Divergent Synthesis of Bioactive Marine Meroterpenoids by Palladium-Catalyzed Tandem Carbene Migratory Insertion

Article abstract of DOI:10.1002/ejoc.201800026

The divergent synthesis of (+)-8-epi-puupehedione, (+)-chromazonarol, (+)-yahazunol, and (+)-yahazunone has been accomplished. The key steps were a palladium-catalyzed tandem carbene migratory insertion of an aryl iodide and a drimanal hydrazone, a highly regioselective enol reduction, an oxa-Stork–Danheiser transposition reaction, an electrocyclization of a conjugated tetraenone, and a redox reaction of dimethoxybenzenes.

Full text of DOI:10.1002/ejoc.201800026

A Journal of
Accepted Article
Title: Divergent Synthesis of Bioactive Marine Meroterpenoids via
Palladium-Catalyzed Tandem Carbene Migratory Insertion
Authors: Yan-Chao Wu, Hong-Shuang Wang, Hui-Jing Li, and Zhen-
Guo Zhang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800026
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10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
Divergent Synthesis of Bioactive Marine Meroterpenoids via
Palladium-Catalyzed Tandem Carbene Migratory Insertion
Hong-Shuang Wang,[a] Hui-Jing Li,*[a] Zhen-Guo Zhang,[a] and Yan-Chao Wu*[a,b]
Abstract: Divergent synthesis of (+)-8-epi-puupehedione, (+)-
chromazonarol, (+)-yahazunol and (+)-yahazunone has been
accomplished by using a palladium-catalyzed tandem carbene
migratory insertion of an aryl iodine and a drimanal hydrazone, a
highly regioselective reduction of enols, an oxa-Stork-Danheiser
transposition reaction, an electrocyclization cyclization of
a
conjugated tetraenone, and a redox reaction of dimethoxybenzenes
as the key steps.
Introduction
Merosesquiterpenes are natural products of mixed biosynthetic
origin (polyketide–terpenoid) containing a sesquiterpene unit
joined to
a
phenolic or quinone moiety.1 Hundreds of
Figure 1. Representatives of merosesquiterpenes.
meroterpenoids with related structures are known, which holds
considerable promise as rich source of lead structures in drug
discovery. These compounds have been of great interest mainly
due to a wide variety of biological activities they exhibit ranging
from anti-fungal to anticancer and anti-HIV.2 Among various
marine merosesquiterpenes, puupehedione (1) was isolated
from Verongid sponge in 1993,3 and 8-epi-puupehedione (2)
was reported as a highly potent angiogenesis inhibitor.4 (+)-
Chromazonarol (4) was isolated from marine sponge Dysidea
pallescens,5 which was an advanced intermediate in preparation
of other related drimane meroterpenoids. 8-Epi-chromazonarol
(5) was isolated from Smenospongia aurea and Smenospongia
echina.6 (+)-Yahazunol (6), an antimicrobial substance, was
discovered by Ochi and co-workers from brown seaweed
Dictyopteris undulata Okamura (Fig. 1).7
The important properties of these marine meroterpenoids
have served to stimulate continual interest in synthetic
community. Accordingly, various synthetic pathways have been
developed for the construction of these bioactive marine natural
products.8–14 In the earlier approaches, Barrero and Armstrong
have relied on the addition of a suitably protected arene
nucleophile, generated by using pyrophoric n- or t-BuLi, to a
cyclic terpenoid moiety, followed by acid-promoted cycloaddition
of olefinic phenols to give 8-epi-puupehedione (2).7 Later on,
Alvarez-Manzaneda and coworkers reported the synthesis of 8-
epi-puupehedione (2) and (+)-chromazonarol (4) by using a
Diels–Alder cycloaddition reaction as one of the key steps.9 Very
recently, Dethe and coworkers developed
catalyzed Friedel–Crafts alkylation along
diastereoselective C–O bond formation reaction to give 8-epi-
puupehedione (2) and (+)-chromazonarol (4) atom-
a
Lewis-acid-
with
a
economically.10 Seifert reported the synthesis of (+)-yahazunol (6)
and related natural products by stereoselective epoxidation
followed by regioselective opening of the oxirane ring.11 Baran
and coworkers have reported an elegant synthesis of C8β-Me
meroterpenoids by using C8β-Me borono-sclareolide as a useful
building block (Fig. 2a) in 2012.12 However, the synthesis of
C8α-Me borono-sclareolide proved to be problematic by our
effort, maybe due to its less stable than the C8β-Me epimer.13
Accordingly, a palladium-catalyzed tandem carbene migratory
insertion of an aryl iodine and a drimanal hydrazone was
developed by us for the synthesis of C8α-Me meroterpenoid-
type marine natural products (Fig. 2b).14 Complementary to this
effort, herein we report an alternative synthesis of C8β-Me
marine meroterpenoids by using a palladium-catalyzed coupling
reaction of an aryl iodine and a drimanal hydrazone, an oxa-
Stork-Danheiser transposition reaction,
a newly developed
regioselective reduction of enols, and an electrocyclization
cyclization of a conjugated tetraenone as the key steps. The
concise natural product syntheses could be used for the
preparation of sufficient quantities of these bioactive marine
meroterpenoids for biological and medical studies.
[a]
[b]
School of Marine Science and Technology,
Harbin Institute of Technology
No. 2, Wenhuaxi Road, Weihai 264209, P. R. China
Email: lihuijing@iccas.ac.cn
http://homepage.hit.edu.cn/pages/lihuijing
Beijing National Laboratory for Molecular Sciences (BNLMS),
Institute of Chemistry Chinese Academy of Sciences
No.2, 1st North Street, Zhongguancun, Beijing 100190, P. R. China
Email: ycwu@iccas.ac.cn
http://homepage.hit.edu.cn/pages/wuyanchao
Supporting information for this article is given via a link at the end of
the document.
Results and Discussion
In connection with our previous work,15 we wish to continue our
research in the divergent synthesis of bioactive marine
meroterpenoids from readily available (+)-sclareolide (9).14,15d,16
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
a) Baran's "boronosclareolide" approach
a) Synthesis of key intermediate 15 and 16
OH
O
MeO
MeO
MeO
OMe
(E)
OMe
O
NNHTs
OH
OMe
AgNO3/K2S2O8
Pd(PPh3)4
K2CO3
I
(Z)
+
+
OMe
OH
B
OH
THF, 90 °C
OH
O
OMe
H
O
OMe
H
H
(+)-Chromazonarol (4)
H
14
13
15 (32%)
16 (54%)
C8β-Me
H
R
b) CAN oxidation of 15/16
Suzuki
conditions
R
C8β-Me
MeO
OH
O
bioactive
OMe
MeO
OMe
meroterpenoids
O
X
CAN
MeCN-H2O, r.t.
H
OMe
+
OMe
OH
O
b) Our palladium-catalyzed coupling strategy
MeO
O
OMe
H
H
H
NNHTs
OH
OMe
15/16
17 (15%)
2 (3%)
I
cat. Pd
C8-Me
bioactive marine
meroterpenoids
+
OMe
OH
c) DDQ oxidation of 15/16
previously
OMe
MeO
MeO
OMe
O
H
OMe
OMe
C8-Me
O
H
DDQ
R
O
acetone-H2O
(4:1), r.t.
NNHTs
OH
OMe
OMe
OH
O
+
cat. Pd
C8β-Me
bioactive marine
meroterpenoids
OH
R
+
This work
I
H
H
H
H
H
C8β-Me
15/16
18 (40%)
2 (19%)
Figure 2. Synthetic strategies on meroterpenoids.
Scheme 2. Our initial endeavors on synthesis of (+)-8-epi-puupehedione (2).
Our natural product synthesis commenced with the preparation
of drimanal hydrazone 13 (Scheme 1). Following our previous
procedure,16a the treatment of (+)-sclareolide (9) with KHMDS in
THF at -78 °C and subsequent reaction with oxygen in the
presence of P(OMe)3 afforded α-hydroxy lactone 10 in 75% yield
Our initial endeavors on the synthesis of (+)-8-epi-
puupehedione is shown in Scheme 2. The cross-coupling
reaction of aryl iodide 14 with drimanal hydrazone 13 was
realized in the presence of Pd(PPh3)4 (5 mol %) and K2CO3 (4.5
equiv.) in THF at 90 °C for 6 hours to afford intermediates 15
and 16 in 32% and 54% yields, respectively (86% overall yield,
Scheme 2a).14 Disappointingly, oxidation of 15/16 with CAN
gave 8-epi-puupehedione (2) in only 3% yield along with by-
product 17 in 15% yield (Scheme 2b). Oxidation of 15/16 with
DDQ afforded 8-epi-puupehedione (2) and by-product 18 in 19%
and 40% yield, respectively (Scheme 2c).
Although the synthesis of 8-epi-puupehedione (2) was
achieved within only 6 longest linear steps, the overall yield is
too low (Scheme 2). Thus, an improved synthesis of (+)-8-epi-
puupehedione (2) is depicted in Scheme 3. Interestingly, the
reduction of enols 15 and 16 with Et3SiH in the presence of TFA
afforded the allylic reduction product 19 in 91% yield. According
to reports in the literature, the allylic reduction uaually took place
in the presence of a transition-metal catalyst with a carbon
nucleophile. Recently, Teichert reported a copper(I)-catalyzed
allylic reduction with (TMSO)2Si(Me)H as the hydride
nucleophile.19 However, the halogen leaving groups (Cl and Br)
showed conversion in the allylic reduction, whereas oxygen-
based leaving groups were not reactive. Therefore, Teichert’s
and our allylic reduction strategy would complement each other
to enrich the reaction diversity. Moreover, treatment of 15 and16
with hydrogen in the presence of Pd/C in MeOH, the allylic
reduction product 19 was obtained in 95% yield, which was an
extension of the palladium-catalyzed formate reduction of allylic
as
a
sole diastereoisomer.17 The 9,11-cis relative
stereochemistry of 10 was deduced from the observed coupling
constant between H9/H11 (J = 12.5 Hz) and was confirmed by
comparing its NMR data with Hua’s report.18 Subsequently, the
reduction of the lactone ring of 10 with LiAlH4 occurred smoothly
at room temperature to generate exclusively lactol 11 in 98%
yield as a single diastereomer. The configuration was confirmed
by the high chemical shift of OH11/OH12 (δ = 6.08, 4.88).
Treatment of 11 with NaIO4 in the presence of K2CO3 at room
temperature afforded the desired β-hydroxy aldehyde in 95%
yield. Condensation of 12 with p-toluenesulfonyl hydrazide in
MeOH at room temperature gave the desired drimanal
hydrazone 13 in 98% yield within 12 hours.
Scheme 1. Synthesis of drimanal hydrazone 13.
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10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
MeO
OMe
OMe
MeO
O
OMe
OMe
MeO
OMe
OMe
treating 22 with CAN in the mixture solvent of MeCN-H2O (v/v,
3:1), 23 could be obtained in 77% yield. Reduction of 23 with
NaBH4 and subsequent reaction with DDQ afforded (+)-
puupehedione (2) in 48% overall yield (2 steps, Scheme 3).12
Scheme 4 shows another synthesis of (+)-8-epi-puupehedione
(2). By treating 22 with IBX at room temperature for 2 hours, by-
product 24 was obtained, in 43% yield, as the sole product.22
Instead, by treatment of 22 with DDQ in the mixture solvent of
DCM-H2O (v/v, 10:1) at room temperature for 2 hours, 22
underwent a facile ring-opening reaction to afford the desirable
product 25 in 62% yield (Scheme 4). 25 was converted into 23
(92% yield) in the presence of p-TsOH via an intramolecular
oxa-Stork-Danheiser transposition. Reduction of 23 with NaBH4
formed (+)-8-epi-puupehenol (3), which underwent DDQ
oxidation to afford (+)-puupehedione (2) in 48% overall yield
from 23 (Scheme 4).12
Scheme 5 illustrates an alternative synthesis of (+)-8-epi-
puupehedione (2). Considering the difficulties of the
demethylation of 8-epi-19-methoxypuupehenol (22), we
anticipated that the methyl group could be removed before ring-
closure. According to Bisai’s report,23 treatment of 20 with 2 M
KOH solution in MeOH, the cyclization product 28 was obtained
instead of the demethylation product 26. We suspected that 20
should be isomerized to intermediate 27 under basic condition
and then electrocyclized to 28.8a,18,24 After screening the reaction
conditions, many inorganic base (t-BuOK, Cs2CO3, NaOH, LiOH,
and K2CO3) and organic base (DABCO, DIPEA, and DMAP)
could promote this process. Inversely, the electrocyclization
could not take place under acid condition (TsOH, H2SO4, and
HCl/MeOH). Fortuitously, by treating 20 with K2CO3 in MeOH at
room temperature, 28 was obtained in 86% yield. Treatment of
28 with DDQ in the mixture solvent of DCM-H2O (v/v, 10:1)
afforded (+)-8-epi-puupehedione (2) in 65% yield (Scheme 5).
Scheme 6 shows the synthesis of (+)-chromazonarol (4), (+)-
yahazunol (6) and (+)-yahazunone (7). The palladium-catalyzed
tandem carbene migratory insertion reaction mentioned
previously was employed in the preparation of enols 30/31 (82%
overall yield) in the presence of Pd(PPh3)4 (5 mol %) and K2CO3
(4.5 equiv.) in THF at 90 °C (Scheme 6). The allylic reduction of
enols 30/31 with Et3SiH was also effective in the presence of
TFA in DCM to furnish 32 in 81% yield (Scheme 6). Treatment of
DDQ,
Acetone-H2O
(10:1)
Et3SiH, TFA,
H
DCM, r.t., 91%
OH
or Pd/C, H2, MeOH,
40 °C, 95%
0 °C, 70%
H
H
H
15/16
19
18
CAN,
MeCN-H2O
(3:1), r.t.
O
OH
OH
MeO
OMe
OMe
OMe
Na2S2O4
TBAB
OMe
+
O
THF-H2O
r.t.
O
H
H
H
17 (9%)
20 (48%)
21
BF3-OEt2,
DCM, r.t.,
87% from 20
O
O
O
OH
O
O
OMe
CAN,
MeCN-H2O
(3:1)
a) NaBH4, EtOH,
r.t., 15 m
O
O
b) DDQ, t-BuOH,
100°C, 16 h
48% (2 steps)
r.t., 77%
H
H
H
(+)-8-Epi-puupehedione (2)
23
22
Scheme 3. An improved synthesis of (+)-8-epi-puupehedione (2).
carbonates.20 Subsequently, treatment of 19 with DDQ in the
mixture solvent of acetone-H2O (v/v, 10:1) at room temperature
afforded by-product 18 in 70% yield and 10% of 19 was
recovered, but no the desired drimanal p-benzoquinone 20. The
above oxidation reaction did not complete even with an excess
of DDQ. When 19 was subjected to CAN oxidation in the mixture
solvent of MeCN-H2O (v/v, 3:1) at room temperature, 20 was
obtained as the major product (48% yield) along with 17 (9%
yield). Treatment of 20 with Na2S2O4 in the presence of TBAB in
the mixture solvent of THF-H2O (v/v, 3:1) at room temperature
gave 21 as a sole product, which was not stable and was used
without further purification. Eventually, the treatment of 21 with
BF3-Et2O afforded the cyclization product 8-epi-19-methoxy
puupehenol (22) in 87% overall yield from 20. Furthermore, by
OH
O
O
OH
O
OMe
OMe
OMe
O
K2CO3, MeOH
r.t., 86%
H
H
H
20
27
28
O
O
O
O
O
OH
DDQ,
DCM-H2O (10:1)
r.t., 65%
H
H
(+)-8-Epi-puupehedione (2)
26
Scheme 4. Another synthesis of (+)-8-epi-puupehedione (2).
Scheme 5. An alternative synthesis of (+)-8-epi-puupehedione (2).
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10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
9 steps, 18% overall yield), (+)-yahazunol (6, 11 steps, 10%
overall yield), and (+)-yahazunone (7, 10 steps, 11% overall
yield). Further exploitation of this strategy for the synthesis of
other natural products with related skeletons are in progress,
which will be reported in due course.
Experimental Section
General experimental methods.
Common reagents and materials were purchased from commercial
sources and were used without further purification. All experiments were
carried out under an argon atmosphere in flame-dried glassware using
standard inert techniques for introducing reagents and solvents unless
otherwise noted. TLC plates were visualized by exposure to ultra violet
light (UV). IR spectra were recorded by using an Electrothemal Nicolet
380 spectrometer. High-resolution mass spectra (HRMS) were recorded
by using an Electrothemal LTQ-Orbitrap mass spectrometer. Melting
points were measured by using a Gongyi X-5 microscopy digital melting
point apparatus and are uncorrected. 1H NMR and 13C NMR spectra
were obtained by using a Bruker Avance III 400 MHz NMR spectrometer.
Compound 10: To a solution of (+)-sclareolide (9, 10.0 g, 40 mmol) in
THF (150 mL) was added KHMDS (60 mL, 1.0 M in THF, 60 mmol) at -
78 °C. The mixture was stirred at -78 °C for 30 minutes, added with
P(OMe)3 (7.4 g, 7.1 mL, 60 mmol) , bubbled with O2 (balloon pressure)
for 30 minutes, stirred at -78 °C for 1 hour, and quenched with aqueous 2
N HCl (150 mL). The resulting mixture was extracted with EtOAc (3 × 150
mL), and the combined organic phases were washed with brine (2 × 150
mL) and dried over anhydrous Na2SO4. After filtration and removal of the
solvent under vacuum, the residue was subjected to flash column
chromatography over silica gel (100–200 mesh) for purification using
EtOAc/petroleum ether (1:20 → 1:15) as eluent to give compound 10 (8.0
g, 75%) as a white solid. M.p.: 147−148 °C ; IR (film): νmax = 3352, 2993,
2946, 2867, 1776, 1759, 1449, 1388, 1294, 1218, 1147, 1022, 1005, 927,
705 cm-1; 1H NMR (400 MHz, CDCl3): δ = 4.49 (d, J = 12.5 Hz, 1H), 2.48
(s, br, OH), 2.05 (td, J = 11.7, 2.9 Hz, 1H), 1.94 (d, J = 12.6 Hz, 1H),
1.92−1.87 (m, 1H), 1.75−1.60 (m, 3H), 1.51−1.41 (m, 2H), 1.38 (s, 3H),
1.33 (dd, J = 3.2, 13.3 Hz, 1H), 1.26−1.16 (m, 2H), 1.07 (dd, J = 12.7, 1.9
Hz, 1H), 1.02 (s, 3H), 0.88 (s, 3H), 0.84 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 178.8, 83.3, 68.5, 64.0, 56.2, 42.0, 39.1, 39.1, 36.7, 33.2,
33.0, 23.2, 20.9, 20.5, 17.9, 15.7 ppm; HRMS (ESI): m/z calcd. for
C16H26O3Na [M + Na]+: 289.1774; found: 256.1769.
Scheme 6. Synthesis of (+)-chromazonarol (4), (+)-yahazunol (6) and (+)-
yahazunone (7).
32 with CAN in the mixture solvent of MeCN-H2O (v/v, 3:1) gave
35 as the major product in 48% yield along with 33 in 6% yield.
Reduction of 34 with Na2S2O4 in the presence of TBAB in the
mixture solvent of THF-H2O (v/v, 3:1) afforded 35 as a sole
product, which was not stable and was used without further
purification. Thus, by treating with BF3-Et2O in DCM at room
temperature,10 35 underwent a cyclization process to generate
(+)-chromazonarol (4) in 82% overall yield from 34 (Scheme 6).
Inspired by the facile DDQ-promoted ring-opening reaction of 22
to 25 as shown in Scheme 4, treatment of (+)-chromazonarol (4)
with DDQ in the mixture solvent of acetone-H2O (v/v, 4:1) gave
the desirable (+)-yahazunone (7)12 in 62% yield (Scheme 6).
Finally, reduction of (+)-yahazunone (7) with Na2S2O4 in the
presence of TBAB in the mixture solvent of THF-H2O (v/v, 3:1)
afforded (+)-yahazunol (6) in 88% yield (Scheme 6).
Compound 11: To an ice-cold solution of the compound 10 (8.0 g, 30
mmol) in dry THF (150 mL) was added LiAlH4 (2.3 g, 60 mmol) in
portions. The mixture was allowed to warm up to room temperature and
stirring was continued for 1 hour, after which time it was then slowly
quenched at 0 °C with 2.3 mL of water, 2.3 mL of an aqueous 15%
NaOH solution followed by 6.9 mL of water to afford a granular inorganic
precipitate. The mixture was filtered over a pad of celite, the solid was
rinsed with CH2Cl2, and the filtrate was extracted with CH2Cl2 (3 × 100
mL). The combined organic phases were washed with brine (2 × 100 mL),
dried over anhydrous Na2SO4, filtered, and concentrated to give
compound 11 (7.9 g, 98%) as a white solid. M.p.: 137−138 °C ; IR (film):
νmax = 3466, 3410, 2921, 2864, 1455, 1383, 1258, 1072, 993, 966, 729
cm−1; 1H NMR (400 MHz, CDCl3): δ = 6.08 (d, J = 4.7 Hz 1H,), 4.88 (dd, J
= 4.4, 3.6 Hz,1H,), 4.78 (d, J = 6.7 Hz, 1H), 3.95 (ddd, J = 10.4, 6.7, 3.4
Hz 1H,), 1.72−1.56 (m, 4H), 1.42 (d, J = 10.9 Hz, 1H), 1.36−1.28 (m, 3H),
1.23 (dd, J = 13.2, 2.3 Hz, 1H), 1.19 (s, 3H), 1.12 (m, 2H), 0.92−0.87 (m,
1H), 0.88 (s, 3H), 0.83 (s, 3H), 0.79 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 104.1, 80.5, 76.4, 65.0, 56.3, 42.0, 40.5, 39.0, 36.1, 33.3,
Conclusions
In conclusion, the facile palladium-catalyzed tandem carbene
migratory insertion of an aryl iodine and a drimanal hydrazone is
proved to be effective to the divergent synthesis of the C8β-Me
bioactive marine meroterpenoids. This key reaction together with
a
highly regioselective reduction of enols, an oxa-Stork-
Danheiser transposition reaction, an electrocyclization
cyclization of conjugated tetraenone, and redox of
a
a
dimethoxybenzenes facilitated the preparation of sufficient
quantities of these natural products for biological and medical
studies, which includes (+)-8-epi-puupehedione (2, 6 steps, 8%
overall yield or 9 steps, 15% overall yield), (+)-chromazonarol (4,
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10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
32.6, 25.0, 20.8, 19.9, 17.7, 15.7 ppm; HRMS (ESI): m/z calcd. for
C16H29O3 [M+ H]+: 269.2111; found: 269.2106.
Compound 16: IR (film): νmax = 3492, 2927, 2359, 1737, 1506, 1463,
1387, 1372, 1240, 1202, 1119, 1031, 943, 877, 813, 690 cm-1; 1H NMR
(400 MHz, Acetone-d6): δ = 6.83 (s, 1H), 6.61 (s, 1H), 6.60 (s, 1H), 3.81
(s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.43 (s, br, 1H), 1.97−1.93 (m, 1H),
1.75−1.69 (m, 1H), 1.64 (dd, J = 12.3, 2.8 Hz, 2H), 1.51 (dt, J = 8.3, 4.0
Hz, 1H), 1.45 (s, 3H), 1.42−1.38 (m, 1H), 1.27 (s, 3H), 1.22−1.18 (m, 2H),
1.12−1.09 (m, 2H), 1.06−0.98 (m, 1H), 0.86 (s, 3H), 0.82 (s, 3H) ppm;
13C NMR (100 MHz, Acetone-d6): δ = 158.7, 152.3, 150.3, 144.6, 124.6,
119.8, 117.2, 100.2, 74.6, 58.1, 57.4, 57.3, 54.7, 44.5, 43.5, 43.2, 41.3,
35.5, 34.9, 34.3, 23.5, 23.1, 21.5, 20.6 ppm; HRMS (ESI): m/z calcd. for
C24H37O4 [M + H]+ 389.2686; found 389.2678.
Compound 12: To an ice-cold solution of compound 11 (7.8 g, 29 mmol)
and K2CO3 (6.0 g, 43.5 mmol) in MeOH (150 mL) was added dropwise a
solution of NaIO4 (9.3 g, 43.5 mmol) in water (100 mL), then warmed to
room temperature. After stirring for 2 hours, the resulting precipitate was
filtered and the filtrate was extracted with AcOEt (3 × 100 mL), washed
with aqueous sodium thiosulfate, brine, dried over Na2SO4. After filtration
and removal of the solvent under vacuum, the residue was subjected to
flash column chromatography over silica gel (100–200 mesh) for
purification using EtOAc/petroleum ether (1:20 → 1:10) as eluent to give
compound 12 (6.6 g, 95%) as a white solid. M.p.: 60−61 °C ; IR (film):
(+)-8-Epi-puupehedione (2) and Compound 17. To a solution of 15/16
(388 mg, 1 mmol) in acetonitrile (15 mL) was dropwised a solution of
CAN (1.2 g, 2.2 mmol) in water (5 mL) at room temperature and the
mixture so obtained was stirred for 45 minutes before it was diluted with
water (20 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined
organic phases were washed with brine (50 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum. The residue was
purified by flash column chromatography over silica gel (100–200 mesh)
with EtOAc/petroleum ether (1:20 → 1:10) to give the (+)-puupehedione
(2, 10 mg, 3 %) as a red solid, along with 17 (58mg, 15%) as a yellow oil.
νmax = 3143, 2925, 1711, 1650, 1462, 1389, 1124, 1085, 937, 917 cm−1
;
1H NMR (400 MHz, CDCl3): δ = 10.00 (s, 1H), 2.32 (s, br, 1H), 2.07 (s,
1H), 1.96−1.88 (m, 1H), 1.81 (td, J = 12.5, 3.2 Hz, 1H), 1.72−1.65 (m 3H),
1.52−1.46 (m, 2H), 1.38 (s, 3H), 1.26−1.22(m, 2H), 1.21−1.15 (m, 1H),
1.11 (s, 3H), 0.99−0.93 (m, 1H), 0.88 (s, 3H), 0.82 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 208.0, 72.6, 71.2, 55.0, 42.7, 41.4, 39.6, 37.3,
33.2, 33.1, 25.1, 21.2, 19.7, 18.0, 17.3 ppm; HRMS (ESI): m/z calcd. for
C15H26O2Na [M + Na]+ 261.1825; found 261.1819.
Compound 13. To a solution of compound 12 (6.0 g, 25 mmol) in MeOH
(5 mL) were added p-toluenesulfonyl hydrazide (4.7 g, 25.25 mmol) at
room temperature. The resulting mixture was stirred at room temperature
for 12 hours. The volatile was removed under vacuum to give compound
13 (10.0 g, 98 %) as a white solid without further purification. M.p.:
120−121 °C; IR (film): νmax = 3473, 2939, 1595, 1460, 1442, 1414, 1332,
1183, 1160, 1080, 1026, 904, 805, 700, 665 cm-1; 1H NMR (400 MHz,
CDCl3): δ = 7.81 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.30 (d, J =
7.8 Hz, 2H), 2.74 (s, br, 2H), 2.41 (s, 3H), 2.01 (d, J = 7.2 Hz, 1H), 1.83
(d, J = 12.8 Hz, 1H), 1.64 (d, J = 13.7 Hz, 1H), 1.48−1.33 (m, 4H),
1.27−1.22 (m, 2H), 1.16 (s, 3H), 1.11 (dd, J = 3.6,14.0 Hz, 1H),
1.06−0.99 (m, 2H), 0.85 (s, 6H), 0.76 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 153.7, 144.0, 134.9, 129.6, 129.6, 127.9, 127.9, 72.4, 63.5,
55.1, 42.8, 41.5, 39.8, 37.4, 33.1, 33.0, 24.5, 21.5, 21.3, 19.9, 18.0, 16.3
ppm; HRMS (ESI): m/z calcd. for C22H34N2O3SNa [M + Na]+ 429.2182;
found 429.2173.
(+)-8-Epi-puupehedione (2): IR (film): νmax
= 2921, 2868, 1668,
1642,1600, 1566, 1457, 1420, 1386, 1258, 1240, 1129, 1064, 1002, 908,
843, 731, 664, 602 cm-1; 1H NMR (400 MHz, CDCl3): δ = 6.26 (s, 1H),
6.12 (s, 1H), 5.92 (s, 1H), 2.20 (dd, J = 9.6, 5.8 Hz, 1H), 1.92−1.89 (m,
2H), 1.82−1.72 (m, 2H), 1.68−1.62 (m, 2H), 1.58 (s, 3H), 1.56−1.25 (m,
1H), 1.47−1.40 (m, 2H), 1.18 (s, 3H), 1.10 (d, J = 12.2 Hz, 1H), 0.92 (s,
3H), 0.89 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 181.0, 179.5,
166.2, 164.1, 137.7, 122.1, 114.3, 107.9, 82.9, 53.0, 41.1, 41.0, 40.2,
37.6, 34.0, 33.1, 30.6, 21.8, 21.6, 19.1, 18.5 ppm; HRMS (ESI): m/z
calcd. for C21H26O3Na [M + Na]+349.1774; found 349.1763. All spectral
data match those of the natural (+)-8-epi-puupehedione.
Compound 17: IR (film): νmax = 2926, 1707, 1605, 1508, 1455, 1390,
1319, 1248, 1203, 1125, 1034, 872, 762 cm-1; 1H NMR (400 MHz,
CDCl3): δ = 6.66 (s, 1H), 6.49 (s, 1H), 6.29 (s, 1H), 3.87 (s, 3H), 3.81 (s,
3H), 3.76 (s, 3H), 3.55 (dd, J = 14.5, 7.2 Hz, 1H), 2.61 (dd, J = 18.9, 6.2
Hz, 1H), 2.33 (dd, J = 12.9, 8.9 1Hz, 1H), 2.09 (d, J = 12.2 Hz, 1H), 2.00
(dd, J = 12.8, 6.3 Hz, 1H), 1.63−1.60 (m, 2H), 1.57−1.49 (m, 2H),
1.30−1.25 (m, 1H,), 1.11 (d, J = 7.5 Hz, 3H), 1.07 (s, 3H), 0.94 (s, 3H),
0.90 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 215.6, 152.5, 151.0,
148.4, 142.8, 118.5, 118.2, 113.1, 97.9, 56.6, 56.5, 56.0, 46.7, 45.5, 41.6,
40.0, 39.1, 35.8, 33.5, 32.7, 22.8, 21.5, 20.1, 19.0 ppm; HRMS (ESI): m/z
calcd. for C23H34O4Na [M + Na]+ 409.2349; found 409.2341.
Compounds 15 and 16. To a solution of 1-iodo-2,4,5-trimethoxybenzene
(14, 1.2 g, 4 mmol) in THF (40 mL) were added 13 (1.6 g, 4 mmol),
K2CO3 (2.5 g, 18 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) at room
temperature. The resulting mixture was heated to 90 °C and stirred at
that temperature for 6 hours before it was cooled to room temperature
and diluted with EtOAc (30 mL). The mixture so obtained was
sequentially filtrated and washed with EtOAc (3 × 20 mL) and then the
filtrate was washed with brine (2 × 50 mL). The organic layer was dried
over anhydrous Na2SO4 and filtered. The solvent was evaporated under
vacuum. The residue was purified by flash column chromatography over
silica gel (100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10)
mixed with a little Et3N to give 15 (502 mg, 32 %) as a yellow solid and
16 (842 mg, 54 %) as a yellow foam.
(+)-Puupehedione (2) and Compound 18. To a solution of 15/16 (388
mg, 1 mmol) in acetone (12 mL) and H2O (3 mL) was added DDQ (454
mg, 2 mmol) at room temperature and the mixture so obtained was
stirred for 1 hour before it was diluted with water (15 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic phases were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash column
chromatography over silica gel (100–200 mesh) with EtOAc/petroleum
ether (1:20 → 1:10) to give the (+)-puupehedione (2, 62 mg, 19 %) as a
red solid, along with 18 (155 mg, 40%) as a white solid.
Compound 15: m.p.: 101−102 °C ; IR (film): νmax = 3565, 2937, 2841,
2359, 2341, 1605, 1508, 1463, 1392, 1326, 1202, 1119, 1075, 1039,
1
1030, 943, 866, 819, 693 cm-1; H NMR (400 MHz, Acetone-d6): δ = 6.93
(s, 1H), 6.64 (s, 1H), 6.28 (s, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H),
2.90 (s, br, 1H), 1.94 (d, J = 13.2 Hz, 1H), 1.84−1.74 (m, 2H), 1.91−1.68
(d, J = 13.2 Hz, 1H), 1.58−1.48 (m, 4H), 1.45−1.40 (m, 2H), 1.37 (s, 3H),
1.34−1.29 (m, 1H), 1.21 (s, 3H), 0.91 (s, 3H), 0.91 (s, 1H) ppm; 13C NMR
(100 MHz, Acetone-d6): δ = 159.3, 152.4, 150.7, 144.8, 123.0, 119.7,
117.6, 100.5, 74.2, 57.9, 57.9, 57.3, 51.9, 43.6, 43.3, 42.4, 42.2, 35.6,
34.4, 32.8, 24.9, 23.0, 21.0, 20.8 ppm; HRMS (ESI): m/z calcd. for
C24H36O4Na [M + Na]+ 411.2506; found 411.2496.
Compound 18: IR (film): νmax = 2938, 1629, 1596, 1511, 1455, 1399,
1354, 1267, 1210, 1177, 1160, 1085, 1024, 909, 820, 799, 777, 728, 646
1
cm-1; H NMR (400 MHz, CDCl3): δ = 7.38 (s, 1H), 6.47 (s, 1H), 3.93 (s,
3H), 3.85 (d, J = 0.9 Hz, 6H), 2.11 (d, J = 6.8 Hz, 2H), 1.74 (dd, J = 13.1,
6.7 Hz, 1H), 1.65−1.54 (m, 2H), 1.51−1.47 (m, 1H), 1.40 (s, 3H),
1.33−1.28 (m, 4H), 1.22 (s, 3H), 1.15 (dd, J = 13.5, 3.0 Hz, 3H), 0.91 (s,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
3H), 0.85 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 198.5, 155.3,
153.9, 145.3, 142.6, 127.8, 120.7, 114.3, 96.9, 56.3, 55.9, 50.5, 42.1,
37.9, 36.2, 33.4, 33.2, 32.2, 21.4, 21.3, 20.6, 18.8, 18.6 ppm; HRMS
(ESI): m/z calcd. for C24H34O4Na [M + Na]+ 409.2349; found 409.2338.
and extracted with EtOAc (3 × 5 mL). The combined organic phases
were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under vacuum to afford 21 as a colorless oil and used
directly without further purification.
Compound 19. To a solution of 15/16 (622 mg, 1.6 mmol) in dry DCM
(15 ml) was added Et3SiH (372 mg, 511 μL, 3.2 mmol) and TFA (182 mg,
119 μL, 1.6 mmol) at room temperature and the mixture so obtained was
stirred for 1 hour before it was diluted with water (20 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic phases were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash column
chromatography over silica gel (100–200 mesh) with EtOAc/petroleum
ether (1:50 → 1:30) to afford 19 (542 mg, 91 %) as a yellow solid. M.p.:
102−103 °C ; IR (film): νmax = 2915, 1598, 1515, 1461, 1393, 1317, 1201,
1117, 1033, 861, 819, 687 cm-1; 1H NMR (400 MHz, CDCl3): δ = 6.66 (s,
1H), 6.50 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.33 (d, J =
17.2 Hz, 1H), 3.19 (d, J = 17.1 Hz, 1H), 2.18−2.07 (m, 2H), 1.75−1.71 (m,
2H), 1.57−1.49 (m, 2H), 1.50 (s, 3H), 1.35−1.25 (m, 3H), 1.20 (d, J = 12.4
Hz, 1H), 1.07 (d, J = 13.2 Hz, 1H), 1.00 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 151.0, 147.1, 142.5, 137.6, 128.6,
121.2, 113.9, 97.3, 56.8, 56.1, 56.1, 52.2, 41.7, 38.8, 36.0, 33.4, 33.2,
33.2, 26.0, 21.6, 20.2, 20.1, 19.0, 18.7 ppm; HRMS (ESI): m/z calcd. for
C24H36O3Na [M + Na]+395.2557; found 395.2549.
Compound 22. To a solution of 21 obtained above in DCM (2 mL) was
dropwised BF3-OEt2 (66 μL, 47 w%, 0.5 mmol) at room temperature and
the mixture so obtained was stirred for 1 hour before it was diluted with
water (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic
phases were washed with brine (10 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum. The residue was purified by
flash column chromatography over silica gel (100–200 mesh) with
EtOAc/petroleum ether (1:20 → 1:10) to afford compound 22 (60 mg,
87 %) as a white solid. M.p.: 105−106 °C ; IR (film): νmax = 3495, 2923,
2359, 1628, 1505, 14541, 1364, 1263, 1238, 1189, 1155, 1111, 1002,
867, 836 cm-1; 1H NMR (400 MHz, CDCl3): δ = 6.51 (s, 1H),6.26 (s, 1H),
3.75 (s, 3H), 2.50 (d, J = 8.7 Hz, 2H), 1.98 (d, J = 12.4 Hz, 1H), 1.71 (d, J
= 12.5 Hz, 1H), 1.64 (d, J = 12.1 Hz, 1H), 1.57−1.53 (m, 1H), 1.47−1.39
(m, 3H), 1.21 (dd, J = 13.1, 3.1 Hz, 1H), 1.15 (s, 3H), 1.06 (d, J = 12.2 Hz,
1H), 0.98 (dd, J = 13.1, 3.8 Hz, 1H), 0.91 (s, 6H), 0.86 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ = 146.4, 145.9, 139.8, 115.0, 113.3, 100.6,
75.8, 56.0, 55.2, 52.5, 41.7, 41.1, 39.0, 36.6, 32.8, 21.4, 21.0, 20.1, 19.5,
18.3, 14.3 ppm; HRMS (ESI): m/z calcd. for C22H32O3Na [M + Na]+
367.2244; found 3672236.
Compound 18. To a solution of 19 (10 mg, 0.15 mmol) in acetone (2 mL)
and H2O (0.2 mL) was added DDQ (68 mg, 0.3 mmol) at room
temperature and the mixture so obtained was stirred for 12 hours. TLC
indicated that the reaction did not finished and additional DDQ (68 mg,
0.3 mmol) was added and was stirred for another 12 hours before it was
diluted with water (3 mL) and extracted with CH2Cl2 (3 × 5 mL). The
combined organic phases were washed with brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under vacuum. The
residue was purified by flash column chromatography over silica gel
(100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to afford 18
(36 mg, 70 %) as a white solid with 19 (6 mg, 10%) recovered.
Compound 23. To a solution of 22 (52 mg, 0.12 mmol) in acetonitrile (3
mL) was dropwised a solution of CAN (132 mg, 0.24 mmol) in water (1
mL) at room temperature and the mixture so obtained was stirred for 30
minutes before it was diluted with water (5 mL) and extracted with CH2Cl2
(3 × 5 mL). The combined organic phases were washed with brine (15
mL), dried over anhydrous Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by flash column chromatography over
silica gel (100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to
give the compound 23 (30 mg, 77 %) as an orange oil. IR (film): νmax
=
2924, 2852, 1680, 1643, 1456, 1388, 1258, 1125, 845 cm-1; 1H NMR
(400 MHz, CDCl3): δ = 6.17 (s, 1H), 5.75 (s, 1H), 2.63 (d, J = 9.2 Hz, 2H),
2.09 (d, J = 11.1 Hz, 1H), 1.80 (d, J = 13.8 Hz, 1H), 1.74−1.69 (m, 2H),
1.64−1.60 (m, 3H), 1.51−1.37 (m, 3H), 1.33 (s, 3H), 1.18 (d, J = 13.8 Hz,
1H), 1.02 (d, J = 12.0 Hz, 1H), 0.90 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 180.3, 178.7, 165.2, 145.2, 128.3,
107.8, 82.0, 55.7, 51.5, 41.5, 40.5, 38.5, 37.0, 33.2, 33.1, 23.5, 21.9,
21.3, 19.5, 18.1, 14.6 ppm; HRMS (ESI): m/z calcd. for C21H28O3Na [M +
Na]+ 351.1931; found 351.1926.
Compound 20. To a solution of 19 (469 mg, 1.26 mmol) in acetonitrile
(15 mL) was dropwised a solution of CAN (1.73 g, 3.15 mmol) in water (5
mL) at room temperature and the mixture so obtained was stirred for 1
hour before it was diluted with water (15 mL) and extracted with CH2Cl2
(3 × 15 mL). The combined organic phases were washed with brine (20
mL), dried over anhydrous Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by flash column chromatography over
silica gel (100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to
give the compound 20 (207 mg, 48 %) as a light yellow solid, along with
17 (44 mg, 9%) as a yellow oil.
(+)-8-Epi-puupehedione (2). To a solution of 23 (26 mg, 0.08 mmol) in
EtOH (2 mL) followed by the addition of NaBH4 (6 mg, 0.16 mmol) and
stirred for 20 minutes at room temperature. The reaction mixture was
cooled to 0 °C and quenched by the dropwise addition of aqueous 2 N
HCl until gas evolution ceased then diluted with EtOAc (15 mL), washed
with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and
concentrated. The crude product was dissolved in 1,4-dioxane (2 mL)
and added with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 36 mg,
0.16 mmol). The resulting mixture was stirred under reflux for 2 hours,
then concentrated under reduced pressure, diluted with ether (10 mL),
washed with saturated aqueous NaHCO3 (3 x 10 mL) and brine (10 mL),
and concentrated. The residue was purified by flash column
chromatography over silica gel (100–200 mesh) with EtOAc/petroleum
ether (1:20 → 1:10) to give 2 (13 mg, 48%) as a red solid.
Compound 20. M.p.: 152−153°C ; IR (film): νmax = 2938, 2847, 1664,
1
1642, 1600, 1455, 1360, 1214, 1195, 1167, 985, 916, 898, 872 cm-1; H
NMR (400 MHz, CDCl3): δ = 6.35 (s, 1H), 5.93 (s, 1H), 3.82 (s, 3H), 3.22
(d, J = 20.2 Hz, 1H), 3.04 (d, J = 20.1 Hz, 1H), 2.12−1.99 (m, 3H), 1.70
(dd, J = 12.6, 6.9 Hz, 1H), 1.62 (s, 1H), 1.51−1.45 (m, 2H), 1.42 (s, 3H),
1.36 (d, J = 11.7 Hz, 1H), 1.16 (d, J = 12.5 Hz, 1H), 1.10−1.03 (m, 2H),
0.95 (s, 3H), 0.89 (s, 3H), 0.82 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 187.7, 182.7, 158.7, 149.8, 134.8, 130.8, 130.5, 107.8, 56.2, 51.8,
41.5, 38.8, 36.1, 33.3, 33.2, 33.1, 26.9, 21.6, 20.0, 19.9, 18.9, 18.8 ppm;
HRMS (ESI): m/z calcd. for C22H30O3Na [M + Na]+ 365.2087; found
365.2077.
Compound 24. To a solution of 22 (7 mg, 0.02 mmol) THF (1 mL) was
added IBX (11 mg, 0.04 mmol) at room temperature and the mixture so
obtained was stirred for 2 hours before it was diluted with water (3 mL)
and extracted with EtOAc (3 × 3 mL). The combined organic phases
were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered,
Compound 21. To a solution of 20 (68 mg, 0.2 mmol) and TBAB (13 mg,
0.04 mmol) in THF (1.5 mL) was dropwised a solution of Na2S2O4 (104
mg, 0.6 mmol) in water (1.5 mL) at room temperature and the mixture so
obtained was stirred for 1 hour before it was diluted with water (5 mL)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
and concentrated under vacuum. The residue was purified by flash
column chromatography over silica gel (100–200 mesh) with
EtOAc/petroleum ether (1:20 → 1:10) to give the compound 24 (6 mg,
87 %) as a red oil. IR (film): νmax = 2923, 2851, 1647, 1633, 1563, 1396,
1214, 1093, 937, 909, 732 cm-1; 1H NMR (400 MHz, CDCl3): δ = 5.65 (s,
1H), 3.75 (s, 3H), 2.46 (dd, J = 16.7, 4.4 Hz, 1H), 2.11−1.99 (m, 3H),
1.80−1.72 (m, 2H), 1.67−1.59 (m, 3H), 1.48−1.39 (m,3H), 1.26 (s, 3H),
1.16 (dd, J = 13.1, 3.7 Hz, 1H), 0.99 (d, J = 12.2 Hz, 1H), 0.89 (s, 3H),
0.86 (s, 3H), 0.83 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 176.7,
175.6, 164.7, 152.7, 107.7, 107.3, 83.1, 56.0, 55.8, 51.6, 41.7, 40.3, 39.2,
37.1, 33.3, 33.1, 21.4, 21.0, 19.7, 18.3, 15.6, 15.0 ppm; HRMS (ESI): m/z
calcd. for C20H30O4Na [M + Na]+ 381.2036; found 381.2028.
before it was diluted with water (3 mL) and extracted with CH2Cl2 (3 × 5
mL). The combined organic phases were washed with brine (10 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under vacuum.
The residue was purified by flash column chromatography over silica gel
(100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to afford 2
(11 mg, 65 %) as an orange-red solid.
Compounds 30 and 31. To a solution of 2-iodo-1,4-dimethoxybenzene
(29, 528 mg, 2 mmol) in THF (20 mL) were added 13 (812 mg, 4 mmol),
K2CO3 (1.24 g, 9 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol) at room
temperature. The resulting mixture was heated to 90 °C and stirred at
that temperature for 6 hours before it was cooled to room temperature
and diluted with EtOAc (20 mL). The mixture so obtained was
sequentially filtrated and washed with EtOAc (3 × 20 mL) and then the
filtrate was washed with brine (2 × 40 mL). The organic layer was dried
over anhydrous Na2SO4 and filtered. The solvent was evaporated under
vacuum. The residue was purified by flash column chromatography over
silica gel (100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10)
mixed with a little Et3N to give 30 (211 mg, 29 %) as a yellow solid and
31 (382 mg, 53 %) as a yellow foam.
Compound 25. To a solution of 22 (52 mg, 0.15 mmol) in DCM (2 mL)
and H2O (0.2 mL) was added DDQ (68 mg, 0.3 mmol) at room
temperature and the mixture so obtained was stirred for 1 hour before it
was diluted with water (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases were washed with brine (15 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under vacuum. The
residue was purified by flash column chromatography over silica gel
(100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to afford 25
(34 mg, 62 %) as a red oil. IR (film): νmax = 2920, 2849, 1671, 1639, 1602,
1459, 1365, 1225, 1201, 1175, 1124, 1081, 1034, 982, 937, 862, 7311
cm-1; 1H NMR (400 MHz, CDCl3): δ = 6.57 (s, 1H),5.91 (s, 1H), 3.81 (s,
3H), 2.65 (dd, J = 14.9, 5.3 Hz, 1H), 2.46 (dd, J = 15.1, 5.1 Hz, 1H),
2.03−1.98 (m, 1H, ), 190−1.87 (m, 1H), 1.68−1.54 (m, 6H), 1.40 (d, J =
12.1 Hz, 2H), 1.20 (s, 3H), 1.13−1.10 (m, 1H), 0.94−0.89 (m, 1H), 0.88 (s,
3H), 0.86 (s, 3H), 0.79 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ =
188.1, 182.2, 158.5, 153.5, 131.1, 107.8, 73.7, 62.0, 56.1, 56.1, 44.7,
41.6, 40.5, 39.5, 33.3, 33.2, 24.7, 23.8, 21.4, 20.4, 18.5, 15.3 ppm;
HRMS (ESI): m/z calcd. for C22H32O4Na [M + Na]+ 383.2193; found
383.2184.
Compound 30: M.p.: 94-95 °C ; IR (film): νmax = 3473, 2927, 2865, 1738,
1
1583, 1492, 1463, 1373, 1217, 1178, 1158, 1045, 943, 806, 713 cm-1; H
NMR (400 MHz, CDCl3): δ = 6.77 (d, J = 8.7 Hz, 1H), 6.71−6.67 (m, 2H),
6.23 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.63 (s, br, 1H), 1.91 (d, J = 12.1
Hz, 1H), 1.86−1.64 (m, 3H), 1.60−1.53 (m, 2H), 1.47−1.42 (m, 2H), 1.38
(s, 3H), 1.31 (dd, J = 11.7, 3.3 Hz, 1H), 1.23 (dd, J = 14.2, 5.0 Hz, 1H),
1.19 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.86 (d, J = 9.9 Hz, 1H) ppm; 13
C
NMR (100 MHz, CDCl3): δ = 158.8, 153.4, 149.8, 131.3, 117.2, 115.4,
112.2, 111.8, 73.3, 56.2, 55.5, 50.8, 41.8, 41.6, 40.7, 39.8, 33.9, 33.0,
31.3, 23.3, 21.6, 19.3, 19.2 ppm; HRMS (ESI): m/z calcd. for C23H34O3Na
[M + Na]+ 381.2400; found 381.2389.
Compound 23. To a solution of 25 (29 mg, 0.08 mmol) in CH2Cl2 (3 mL)
were added p-TsOH (21 mg, 0.12 mmol) at room temperature and stirred
for 15 minutes. The resulting mixture was washed with saturated
aqueous NaHCO3, dried over anhydrous Na2SO4, and evaporated under
vacuum. The residue was purified by flash column chromatography over
silica gel (100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to
give the compound 23 (24 mg, 92 %) as an orange oil.
Compound 31: IR (film): νmax = 3472, 2927, 2866, 1738, 1583, 1492,
1463, 1372, 1217, 1178, 1158, 1045, 942, 806, 793, 713, 694 cm-1; 1H
NMR (400 MHz, MeOD): δ = 6.83 (d, J = 8.9 Hz, 1H), 6.77 (s, 1H), 6.72
(d, J = 8.7 Hz, 1H), 6.29 (s, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 1.94 (d, J =
12.2 Hz, 1H), 1.79−1.86 (m, 1H), 1.75 (d, J = 14.5 Hz, 1H), 1.60−1.53 (m,
3H), 1.75 (d, J = 14.5 Hz, 1H), 1.49 (d, J = 13.4 Hz, 1H), 1.43 (d, 1H,
J=12.4Hz), 1.36 (s, 3H), 1.33 (d, J = 4.0 Hz, 1H), 1.22 (s, 3H), 1.08−1.04
(m, 1H), 0.92 (s, 6H) ppm; 13C NMR (100 MHz, MeOD): δ = 158.9, 154.8,
151.5, 132.6, 119.9, 117.3, 113.1, 112.9, 74.5, 56.7, 56.0, 51.8, 43.0,
42.8, 42.0, 41.4, 35.0, 33.6, 31.3, 24.1, 22.1, 20.4, 20.3 ppm; HRMS
(ESI): m/z calcd. for C23H34O3Na [M + Na]+ 381.2400; found 381.2387.
Compound 28. To a solution of 20 (34 mg, 0.1 mmol) in MeOH (2 mL)
was added K2CO3 (28 mg, 0.2 mmol) at room temperature and the
mixture so obtained was stirred for 45 minutes before it was diluted with
water (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic
phases were washed with brine (10 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum. The residue was purified by
flash column chromatography over silica gel (100–200 mesh) with
EtOAc/petroleum ether (1:20 → 1:10) to afford 28 (32 mg, 92 %) as a
yellow oil. IR (film): νmax = 3497, 2925, 2865, 1624, 1499, 1444, 1367,
1289, 1257, 1194, 1163, 1129, 1081, 936, 878, 793, 735 cm-1; 1H NMR
(400 MHz, CDCl3): δ = 6.56 (s, 1H), 6.39 (s, 1H), 6.03 (s, 1H), 5.23 (s, br,
1H), 3.82 (s, 3H), 2.17 (d, J = 12.6 Hz, 1H), 1.94 (d, J = 11.6 Hz, 1H),
1.88 (dd, J = 13.5, 4.3 Hz, 1H), 1.79−1.63 (m, 2H), 1.57 (d, J = 14.6 Hz,
1H), 1.51−1.42 (m, 2H), 1.39 (s, 3H), 131−1.23 (m, 1H), 1.18−1.16 (m,
1H), 1.13 (s, 3H), 1.10 (d, J = 13.2 Hz, 1H), 0.91 (s, 3H), 0.86 (s, 3H)s
ppm; 13C NMR (100 MHz, CDCl3): δ = 149.9, 146.0, 145.0, 139.5, 116.0,
113.9, 111.4, 99.8, 77.8, 55.9, 52.1, 41.5, 41.5, 38.9, 37.9, 33.5, 33.2,
26.0, 23.4, 21.6, 21.1, 19.2, 18.8, 17.2 ppm; HRMS (ESI): m/z calcd. for
C22H30O3Na [M + Na]+ 365.2087; found 365.2081.
Compound 32. To a solution of 30/31 (538 mg, 1.5 mmol) in dry DCM
(15 ml) was added Et3SiH (523 mg, 719 μL, 4.5 mmol) and TFA (342 mg,
223 μL, 3 mmol) at room temperature and the mixture so obtained was
stirred for 1 hour before it was diluted with water (20 mL) and extracted
with CH2Cl2 (3 × 15 mL). The combined organic phases were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash column
chromatography over silica gel (100–200 mesh) with EtOAc/petroleum
ether (1:50 → 1:30) to afford 32 (421 mg, 82 %) as a colorless oil. IR
(film): νmax = 2936, 2829, 1589, 1492, 1462, 1373 1273, 1234, 1213,
1177, 1112, 1052, 879, 791, 738, 711 cm-1; 1H NMR (400 MHz, CDCl3): δ
= 6.75 (d, J = 8.4 Hz, 1H), 6.67−6.64 (m, 2H), 3.82 (s, 3H), 3.76 (s, 3H),
3.38 (d, J = 17.8 Hz, 1H), 3.23 (d, J = 17.8 Hz, 1H), 2.18 (dd, J = 10.8,
7.4 Hz, 1H), 2.07 (dd, J = 17.6, 6.2 Hz, 1H), 1.73 (dd, J = 12.4, 6.9 Hz,
1H), 1.56−1.51 (m, 2H,), 1.49 (s, 3H), 1.34 (d, J = 13.3 Hz, 2H), 1.27 (d,
J = 6.0 Hz, 2H), 1.10 (dd, J = 13.0, 3.7 Hz, 1H),1.01 (s, 3H), 0.98−1.94
(m, 1H), 0.91 (s, 3H), 0.85 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ =
153.3, 151.4, 137.1, 131.2, 128.9, 116.0, 110.1, 109.0, 55.7, 55.5, 51.9,
41.7, 38.8, 35.9, 33.4, 33.3, 33.2, 26.8, 21.7, 20.2, 20.1, 19.1, 18.8 ppm;
(+)-Puupehedione (2). To a solution of 28 (17 mg, 0.05 mmol) in DCM (1
mL) and H2O (0.1 mL) was added DDQ (23 mg, 0.1 mmol) at room
temperature and the mixture so obtained was stirred for 30 minutes
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800026
European Journal of Organic Chemistry
FULL PAPER
HRMS (ESI): m/z calcd. for C23H34O2Na [M + Na]+ 365.2451; found
365.2444.
33.4, 33.1, 22.4, 21.5, 20.6, 19.7, 18.5, 14.8 ppm; HRMS (ESI): m/z
calcd. for C21H30O2Na [M + Na]+ 314.2240; found 314.2233.
Compounds 33 and 34. To a solution of 32 (370 mg, 1.08 mmol) in
acetonitrile (20 mL) was dropwised a solution of CAN (1.18 g, 2.16 mmol)
in water (10 mL) at room temperature and the mixture so obtained was
stirred for 30 minutes before it was diluted with water (20 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were
washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash column
chromatography over silica gel (100–200 mesh) with EtOAc/petroleum
ether (1:20 → 1:10) to give the compound 34 (162 mg, 48 %) as a yellow
solid, along with 33 (22 mg, 6%) as a colorless oil.
(+)-Yahazunone (7). To a solution of 4 (31 mg, 0.1 mmol) in acetone (2
mL) and H2O (0.5 mL) was added DDQ (68 mg, 0.3 mmol) at room
temperature and the mixture so obtained was stirred for 30 minutes
before it was diluted with water (5 mL) and extracted with CH2Cl2 (3 × 5
mL). The combined organic phases were washed with brine (2 × 10 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under vacuum.
The residue was purified by flash column chromatography over silica gel
(100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to afford 7
(20 mg, 62 %) as a yellow solid. M.p.: 131−132 °C; IR (film): νmax = 3532,
2927, 2866, 1607, 1462, 1387, 1294, 1086, 894 cm-1; 1H NMR (400 MHz,
CDCl3): δ = 6.74 (d, J = 9.9 Hz, 1H), 6.67 (d, J = 10.0, 2.4 Hz, 1H), 6.63
(s, 1H), 2.62 (dd, J = 15.1, 6.0 Hz, 1H), 2.47 (dd, J = 15.2, 5.1 Hz, 1H),
1.87 (dt, J = 12.2, 3.0 Hz, 1H), 1.68−1.62 (m, 2H), 1.60−1.52 (m, 3H),
1.44−1.34 (m, 2H), 1.28-1.24 (m, 1H), 1.20 (s, 3H), 1.16−1.13 (m, 1H),
1.11 (dt, J = 13.7, 4.1 Hz, 1H), 0.92 (dd, J = 11.9, 1.7 Hz, 1H), 0.87 (s,
3H), 0.86 (s, 3H), 0.79 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ =
188.0, 187.7, 152.6, 137.0, 136.1, 132.8, 73.9, 61.6, 56.1, 44.8, 41.6,
40.4, 39.4, 33.4, 33.2, 24.6, 23.7, 21.4, 20.4, 18.5, 15.2 ppm; HRMS
(ESI): m/z calcd. for C21H30O3Na [M + Na]+ 353.2087; found 353.2082.
Compound 33. IR (film): νmax = 2993, 2926, 2853, 1492, 1463, 1278,
1
1220, 1178, 1050, 1028, 908, 802, 732 cm-1; H NMR (400 MHz, CDCl3):
δ = 6.75−6.71 (d, 3H), 6.26 (s, 1H), 5.59 (s, 1H), 3.77 (s, 3H), 3.74 (s,
3H), 2.27 (d, J = 18.5 Hz, 1H), 2.09−2.03 (m, 1H), 1.90−1.85 (m, 1H),
1.70−1.55 (m, 3H), 1.49 (s, 3H), 1.45 (d, J = 12.9 Hz, 1H), 1.26−1.14 (m,
2H), 1.05 (s, 3H), 0.96 (s, 3H), 0.88 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 153.0, 151.8, 151.3, 131.4, 130.6, 128.6, 117.3, 115.7, 112.0,
111.3, 56.2, 55.7, 48.1, 42.3, 38.7, 38.0, 33.8, 32.5, 25.2, 22.9, 21.8,
19.5, 19.2 ppm; HRMS (ESI): m/z calcd. for C23H30O2Na [M + Na]+
361.2138; found 361.2133.
(+)-Yahazunol (6). To a solution of 7 (10 mg, 0.03 mmol) and TBAB (2
mg, 0.006 mmol) in THF (1 mL) was dropwised a solution of Na2S2O4 (16
mg, 0.09 mmol) in water (1 mL) at room temperature and the mixture so
obtained was stirred for 1 hour before it was diluted with water (3 mL)
and extracted with EtOAc (3 × 5 mL). The combined organic phases
were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under vacuum. The residue was purified by flash
column chromatography over silica gel (100–200 mesh) with
EtOAc/petroleum ether (1:20 → 1:10) to afford 6 (8 mg, 85 %) as a white
solid. M.p.: 142−143 °C ; IR (film): νmax = 3362, 3259, 2920, 2850, 1712,
1645, 1504, 1456, 1389, 1232, 1096, 872, 801, 671 cm-1; 1H NMR (400
MHz, CDCl3): δ = 8.75 (d, J = 3.7 Hz, 1H, OH), 7.43 (s, 1H, OH), 6.65 (d,
J = 2.7 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 6.48 (dd, J = 8.6, 2.8 Hz, 1H),
4.86 (d, J = 10.5 Hz, 1H, OH), 2.87 – 2.82 (m, 1H), 2.39 (dd, J = 14.9, 6.1
Hz, 1H), 1.92 (td, J = 12.4, 3.2 Hz, 1H), 1.86-1.81 (m, 2H), 1.70−1.64 (m,
2H), 1.61−1.54 (m, 3H), 1.38−1.30 (m, 3H), 1.29 (s, 3H), 1.10 (td, J =
13.7, 4.4 Hz, 1H), 0.97 (s, 3H), 0.93 (dd, J = 11.5, 2.4 Hz, 1H), 0.86 (s,
3H), 0.82 (s, 3H), 0.72 (dt, J = 13.1, 3.5 Hz, 1H) ppm; 13C NMR (100
MHz, CDCl3): δ = 150.3, 149.6, 131.0, 118.8, 117.4, 114.2, 75.0, 62.2,
56.8, 44.4, 42.4, 41.3, 40.5, 33.7, 33.7, 27.8, 24.5, 21.7, 21.1, 18.9, 15.8
ppm; HRMS (ESI): m/z calcd. for C21H32O3Na [M + Na]+ 355.2244; found
355.2240.
Compound 34: IR (film): νmax = 2923, 1654, 1598, 1458, 1375,
1301,1056, 914, 897 cm-1; 1H NMR (400 MHz, CDCl3): δ = 6.77 (d, J =
10.0 Hz, 1H), 6.70 (d, J = 10.2 Hz, 1H), 6.41 (s, 1H), 3.20 (d, J = 20.0 Hz,
1H), 3.04 (d, J = 20.0 Hz, 1H), 2.11 (dd, J = 10.7, 7.5 Hz, 1H), 2.04 (dd, J
= 17.7, 6.3 Hz, 1H), 1.71 (dd, J = 12.9, 7.0 Hz, 1H), 1.63−1.54 (m, 2H),
1.49 (dd, J = 11.2, 4.2 Hz, 2H), 1.43 (s, 3H), 1.36 (d, J = 11.0 Hz, 2H),
1.17 (d, J = 12.5 Hz, 1H), 1.06 (dd, J = 14.1, 4.0 Hz, 1H), 0.96 (s, 3H),
0.89 (s, 3H), 0.82 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.2,
187.8, 148.7, 136.8, 136.3, 134.5, 132.7, 130.6, 51.8, 41.4, 38.7, 36.1,
33.3, 33.2, 33.1, 26.8, 21.6, 20.0, 19.9, 18.8, 18.7 ppm; HRMS (ESI): m/z
calcd. for C21H29O2 [M + H]+ 313.2162; found 313.2156.
Compound 35. To a solution of 34 (156 mg, 0.5 mmol) and TBAB (32
mg, 0.1 mmol) in THF (5 mL) was dropwised a solution of Na2S2O4 (261
mg, 1.5 mmol) in water (5 mL) at room temperature and the mixture so
obtained was stirred for 1.5 hours before it was diluted with water (5 mL)
and extracted with EtOAc (3 × 10 mL). The combined organic phases
were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under vacuum to afford 35 as a colorless foam and
used directly without further purification.
(+)-Chromazonarol (4). To a solution of 35 obtained above in DCM (5
mL) was dropwised BF3-OEt2 (164 μL, 47 w%, 1.25 mmol) at room
temperature and the mixture so obtained was stirred for 1 hour before it
was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic phases were washed with brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under vacuum. The
residue was purified by flash column chromatography over silica gel
(100–200 mesh) with EtOAc/petroleum ether (1:20 → 1:10) to afford
compound 4 (129 mg, 82 %) as a colorless oil. IR (film): νmax = 3374,
2927, 2866, 1493, 1455, 1377, 1261, 1232, 1127, 1080, 937, 906, 807,
792, 733 cm-1; 1H NMR (400 MHz, CDCl3): δ = 6.62 (d, J = 8.0 Hz, 1H),
6.58−6.53 (m, 2H), 4.72 (s, br, 1H), 2.57 (d, J = 8.0 Hz, 2H), 2.04 (d, J =
12.0 Hz, 1H), 1.75 (d, J = 14.4 Hz, 1H), 1.70−1.65 (m, 2H), 1.63−1.58 (m,
2H), 1.45 (d, J = 20.1 Hz, 1H), 1.39−1.30 (m, 2H), 1.20–1.13 (m, 4 H (s
at 1.17)), 1.02 (d, J = 12.1 Hz, 1H), 0.93 (d, J = 11.5 Hz, 1H), 0.90 (s, 3H),
0.87 (s, 3H), 0.84 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 148.5,
147.1, 123.2, 117.4, 115.7, 114.2, 76.8, 56.1, 52.0, 41.8, 41.1, 39.2, 36.7,
Acknowledgements
This project was supported by the National Science Foundation
of China (Grant No. 21672046, 21372054, and 21272046),
and the Fundamental Research Funds for the Central Univercitie
s (Grant No. HIT.NSRIF. 201701).
Keywords: Synthesis • natural products • meroterpenoids • (+)-
8-epi-puupehedione• palladium-catalyzed
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10.1002/ejoc.201800026
European Journal of Organic Chemistry
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Divergent synthesis of (+)-8-epi-
puupehedione, (+)-chromazonarol,
(+)-yahazunol and (+)-yahazunone
with the use of a palladium-catalyzed
tandem carbene migratory insertion of
an aryl iodine and a drimanal
hydrazone, a highly regioselective
reduction of enols, an oxa-Stork-
Danheiser transposition reaction, an
electrocyclization cyclization of a
conjugated tetraenone, and a redox
reaction of dimethoxybenzenes as the
key steps.
Hong-Shuang Wang, Hui-Jing Li,* Zhen-
Guo Zhang, and Yan-Chao Wu*
Page No. – Page No.
Divergent Synthesis of Bioactive
Marine Meroterpenoids via Palladium-
Catalyzed Tandem Carbene Migratory
Insertion
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