Total Synthesis of Catunaregin and Preliminary Evaluation of Its Antitumor Activity

Article abstract of DOI:10.1002/ejoc.201800219

The total synthesis of catunaregin in both racemic and optically active forms was accomplished. The enantioselective synthesis uses the Evans aldol strategy, with an oxazolidinone or thiazolidinethione as the chiral auxiliary. The key features include a syn-selective aldol reaction to form the Evans-syn or non-Evans-syn product, and a successive ketalization reaction of a furanyl diol derivative under acidic conditions. The biological properties of the synthetic racemate and both enantiomers were evaluated against A549 and HL-60 human cancer cells.

Full text of DOI:10.1002/ejoc.201800219

A Journal of
Accepted Article
Title: Total Synthesis of Catunaregin and Preliminary Evaluation of its
Antitumor Activity
Authors: Hideki Abe, Takuma Hikichi, Kosuke Emori, Akihito Yokosuka,
Yoshihiro Mimaki, Toyoharu Kobayashi, and Hisanaka Ito
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800219
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800219
Supported by

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
Total Synthesis of Catunaregin and Preliminary Evaluation of its
Antitumor Activity
Hideki Abe*[a,b], Takuma Hikichi[a], Kosuke Emori[a], Akihito Yokosuka[c], Yoshihiro Mimaki[c], Toyoharu
Kobayashi[a], and Hisanaka Ito*[a]
Abstract: Total synthesis of catunaregin in both racemic and
optically active forms was accomplished. This enantioselective
synthesis employs Evans aldol methodology using oxazolidinone or
thiazolidinethione as the chiral auxiliary. The key features include a
syn selective aldol reaction to form the Evans-syn or Non-Evans-syn
product, and successive ketalization of a furanyl diol derivative under
acidic conditions. The biological properties of the synthetic racemate
and both enantiomers were evaluated against A549 and HL-60
human cancer cells.
Herein, we describe in detail the stereoselective synthesis of (±)-
catunaregin and the asymmetric synthesis of (+)- and (–)-
catunaregin, which include a syn selective aldol reaction and
construction of the oxygen-bridged furopyran skeleton by
successive ketalization. In addition, their cytotoxic activities
against human non-small cell lung cancer A549 cells and human
promyelocytic leukemia HL-60 cells were investigated.
OMe
OH
OMe
OH
Me
O
Me
O
O
O
Me
Me
O
O
H
H
Introduction
catunaregin (1)
epicatunaregin (2)
The mangrove plant is a rich source for biologically active
natural products.[1] Many kinds of natural products, alkaloids,
flavonoids, lignans, limonoids, and terpenoids, have been
isolated from mangrove plants and mangrove-associated fungi
or bacteria.[2] In 2010, Zhang and co-workers reported two
Figure 1. Structures of catunaregin (1) and epicatunaregin (2).
Results and Discussion
unprecedented
norneolignans,
catunaregin
(1)
and
The synthetic strategy for both enantiomers of novel tricyclic
norneolignan 1 is outlined in Scheme 1. The target norneolignan
(+)-1 or (–)-1 could be obtained by the construction of the
tricyclic skeleton 7 by successive ketalization of furanyl diol
derivatives, which would be obtained by reductive cleavage of
the chiral auxiliary of aldol products 6 or 8, respectively, followed
by removal of the protecting group of the phenolic hydroxyl
group. The aldol product 6 would be produced by syn selective
aldol reaction with vanillin derivative 5 and the furan derivative 3
with the 4-benzyloxazolidinone tether as a chiral auxiliary. On
the other hand, the aldol product 8 would be obtained as the
epicatunaregin (2), isolated from the stem bark of Catunaregam
spinosa Tirveng, a Chinese mangrove associate (Figure 1).[3a]
They were found to exhibit inhibition against mammary cancer
F10 cell lines. In an additional report, Luo and Yao described
that catunaregin (1) inhibited different VEGF‐induced angiogenic
phenotypes of HUVECs in vitro and vessel formation in
transgenic zebrafish.[3b] The optical rotation value of the natural
catunaregin (1) is very low {[α]D20 = +1.4 (c 0.8, MeOH)}, leading
Zhang to surmise that the natural catunaregin is virtually
racemic as a result of its biosynthetic pathway, which includes
the production of benzofuran norneolignans with no
enantioselective reduction. The structural features and biological
properties of 1 attracted our attention, and we began a synthetic
study of the unique norneolignan 1 in optically pure form. Very
recently, we reported the total synthesis of (+)-catunaregin (1) in
enantiomerically pure form using the Evans aldol strategy.[4]
Non-Evans-syn
product
by
aldol
reaction
between
thiazolidinethione derivative 4 and vanillin derivative 5.
O
OH
Ar
Xc*
O
O
1) reduction
Evans-syn
Ar
O
2) successive
ketalization
from 3: X = O
H
(+)-7
O
[a]
[b]
[c]
Dr. H. Abe, T. Hikichi, K. Emori, Dr. T. Kobayashi, and Prof. H. Ito
School of Life Sciences
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: itohisa@toyaku.ac.jp; URL: http://www.ls.toyaku.ac.jp/~lbc-
11/pg121.html
Dr. H. Abe (current address)
Department of Chemical and Biological Sciences, Faculty of
Science
O
X
O
6
OMe
X
N
(+)-1
(–)-1
Ar-CHO 5: Ar =
OH
Ar
Oo-Ns
Bn
3: X = O
4: X = S
O
Xc*
O
O
1) reduction
Non-Evans-syn
Ar
O
Japan Women’s University
2) successive
ketalization
from 4: X = S
2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681, Japan
E-mail: abehi@fc.jwu.ac.jp; URL: http://mcm-www.jwu.ac.jp/~abeh/
Dr. A. Yokosuka, and Prof. Y. Mimaki
H
O
(–)-7
8
School of Pharmacy
Scheme 1. Synthetic strategy for the optically active catunaregin (1).
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
Our investigation started from the synthesis of (±)-catunaregin in
order to study the successive ketalization, which is an important
key step in this project (Scheme 1). The furan derivative 12 was
synthesized from tert-butyl acetoacetate (9) in three steps
according to the reported procedure.[5] Results of the aldol
reaction of the furan derivative 12 with O-o-nitrobenzenesulfonyl
(Ns)[6] vanillin derivative 5 are shown in Table 1. Aldol reactions
via lithium or sodium enolate intermediates using LHMDS or
NHMDS as bases gave a mixture of syn- and anti-adducts 13
and 14 in moderate yield (entries 1 and 2). However the desired
syn-adduct 13 was obtained in low yield or as the minor product.
On the other hand, reaction via the borane enolate with a
combination of di-n-butylboryl trifluoromethanesulfonate and
diisopropyl(ethyl)amine afforded the syn-adduct 13 in 87% yield
with high selectivity. Although the relative configuration of these
aldol adducts were not determined at this stage, they were
Table 1. Aldol reaction of the furan derivative 12 and O-o-Ns-vanillin
derivative 5.
yield (%)[a]
entry
conditions
13
25
15
87
14
23
46
4
1
2
3
LHMDS, THF, –78 °C, 1 h
NHMDS, THF, –78 °C, 2 h
n-Bu2BOTf, i-Pr2NEt, THF, –78 °C, 2 h
[a] Isolated yields.
assigned by X-ray crystallography of the acetonide derivatives
16,[7] derived in a two-step operation including reduction of the
ester moiety, followed by protection of the resulting 1,3-diol as
an acetonide group.
With the desired diol 15 in hand, our investigation advanced to
the main stage of this synthetic study. Construction of the
tricyclic skeleton of catunaregin 1 by successive ketalization of
the furanyl diol derivative was attempt as shown in Table 2. First,
the ketalization reaction under aqueous conditions was carried
out (entries 1–4). Although the reaction using of acetic acid as a
Brønsted acid at room temperature did not proceeded, the
Table 2. The successive ketalization of the furanyl diol derivative 15.
OH
OMe
OMe
Table 2
O
O
HO
OR
O
Oo-Ns
H
O
(±)-7: R = o-Ns
15
PhSH, Cs2CO3
MeCN, rt, 2 h
(quant.)
(±)-1: R = H
[(±)-catunaregin]
entry
1
conditions
AcOH, H2O, rt, 144 h
yield (%)[a] [brsm] [b]
n.r.
30 [39]
trace
12
2
AcOH, H2O, 80 °C, 48 h
3
EtCO2H, H2O, 80 °C, 48 h
4
CF3CO2H, H2O, 80 °C, 18 h
5
CF3CO2H, CH2Cl2, rt, 14 h
59
6
AcOH, CH2Cl2, rt, 144 h
n.r.
7
conc. H2SO4 (10 equiv.), THF, rt, 48 h
MeSO3H (10 equiv.), MeOH, rt, 96 h
TsOH·H2O (10 equiv.), CH2Cl2, rt, 42 h
MeSO3H (10 equiv.), CH2Cl2, rt, 1 h
MeSO3H (1.0 equiv.), CH2Cl2, rt, 1 h
68
8
64
9
quant.
83
10
11
quant.
[a] Isolated yields. [b] Based on recovered starting material.
Scheme 2. Synthesis of the syn-adduct 13 and its acetonide derivative 16.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
heated condition in presence of acetic acid afforded the desired
product in 30% yield along with small amount of diol 15 (entry 2).
When the use of propionic acid, which is a weaker acid than
acetic acid at 80 °C, a trace amount of the tricyclic compound
in Scheme 4. The syn selective Evans aldol reaction[9] of 3 with
O-o-Ns-vanillin
derivative
5
using
di-n-butylboryl
trifluoromethanesulfonate and diisopropyl(ethyl)amine gave the
desired Evans-syn product 6 exclusively in 98% yield. The
was detected in 1H NMR spectrum of the crude product (entry 3). absolute stereochemistry at C1 of 6 was determined by the
Treatment with trifluoroacetic acid, stronger acid than acetic acid
yielded the compound 7 in 12% yield along with the complex
mixture (entry 4). In absence of water, compound 7 was
obtained in good yield (entries 5, 7–11) except in the case of
acetic acid (entry 6). Treatment of 15 with concentrated sulfuric
acid in THF afforded 7 in 68% yield.[8] It was found that
methanesulfonic acid and p-toluenesulfonic acid were the best
acid reagents in this ketalization reaction. The reaction
conditions using methanesulfonic acid (1.0 equiv.) in CH2Cl2 at
room temperature for 1 h gave the desired tricyclic compound 7
in quantitative yield (entry 11). Finally, removal of the o-Ns group
of (±)-7 by treatment with thiophenol and cesium carbonate[6]
gave the target compound 1 in quantitative yield. The NMR, IR
and mass spectral data of the synthetic sample were identical to
those of natural catunaregin.
improved Mosher’s method.[11] Thus, the alcohol
6 was
transformed with (R)- and (S)-MTPA chlorides to (S)- and (R)-
1
MTPA esters 18 and 19, respectively. From H NMR spectral
analysis, the absolute configuration at the C1 asymmetric
carbon was determined as S.[12]
n-Bu2BOTf
i-Pr2NEt
OHC
OMe
O
O
OH
O
O
O
Oo-Ns
OMe
1
O
N
5
O
N
CH2Cl2
Oo-Ns
Bn
–78 °C, 3 h
Bn
O
(98%, d.r. > 95:5)
3
6
With the establishment of the synthetic route of (±)-catunaregin
by successive ketalization, we focused our efforts on the
asymmetric synthesis of catunaregin in enantiomerically pure
form. For the Evans aldol methodology,[9] introduction of the
chiral auxiliary to the furan derivative was carried out as shown
in Scheme 3. Installation of the (S)-4-benzyloxazolidinone group
as the chiral auxiliary was achieved by a three-step operation:
saponification of methyl ester 12 to give carboxylic acid 17,[10]
and transformation of the carboxylic acid to the mixed anhydride,
followed by addition of the lithiated oxazolidinone to afford 3 in
93% yield. On the other hand, the thiazolidinethione derivative 4
was obtained by condensation of carboxylic acid 17 and (S)-4-
a) (R)-MTPACl
pyridine, CH2Cl2
rt, 5 h (77% for 18)
O
O
OR
OMe
Oo-Ns
O
N
b) (S)-MTPACl
pyridine, CH2Cl2
rt, 5 h (93% for 19)
Bn
O
18: R = (S)-MTPA
19: R = (R)-MTPA
Scheme 4. Synthesis of the Evans-syn-product 6 and its MTPA esters for
determination of the absolute configuration.
Although direct removal of the chiral oxazolidinone auxiliary of 6
by reduction was carried out, all attempts for a retro aldol
reaction caused by the naked hydroxyl group at the benzylic
position of 6 failed. Thus, after treatment of 6 with TESOTf and
benzylthiazolidinethione
using
1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC) in high yield.
CO2H
CO2Me
3 M NaOH
MeOH
rt, 2 h
(98%)
O
O
O
OH
O
OTES
TESOTf
DBU
O
O
OMe
OMe
12
17
O
N
O
N
CH2Cl2
Oo-Ns
Oo-Ns
Bn
Bn
a) PivCl, Et3N, THF
–78 °C to 0 °C, 1 h
then
–50 °C, 20 h
(90%)
O
O
6
20
(S)-4-benzyloxazolidinone
n-BuLi, THF
–78 °C to 0 °C, 1 h (93% for 3)
O
OTES
X
O
OMe
LiBH4
MeSO3H
HO
X
N
b) (S)-4-benzylthiazolidinethione
EDC, DMAP, CH2Cl2
rt, 24 h (quant. for 4)
THF–EtOH (1:1)
rt, 2 h
CH2Cl2
rt, 1 h
(76%)
Oo-Ns
Bn
O
3: X = O
4: X = S
(83%)
(–)-21
PhSH
OMe
OH
OMe
Scheme 3. Installation of chiral auxiliaries to carboxylic acid 17.
Cs2CO3
O
O
O
O
Oo-Ns
O
O
MeCN
rt, 2 h
H
H
Having the desired furan derivatives with tethered chiral
auxiliaries in hand, the asymmetric synthesis of catunaregin
using the oxazolidinone derivative 3[4] was worked out as shown
(+)-1
(+)-7
(quant.)
Scheme 5. Synthesis of (+)-catunaregin [(+)-1].
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
DBU at –50 °C, hydride reduction of the resulting TES ether 20
with LiBH4 under mild conditions gave the primary alcohol (–)-21, the synthetic sample {[α]D –38.6 (c 1.00, MeOH)} derived from
previously synthesized (+)-1.[4] In addition, the optical rotation of
25
the precursor to successive ketalization, in 75% yield over 2
steps (Scheme 5). Treatment of 21 with methanesulfonic acid in
CH2Cl2 at room temperature for 1 h gave the desired tricyclic
compound (+)-7 in 76% yield. Finally, elimination of the o-
Nsgroup of 7 gave the target molecule 1 in quantitative yield.
The spectral data of the synthetic sample 1 was identical to
those of the reported natural catunaregin (1). The optical rotation
of the synthetic sample was [α]D +38.6 (c 1.00, MeOH). This
result confirms that natural catunaregin was isolated in the
racemic form as speculated by Zhang.
the Non-Evans-syn product 8 had the opposite rotation of
compound (+)-1 {[α]D +38.6 (c 1.00, MeOH)} synthesized from
the Evans-syn adduct 6. As a result, asymmetric total synthesis
of (+)/(–)-catunaregin was achieved by the Evans aldol strategy.
This is the first report of catunaregin in both enantiomerically
pure forms.
25
25
S
O
OTES
TESOTf
DBU
OMe
LiBH4
S
N
8
THF–EtOH (1:1)
rt, 1 h
CH2Cl2
–78 °C, 15 h
(86%)
Oo-Ns
Bn
With (+)-catunaregin [(+)-1] in enantiomerically pure form
synthesized, the asymmetric synthetic study using the
thiazolidinethione derivative 4 was undertaken. After many
attempts toward the syn selective aldol reaction of 4 with vanillin
O
(95%)
24
OTES
OMe
OR
OMe
MeSO3H
O
O
derivative
combination
5
to produce the Non-Evans-syn product, the
of titanium tetrachloride and
HO
O
CH2Cl2, rt, 1 h
(66%)
Oo-Ns
H
(–)-7: R = o-Ns
tetramethylethylenediamine gave the best result to afford the
desired aldol product 8 in 72% yield as the sole product. The
absolute configuration of the newly produced asymmetric carbon
of 8 was also assigned by the improved Mosher’s method.[11]
From the 1H NMR spectral analysis of (S)- and (R)-MTPA esters
22 and 23, prepared from (R)- and (S)-MTPA chlorides,
respectively, the absolute configuration at the C1 asymmetric
carbon was determined as R.[12]
O
(+)-21
PhSH, Cs2CO3
MeCN, rt, 2 h
(quant.)
(–)-1: R = H
Scheme 7. Synthesis of (–)-catunaregin [(–)-1].
Since racemic sample (±)-catunaregin and enantiomerically pure
samples (+)- and (–)-catunaregin were obtained by this synthetic
project, we were interested in their biological activities. To
explore new possibilities, the biological properties of our
synthetic samples were evaluated for their in vitro cytotoxic
activities against A549 human lung adenocarcinoma cells and
HL-60 human promyelocytic leukemia cells. Unfortunately, none
of the three synthetic compounds, (±)-1, (+)-1, and (–)-1
exhibited cytotoxic activities (> 30 µM) against these cell lines.
TiCl4, TMEDA
OHC
OMe
S
O
OH
O
S
O
Oo-Ns
OMe
1
5
S
N
S
N
CH2Cl2
Oo-Ns
Bn
–78 °C, 18 h
Bn
O
(72%, d.r. > 95:5)
4
8
This result is only
a part for the biological research of
catunaregin. As there is room for consideration using other cell
lines, these synthetic samples remain biological attractive.
a) (R)-MTPACl
pyridine, CH2Cl2
rt, 3 h (96% for 22)
S
O
OR
OMe
Oo-Ns
S
N
b) (S)-MTPACl
pyridine, CH2Cl2
rt, 3 h (95% for 23)
Bn
Conclusions
O
22: R = (S)-MTPA
23: R = (R)-MTPA
In summary, the total synthesis of catunaregin 1, isolated from
the stem bark of Catunaregam spinosa Tirveng, a Chinese
mangrove associate, was achieved. The key features include a
syn selective aldol reaction including Evans aldol methodology,
and successive ketalization of the furanyl alcohol derivative
under acidic conditions. This synthetic methodology led us to a
very concise total synthesis of the tricyclic natural product.
Further biological investigations of enantiomerically pure
catunaregin are now in progress in our laboratory.
Scheme 6. Synthesis of the Non-Evans-syn-product 8 and its MTPA esters to
determination for the absolute configuration.
After reductive cleavage of the chiral auxiliary of 8 in a two-step
procedure, protection of the secondary hydroxy group as a TES
ether, followed by hydride reduction of 24 with lithium
borohydride, the successive ketalization precursor (+)-21 was
afforded in 82% yield for the 2 steps. Subsequent successive
ketalization, and cleavage of the Ns group of the resulting
tricyclic compound (–)-7 afforded the desired product 1 in
moderate yield. All spectral data were identical with those of the
Experimental Section
General
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
All reactions involving air- and moisture-sensitive reagents were carried
out using standard syringe-septum cap techniques. Unless otherwise
noted, all solvents and reagents were obtained from commercial
suppliers and used without further purification. Routine monitoring of
reactions were carried out Merck silica gel 60 F254 TLC plates. Column
chromatography was performed on Kanto Chemical Silica Gel 60N
(spherical, neutral 60–230 µm) with the solvents indicated. Measurement
of optical rotations was performed with a JASCO P-2200 automatic
digital polarimeter. Melting points were taken on a Yanako MP-S3 micro
melting point apparatus and are uncorrected. 1H and 13C NMR spectra
were measured with a JASCO ECZ 400S (400 MHz) or a Burker AV-600
(600 MHz) spectrometer. Chemical shifts were expressed in ppm using
CHCl3 (7.26 ppm for 1H NMR, 77.0 ppm for 13C NMR) in CDCl3 as
internal standard. Infrared spectral measurements were carried out with a
JASCO FT/IR-4700 and only noteworthy absorptions were listed. HRMS
colorless liquid. Those spectra data were identified for those of previous
report.[4]
Methyl 2-(2,5-dimethylfuran-3-yl)acetate (12).
To a stirred solution of 11 (11.8 g, 41.2 mmol) in CH2Cl2 (140 mL) was
added trifluoroacetic acid (24.5 mL, 37.6 g, 330 mmol) at 0 °C. After
stirred for 18 h at room temperature, the mixture was concentrated in
vacuo. The resulting residue was purified by column chromatography
(hexane–AcOEt, 9:1) to afford 12 (4.30 g, 25.6 mmol, 62%) as a pale
yellow oil. Those spectra data were identified for those of previous
report.[4]
spectra were measured on
a Micromass LCT spectrometer. X-ray
crystallographic analysis was taken with Burker APEX2 Ultra TXS.
(2R*,3S*)-Methyl 2-(2,5-dimethylfuran-3-yl)-3-hydroxy-3-(3-methoxy-4-(2-
nitrophenylsulfonyloxy)phenyl)propanoate (13) and (2S*,3S*)-methyl 2-
(2,5-dimethylfuran-3-yl)-3-hydroxy-3-(3-methoxy-4-(2-
tert-Butyl 2-acetyl-4-oxopentanoate (10).
nitrophenylsulfonyloxy)phenyl)propanoate (14).
To a stirred suspension of sodium hydride (55% dispersion in mineral oil,
6.58 g, 157 mmol) in THF (400 mL) was added dropwise tert-butyl
acetoacetate (9) (20.0 mL, 19.1 g, 121 mmol) at 0°C. After stirred for 0.5
h at 0°C, to this reaction mixture was added dropwise α-chloroacetone
(12.5 mL, 14.5 g, 157 mmol) at 0 °C, and then stirred for 18 h at room
To a stirred solution of 12 (698 mg, 4.15 mmol) in CH2Cl2 (17 mL) were
added dropwise N,N-diisopropylethylamine (2.59 mL, 1.92 g, 14.8 mmol),
and di-n-butylboryl trifluoromethanesulfonate (1.0 M in CH2Cl2, 4.80 mL,
4.80 mmol) at 0 °C. After stirred for 30 min at 0 °C, to this mixtre was
added dropwise a solution of O-o-Ns-vanillin 5 (1.00 g, 2.96 mmol) in
CH2Cl2 (10 mL) at –78 °C. After stirred for 4 h at –78 °C, the reaction was
quenched with MeOH (5 mL) and saturated NH4Cl aqueous solution (15
mL) at –78 °C, and extracted with CHCl3 (2 × 50 mL). The combined
organic layers were washed with brine, and the washed solution was
dried over Na2SO4. The dried solution was filtered, and the filtrate was
concentrated in vacuo. The resulting residue was purified by column
chromatography (hexane–AcOEt, 2:1) to afford 13 (1.30 g, 2.57 mmol,
87%) as pale yellow amorphous solids and 14 (62.8 mg, 0.124 mmol,
4%) as pale yellow amorphous solids.
temperature. The reaction mixture was quenched with 1.0
M HCl
aqueous solution (100 mL) at 0 °C, and extracted with ether (2 × 300 mL).
The combined organic layers were washed with brine, and the washed
solution was dried over MgSO4. The dried solution was filtered and the
filtrate was concentrated in vacuo. The resulting residue was purified by
column chromatography (hexane–AcOEt, 7:1) to afford the intermediate
10 (19.5 g, 91.0 mmol, 75%) as a colorless liquid. Those spectra data
were identified for those of previous report.[4]
1-tert-Butyl 4-methyl 2-acetyl-2-(2-oxopropyl)succinate (11).
Data for 13
To a stirred suspension of sodium hydride (55% dispersion in mineral oil,
2.88 g, 65.8 mmol) in THF (170 mL) was added dropwise 10 (10.9 g,
50.9 mmol) at 0 °C. After stirred for 0.5 h at room temperature, to this
mixture was added dropwise methyl bromoacetate (5.30 mL, 8.56 g, 56.0
mmol) at 0 °C, and then stirred for 18 h at room temperature. The
reaction mixture was quenched with 1.0 M HCl aqueous solution (80 mL)
and extracted with Et2O (2 × 200 mL). The combined organic layers were
washed with brine, and the washed solution was dried over MgSO4. The
dried solution was filtered and the filtrate was concentrated in vacuo. The
resulting residue was purified by column chromatography (hexane–
AcOEt, 4:1) to afford the intermediate 11 (11.8 g, 41.2 mmol, 81%) as a
IR (neat) 3541, 3098, 3020, 2952, 2921, 2885, 2849, 1732, 1604, 1587,
1547, 1503, 1464, 1438, 1420, 1386, 1272, 1200, 1176, 1147, 1112,
1060, 1032, 1010, 925, 864, 853, 827, 758, 654, 591 cm–1; 1H NMR (400
MHz, CDCl3) δ 8.00 (1H, dd, J = 8.0, 1.4 Hz), 7.87 (1H, dd, J = 7.8, 1.4
Hz), 7.81 (1H, ddd, J = 7.8, 7.8, 1.4 Hz), 7.70 (1H, ddd, J = 7.8, 7.8, 1.4
Hz), 7.13 (1H, d, J = 8.2 Hz), 6.82 (1H, dd, J = 8.2, 1.8 Hz), 6.75 (1H, d, J
= 1.8 Hz), 6.03 (1H, s), 5.17 (1H, d, J = 5.5 Hz), 3.63 (3H, s), 3.53 (1H, d,
J = 5.5 Hz), 3.48 (3H, s), 2.22 (3H, s), 1.85 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 173.2, 151.1, 149.8, 148.6, 148.3, 141.6, 137.5, 134.9, 131.8,
131.5, 129.9, 124.6, 123.6, 118.5, 112.3, 111.1, 106.6, 73.5, 55.5, 52.1,
49.9, 13.4, 10.9; HRMS (ESI–TOF) calcd for C23H23NO10SNa ([M + Na]+)
528.0940, found 528.0945.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
Data for 14
triethylamine, and the mixture was concentrated in vacuo. The resulting
residue purified by column chromatography (hexane–AcOEt, 3:2) to
afford 16 (66.3 mg, 0.128 mmol, 87%) as colorless needles.
IR (neat) 3548, 3489, 3099, 3022, 2952, 2922, 2849, 1736, 1604, 1547,
1503, 1386, 1269, 1200, 1112, 1059, 1031, 853, 758, 591 cm–1; 1H NMR
(400 MHz, CDCl3) δ 7.96 (1H, dd, J = 7.8, 1.4 Hz), 7.86 (1H, d, J = 7.8
Hz), 7.81 (1H, ddd, J = 7.5, 7.5, 1.4 Hz), 7.69 (1H, ddd, J = 7.7, 7.7, 1.5
Hz), 7.04 (1H, dd, J = 8.5, 2.1 Hz), 6.71 (1H, d, J = 9.1 Hz), 6.66 (3H, d, J
= 1.8 Hz), 2.16 (3H, s), 1.66 (3H, s); 13C NMR (100 MHz, CDCl3) δ 173.7,
150.9, 149.9, 148.4, 147.8, 141.8, 137.6, 134.8, 131.8, 131.5, 130.1,
124.7, 123.6, 118.7, 113.5, 111.0, 105.5, 74.9, 55.6, 52.3, 50.9, 13.4,
10.7; HRMS (ESI–TOF) calcd for C23H23NO10SNa ([M + Na]+) 528.0940,
found 528.0939.
Mp. 176-179 ºC (AcOEt); IR (KBr) 3568, 3456, 3097, 2994, 2941, 2920,
2876, 1605, 1579, 1547, 1503, 1465, 1442, 1419, 1383, 1261, 1235,
1217, 1200, 1181, 1150, 1112, 1086, 1062, 1034, 1020, 854, 822, 783,
758, 593, 541 cm–1 1H NMR (400 MHz, CDCl3) δ 7.92 (1H, dd, J = 7.8,
;
1.4 Hz), 7.87 (1H, dd, J = 7.8, 1.4 Hz), 7.79 (1H, ddd, J = 7.8, 7.8, 1.4
Hz), 7.69 (1H, ddd, J = 7.8, 7.8, 1.4 Hz), 7.07 (1H, d, J = 8.7 Hz), 6.71
(1H, dd, J = 8.2, 1.8 Hz), 6.52 (1H, d, J = 1.8 Hz), 6.36 (1H, s), 5.23 (1H,
d, J = 3.2 Hz), 4.46 (1H, dd, J = 11.4, 3.2 Hz), 3.90 (1H, dd, J = 11.7, 1.1
Hz), 3.35 (3H, s), 2.51 (1H, ddd, J = 3.0, 3.0, 1.2 Hz), 2.18 (3H, d, J = 2.7
Hz), 1.62 (3H, s), 1.59 (3H, s), 1.50 (3H, s); 13C NMR (100 MHz, CDCl3)
δ 150.7, 148.3, 148.2, 146.6, 141.3, 137.1, 134.7, 131.8, 131.6, 130.0,
124.7, 123.2, 118.3, 116.6, 111.3, 108.8, 99.3, 73.5, 65.0, 55.3, 36.4,
29.7, 18.9, 13.4, 10.6; HRMS (ESI–TOF) calcd for C25H27NO9SNa ([M +
Na]+) 540.1304, found 540.1309.
4-((1S*,2R*)-2-(2,5-Dimethylfuran-3-yl)-1,3-dihydroxypropyl)-2-
methoxyphenyl 2-nitrobenzenesulfonate (15).
To a stirred suspension of LiAlH4 (7.51 mg, 0.198 mmol) in THF (2 mL)
was added a solution of 13 (50.0 mg, 0.0989 mmol) in THF (0.2 mL) at
0 °C. After stirred for 0.5 h at 0 °C, the reaction was quenched with
saturated potassium sodium tartrate aqueous solution (10 mL) at 0 °C,
and extracted with CHCl3 (3 × 50 mL). The combined organic layers were
washed with brine, and the washed solution was dried over MgSO4. The
dried solution was filtered and the filtrate was concentrated in vacuo. The
resulting residue was purified by column chromatography (hexane–
EtOAc, 1:11) to afford the intermediate 15 (31.6 mg, 0.0662 mmol, 67%)
as colorless gum.
4-((1R*,3S*,3aR*,6S*,7aR*)-1,6-Dimethylhexahydro-1H-1,6-
epoxyfuro[3,4-c]pyran-3-yl)-2-methoxyphenyl
2-nitrobenzenesulfonate
[(±)-7].
To a stirred solution of 15 (50.0 mg, 1.05 mmol) in CH2Cl2 (1 mL) was
added methanesulfonic acid (6.8 µL, 10.1 mg, 1.05 mmol) at room
temperature. After stirred for 1 h at the same temperature, the reaction
was quenched with sat. NaHCO3, and extracted with CH2Cl2. The
combined organic layers were washed with H2O, and dried over Na2SO4.
The dried solution was filtered, and the filtrate was concentrated in vacuo.
The resulting residue was purified by column chromatography (hexane–
AcOEt, 1:9) to afford (±)-7 (52.8 mg, 0.105 mmol, quant.) as colorless
amorphous solids.
IR (neat) 3558, 3399, 3099, 3008, 2921, 1717, 1604, 1546, 1502, 1465,
1419, 1384, 1271, 1199, 1175, 1110, 1059, 1031, 864, 853, 765 cm–1; 1H
NMR (400 MHz, CDCl3) δ 8.02 (1H, dd, J = 8.0, 1.1 Hz), 7.87 (1H, dd, J =
7.8, 1.4 Hz), 7.81 (1H, ddd, J = 7.8, 7.8, 1.2 Hz), 7.71 (1H, ddd, J = 7.7,
7.7, 1.2 Hz), 7.14 (1H, d, J = 8.2 Hz), 6.81 (1H, dd, J = 8.5, 1.2 Hz), 6.75
(1H, d, J = 1.8 Hz), 5.95 (1H, s), 4.92 (1H, d, J = 5.5 Hz), 3.75 (2H, d, J =
6.4 Hz), 3.50 (3H, s), 2.83 (1H, q, J = 6.1 Hz), 2.23 (3H, s), 1.88 (3H, s);
13C NMR (100 MHz, CDCl3) δ 151.1, 149.9, 148.3, 143.5, 137.3, 134.9,
131.8, 131.6, 130.0, 124.7, 123.6, 118.6, 114.8, 111.0, 106.1, 74.2, 63.9,
55.5, 46.1, 29.6, 13.5, 11.1; HRMS (ESI–TOF) calcd for C22H23NO9SNa
([M + Na]+) 500.0991, found 500.0995.
IR (neat) 3502, 3096, 2985, 2936, 2879, 2360, 2341, 1732, 1604, 1546,
1505, 1465, 1453, 1385, 1274, 1200, 1166, 1112, 1059, 1032, 942, 896,
;
852, 758, 592 cm–1 1H NMR (400 MHz, CDCl3) δ 8.02 (1H, dd, J = 8.0,
1.6 Hz), 7.87 (1H, d, J = 7.8 Hz), 7.82 (1H, ddd, J = 7.8, 7.8, 1.2 Hz),
7.71 (1H, ddd, J = 7.5, 7.5, 1.2 Hz), 7.15 (1H, dd, J = 8.7, 1.8 Hz), 6.86–
6.82 (2H, m), 4.97 (1H, d, J = 4.1 Hz), 3.76 (2H, d, J = 1.8 Hz), 3.56 (3H,
d, J = 0.9 Hz), 2.68 (1H, dd, J = 10.5, 3.7 Hz), 2.47 (1H, dddd, J = 10.2,
3.9, 2.0, 1.9 Hz), 2.26 (1H, d, J = 12.8 Hz), 1.88 (1H, dd, J = 12.6, 3.9
Hz), 1.60 (3H, s), 1.48 (3H, s); 13C NMR (100 MHz, CDCl3) δ 151.5, 148.3,
143.5, 137.5, 134.8, 131.9, 131.6, 130.1, 124.7, 124.3, 117.8, 115.5,
110.2, 106.1, 84.6, 62.9, 55.6, 48.0, 45.5, 33.2, 24.7, 22.5; HRMS (ESI–
TOF) calcd for C22H23NO9SNa ([M + Na]+) 500.0991, found 500.0989.
4-((4S*,5R*)-5-(2,5-Dimethylfuran-3-yl)-2,2-dimethyl-1,3-dioxan-4-yl)-2-
methoxyphenyl 2-nitrobenzenesulfonate (16).
To a stirred solution of 15 (70.0 mg, 0.147 mmol) in acetone (1.6 mL)
was added 2,2-dimethoxypropane (0.4 mL, 340 mg, 3.26 mmol) and p-
toluenesulfonic acid monohydrate (2.8 mg, 14.7 µmol) at room
temperature. After stirred for 0.5 h, the reaction was quenched with
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
4-((1R*,3S*,3aR*,6S*,7aR*)-1,6-Dimethylhexahydro-1H-1,6-
To a stirred solution of 17 (1.75 g, 11.4 mmol) and triethylamine (1.75 mL,
1.26 g, 12.6 mmol) in THF (38 mL) was added dropwise pivaloyl chloride
(1.54 mL, 1.51 g, 12.5 mmol) at –78 °C, and the reaction mixture was
stirred for 1 h at 0 °C. To this mixture was added dropwise a solution of
lithium (S)-4-benzyl-2-oxooxazolin-3-ide in THF (42 mL), prepared from
(S)-4-benzyloxazolidin-2-one (2.22 g, 12.5 mmol) and n-buthyllithium
(1.63 M in hexane, 7.69 mL, 12.5 mmol), at –78 °C. After stirred for 1 h at
0 °C, the reaction was quenched with saturated NH4Cl aqueous solution
(50 mL), and extracted with AcOEt (2 × 120 mL). The combined organic
layers were washed with brine, dried over MgSO4. The dried solution was
filtered, and the filtrate was concentrated in vacuo. The resulting residue
was purified by column chromatography (hexane–AcOEt, 4:1) to afford 3
(3.30 g, 10.5 mmol, 93%) as colorless oil.
epoxyfuro[3,4-c]pyran-3-yl)-2-methoxyphenol [(±)-catunaregin (1)].
To a stirred solution of (±)-7 (50.0 mg, 0.105 mmol) and cesium
carbonate (171 mg, 0.524 mmol) in MeCN (1 mL) was added dropwise
thiophenol (33 µL, 34.7 mg, 0.314 mmol) at 0 °C, and the mixture was
stirred for 2 h at room temperature. The reaction was quenched with
saturated NH4Cl aqueous solution, and the mixture was extracted with
AcOEt (2 × 30 mL). The combined organic layers were washed with brine,
dried over MgSO4. The dried solution was filtered, and the filtrate was
concentrated in vacuo. The resulting residue was purified by column
chromatography (hexane–AcOEt, 1:1) to afford (±)-1 (30.8 mg, 0.105
mmol, quant.) as colorless amorphous solids.
25
IR (neat) 3408, 2984, 2937, 2879, 1608, 1603, 1517, 1460, 1450, 1432,
1385, 1331, 1270, 1238, 1195, 1170, 1113, 1057, 1032, 942, 847, 819,
;
794, 762 cm–1 1H NMR (400 MHz, CDCl3) δ 6.86 (1H, d, J = 8.2 Hz),
[α]D +56.4 (c 1.00, CHCl3); IR (neat) 3029, 2981, 2921, 1781, 1701,
1584, 1454, 1390, 1356, 1211, 1197, 1111, 1052, 994, 762, 747, 703
cm–1; 1H NMR (400 MHz, CDCl3) δ 7.34–7.24 (3H, m), 7.19–7.16 (2H, m),
5.92 (1H, s), 4.70–4.64 (1H, m), 4.22 (1H, B part of ABX, J = 9.2, 7.6 Hz),
4.18 (1H, A part of ABX, J = 9.2, 3.2 Hz), 3.94 and 4.01 (2H, ABq, J =
17.0 Hz), 3.29 (1H, dd, J = 13.3, 3.2 Hz), 2.77 (1H, dd, J = 13.3, 9.6 Hz),
2.24 (3H, s), 2.23 (3H, s); 13C NMR (100 MHz, CDCl3) δ 171.0, 153.4,
149.6, 147.5, 135.1, 129.4 (2C), 128.9 (2C), 127.3, 111.4, 107.9, 66.1,
55.2, 37.7, 31.9, 13.4, 11.5; HRMS (ESI–TOF) calcd for C18H19NO4Na
([M + Na]+) 336.1212, found 336.1208.
6.81–6.77 (2H, m), 5.71 (1H, br s), 4.93 (1H, d, J = 4.1 Hz), 3.87 (3H, s),
3.76–3.73 (2H, m), 2.70 (1H, dd, J = 10.5, 4.1 Hz), 2.48 (1H, dddd, J =
10.5, 4.1, 1.8, 1.8 Hz), 2.25 (1H, d, J = 12.4 Hz), 1.88 (1H, dd, J = 12.4,
4.1 Hz), 1.60 (3H, s), 1.48 (3H, s); 13C NMR (100 MHz, CDCl3) δ 146.5,
145.1, 134.4, 118.7, 115.2, 114.4, 108.5, 105.9, 85.3, 62.9, 55.8, 47.7,
45.7, 33.2, 24.7, 22.5; HRMS (ESI–TOF) calcd for C16H20O5Na ([M +
Na]+) 315.1208, found 315.1207.
2-(2,5-Dimethylfuran-3-yl)acetic acid (17).
(S)-1-(4-Benzyl-2-thioxothiazolidin-3-yl)-2-(2,5-dimethylfuran-3-
yl)ethanone (4).
To a stirred solution of 12 (2.99 g, 17.8 mmol) in MeOH (35 mL) were
added 3.0 M NaOH aqueous solution (12.5 mL) at room temperature.
After stirred for 2 h at same temperature, the reaction was acidified by
adding 1.0 M HCl aqueous solution, and extracted with CHCl3 (3 × 150
mL). The combined organic layers were washed with brine, dried over
MgSO4. The dried solution was filtered, and the filtrate was concentrated
in vacuo. The resulting residue was purified by recrystallization (hexane)
to afford 17 (2.70 g, 17.5 mmol, 98%) as colorless needles.
To a stirred solution of 17 (376 mg, 2.39 mmol) in CH2Cl2 (6.25 mL) was
added (S)-4-benzylthiazolidine-2-thione (250 mg, 1.19 mmol), 1-ethyl-3-
(3-dimethylamiopropyl)carbodiimide hydrochloride salt (343 mg, 1.79
mmol) and 4-dimethylaminopyridine (7.3 mg, 0.0597 mmol) at 0 °C, and
the reaction mixture was stirred for 24 h at room temperature. The
reaction was quenched with 1.0 M HCl aqueous solution (10 mL), and
extracted with Et2O (2 × 50 mL). The combined organic layers were
washed with 3.0 M NaOH aqueous solution, brine, dried over Na2SO4.
The dried solution was filtered, and the filtrate was concentrated in vacuo.
The resulting residue was purified by column chromatography (hexane–
AcOEt, 4:1) to afford 4 (412 mg, 1.19 mmol, quant.) as colorless oil.
Mp: 52–54 °C (hexane); IR (KBr) 3407, 3104, 2985, 2949, 2924, 2676,
;
1713, 1586, 1434, 1415, 1229, 1099, 991, 926, 800 cm–1 1H NMR (400
MHz, CDCl3) δ 5.88 (1H, s), 3.34 (2H, s), 2.22 (3H, s), 2.20 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 178.2, 149.7, 147.2, 111.4, 107.7, 30.8, 13.4,
11.3; HRMS (ESI–TOF) calcd for C8H10O3Na ([M + Na]+) 177.0528,
found 177.0527; Anal. Calcd for C8H10O3: C, 62.33; H, 6.54. Found: C,
62.20, 6.51.
25
[α]D +56.4 (c 1.00, CHCl3); IR (neat) 3029, 2981, 2921, 1781, 1701,
1584, 1454, 1390, 1356, 1211, 1197, 1111, 1052, 994, 762, 747, 703
cm–1; 1H NMR (400 MHz, CDCl3) δ 7.34–7.24 (3H, m), 7.19–7.16 (2H, m),
5.92 (1H, s), 4.70–4.64 (1H, m), 4.22 (1H, A part of ABX, J = 9.2, 7.6 Hz),
4.18 (1H, B part of ABX, J = 9.2, 3.2 Hz), 4.01 and 3.94 (2H, ABq, J =
17.0 Hz), 3.29 (1H, dd, J = 13.3, 3.2 Hz), 2.77 (1H, dd, J = 13.3, 9.6 Hz),
2.24 (3H, s), 2.23 (3H, s); 13C NMR (100 MHz, CDCl3) δ 171.0, 153.4,
149.6, 147.5, 135.1, 129.4 (2C), 128.9 (2C), 127.3, 111.4, 107.9, 66.1,
(S)-4-Benzyl-3-[2-(2,5-dimethylfuran-3-yl)acetyl]oxazolidin-2-one (3).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
55.2, 37.7, 31.9, 13.4, 11.5; HRMS (ESI–TOF) calcd for C18H19NO4Na
([M + Na]+) 336.1212, found 336.1208.
chromatography (hexane–AcOEt, 2:1) to afford 18 (51.4 mg, 0.0593
mmol, 77%) as colorless amorphous solids.
20
[α]D –12.5 (c 0.34, CHCl3); IR (neat) 3430, 3027, 2950, 2922, 2849,
1774, 1752, 1696, 1638, 1606, 1546, 1502, 1452, 1389, 1362, 1271,
1255, 1201, 1182, 1113, 1022, 999, 863, 851, 760, 717 cm–1 1H NMR
;
4-[(1S,2S)-3-((S)-4-Benzyl-2-oxooxazolidin-3-yl)-2-(2,5-dimethylfuran-3-
yl)-1-hydroxy-3-oxopropyl]-2-methoxyphenyl 2-nitrobenzenesulfonate (6).
(600 MHz, CDCl3) δ 8.09 (1H, d, J = 7.9 Hz), 7.84–7.80 (1H, m), 7.79–
7.72 (2H, m), 7.39–7.35 (1H, m), 7.29–7.27 (2H, m), 7.23–7.20 (3H, m),
7.19–7.14 (3H, m), 7.07 (1H, dd, J = 8.4, 1.8 Hz), 7.02 (1H, d, J = 1.9 Hz),
6.97–6.92 (2H, m), 6.49 (1H, d, J = 10.0 Hz), 6.10 (1H, s), 5.65 (1H, d, J
= 10.0 Hz), 4.52–4.46 (1H, m), 4.08 (1H, A part of ABX, J = 9.0, 8.4 Hz),
4.02 (1H, B part of ABX, J = 9.0, 3.6 Hz), 3.54 (3H, s), 3.26 (3H, m), 2.95
(1H, dd, J = 13.6, 3.4 Hz), 2.68 (1H, dd, J = 13.6, 8.3 Hz), 2.25 (3H, s),
1.93 (3H, s); 13C NMR (150 MHz, CDCl3) δ 170.1, 165.5, 152.9, 151.6,
150.1, 149.9, 148.4, 138.4, 137.7, 135.0, 134.4, 132.0, 131.8, 131.5,
129.9, 129.42 (2C), 129.36, 128.7 (2C), 128.2 (2C), 127.3, 126.9 (2C),
124.4, 124.3, 123.2 (q, J = 288.7 Hz), 120.5, 112.64, 112.56, 105.8, 84.3
(q, J = 27.5 Hz), 77.04, 65.7, 55.7, 55.3, 54.5, 45.1, 37.1, 13.6, 11.2;
HRMS (ESI–TOF) calcd for C42H37F3N2O13SNa ([M + Na]+) 889.1866,
found 889.1856.
To a stirred solution of 4 (1.31 g, 4.18 mmol) in CH2Cl2 (14 mL) were
added dropwise N,N-diisopropylethylamine (0.981 mL, 0.728 g, 5.63
mmol), and di-n-butylboryl trifluoromethanesulfonate (1.0 M in CH2Cl2,
4.74 mL, 4.74 mmol) at 0 °C. After stirred for 45 min at 0 °C, to this
mixtre was added dropwise a solution of O-o-Ns-vanillin 5 (1.00 g, 2.96
mmol) in CH2Cl2 (10 mL) at –78 °C. After stirred for 2.5 h at –78 °C, the
reaction was quenched with MeOH (40 mL) and saturated NH4Cl
aqueous solution (40 mL) at –78 °C, and extracted with CHCl3 (2 × 200
mL). The combined organic layers were washed with brine, and the
washed solution was dried over Na2SO4. The dried solution was filtered,
and the filtrate was concentrated in vacuo. The resulting residue was
purified by column chromatography (hexane–AcOEt, 2:1) to afford 6
(1.89 g, 2.90 mmol, 98%) as colorless oil.
[α]D25 +4.7 (c 1.00, CHCl3); IR (neat) 3502, 3088, 2921, 2850, 1774, 1690,
1604, 1545, 1501, 1385, 1364, 1272, 1199, 1111, 1031, 864, 852, 760
cm–1; 1H NMR (400 MHz, CDCl3) δ 8.05–8.00 (1H, m), 7.85–7.76 (2H, m),
7.75–7.68 (1H, m), 7.29–7.22 (3H, m), 7.11 (1H, d, J = 8.4 Hz), 7.08–
7.01 (2H, m), 6.91–6.84 (2H, m), 6.13 (1H, s), 5.18 (1H, d, J = 6.8 Hz),
5.15 (1H, d, J = 6.8 Hz), 4.60–4.53 (1H, m), 4.12–4.02 (2H, m), 3.49 (3H,
s), 3.09 (1H, dd, J = 13.6, 3.2 Hz), 3.06–2.90 (1H, br s), 2.67 (1H, dd, J =
13.6, 9.2 Hz), 2.26 (3H, s), 2.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ
172.7, 152.7, 151.2, 150.2, 150.1, 148.3, 141.5, 137.7, 134.9, 134.6,
131.8, 131.6, 129.9, 129.4 (2C), 128.8 (2C), 127.3, 124.5, 123.7, 119.2,
112.1, 111.3, 106.4, 74.2, 65.8, 55.5, 54.7, 47.6, 37.3, 13.5, 11.3; HRMS
(ESI–TOF) calcd for C32H30N2O11SNa ([M + Na]+) 673.1468, found
673.1465.
(R)-(1S,2S)-3-((S)-4-Benzyl-2-oxooxazolidin-3-yl)-2-(2,5-dimethylfuran-3-
yl)-1-[3-methoxy-4-(2-nitrophenylsulfonyloxy)phenyl]-3-oxopropyl 3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate (19).
To a stirred solution of 6 (50.0 mg, 0.0768 mmol) in CH2Cl2 (1 mL) was
added pyridine (31.0 µL, 30.4 mg, 0.384 mmol), and (S)-(+)-α-methoxy-
α-trifluoromethylphenylacetyl chloride (28.8 µL, 38.8 mg, 0.154 mmol) in
0 °C. After stirred for 5 h at room temperature, the reaction was
quenched with saturated NH4Cl aqueous solution (3 mL), and extracted
with CHCl3 (3 × 10 mL). The combined organic layers were washed with
brine, dried over Na2SO4. The dried solution was filtered, and the filtrate
was concentrated in vacuo. The resulting residue was purified by column
chromatography (hexane–AcOEt, 2:1) to afford 19 (61.9 mg, 0.0714
mmol, 93%) as colorless amorphous solids.
20
(S)-(1S,2S)-3-[(S)-4-Benzyl-2-oxooxazolidin-3-yl]-2-(2,5-dimethylfuran-3-
yl)-1-[3-methoxy-4-(2-nitrophenylsulfonyloxy)phenyl]-3-oxopropyl 3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate (18).
[α]D +16.8 (c 0.62, CHCl3); IR (neat) 3432, 3026, 2950, 2923, 2850,
1775, 1753, 1696, 1637, 1606, 1546, 1502, 1452, 1389, 1365, 1270,
;
1255, 1202, 1182, 1113, 1030, 1000, 864, 851, 760 cm–1 1H NMR (600
MHz, CDCl3) δ 8.11–8.08 (1H, m), 7.84–7.80 (1H, m), 7.77–7.73 (2H, m),
7.37–7.33 (1H, m), 7.27–7.21 (5H, m), 7.12–7.06 (3H, m), 6.99–6.94 (3H,
m), 6.82 (1H, d, J = 1.9 Hz), 6.34 (1H, d, J = 10.2 Hz), 6.20 (1H, s), 5.66
(1H, d, J = 10.2 Hz), 4.51–4.46 (1H, m), 4.05 (1H, B part of ABX, J = 9.1,
8.3 Hz), 4.00 (1H, A part of ABX, J = 9.1, 3.0 Hz), 3.41 (3H, s), 3.26 (3H,
m), 2.98 (1H, dd, J = 13.6, 3.2 Hz), 2.69 (1H, dd, J = 13.6, 8.3 Hz), 2.28
(3H, s), 2.18 (3H, s); 13C NMR (150 MHz, CDCl3) δ 170.1, 165.3, 152.8,
151.4, 150.3, 150.1, 148.4, 138.3, 137.5, 134.9, 134.5, 131.84, 131.81,
131.6, 129.9, 129.5, 129.4 (2C), 128.8 (2C), 128.2 (2C), 127.3, 127.1
To a stirred solution of 6 (50.0 mg, 0.0768 mmol) in CH2Cl2 (1 mL) was
added pyridine (31.0 µL, 30.4 mg, 0.384 mmol), and (R)-(–)-α-methoxy-
α-trifluoromethylphenylacetyl chloride (28.8 µL, 38.8 mg, 0.154 mmol) in
0 °C. After stirred for 5 h at room temperature, the reaction was
quenched with saturated NH4Cl aqueous solution (3 mL), and extracted
with CHCl3 (3 × 10 mL). The combined organic layers were washed with
brine, dried over Na2SO4. The dried solution was filtered, and the filtrate
was concentrated in vacuo. The resulting residue was purified by column
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
(2C), 124.4, 124.1, 123.2 (q, J = 288.7 Hz), 120.7, 113.4, 112.0, 105.7,
84.5 (q, J = 27.5 Hz), 77.9, 65.7, 55.5, 55.1, 54.5, 45.3, 37.1, 13.6, 11.5;
HRMS (ESI–TOF) calcd for C42H37F3N2O13SNa ([M + Na]+) 889.1866,
found 889.1863.
washed with brine, dried over Na2SO4. The dried solution was filtered,
and the filtrate was concentrated in vacuo. The resulting residue was
purified by column chromatography (hexane–AcOEt, 2:1) to afford (–)-21
(64.5 mg, 0.109 mmol, 83%) as pale yellow oil.
[α]D25 –27.0 (c 0.3, CHCl3); IR (neat) 3582, 3419, 3098, 2955, 2914, 2877,
1732, 1604, 1548, 1500, 1464, 1417, 1387, 1282, 1266, 1200, 1148,
1
1111, 1007, 866, 851, 761, 741, 591 cm–1; H NMR (400 MHz, CDCl3) δ
4-[(1S,2S)-3-((S)-4-Benzyl-2-oxooxazolidin-3-yl)-2-(2,5-dimethylfuran-3-
yl)-3-oxo-1-(triethylsilyloxy)propyl]-2-methoxyphenyl
2-
7.97–7.94 (1H, m), 7.86–7.78 (2H, m), 7.70–7.65 (1H, m), 7.07 (1H, dd, J
= 8.2 Hz), 6.69 (1H, dd, J = 8.2, 1.8 Hz), 6.55 (1H, d, J = 1.8 Hz), 5.77
(1H, s), 4.93 (1H, d, J = 3.7 Hz), 3.84 (1H, dd, J = 10.5, 7.3 Hz), 3.70 (1H,
dd, J = 10.5, 7.3 Hz), 3.38 (3H, s), 2.77 (1H, ddd, J = 7.3, 7.3, 3.7 Hz),
2.18 (3H, s), 1.79 (1H, br s), 1.72 (3H, s), 0.87–0.82 (9H, m), 0.41–0.55
(6H, m),; 13C NMR (100 MHz, CDCl3) δ 150.7, 148.8, 148.5, 148.0, 144.2,
137.1, 134.7, 131.6 (2C), 130.0, 124.6, 123.3, 118.4, 115.1, 111.3, 106.8,
74.9, 63.7, 55.3, 46.9, 13.4, 10.9, 6.67 (3C), 4.65 (3C); HRMS (ESI–
TOF) calcd for C28H37NO9SSiNa ([M + Na]+) 614.1856, found 614.1860.
nitrobenzenesulfonate (20).
To a stirred solution of 6 (500 mg, 0.768 mmol) in CH2Cl2 (4 mL) were
added dropwise 1,8-diazabicyclo[5.4.0]undec-7-ene (0.689 mL, 703 mg,
4.62 mmol), and triethylsilyl trifluoromethanesulfonate (0.434 mL, 508 mg,
1.92 mmol) at –78 °C, and the mixture was stirred for 20 h at –50 °C. The
reaction was quenched with saturated NH4Cl aqueous solution (5 mL),
and extracted with CHCl3 (3 × 20 mL). The combined organic layers were
washed with brine, dried over Na2SO4. The dried solution was filtered,
and the filtrate was concentrated in vacuo. The resulting residue was
purified by column chromatography (hexane–AcOEt, 2:1) to afford 20
(527 mg, 0.689 mmol, 90%) as colorless gum.
4-((1R,3S,3aR,6S,7aR)-1,6-Dimethylhexahydro-1H-1,6-epoxyfuro[3,4-
c]pyran-3-yl)-2-methoxyphenyl 2-nitrobenzenesulfonate [(+)-7].
25
[α]D +10.9 (c 1.00, CHCl3); IR (neat) 3028, 2955, 2915, 2876, 2360,
2341, 1776, 1696, 1604, 1548, 1501, 1389, 1281, 1201, 1111, 1004, 891,
859, 655, 591 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J = 8.2 Hz),
7.84–7.77 (2H, m), 7.75–7.67 (1H, m), 7.30–7.20 (3H, m), 7.11–7.01 (3H,
m), 6.99 (1H, d, J = 1.4 Hz), 6.88 (1H, dd, J = 8.2, 1.8 Hz), 6.20 (1H, s),
5.25 (1H, d, J = 8.2 Hz), 5.00 (1H, d, J = 8.2 Hz), 4.42–4.36 (1H, m),
4.03–3.92 (2H, m), 3.50 (3H, s), 3.06 (1H, dd, J = 13.5, 3.0 Hz), 2.65 (1H,
dd, J = 13.5, 8.9 Hz), 2.25 (3H, s), 2.21 (3H, s), 0.71 (9H, t, J = 7.9 Hz),
0.34 (6H, q, J = 7.9 Hz); 13C NMR (100 MHz, CDCl3) δ 171.5, 152.9,
151.1, 149.3, 149.2, 148.4, 144.0, 137.4, 134.89, 134.87, 131.7, 131.5,
129.8, 129.4 (2C), 128.7 (2C), 127.2, 124.4, 123.4, 119.4, 114.4, 111.3,
106.7, 75.9, 65.6, 55.6, 54.9, 49.0, 37.3, 13.5, 11.6, 6.4 (3C), 4.5 (3C);
HRMS (ESI–TOF) calcd for C38H44N2O11SSiNa ([M + Na]+) 787.2333,
found 787.2331.
The title compound (+)-7 (30.8 mg, 0.0645 mmol, 76%) was obtained by
same procedue to (±)-7 with (–)-21 (50.0 mg, 0.0845 mmol) and
methanesulfonic acid (8.12 mg, 5.5 µL, 0.0845 mmol) as colorless
amorphous solids.
25
[α]D +33.3 (c 0.55, CHCl3); IR (neat) 3502, 3096, 2985, 2936, 2879,
2360, 2341, 1732, 1604, 1546, 1505, 1465, 1453, 1385, 1274, 1200,
;
1166, 1112, 1059, 1032, 942, 896, 852, 758, 592 cm–1 1H NMR (400
MHz, CDCl3) δ 8.03 (1H, d, J = 7.8 Hz), 7.88–7.85 (1H, m), 7.84–7.79
(1H, m), 7.74–7.68 (1H, m), 7.15 (1H, d, J = 8.7 Hz), 6.86–6.82 (2H, m),
4.98 (1H, d, J = 3.7 Hz), 3.78–3.75 (2H, m), 3.57 (3H, s), 2.68 (1H, dd, J
= 10.1, 3.7 Hz), 2.50–2.45 (1H, m), 2.26 (1H, d, J = 12.4 Hz), 1.88 (1H,
dd, J = 12.4, 4.1 Hz), 1.60 (3H, s), 1.48 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 151.5, 148.4, 143.5, 137.5, 134.8, 131.9, 131.6, 130.2, 124.7,
124.3, 117.8, 115.5, 110.2, 106.1, 84.6, 63.0, 55.6, 48.0, 45.5, 33.2, 24.7,
22.5; HRMS (ESI–TOF) calcd for C22H23NO9SNa ([M + Na]+) 500.0991,
found 500.0994.
4-[(1S,2R)-2-(2,5-Dimethylfuran-3-yl)-3-hydroxy-1-(triethylsilyloxy)propyl]-
2-methoxyphenyl 2-nitrobenzenesulfonate [(–)-21].
To a stirred suspension of lithium chloride (55.4 mg, 1.31 mmol) in THF–
EtOH (1:1, 2.6 mL) was added sodium borohydride (49.5 mg, 1.31 mmol)
at room temperature, and the mixture was stirred for 0.5 h at room
temperature. To this mixture was added dropwise a solution of 20 (100
mg, 0.131 mmol) in THF–EtOH (1:1, 1.3 mL) at room temperature, and
the mixture was stirred for 2 h at the same temperature. The reaction
was quenched with saturated NH4Cl aqueous solution (5 mL), and
extracted with CHCl3 (3 × 20 mL). The combined organic layers were
4-((1R,3S,3aR,6S,7aR)-1,6-Dimethylhexahydro-1H-1,6-epoxyfuro[3,4-
c]pyran-3-yl)-2-methoxyphenol [(+)-catunaregin (1)].
The title compound (+)-1 (22.6 mg, 0.0773 mmol, quant.) was obtained
by same procedue to (±)-1 with (+)-7 (37.0 mg, 0.0775 mmol) and
thiophenol (23.8 µL, 25.6 mg, 0.232 mmol) and cesium carbonate (126
mg, 0.387 mmol) as colorless amorphous solids.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
25
24
The title compound 22 (47.0 mg, 0.0523 mmol, 96%) was obtained by
same procedue to 18 with 8 (37.1 mg, 0.0543 mmol), pyridine (26.3 µL,
[α]D +38.5 (c 0.350, MeOH); [α]D +40.3 (c 0.405, CHCl3); IR (neat)
3408, 2984, 2937, 2879, 1608, 1603, 1517, 1460, 1450, 1432, 1385,
1331, 1270, 1238, 1195, 1170, 1113, 1057, 1032, 942, 847, 819, 794,
25.8
mg,
0.326
mmol),
and
(R)-(–)-α-methoxy-α-
762 cm–1 1H NMR (400 MHz, CDCl3) δ 6.90–6.86 (1H, m), 6.83–6.77
;
trifluoromethylphenylacetyl chloride (30.5 µL, 41.2 mg, 0.163 mmol) as
(2H, m), 5.60 (1H, s), 4.95 (1H, d, J = 4.1 Hz), 3.91 (3H, s), 3.73–3.78
(2H, m), 2.71 (1H, dd, J = 10.1, 3.7 Hz), 2.52–2.46 (1H, m), 2.26 (1H, d, J
pale yellow oil.
= 12.3 Hz), 1.88 (1H, dd, J = 12.3, 3.7 Hz), 1.60 (3H, s), 1.49 (3H, s); 13
C
[α]D25 +41.8 (c 1.0, CHCl3); IR (neat) 3088, 3064, 3028, 2980, 2949, 2923,
NMR (100 MHz, CDCl3) δ 146.5, 145.2, 134.4, 118.8, 115.3, 114.4, 108.6,
105.9, 85.3, 62.9, 55.9, 47.8, 45.7, 33.3, 24.8, 22.6; HRMS (ESI–TOF)
calcd for C16H20O5Na ([M + Na]+) 315.1208, found 315.1201.
2851, 1753, 1687, 1605, 1548, 1505, 1465, 1453, 1389, 1343, 1257,
1183, 1167, 1116, 1040, 1018, 1009, 866, 851, 823, 760, 703, 591 cm–1
;
1H NMR (400 MHz, CDCl3) δ 7.87–7.73 (3H, m), 7.54 (1H, ddd, J = 7.7,
7.5, 1.1 Hz), 7.39–7.23 (7H, m), 7.20–7.15 (2H, m), 7.13–7.05 (3H, m),
7.00 (1H, dd, J = 8.2, 1.8 Hz), 6.88 (1H, d, J = 1.8 Hz), 6.84 (1H, d, J =
9.6 Hz), 6.38 (1H, d, J = 9.6 Hz), 6.06 (1H, s), 5.19 (1H, ddd, J = 10.3,
6.7, 3.6 Hz), 3.43 (3H, s), 3.27 (3H, s), 3.17 (1H, dd, J = 11.7, 7.1 Hz),
2.73 (1H, dd, J = 11.0, 3.2 Hz), 2.65 (1H, dd, J = 13.3, 3.7 Hz), 2.24 (3H,
s), 2.08 (3H, s); 13C NMR (100 MHz, CDCl3) δ 201.6, 171.1, 165.4, 151.3,
150.4, 150.0, 148.3, 138.4, 137.1, 136.2, 134.8, 131.9, 131.8, 131.4,
129.9, 129.5, 129.3 (2C), 128.9 (2C), 128.2 (2C), 127.2, 127.1 (2C),
124.7, 123.7, 123.2 (q, J = 288.9 Hz), 121.3, 113.5, 112.6, 105.8, 84.5 (q,
J = 27.3 Hz), 78.4, 69.1, 55.5, 55.1, 45.1, 36.3, 31.1, 13.5, 12.1; 19F NMR
4-((1R,2R)-3-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-2-(2,5-dimethylfuran-
3-yl)-1-hydroxy-3-oxopropyl)-2-methoxyphenyl 2-nitrobenzenesulfonate
(8).
To a stirred solution of 4 (102.0 mg, 0.296 mmol) in CH2Cl2 (1.49 mL)
was added dropwise tetramethylethylenediamine (48.6 µL, 37.9 mg,
0.326 mmol) and a solution of titanium chloride (65.0 µL, 112 mg, 0.593
mmol) in CH2Cl2 (0.6 mL) at –78 °C. After stirred for 2 h at –78°C, to this
reaction mixture was added dropwise a solution of 5 (50.0 mg, 0.148
mmol) in CH2Cl2 (0.75 mL) at –78 °C. After stirred for 18 h at –78 °C, the
reaction was quenched by adding methanol (1 mL) and saturated NH4Cl
aqueous solution (3 mL), and extracted with CHCl3 (3 × 15 mL). The
combined organic layers were washed with brine, dried over Na2SO4.
The dried solution was filtered, and the filtrate was concentrated in vacuo.
The resulting residue was purified by column chromatography (hexane–
AcOEt, 2:1) to afford 8 (72.1 mg, 0.106 mmol, 72%) as colorless gum.
(376 MHz, CDCl3)
δ –7.34 (3F, s); HRMS (ESI–TOF) calcd for
C42H37F3N2O11S3Na ([M + Na]+) 921.1409, found 921.1429.
(R)-(1R,2R)-3-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-2-(2,5-
dimethylfuran-3-yl)-1-[3-methoxy-4-(2-nitrophenylsulfonyloxy)phenyl]-3-
oxopropyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (23).
The title compound 23 (46.8 mg, 0.0521 mmol, 95%) was obtained by
same procedue to 19 with 8 (37.3 mg, 0.0546 mmol), pyridine (26.5 µL,
25.9
mg,
0.328
mmol),
and
(S)-(–)-α-methoxy-α-
25
[α]D +31.9 (c 0.17, CHCl3); IR (neat) 3515, 3381, 3087, 3064, 3025,
trifluoromethylphenylacetyl chloride (30.7 µL, 41.4 mg, 0.164 mmol) as
2960, 2938, 2855, 1766, 1681, 1604, 1546, 1503, 1386, 1263, 1200,
;
1112, 1032, 861, 853, 755, 703, 590, 539 cm–1 1H NMR (400 MHz,
pale yellow oil.
[α]D25 +86.4 (c 1.0, CHCl3); IR (neat) 3097, 3064, 3028, 2984, 2950, 2923,
CDCl3) δ 7.96–7.76 (3H, m), 7.64 (1H, ddd, J = 7.7, 7.7, 1.5 Hz), 7.40–
7.24 (5H, m), 7.09 (1H, ddd, J = 8.2, 1.6, 1.6 Hz), 6.87 (1H, d, J = 8.2 Hz),
6.81 (2H, m), 6.17 (1H, q, J = 1.4 Hz), 5.95 (1H, s), 5.28 (1H, s), 5.27 (1H,
s), 3.47 (3H, d, J = 1.8 Hz), 3.23 (1H, dd, J = 11.3, 7.0 Hz), 3.11 (1H, dd,
J = 13.3, 2.7 Hz), 2.97 (1H, dd, J = 12.3, 11.4 Hz), 2.82 (1H, d, J = 11.4
Hz), 2.20 (3H, m), 1.74 (3H, s); 13C NMR (100 MHz, CDCl3) δ 201.7,
174.7, 151.2, 149.9, 149.8, 148.4, 141.4, 137.6, 136.2, 134.7, 131.8,
131.6, 130.1, 129.4 (2C), 128.9 (2C), 127.3, 124.7, 123.6, 119.1, 111.8,
111.5, 106.9, 73.8, 69.1, 55.6, 47.5, 36.6, 31.7, 13.5, 11.5; HRMS (ESI–
TOF) calcd for C32H30N2O9S3Na ([M + Na]+) 705.1011, found 705.1024.
2850, 1751, 1688, 1605, 1548, 1505, 1464, 1453, 1389, 1343, 1257,
1187, 1168, 1116, 1040, 1018, 999, 866, 851, 824, 759, 703, 591 cm–1
;
1H NMR (400 MHz, CDCl3) δ 7.85–7.73 (3H, m), 7.53 (1H, ddd, J = 7.7,
7.7, 1.1 Hz), 7.40–7.23 (7H, m), 7.22–7.09 (7H, m), 6.80 (1H, d, J = 9.6
Hz), 6.54 (1H, d, J = 9.1 Hz), 5.96 (1H, s), 5.15 (1H, ddd, J = 10.6, 7.0,
3.6 Hz), 3.55 (3H, s), 3.27 (3H, s), 3.15 (1H, dd, J = 11.7, 7.1 Hz), 2.80–
2.70 (1H, m), 2.65 (1H, dd, J = 13.3, 3.2 Hz), 2.21 (3H, s), 1.81 (3H, s);
13C NMR (100 MHz, CDCl3) δ 201.7, 171.1, 165.5, 151.5, 149.96, 149.94,
148.3, 138.5, 137.4, 136.2, 134.8, 132.1, 131.7, 131.4, 129.9, 129.34,
129.27 (2C), 128.9 (2C), 128.2 (2C), 127.2, 126.9 (2C), 124.7, 124.0,
122.8 (q, J = 288.9 Hz), 121.2, 113.0, 112.8, 105.7, 84.3 (q, J = 27.3 Hz),
77.6, 69.2, 55.8, 55.4, 44.9, 36.3, 31.1, 13.5, 11.8; 19F NMR (376 MHz,
CDCl3) δ –7.68 (3F, s); HRMS (ESI–TOF) calcd for C42H37F3N2O11S3Nas
([M + Na]+) 921.1409, found 921.1404.
(S)-(1R,2R)-3-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-2-(2,5-
dimethylfuran-3-yl)-1-[3-methoxy-4-(2-nitrophenylsulfonyloxy)phenyl]-3-
oxopropyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (22).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
4-((1R,2R)-3-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-2-(2,5-dimethylfuran-
111.3, 106.8, 74.9, 63.7, 55.4, 46.9, 13.4, 11.0, 6.7 (3C), 4.7 (3C). HRMS
(ESI–TOF) calcd for C28H37NO9SSiNa ([M + Na]+) 614.1856, found
614.1855.
3-yl)-3-oxo-1-(triethylsilyloxy)propyl)-2-methoxyphenyl
2-
nitrobenzenesulfonate (24).
To a stirred solution of 8 (34.5 mg, 0.0505 mmol) in CH2Cl2 (0.3 mL)
were added dropwise triethylsilyl trifluoromethanesulfonate (28.5 µL, 33.4
4-((1S,3R,3aS,6R,7aS)-1,6-Dimethylhexahydro-1H-1,6-epoxyfuro[3,4-
mg, 0.126 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (45.2 µL, 46.2
mg, 0.303 mmol) at –78 °C, and the mixture was stirred for 15 h at –
78 °C. The reaction was quenched with saturated NH4Cl aqueous
solution (5 mL), and extracted with CHCl3 (3 × 20 mL). The combined
organic layers were washed with brine, dried over Na2SO4. The dried
solution was filtered, and the filtrate was concentrated in vacuo. The
resulting residue was purified by column chromatography (hexane–
AcOEt, 2:1) to afford 24 (34.6 mg, 0.0434 mmol, 86%) as yellow needles.
c]pyran-3-yl)-2-methoxyphenyl 2-nitrobenzenesulfonate [(–)-7].
The title compound (–)-7 (26.6 mg, 0.0557 mmol, 66%) was obtained by
same procedue to (+)-7 from (+)-21 (50.0 mg, 0.0845 mmol) with
methanesulfonic acid (5.5 µl, 8.15 mg, 0.0845 mmol) in CH2Cl2 (1 mL) as
colorless amorphous solids.
25
[α]D –30.6 (c 1.00, CHCl3); IR (neat) 3502, 3096, 2985, 2936, 2879,
Mp: 131-133 ºC (Et2O); [α]D25 +93.2 (c 1.00, CHCl3); IR (KBr) 3087, 3064,
3027, 2954, 2914, 2876, 1688, 1604, 1548, 1501, 1463, 1389, 1343,
1256, 1200, 1162, 1112, 1099, 1036, 1007, 876, 851, 834, 752, 703, 590
2360, 2341, 1732, 1604, 1546, 1505, 1465, 1453, 1385, 1274, 1200,
;
1166, 1112, 1059, 1032, 942, 896, 852, 758, 592 cm–1 1H NMR (400
MHz, CDCl3) δ 8.03 (1H, dd, J = 8.0, 1.1 Hz), 7.86 (1H, dd, J = 8.2, 1.4
Hz), 7.81 (1H, ddd, J = 7.8, 7.8, 1.4 Hz), 7.71 (1H, ddd, J = 7.7, 7.5, 1.4
Hz, 1H), 7.15 (1H, d, J = 8.7 Hz), 6.87–6.82 (2H, m), 4.98 (1H, d, J = 3.7
Hz), 3.77 (2H, d, J = 2.3 Hz), 3.57 (3H, d, J = 5.5 Hz), 2.68 (1H, dd, J =
10.1, 3.7 Hz), 2.47 (1H, dddd, J = 10.2, 3.9, 2.0, 2.0 Hz), 2.26 (1H, d, J =
12.3 Hz), 1.87 (1H, dd, J = 12.6, 3.9 Hz), 1.60 (3H, s), 1.48 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 151.5, 148.4, 143.5, 137.5, 134.8, 131.9, 131.6,
130.2, 124.7, 124.3, 117.8, 115.5, 110.2, 106.0, 84.6, 62.9, 55.6, 48.0,
45.5, 33.2, 24.7, 22.5; HRMS (ESI–TOF) calcd for C22H23NO9SNa ([M +
Na]+) 500.0991, found 500.0990.
1
cm–1; H NMR (400 MHz, CDCl3) δ 7.82 (1H, dd, J = 8.0, 1.1 Hz), 7.78–
7.67 (2H, m), 7.48 (1H, ddd, J = 7.7, 7.7, 1.1 Hz), 7.36–7.23 (3H, m),
7.22–7.17 (2H, m), 7.07 (1H, d, J = 1.8 Hz), 7.02 (1H, d, J = 8.2 Hz), 6.95
(1H, dd, J = 8.2, 1.8 Hz), 6.48 (1H, d, J = 8.2 Hz), 6.07 (1H, s), 5.24 (1H,
ddd, J = 10.7, 7.2, 3.7 Hz), 5.08 (1H, d, J = 8.2 Hz), 3.51 (3H, s), 3.16
(1H, dd, J = 11.4, 7.3 Hz), 2.76–2.65 (2H, m), 2.58 (1H, dd, J = 13.3, 3.2
Hz), 2.22 (3H, s), 2.18 (3H, s), 0.75–0.66 (9H, m), 0.42–0.26 (6H, m); 13
C
NMR (100 MHz, CDCl3) δ 201.3, 172.4, 151.1, 149.5, 149.4, 148.4, 143.6,
137.6, 136.6, 134.6, 131.6, 131.5, 130.0, 129.3 (2C), 128.9 (2C), 127.1,
124.6, 123.3, 120.2, 114.7, 112.2, 106.5, 76.4, 68.9, 55.7, 48.6, 36.1,
30.8, 13.5, 12.3, 6.4 (3C), 4.5 (3C); HRMS (ESI–TOF) calcd for
C38H44N2O9S3SiNa ([M + Na]+) 819.1876, found 819.1878.
4-((1S,3R,3aS,6R,7aS)-1,6-Dimethylhexahydro-1H-1,6-epoxyfuro[3,4-
c]pyran-3-yl)-2-methoxyphenol [(–)-catunaregin (1)].
4-[(1R,2S)-2-(2,5-Dimethylfuran-3-yl)-3-hydroxy-1-(triethylsilyloxy)propyl]-
2-methoxyphenyl 2-nitrobenzenesulfonate [(+)-21].
The title compound (–)-1 (31.6 mg, 0.108 mmol, quant.) was obtained by
same procedue to (+)-1 with (–)-7 (51.7 mg, 0.108 mmol) and thiophenol
(33.2 µL, 35.8 mg, 0.325 mmol) and cesium carbonate (177 mg, 0.542
mmol) as colorless amorphous solids.
The title compound (+)-21 (120 mg, 0.203 mmol, 95%) was obtained by
same procedue to (–)-21 from 24 (170 mg, 0.222 mmol) with lithium
chloride (94.2 mg, 2.22 mmol) and sodium borohydride (84.1 mg, 2.22
mmol) as pale yellow oil.
[α]D25 –37.5 (c 0.30, MeOH); [α]D25 –64.4 (c 0.12, CHCl3); IR (neat) 3408,
25
2984, 2937, 2879, 1608, 1603, 1517, 1460, 1450, 1432, 1385, 1331,
1270, 1238, 1195, 1170, 1113, 1057, 1032, 942, 847, 819, 794, 762 cm–
[α]D +30.5 (c 1.00, CHCl3); IR (neat) 3582, 3419, 3098, 2955, 2914,
2877, 1732, 1604, 1548, 1500, 1464, 1417, 1387, 1282, 1266, 1200,
;
1148, 1111, 1007, 866, 851, 761, 741, 591 cm–1 1H NMR (400 MHz,
1
;
1H NMR (400 MHz, CDCl3) δ 6.88 (1H, d, J = 8.7 Hz), 6.83–6.77 (2H,
m), 5.64–5.56 (1H, br s), 4.95 (1H, d, J = 3.7 Hz), 3.89 (3H, s), 3.76 (2H,
d, J = 2.3 Hz), 2.71 (1H, dd, J = 10.3, 3.9 Hz), 2.49 (1H, dddd, J = 10.3,
3.8, 2.0, 2.0 Hz), 2.27 (1H, d, J = 12.3 Hz), 1.88 (1H, dd, J = 12.3, 4.1
Hz), 1.60 (3H, s), 1.49 (3H, s); 13C NMR (100 MHz, CDCl3) δ 146.5,
145.2, 134.4, 118.8, 115.3, 114.4, 108.6, 105.9, 85.3, 63.0, 55.9, 47.8,
45.8, 33.3, 24.8, 22.6; HRMS (ESI–TOF) calcd for C16H20O5Na ([M +
Na]+) 315.1208, found 315.1204.
CDCl3) δ 7.96 (1H, dd, J = 7.8, 1.4 Hz), 7.85 (1H, dd, J = 8.0, 1.6 Hz),
7.80 (1H, ddd, J = 7.7, 7.5, 1.4 Hz), 7.68 (1H, ddd, J = 7.7, 7.7, 1.5 Hz),
7.07 (1H, d, J = 8.2 Hz), 6.69 (1H, dd, J = 8.2, 1.8 Hz), 6.56 (1H, d, J =
1.8 Hz), 5.77 (1H, s), 4.93 (1H, d, J = 3.7 Hz), 3.84 (1H, dd, J = 10.5, 7.3
Hz), 3.70 (1H, dd, J = 10.5, 6.9 Hz), 3.37 (3H, d, J = 14.2 Hz), 2.78 (1H,
ddd, J = 7.4, 7.2, 3.8 Hz), 2.18 (3H, s), 1.72 (3H, s), 0.89–0.81 (9H, m),
0.56–0.41 (6H, m); 13C NMR (100 MHz, CDCl3) δ 150.7, 148.9, 148.5,
148.0, 144.2, 137.1, 134.7, 131.6 (2C), 130.0, 124.6, 123.3, 118.5, 115.1,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
Cell culture assays
Keyzers, M. H. G. Munro, M. R. Prinsep, Nat. Prod. Rep. 2013, 30, 237–
323; e) J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro, M. R.
Prinsep, Nat. Prod. Rep. 2014, 31, 160–258; f) J. W. Blunt, B. R. Copp, R.
A. Keyzers, M. H. G. Munro, M. R. Prinsep, Nat. Prod. Rep. 2015, 32,
116–211; g) J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro, M. R.
Prinsep, Nat. Prod. Rep. 2016, 33, 382–431.
A549 cells (JCRB 0076) and HL-60 cells (JCRB 0085) were obtained
from the Japanese Collection of Research Bioresources (Osaka, Japan).
A549 cells or HL-60 cells were cultured in MEM or RPMI 1640 medium
containing heat-inactivated 10%(v/v) FBS supplemented with L-glutamine,
100 unit/mL penicillin G sodium salt, and 100 µg/mL streptomycin sulfate
in a humidified incubator at 37 °C with 5% CO2. The cell growth was
measured with an MTT reduction assay.[13] They (A549: 1 x 104 cells/mL,
HL-60: 4 x 104 cells/mL) were continuously treated with each compound
for 72 h, and cell viability was measured with an MTT reduction assay
procedure. Dose–response curves were plotted for (±)-1, (+)-1, and (–)-1,
and the concentrations giving 50% inhibition (IC50) were calculated.
[2] a) J. Wu, Q. Xiao, J. Xu, M.-Y. Li, J.-Y. Pan, M.-h. Yang, Nat. Prod. Rep.
2008, 25, 955–981; b) M.-Y. Li, Q. Xiao, J.-Y. Pan, J. Wu, Nat. Prod. Rep.
2009, 26, 281–298.
[3] a) G.-C. Gao, X.-M. Luo, X.-Y. Wei, S.-H. Qi, H. Yin, Z.-H. Xiao and S.
Zhang, Helv. Chim. Acta 2010, 93, 339–344; b) J.-X. Liu, M.-Q. Luo, M.
Xia, Q. Wu, S.-M. Long, Y. Hu, G.-C. Gao, X.-L. Yao, M. He, H. Su, X.-M.
Luo and S.-Z. Yao, Mar. Drugs 2014, 12, 2790–2801.
[4] H. Abe, T. Hikichi, K. Emori, T. Kobayashi, H. Ito, Org. Chem. Front. 2016,
3, 1084–1086.
[5] F. Stauffer, R. Neier, Org. Lett. 2000, 2, 3535–3537.
[6] a) T. Kan, T. Fukuyama, Chem. Commun. 2004, 353; b) T. Kan, T.
Fukuyama, J. Syn. Org. Chem. Jpn 2001, 59, 779.
[7] CCDC 1587434 containes the supplemental crystallographic data of 16 for
this paper.
Acknowledgements
[8] In our previous communication (ref. 4), the combination of concentrated
sulfuric acid and THF gave the best result.
This work was supported by Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
[9] D. A. Evans, J. V. Nelson, E. Vogel, T. R. Taber, J. Am. Chem. Soc. 1981,
103, 3099.
[10] D. Mackay, E. G. Neeland and N. J. Taylor, J. Org. Chem. 1986, 51, 2351.
[11] a) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc.
1991, 113, 4092–4096; b) J. M. Seco, E. Quiñoá, R. Riguera, Chem. Rev.
2004, 104, 17–117.
Keywords: catunaregin • norneolignan • Evans aldol reaction •
enantioselective synthesis • biological property
[12] The detailed experimental results are described in the Supporting
Information.
[1] a) J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote, M. R. Prinsep,
Nat. Prod. Rep. 2010, 27, 165–237; b) J. W. Blunt, B. R. Copp, M. H. G.
Munro, P. T. Northcote, M. R. Prinsep, Nat. Prod. Rep. 2011, 28, 196–268;
c) J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro, M. R. Prinsep,
Nat. Prod. Rep. 2012, 29, 144–222; d) J. W. Blunt, B. R. Copp, R. A.
[13] a) A. Yokosuka, K. Takagi, Y. Mimaki, J. Nat. Med. 2013, 67, 590–598; b)
J. M. Sargent, C. G. Taylor, Br. J. Cancer 1989, 60, 206–210.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800219
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Hideki Abe*[a,b], Takuma Hikichi[a],
Kosuke Emori[a], Akihito Yokosuka[c],
Yoshihiro Mimaki[c], Toyoharu
Kobayashi[a], and Hisanaka Ito* [a]
Page No. – Page No.
Total Synthesis of Catunaregin and
Preliminary Evaluation of Its
Antitumor Activity
Total synthesis of catunaregin in both racemic and optically active forms was
accomplished. This enantioselective synthesis employs Evans aldol methodology
using oxazolidinone or thiazolidinethione as the chiral auxiliary. The key features
include a syn selective aldol reaction to form the Evans-syn or Non-Evans-syn
product, and successive ketalization of a furanyl diol derivative under acidic
conditions.
This article is protected by copyright. All rights reserved.