, s), 1.62 (1H, m), 1.81–1.91 (2H, m), 2.00–2.12 (2H, m),
®
13
2
1
6
2
.46 (1H, dq, J = 6.6, 7.0 Hz); C NMR (100 MHz, CDCl ) δ
3
(
4.74, 19.67, 19.88, 21.02, 27.17, 27.46, 37.86, 52.08, 64.58,
+
8.81, 210.62; HRMS (ESI) calcd for C H NaO [M+Na] :
1
1
18
2
1
05.1205, found 205.1194. Compound 9: H NMR (300 MHz,
3
CDCl ) δ 0.97 (3H, d, J = 7.2 Hz), 0.98 (3H, d, J = 6.9 Hz), 1.18
20
3
(
(
9
3
(3H, s), 1.41 (3H, s), 1.65–2.03 (4H, m), 2.10–2.20 (1H, m), 2.65
(1H, dq, J = 4.8, 7.2 Hz).
−1
1
3
4
.4.
(3R,5S,6R)-5-Allyl-2,2,5,6-tetramethyl-1-
Hz), 0.97 (3H, s), 1.49 (1H, ddt, J = 14.0, 5.6, 10.0 Hz), 1.75
(1H, m), 1.75 (3H, s), 1.75 (1H, dd, J = 14.4, 5.7 Hz), 1.87 (3H,
s), 2.00 (1H, m), 2.02 (1H, dd, J = 14.4, 4.6 Hz), 2.36 (1H, m),
oxaspiro[2.5]octan-4-one (10)
To a solution of 8 (9.34 g, 51.2 mmol) in THF (93 mL),
KHMDS (0.5 M in toluene; 113 mL, 56.3 mmol) was added
dropwise over 10 min at −78 °C. After stirring for 1 h at 0 °C,
allyl bromide (10.5 mL, 121 mmol) was added dropwise at −78
C. The reaction mixture was allowed to warm to room
temperature with stirring overnight. The reaction mixture was
poured into sat. aq. NH Cl and extracted with Et O. The extract
2
.54 (1H, m), 3.28 (3H, s), 3.30 (3H, s), 4.39 (1H, dd, J = 5.7, 4.6
13
Hz); C NMR (100 MHz, CDCl ) δ 15.77, 18.27, 21.61, 22.61,
3
2
1
2
8.10, 28.24, 37.35, 39.60, 50.58, 53.12, 53.22, 103.09, 131.85,
+
40.32, 209.30; HRMS (ESI) calcd for C H NaO [M+Na] :
15
26
3
°
77.1780, found 277.1795.
4.7. (2S,3R,6S)-2-(2,2-Dimethoxyethyl)-6-isopropenyl-2,3,6-
4
2
was washed with brine, dried (MgSO ) and concentrated in
trimethylcyclohexanone (14)
4
vacuo. The residue (13.6 g) was chromatographed on silica gel
To a mixture of KHMDS (0.5 M in toluene; 55 mL, 27.5
mmol) in DMF (41 mL), a solution of 13 (3.50 g, 13.7 mmol) in
DMF (41 mL) was added dropwise over 0.5 h at −78 °C. After
stirring for 0.5 h at −78 °C, MeI (2.6 mL, 41 mmol) was added
dropwise, and the stirring was continued for 2 h. The reaction
(250 g). Elution with hexane/EtOAc (50/1–10/1) gave 10 (11.0 g,
9
7%) as a pale yellow oil, which was then crystallization from
20
hexane to give colorless prisms. [α]D +26.6 (c 1.44, CHCl ); mp
3
6
9
2.0–63.0 °C; IR (KBr): 2967, 1710, 1458, 1377, 1138, 1092,
−1 1
89, 977, 921, 887 cm ; H NMR (400 MHz, CDCl ) δ 0.96
3
mixture was then poured into sat. aq. NH Cl and extracted with
4
(
(
3H, d, J = 7.2 Hz), 1.05 (3H, s), 1.17 (3H, s), 1.45 (3H, s), 1.56
1H, m), 1.85 (1H, m), 1.97 (1H, dd, J = 13.7, 6.5 Hz), 2.13 (1H,
Et O. The extract was successively washed with sat. aq. NaHCO
2
3
and brine, dried (Na SO ) and concentrated in vacuo. The residue
2
4
m), 2.18–2.27 (2H, m), 2.53 (1H, dd, J = 13.7, 8.4 Hz), 5.07–5.14
13
(3.4 g) was chromatographed on silica gel (160 g). Elution with
(
2H, m), 5.70 (1H, dddd, J = 16.2, 10.6, 8.4, 6.5 Hz); C NMR
hexane/EtOAc (100/1–20/1) gave 14 (3.45 g, 94%) as a colorless
(
100 MHz, CDCl ) δ 15.42, 18.73, 19.64, 20.41, 25.83, 26.09,
20
3
oil. [α]D −47.5 (c 1.18, CHCl ); IR (film): 2934, 2829, 1697,
3
3
6.51, 40.38, 53.38, 64.74, 68.45, 118.74, 132.50, 210.65;
−1
1
+
1457, 1372, 1124, 1075, 1050, 1017, 991 cm ; H NMR (400
HRMS (ESI) calcd for C H NaO [M+Na] : 245.1518, found
14
22
2
MHz, CDCl ) δ 0.90 (3H, d, J = 6.8 Hz), 1.00 (3H, s), 1.20 (3H,
3
2
45.1495.
s), 1.52 (1H, dd, J = 14.4, 5.2 Hz), 1.50–1.67 (2H, m), 1.70 (3H,
s), 1.83 (1H, m), 2.09–2.20 (2H, m), 2.33 (1H, dd, J = 14.4, 5.2
Hz), 3.25(3H, s), 3.26 (3H, s), 4.33 (1H, t, J = 5.2 Hz), 4.91 (1H,
4
.5. (3R,5S,6R)-5-(2,2-Dimethoxyethyl)-2,2,5,6-tetramethyl-1-
oxaspiro[2.5]octan-4-one (12)
13
br s), 4.92 (1H, s); C NMR (100 MHz, CDCl ) δ 16.04, 20.32,
3
Ozone, generated from ON-3-2 ozonator (Nippon Ozone Co.,
Ltd.), was bubbled into a solution of 10 (1.11 g, 4.99 mmol) in
MeOH (100 mL) at −78 °C until saturation. After removal of
excess ozone by a stream of Ar, the reaction mixture was
2
5
1.48, 25.83, 25.93, 32.76, 34.56, 39.38, 50.43, 52.78, 52.82,
3.52, 102.89, 111.33, 147.98, 217.37; HRMS (ESI) calcd for
+
C H NaO [M+Na] : 291.1936, found 291.1961.
16
28
3
quenched with Me S (2.2 mL, 15 mmol) at −78 °C. After stirring
4.8. (2S,3R,6S)-2-(2,2-Dimethoxyethyl)-1-(ethoxyethynyl)-6-
2
overnight with warming to room temperature, NH Cl (0.10 g, 1.9
isopropenyl-2,3,6-trimethylcyclohexanol (19)
4
mmol) was added to the reaction mixture, which was then heated
To a solution of ethoxyacetylene (50 wt% in hexane; 0.88 mL,
.5 mmol) in THF (4 mL), n-BuLi (1.65 M in hexane; 2.28 mL,
.76 mmol) was added dropwise at −78 °C. After stirring for 0.5
h, a solution of 14 (67 mg, 0.25 mmol) in THF (3 mL) was added
under reflux for 0.5 h. After cooling, NaHCO (300 mg, 3.6
3
4
3
mmol) was added, and the mixture was concentrated in vacuo.
The residue was poured into sat. aq. Na CO and extracted with
2
3
toluene. The extract was washed with brine, dried (MgSO ) and
4
dropwise. After stirring at −78 °C for 15 min and at 0 °C
concentrated in vacuo. The residue (1.40 g) was
chromatographed on silica gel (50 g). Elution with
hexane/EtOAc (10/1–5/1) gave 12 (1.06 g, 79%) as a colorless
overnight, the reaction mixture was quenched with sat. aq. NH Cl
4
and extracted with Et O. The extract was successively washed
2
2
0
with sat. aq. NaHCO and brine, dried (MgSO ) and concentrated
3
4
oil. [α]D −0.3 (c 0.95, CHCl ); IR (film): 2936, 1716, 1456,
1
3
−1
1
in vacuo. The residue (155 mg) was chromatographed on silica
378, 1192, 1120, 1057, 994, 920, 887 cm ; H NMR (400
gel (8 g). Elution with hexane/EtOAc (10/1) gave 19 (84 mg,
MHz, CDCl ) δ 0.96 (3H, d, J = 6.8 Hz), 1.10 (3H, s), 1.17 (3H,
20
3
9
(
9%) as a pale yellow oil. [α]D −54.4 (c 1.32, CHCl ); IR
3
s), 1.43 (3H, s), 1.51 (1H, dd, J = 14.4, 3.6 Hz), 1.57 (1H, m),
film): 3402, 2936, 2259, 1385, 1119, 1084, 1042, 1026, 913,
1
3
.84 (1H, m), 2.07 (1H, dd, J = 14.4, 6.0 Hz), 2.13–2.30 (3H, m),
−1 1
13
883 cm ; H NMR (400 MHz, CDCl
Hz), 1.05 (3H, s), 1.15 (3H, s), 1.34 (3H, t, J = 7.0 Hz), 1.35–
.70 (4H, m), 1.56 (1H, dd, J = 15.0, 2.4 Hz), 1.99 (3H, s), 2.00
3
) δ 0.85 (3H, d, J = 6.8
.27 (3H, s), 3.34 (3H, s), 4.40 (1H, dd, J = 6.0, 3.6 Hz);
C
NMR (100 MHz, CDCl ) δ 15.68, 18.80, 19.78, 20.40, 26.00,
3
1
2
2
6.32, 37.54, 38.66, 52.05, 52.51, 53.50, 64.92, 68.46, 102.24,
+
(1H, m), 2.35 (1H, dd, J = 15.0, 7.6 Hz), 3.31 (3H, s), 3.34 (3H,
s), 4.02 (2H, q, J = 7.0 Hz), 4.35 (1H, s), 4.71 (1H, dd, J = 7.6,
10.06; HRMS (ESI) calcd for C H NaO [M+Na] : 293.1729,
15
26
4
found 293.1713.

6
Tetrahedron
13
2
.4 Hz), 4.75 (2H, m); C NMR (100 MHz
A
, C
C
D
C
Cl
E
)
P
δ
T
14
E
.5
D
7, MA(M
NU
g
SO
S
) a
C
R
ndIPco
T
ncentrated in vacuo. The residue (17 mg) was
3
4
1
4
4.72, 16.63, 20.28, 23.50, 27.30, 34.02, 38.26, 41.77, 43.02,
6.45, 47.72, 51.84, 52.50, 73.95, 77.83, 95.06, 102.85, 109.69,
purified by PTLC to give 20 (10 mg, 68%) as a colorless oil.
+
4.12. (4R,4aS,7R,8S,8aS)-8-(2,2-Dimethoxyethyl)-4,4a,7,8-
tetramethyloctahydronaphthalen-2(1H)-one (24)
1
55.81; HRMS (ESI) calcd for C H NaO [M+Na] : 361.2355,
20
34
4
found 361.2330.
To a solution of Li (173 mg, 24.9 mmol) in liq. NH (230
3
4
.9. (4aS,7R,8S)-8-(2,2-Dimethoxyethyl)-4,4a,7,8-tetramethyl-
,6,7,8-tetrahydronaphthalen-2(4aH)-one (20) and
3aS,4R,6aS,10aS)-2-methoxy-3a,4,6a,7-tetramethyl-
,3a,4,5,6,6a-hexahydro-2H-naphtho[8a,1-b]furan-9(10H)-one
21)
mL), a solution of t-BuOH (475 µL, 5.04 mmol) in THF (10 mL)
and a solution of 20 (368 mg, 1.25 mmol) in THF (10 mL) were
added dropwise at −78 °C. After stirring for 1 h at the same
temperature, the reaction mixture was quenched by cautious
addition of NH Cl. After removal of NH at room temperature,
5
(
3
(
4
3
To a solution of 19 (10 mg, 0.030 mmol) in MeOH (1 mL), p-
the residue was diluted with a mixture of Et O and sat. aq.
2
TsOH·H O (0.16 M in MeOH; 10 µL, 1.6 µmol) was added at
NaHCO . The organic layer was separated and the aqueous layer
2
3
room temperature. After stirring at room temperature overnight,
was extracted with Et O. The combined organic layer was
2
the reaction mixture was neutralized by addition of NaHCO and
successively washed with sat. aq. NaHCO3 and brine, dried
3
evaporated. The residue was extracted with Et O, and the extract
(MgSO ) and concentrated in vacuo. The residue (369 mg) was
2
4
was successively washed with water and brine, dried (MgSO4)
and concentrated in vacuo. The residue (8 mg) was purified by
PTLC to give 20 (4.0 mg, 46%; more polar) and 21 (3.0 mg,
chromatographed on silica gel (15 g). Elution with
hexane/EtOAc (50/1–2/1) gave 24 (232 mg, 63%) as a colorless
2
0
oil. [α]D +41.9 (c 1.32, CHCl ); IR (film): 2954, 2829, 1715,
3
20
−1
1
3
6%; less polar) both as a colorless oil. Compound 20; [α]D
1443, 1387, 1192, 1120, 1054, 984, 961 cm ; H NMR (400
+
8.2 (c 2.58, CHCl ); IR (film): 2951, 1660, 1625, 1452, 1385,
MHz, CDCl ) δ 0.73 (3H, s), 0.84 (3H, d, J = 6.4 Hz), 0.86 (3H,
3
3
−1 1
1
0
1
3
192, 1117, 1048, 1006, 898 cm ; H NMR (400 MHz, CDCl ) δ
d, J = 6.4 Hz), 0.94 (3H, s), 1.03 (1H, dt, J = 13.0, 8.7 Hz), 1.40–
1.46 (2H, m), 1.49–1.63 (5H, m), 1.75 (1H, dt, J = 12.8, 3.3 Hz),
2.10–2.17 (2H, m), 2.24 (1H, t, J = 14.2 Hz), 2.46 (1H, br d, J =
3
.80 (3H, d, J = 7.2 Hz), 1.09 (3H, s), 1.36 (3H, s), 1.41 (1H, m),
.55–1.75 (3H, m), 1.90–2.10 (3H, m), 1.99 (3H, s), 3.24 (3H, s),
.27 (3H, s), 4.28 (1H, dd, J = 5.6, 1.2 Hz), 6.07 (1H, s), 6.31
1
3
12.8 Hz), 3.26 (3H, s), 3.27 (3H, s), 4.38 (1H, t, J = 4.8 Hz);
C
13
(1H, s); C NMR (100 MHz, CDCl ) δ 16.18, 19.40, 24.27,
NMR (100 MHz, CDCl ) δ 12.53, 14.85, 16.24, 17.10, 27.11,
3
3
2
1
6.30, 27.57, 33.95, 36.40, 41.95, 43.65, 43.92, 52.41, 102.50,
36.54, 37.57, 38.44, 38.80, 39.19, 40.03, 45.64, 46.32, 49.64,
51.89, 53.42, 101.79, 211.72; HRMS (ESI) calcd for C H NaO
[M+Na] : 319.2249, found 319.2241.
25.71, 126.01, 167.77, 171.98, 186.78; HRMS (ESI) calcd for
1
8
32
3
+
+
C H NaO (M+Na) : 315.1936, found 315.1917. Compound 21;
18
28
3
2
0
[
α]D +120.4 (c 1.05, CHCl ); IR (film): 2957, 1667, 1460, 1379,
3
−1
1
4.13. (4aR,7R,8S,8aR)-8-(2,2-Dimethoxyethyl)-4,4a,7,8-
tetramethyl-4a,5,6,7,8,8a-hexahydronaphthalen-2(1H)-one (25)
1
327, 1274, 1107, 1028, 1000, 971 cm ; H NMR (400 MHz,
CDCl ) δ 0.88 (3H, d, J = 6.8 Hz), 0.96 (3H, s), 1.27 (3H, s),
3
1
.36–1.51 (3H, m), 1.55 (1H, dt, J = 11.6, 3.2 Hz), 1.71 (1H, dd,
J = 13.6, 5.0 Hz), 1.85 (1H, m), 1.90 (3H, s), 2.24 (1H, dd, J =
3.6, 6.6 Hz), 2.72 (1H, d, J = 16.8 Hz), 2.88 (1H, d, J = 16.8
Hz), 3.20 (3H, s), 4.86 (1H, dd, J = 6.6, 5.0 Hz), 5.81 (1H, br s);
To a solution of 24 (198 mg, 0.668 mmol) in THF (20 mL),
LHMDS (1.0 M in THF; 1.3 mL, 1.3 mmol) was added dropwise
over 10 min at −78 °C. After stirring for 15 min at –78 °C and for
2 h at −40 °C, a solution of TMSCl (255 µL, 2.01 mmol) and
1
13
C NMR (100 MHz, CDCl ) δ 15.17, 16.62, 19.46, 22.48, 26.31,
Et N (28 µL) in THF (1.4 mL) was added dropwise at −78 °C.
3
3
2
1
9.77, 35.86, 42.34, 42.73, 45.58, 46.81, 55.68, 89.43, 102.58,
25.43, 168.23, 198.57; HRMS (ESI) calcd for C H NaO
After stirring for 0.5 h at the same temperature, the reaction
17
26
3
mixture was poured into sat. aq. NaHCO and extracted with
3
+
[
M+Na] : 301.1780, found 301.1770.
Et O. The extract was washed with brine, dried (Na CO ) and
2
2
3
concentrated in vacuo to give the crude product (280 mg). This
was employed for the next step without further purification.
4
.10. (4aS,7R,8S)-4,4a,7,8-Tetramethyl-8-(2-oxoethyl)-
5
,6,7,8-tetrahydronaphthalen-2(4aH)-one (23)
To a solution of the crude product (280 mg) in CH CN (28
3
To a suspension of 21 (30 mg, 0.10 mmol) and MS4A (30 mg)
mL), Pd(OAc)2 (195 mg, 0.869 mmol) was added, and the
reaction mixture was stirred at room temperature for 2 days.
in CH Cl (1 mL), BBr (1.0 M in CH Cl ; 110 µL, 0.11 mmol)
2
2
3
2
2
was added dropwise over at −78 °C. After stirring for 2 h at −78
C, the reaction mixture was allowed to warm to room
®
After filtration through Celite pad, the filtrate was concentrated
°
in vacuo. The residue (307 mg) was chromatographed on silica
gel (15 g). Elution with hexane/EtOAc (5/1–2/1) gave 25 (193
temperature with stirring over 2.5 h. The reaction mixture was
quenched with sat. aq. NaHCO and extracted with Et O. The
3
2
20
mg, 98%, two steps) as a pale yellow oil. [α]D −5.8 (c 1.10,
extract was washed with brine, dried (Na SO ) and concentrated
2
4
CHCl ); IR (film): 2930, 1670, 1617, 1437, 1380, 1325, 1279,
3
in vacuo. The residue (28 mg) was chromatographed on silica gel
2 g). Elution with hexane/EtOAc (20/1–1/1) gave 23 (13 mg,
−1 1
1
191, 1118, 1048 cm ; H NMR (400 MHz, CDCl ) δ 0.77 (3H,
3
(
5
(
2
1
1
1
s), 0.85 (3H, d, J = 6.8 Hz), 1.09 (3H, s), 1.34 (1H, ddd, J = 12.5,
2%) as a pale yellow oil. H NMR (300 MHz, CDCl ) δ 0.98
3
9
1
1
3
.7, 7.5 Hz), 1.45–1.54 (2H, m), 1.60 (1H, m), 1.57 (1H, dd, J =
5.3, 4.4 Hz), 1.66 (1H, dd, J = 15.3, 5.6 Hz), 1.80 (1H, dt, J =
2.5, 3.2 Hz), 1.86 (3H, d, J = 1.6 Hz), 1.94 (1H, dd, J = 13.6,
.2), 2.31 (1H, dd, J = 17.6, 13.6 Hz), 2.53 (1H, dd, J = 17.6, 3.2
3H, d, J = 6.3 Hz), 1.23 (3H, s), 1.39 (3H, s), 1.43–1.97 (5H, m),
.00 (3H, s), 2.55 (1H, dd, J = 2.7, 17.5 Hz), 2.94 (1H, dd, J =
.7, 17.5 Hz), 6.07 (1H, s), 6.23 (1H, s), 9.67 (1H, dd, J = 2.7,
.7 Hz). This was employed for the next step immediately.
Hz), 3.22 (3H, s), 3.24 (3H, s), 4.37 (1H, dd, J = 5.6, 4.4 Hz),
13
4
.11.
(4aS,7R,8S)-8-(2,2-Dimethoxyethyl)-4,4a,7,8-
5.69 (1H, br s); C NMR (100 MHz, CDCl ) δ 16.04, 17.44,
3
tetramethyl-5,6,7,8-tetrahydronaphthalen-2(4aH)-one (20)
18.26, 18.90, 26.90, 35.40, 35.47, 36.87, 38.43, 39.97, 39.99,
4
6.56, 51.79, 53.27, 101.57, 125.51, 172.15, 200.37; HRMS
To a solution of 23 (13 mg, 0.053 mmol) and HC(OMe) (55
+
3
(ESI) calcd for C H NaO [M+Na] : 317.2093, found 317.2077.
18 30 3
µL, 0.05 mmol) in CH Cl (1.3 mL), p-TsOH·H O (1.0 mg, 5.3
2
2
2
µmol) was added at room temperature. After stirring overnight,
4.14. (2R,4aR,7R,8S,8aR)-8-(2,2-Dimethoxyethyl)-4,4a,7,8-
tetramethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-2-ol (26)
the reaction mixture was quenched with sat. aq. NaHCO and
3
extracted with CH Cl . The extract was washed with brine, dried
2
2

7
To a solution of 25 (157 mg, 0.533 mmol)
260 mg, 0.698 mmol) in EtOH (99%; 5 mL) and CH Cl (5 mL),
A
a
C
nd
C
C
E
eC
P
l
T
·7
E
H
D
O
2
MAN
4
U
.17
S
.
CRIPT
(1S,2R,4aR,8aR)-(1,2,4a,5-Tetramethyl-
3
(
1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl)acetaldehyde
2
2
a solution of NaBH (30 mg, 0.80 mmol) in EtOH (99%; 2 mL)
(callicarpenal, 1)
4
was added dropwise at −78 °C. After stirring for 10 min, the
reaction mixture was quenched with sat. aq. NaHCO3 and
extracted with CH Cl . The extract was dried (MgSO ) and
A solution of 17 (12 mg, 0.042 mmol) in aq. AcOH (80%; 1
mL) was stirred for 1 h at room temperature. The reaction
mixture was concentrated in vacuo, and the residue was diluted
with sat. aq. NaHCO and extracted with Et O. The extract was
2
2
4
concentrated in vacuo. The residue (181 mg) was
chromatographed on silica gel (10 g). Elution with
hexane/EtOAc (10/1–3/1) gave 26 (157 mg, quant.) as colorless
3
2
washed with brine, dried (MgSO ) and concentrated in vacuo.
4
2
0
The residue (10 mg) was chromatographed on silica gel (0.8 g).
Elution with hexane/EtOAc (40/1) gave 1 (9 mg, 91%) as a
crystals. [α]D +8.7 (c 1.36, CHCl ); mp 84.0–85.0 °C; IR (KBr):
3
−1
3
203, 2961, 2940, 2911, 2874, 1452, 1118, 1041, 981, 906 cm ;
H NMR (400 MHz, CDCl ) δ 0.72 (3H, s), 0.83 (3H, d, J = 7.2
1
colorless oil. Recrystallization from acetonitrile gave colorless
3
20
prisms. [α]D −58.5 (c 0.91, CHCl ); mp 49.0-50.0 °C; IR (KBr):
3
Hz), 1.04 (3H, s), 1.15 (1H, ddd, J = 12.6, 9.9, 7.3 Hz), 1.25–1.65
3
010, 2995, 2959, 2868, 2833, 1713, 1456, 1389, 1075, 1039
(6H, m), 1.61 (3H, s), 1.70 (1H, dt, J = 12.6, 3.2 Hz), 1.73 (1H,
−1 1
cm ; H NMR (400 MHz, CDCl ) δ 0.81 (3H, s), 0.95 (3H, d, J
3
dd, J = 15.2, 6.0 Hz), 2.06 (1H, dd, J = 10.8, 6.0 Hz), 3.27 (3H,
s), 3.29 (3H, s), 4.21 (1H, m), 4.40 (1H, dd, J = 5.6, 4.0 Hz), 5.21
=
6.8 Hz), 1.00 (3H, s), 1.20 (1H, m), 1.42–1.77 (7H, m), 1.57
(3H, s), 1.96–2.05 (2H, m), 2.16 (1H, dd, J = 14.6, 3.2 Hz), 2.46
1H, dd, J = 14.6, 3.6 Hz), 5.18 (1H, br s), 9.83 (1H, dd, J = 3.6,
13
(
1H, br s); C NMR (100 MHz, CDCl ) δ 16.18, 17.80, 17.93,
3
(
2
5
0.01, 27.25, 29.67, 36.28, 36.90, 38.20, 38.73, 40.48, 45.91,
13
3
.2 Hz); C NMR (100 MHz, CDCl ) δ 16.27, 17.21, 17.92,
3
1.83, 53.26, 69.32, 101.96, 124.51, 147.58; HRMS (ESI) calcd
+
18.94, 19.87, 26.56, 27.30, 36.42, 38.42, 39.03, 41.67, 49.36,
1.74, 120.55, 143.61, 203.88; HRMS (APCI) calcd for C H O
for C H NaO [M+Na] : 319.2249, found 319.2270.
18
32
3
5
1
6
25
−
4
.15. (2R,4aR,7R,8S,8aR)-8-(2,2-Dimethoxyethyl)-4,4a,7,8-
tetramethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-2-yl acetate
27)
[M−H] : 233.1905, found 233.1910.
(
Acknowledgments
To a solution of 26 (132 mg, 0.445 mmol) and 4-DMAP (1.1
g, 8.9 mmol) in CH Cl (10 mL), Ac O (205 µL, 2.22 mmol) was
added dropwise at 0 °C. After stirring for 15 min, the reaction
Our thanks are due to T. Hasegawa Co., Ltd. for financial
support. We also thank Professor Dr. Eiichi Nakamura and
Professor Dr. Hayato Tsuji for HRMS (APCI) analysis.
2
2
2
mixture was quenched with sat. aq. NaHCO and extracted with
3
CH Cl . The extract was dried (Na SO ) and concentrated in
2
2
2
4
Appendix A. Supplementary data
Supplementary data related to this article can be found at ~.
References and notes
vacuo. The residue (1.2 g) was chromatographed on silica gel (50
g). Elution with hexane/EtOAc (10/1) gave 27 (146 mg, 97%) as
2
0
a colorless oil. [α]D +60.5 (c 1.19, CHCl ); IR (film): 2955,
1
3
−1
1
732, 1448, 1372, 1242, 1120, 1049, 1019, 986, 966 cm ; H
NMR (400 MHz, CDCl ) δ 0.72 (3H, s), 0.84 (3H, d, J = 6.8 Hz),
3
1
(
.06 (3H, s), 1.18 (1H, ddd, J = 12.6, 8.7, 6.2 Hz), 1.38–1.64
6H, m), 1.62 (3H, s), 1.70 (1H, dd, J = 15.1, 5.5 Hz), 1.71 (1H,
dt, J = 12.6, 3.2 Hz), 2.05 (1H, m), 2.05 (3H, s), 3.28 (3H, s),
.34 (3H, s), 4.41 (1H, dd, J = 5.7, 4.3 Hz), 5.16 (1H, br s), 5.31
1
2
3
4
.
.
.
.
Cantrell CL, Klun JA, Bryson CT, Kobaisy M, Duke SO. J Agric
Food Chem. 2005;53:5948–5953.
Carroll JF, Cantrell CL, Klun JA, Kramer M. Exp Appl Acarol.
2007;41:215–224.
3
13
Chen J, Cantrell CL, Duke SO, Allen ML. J Econ Entomol.
(1H, m); C NMR (100 MHz, CDCl ) δ 16.20, 17.88, 19.79,
3
2
008;101:265–271.
(a) Hagiwara H, Inome K, Uda H. Tetrahedron Lett.
994;35:8189–8192; (b) Hagiwara H, Inome K, Uda H. J Chem
2
5
1.48, 25.30, 27.20, 36.12, 36.88, 38.26, 38.73, 40.48, 45.79,
1.97, 53.54, 72.23, 102.04, 120.28, 149.55, 170.92; HRMS
1
+
(ESI) calcd for C H NaO [M+Na] : 361.2355, found 361.2361.
20
34
4
Soc Perkin Trans 1. 1995;7:757–764.
5
.
Ling T, Xu J, Smith R, Ali A, Cantrell CL. Theodorakis EA.
Tetrahedron. 2011;67:3023–3029.
4
.16.
(3R,4S,4aR,8aR)-4-(2,2-Dimethoxyethyl)-3,4,8,8a-
tetramethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalene (17)
6. (a) Ling T, Xiang AX, Theodorakis EA. Angew Chem Int Ed.
999;38:3089-3091; (b) Ling T, Poupon E, Rueden EJ, Kim SH,
Theodorakis EA. J Am Chem Soc. 2002;124:12261–12267.
7. Zair T, Santelli-Rouvier C, Santelli M. J Org Chem.
1993;58:2686–2693.
1
To a solution of Li (3 mg, 0.4 mmol) in liq. NH (10 mL), a
solution of 27 (17 mg, 0.059 mmol) in THF (15 mL) was added
dropwise at −78 °C. After stirring for 1.5 h, the reaction mixture
was quenched by cautious addition of NH Cl. After removal of
3
8
.
(a) Katsuhara J, J Org Chem. 1967;32:797–799; (b) Ismaili-Alaoui
M, Benjilali B, Buisson D, Azerad R. Tetrahedron Lett.
4
NH at room temperature, the residue was diluted with a mixture
3
1
992 ;33:2349–2352.
of Et O and sat. aq. NaHCO . The organic layer was separated
and the aqueous layer was extracted with Et O. The combined
2
3
9. Patra A, Bandyopadhyay M, Mal D. Tetrahedron Lett.
2003;44:2355–2357.
2
organic layer was successively washed with sat. aq. NaHCO and
10. Palomo C, Oiarbide M, Mielgo A, González A, García JM, Landa
C, Lecumberri A, Linden A. Org Lett. 2001;3:3249–3252.
3
brine, dried (MgSO ) and concentrated in vacuo. The residue (14
4
1
1. Scholl M, Ding S, Lee CW, Grubbs RH. Org Lett. 1999;1:953–
56.
2. Zhang L, Sun J, Kozmin SA. Tetrahedron. 2006;62:11371–11380.
mg) was chromatographed on silica gel (0.5 g). Elution with
9
hexane/EtOAc (40/1) gave 17 (12 mg, 86%) as a colorless oil.
1
2
0
[
1
α]D −41.2 (c 1.18, CHCl ); IR (film): 2954, 2830, 1448, 1381,
13. Ito Y, Hirao T, Saegusa T. J Org Chem. 1978;43:1011–1103.
14. Gemal AL, Luche JL. J Am Chem Soc. 1981;103:5454–5459.
3
−1
1
191, 1119, 1076, 1050, 989, 961 cm ; H NMR (400 MHz,
1
5. Cantrell CL, Klun JA, Pridgeon J, Becnel J, Green III S, Fronczek
FR. Chem Biodiv. 2009;6:447–458.
CDCl ) δ 0.70 (3H, s), 0.83 (3H, d, J = 6.8 Hz), 0.99 (3H, s), 1.19
3
(1H, m), 1.35–1.48 (4H, m), 1.58 (3H, br d, J = 2.0), 1.57–1.73
1
6. Tamogami S, Awano K, Amaike M, Takagi Y, Kitahara T.
Flavour Frgr J. 2001;16:349–352.
(
5H, m), 2.00 (2H, m), 3.29 (3H, s), 3.30 (3H, s), 4.42 (1H, t, J =
13
4
1
3
.8 Hz), 5.18 (1H, br s); C NMR (100 MHz, CDCl ) δ 16.23,
3
7.86, 18.03, 18.90, 20.01, 26.73, 27.55, 36.69, 37.19, 38.35,
8.55, 40.68, 47.27, 52.27, 53.05, 102.36, 120.61, 144.29;
+
HRMS (ESI) calcd for C H NaO [M+Na] : 303.2300, found
18
32
2
3
03.2322.

ACCEPTED MANUSCRIPT
Highlights：
A novel synthesis of (−)-callicarpenal was achieved.
Callicarpenal is a tetranorditerpene aldehyde with a potent mosquito repellent activity.
Prins-type cyclization based on Meyer-Schuster rearrangement was featured as a key step.