An Optimized and General Synthetic Strategy To Prepare Arylnaphthalene Lactone Natural Products from Cyanophthalides

Article abstract of DOI:10.1002/ejoc.201601611

A simple method for the preparation of arylnaphthalene lactone natural products was developed and used to synthesize diphyllin (10), justicidin A (12), cilinaphthalide B (13), taiwanin E (15), chinensinaphthol (16), taiwanin E methyl ether (17), chinensin

Full text of DOI:10.1002/ejoc.201601611

A Journal of
Accepted Article
Title: An Optimized and General Synthetic Strategy to Prepare
Arylnaphthalene Lactone Natural Products from Cyanophthalides
Authors: Taejung Kim, Kyu Hyuk Jeong, Ki Sung Kang, Masaya
Nakata, and Jungyeob Ham
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601611
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601611
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10.1002/ejoc.201601611
European Journal of Organic Chemistry
FULL PAPER
An Optimized and General Synthetic Strategy to Prepare
Arylnaphthalene Lactone Natural Products from Cyanophthalides
Taejung Kim,[a,b] Kyu Hyuk Jeong,[a] Ki Sung Kang,[c] Masaya Nakata,[b] and Jungyeob Ham*[a,d]
Abstract: In this study, a novel and simple method for the preparation
of various arylnaphthalene lactone natural products was developed
and used to synthesize diphyllin (10), justicidin A (12), cilinaphthalide
B (13), taiwanin E (15), chinensinaphthol (16), taiwanin E methyl ether
(17), chinensinaphthol methyl ether (18), justicidin C (21) and
justicidin D (22). The syntheses proceeded via HauserKraus
annulation of cyanophthalides (7a and 7b) and SuzukiMiyaura cross-
coupling of arylnaphthalene lactones having a sulfonate group (9, 14,
19, and 20) with the corresponding potassium aryltrifluoroborates.
reaction[16] of naphthalene lactones having sulfonate group 1 with
corresponding boron reagents to give type-A or -B
arylnaphthalene lactones natural products. Using this method, we
have constructed a regioselective arylnaphthalene lactone natural
product-like library in order to study the anti-tumor activity of this
type of naturomimetic compound.
Introduction
Arylnaphthalene lactone natural products are plant-derived lignan
compounds[1] and have a wide range of biological properties;
including anticancer,[2] antiplatelet,[3] antiviral,[4] piscicidal,[1p]
phosphodiest-erase inhibition,[5] 5-lipooxygenase inhibition,[6] HIV
reverse transcriptase inhibition,[7] and antibacterial activities.[8]
Furthermore, the unique and simple structure of arylnaphthalene
lactones can be used as a template for lead compounds in the
development of new drugs derived from natural products.[9]
Since their chemical structure was first reported in the 1960’s,
numerous synthetic strategies to efficiently prepare these natural
lignans have been developed, including the tandem reaction of 2-
alkynylbenzonitrile,[10] Pd-catalyzed [2+2+2] cocyclization of
Scheme 1. Retrosynthetic analysis of type A and B arylnaphthalene lactone
natural products and related compounds.
Results and Discussion
arynes
and
diynes,[11]
the
ring
intramolecular
reaction,[13]
and
expansion
of
First, we prepared cyanophthalides 7a and 7b as key
benzocyclobutenones,[12]
the
dehydro
sequential
intermediates
from
commercially
available
2-
(Pummerer)DielsAlder
bromobenzaldehydes 4a and 4b by a reproducible chemical
methods. 4a and 4b were transformed into the corresponding 1,3-
dioxolanes 5a and 5b by reacting with ethylene glycol in benzene
at reflux temperature in the presence of para-toluenesulfonic acid
(Scheme 2). Thereafter, amidation of the lithiated 2-(2-bromo-
phenyl)-1,3-dioxolanes 5a and 5b with N,N-dimethylcarbamoyl
chloride, and deprotection of the 1,3-dioxolanes by acid treatment,
gave 2-formylbenzamides 6a and 6b. Cyanophthalides 7a and 7b
were synthesized by a general literature procedure: 6a and 6b
reacted with trimethylsilyl cyanide in the presence of 0.3
equivalents of both KCN and 18-crown-6, followed by treatment
of the -trimethylsilyl oxybenzyl cyanide intermediate with acetic
acid.[17] Cyanophthalides 7a and 7b are afforded in 73% and 72%
yields, respectively, over three steps.
Next, we investigated the optimal reaction conditions for the
HauserKraus annulation with cyanophthalide and -
crotonolactone in the presence of a base. Owing to the instability
of the dilithium naphthalenedioxide intermediate I-3, it was
necessary to use a suitable electrophile for the synthesis of stable
naphthalenediol or mono-protected naphthalene lactone adducts.
The results of screening for optimal reaction conditions are
summarized in Table 1. When the reaction of cyanophthalide 7a
with -crotonolactone in the presence of lithium bis(trimethylsilyl)
HornerEmmonsClaisen condensation.[14] However, previous
methods are limited to obtain arylnaphthalene lactone natural
product derivatives having basic sensitive functional groups on
aryl moiety.
Herein, we report a highly efficient synthetic method for the
synthesis of arylnaphthalene lactone natural products using
cyanophthalides as the starting material. The retrosynthetic
analysis illustrated in Scheme 1: (1) HauserKraus annulation[15]
of cyanophthalides 3 and (2) SuzukiMiyaura cross-coupling
[a]
[b]
Natural Constituents Research Center, Korea Institute of Science
and Technology (KIST), Gangneung 25451, Republic of Korea
E-mail: ham0606@kist.re.kr
http://gn.kist.re.kr
Department of Applied Chemistry, Faculty of Science and
Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
College of Korean Medicine, Gachon University,
Seongnam 13120, Republic of Korea
Department of Biological Chemistry, University of Science and
Technology (UST), Daejeon 34113, Republic of Korea
[c]
[d]
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201601611
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of the reaction conditions and scope of cyanophthalides
and electrophiles.[a]
Scheme 2. Preparation of cyanophthalides 7a and 7b from the corresponding
2-bromobenzaldehydes.
entry
1
temp.
-78 oC
electrophile
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
Boc2O
MsCl
R5
R6
yield (%)b
0 [c]
0 [d]
0 [d]
23
o
amide (LHMDS) was performed in THF solvent at -78 C with
2
0 oC
rt
AcOH as an electrophile (proton donor), Michael-type addition
product alone was obtained in 76% yield (Table 1, entry 1) instead
of the desired product 8aa (see Figure 1). Moreover, when the
reaction temperature increases to 0 oC and/or rt, insoluble
polymerized side-products were generated from dilithium
naphthalenedioxide or naphthalenediol[18] in quantitative yields
(Table 1, entries 2 and 3). Therefore, we had to determine the
optimum reaction temperature for increasing the stability of the
dilithium naphthalene dioxide intermediate.
As shown in Table 1, the maximum yield of annulated product
8aa was obtained at -30 oC in same reaction reagents (Table 1,
entries 46). Fortunately, when di-tert-butyl dicarbonate (Boc2O)
and methanesulfonyl chloride (MsCl) were used as electrophiles,
the regioselective mono Boc and Ms protected products of less
sterically hindered alcohol (not formed oxygen-metal bonding)
were isolated in good yields of 83%, respectively (Table 1, entries
7 and 8). By contrast, reactions using p-toluenesulfonyl chloride
(TsCl) or p-nitrobenzenesulfonyl chloride (NsCl) as electrophiles
yielded only small amounts of target molecules, owing to the poor
reactivities for the dilithium naphthalenedioxide at low
temperature (Table 1, entries 9 and 10). Also, when using
iodomethane (MeI), the corresponding di-protected product was
obtained in higher yield than that of desired product (Table 1,
entry 11). Finally, as expected, changing the starting material to
cyanophthalide 7b with Boc2O and MsCl provides the desired
product in 80% and 76% yields, respectively (Table 1, entries 12
and 13).
3
4
-50 oC
-30 oC
-20 oC
-30 oC
-30 oC
-30 oC
-30 oC
-30 oC
-30 oC
-30 oC
H
H
H
H
H
H
H
H
H
H
H
5
H
89
6
H
82
7
Boc
Ms
Ts
Ns
Me
Boc
Ms
83
8
83
9
TsCl
31
10
11
12
13
NsCl
26
MeI
12[e]
80[f]
76[f]
Boc2O
MsCl
[a] All reactions were performed on a 2.0-mmol scale in the presence of -
crotonolactone (1.5 equiv.), LHMDS (3.0 equiv.), and an electrophile (1.03.0
equiv.). [b] Isolated yields. [c] Michael-type side-product was obtained in 76%
yield. [d] Undetermined black-colour polymer was obtained. [e] Dimethylated
product of I-3 was obtained in 19% yield. [f] 7b was used as a starting material.
Using the optimized HauserKraus annulation conditions, we
focused our attention on the total syntheses of various
arylnaphthalene
lactone
natural
products.
Although
naphthalenediol lactone 8aa was easily prepared in 89% yield, it
appears to be unstable under the basic conditions and needed for
the protection of the phenolic alcohol. Therefore, we used
naphthalene lactones 8ab, 8ac, 8ba, and 8bb as key
intermediates for the total syntheses of natural arylnaphthalene
lactones.
Figure 1. Synthesized naphthalene lactone analogs.
For the synthesized diphyllin (10), justicidin A (12), and
cilinaphthalide B (13) (Scheme 3), the phenolic alcohol group was
converted to trifluoromethanesulfonate (-OTf) using Tf2O, and
then subjected to SuzukiMiyaura cross-coupling reaction with
the corresponding potassium aryltrifluoroborates in the presence
of 10 mol% of Pd(OAc)2, 20 mol% of tricyclohexylphosphine
(PCy3), and 3.0 equivalents of Cs2CO3 in aqueous 1,4-dioxane at
under refluxing conditions (Method A).[19] From the coupling
reaction with 9, the desired products diphyllin (10) and 11 were
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10.1002/ejoc.201601611
European Journal of Organic Chemistry
FULL PAPER
cilinaphthalide B (13) in 88% and 90%, respectively. Moreover,
the total synthesis of arylnaphthalene lactones from 8ba proceeds
easily to give the corresponding natural products such as taiwanin
E (15), chinensinaphthol (16), taiwanin E methyl ether (17) and
chinensinaphthol methyl ether (18) in overall yields of 51.4% (6
steps), 51.9% (6 steps), 45.2% (7 steps), and 46.8% (7 steps),
respectively (Scheme 4).
Scheme 5. Total synthesis of justicidin C (21) and D (22) from 8ac and 8bb.
Scheme 3. Total synthesis of diphyllin (10), justicidin A (12), and cilinaphthalide
B (13) from 8ab.
Finally, we examined the total synthesis of type-B
arylnaphthalene lactone natural products. The methylation of both
8ac and 8bb were successfully carried out using MeI and K2CO3
in acetone, followed by SuzukiMiyaura cross-coupling reaction
of Method
B (10 mol% of Pd(OAc)2, 20 mol% of 2-
dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (RuPhos), and
3.0 equivalents of Cs2CO3 in aqueous t-BuOH at under refluxing
conditions) with potassium 1,3-benzodioxol-5-yltrifluoroborate[20]
to afford justicidin C (21) and justicidin D (22) in overall yields of
55.6% (6 steps) and 49.9% (6 steps), respectively (Scheme 5).
Conclusions
In summary, we have demonstrated a new synthetic scheme for
the preparation of naphthalene lactone skeletons via
HauserKraus annulation from cyanophthalides 7a and 7b.
Moreover, we have successfully synthesized various biologically
active arylnaphthalene lactone natural products, such as diphyllin
(10), justicidin A (12), cilinaphthalide B (13), taiwanin E (15),
chinensinaphthol (16), taiwanin
E
methyl ether (17),
chinensinaphthol methyl ether (18), justicidin C (21), and justicidin
D (22). Further investigation of the synthesis and evaluation of
arylnaphthalene lactone natural products is currently in progress
in our laboratory.
Scheme 4. Total synthesis of taiwanin E (15), chinensinaphthol (16), taiwanin
E methyl ether (17) and chinensinaphthol methyl ether (18) from 8ba.
Experimental Section
successfully obtained in 97% and 91% yields, respectively. In
addition, methylation of the alcohol using MeI and K2CO3 in
acetone yields two natural products, justicidin A (12) and
General Experimental Details: 1H NMR spectra were recorded on
BRUKER AVANCE 400 spectrometer and the chemical shifts were
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10.1002/ejoc.201601611
European Journal of Organic Chemistry
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added ethylene glycol (4.08 g, 66 mmol) and p-toluenesulfonic acid
monohydrate (209 mg, 1.1 mmol) in one portion. The resulting mixture was
refluxed for 5 hours. The mixture was cooled to room temperature,
quenched with saturated aqueous NaHCO3 solution and extracted with
EtOAc. The extracts were washed with saturated aqueous NaCl solution,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (hexane:ethyl acetate, 5:1)
on silica gel to afford 5b (5.96 g, quant.) as white solids. mp = 65.5-66.3
reported in parts per million (ppm) relative to internal standard TMS (0
ppm) for CDCl3 and internal solvent DMSO (2.5 ppm) for DMSO-d6. The
peak patterns are indicated as follows: s, singlet; d, doublet; bs, broad
singlet; dd, doublet of doublet; t, triplet; m, multiplet; q, quartet. The
coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were
obtained on the same spectrometer and referenced to the internal solvent
signals (central peak is 77.0 ppm or 39.5 ppm in CDCl3 or DMSO-d6,
respectively). CDCl3 and DMSO-d6 were used as the NMR solvents. Mass
spectra were determined with LCMS-2020 (Shimadzu Corporation) for
ESI-MS, JMS-700 (Jeol) for EI-HRMS and DFS (Thermo Scientific) for
FAB-HRMS. FT-IR spectra were recorded on ATR plate. Flash column
chromatography was performed over silica gel 200-300. All reagents were
weighed and handled in air at room temperature and all reactions were
performed under an air atmosphere. Unless otherwise noted, all reagents
were purchased from commercial suppliers without further purification.
1
oC. H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 6.99 (s, 1H), 6.00 (s, 1H),
5.97 (s, 1H), 4.15-4.09 (m, 2H), 4.07-4.01 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 149.0, 147.5, 130.0, 113.9, 112.8, 107.7, 102.6, 101.9, 65.4. FT-
IR (ATR): 1390, 1231, 1074, 1020, 923, 863, 833, 765, 685 cm-1. ESI-MS:
m/z calcd for C10H10BrO4 [M+H]+ 272.98, found 273.00. The spectroscopic
data were in agreement with that reported in the literature.[22]
6-Formyl-N,N-dimethylbenzo[d][1,3]dioxole-5-carboxamide (6b):
A
solution of 5-bromo-6-(1,3-dioxolan-2-yl)benzo[1,3]dioxole 5b (500 mg,
1.84 mmol) in THF (18.4 mL) was cooled to -78 oC under an atmosphere
of argon and n-BuLi (2.39 mL, 2.39 mmol of a 1.0 M solution) was added
slowly. The solution turned yellow and was stirred for a further 5 min. N,N-
Dimethylcarbamoyl chloride (237 mg, 2.21 mmol) was added and the
mixture warmed to 0 oC. The reaction was quenched by the addition of
18.4 mL of a 2N HCl solution. The resulting clear colorless solution was
stirred for 30 min at 0 oC to complete deprotection of the acetal group. The
solution was extracted using EtOAc, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography (hexane:ethyl acetate, 4:1) on silica gel to afford 6b
(333.5 mg, 82%) as white solids. mp = 114.1-114.8 oC. 1H NMR (400 MHz,
CDCl3) δ 9.89 (s, 1H), 7.31 (s, 1H), 6.74 (s, 1H), 6.05 (s, 2H), 3.10 (s, 3H),
2.81 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 188.4, 168.4, 152.6, 148.7,
136.6, 127.9, 107.6, 107.0, 102.5, 38.8, 34.9. FT-IR (ATR): 1609, 1490,
1395, 1261, 1215, 1104, 1025, 928, 908, 876, 864, 766 cm-1. EI-HRMS:
m/z calcd for C11H11NO4 [M]+ 221.0688, found 221.0688.
Experimental Procedures and Analytical Datas:
2-(2-Bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (5a): To a solution of
2-bromo-4,5-dimethoxybenzaldehyde (4a) (5.0 g, 20.5 mmol) in benzene
(205 mL) were added ethylene glycol (3.82 g, 61.5 mmol) and p-
toluenesulfonic acid monohydrate (195 mg, 1.0 mmol) in one portion. The
resulting mixture was refluxed for 5 hours. The mixture was cooled to room
temperature, quenched with saturated aqueous NaHCO3 solution and
extracted with EtOAc. The extracts were washed with saturated aqueous
NaCl solution, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography (hexane:
ethyl acetate, 5:1) on silica gel to afford 5a (5.84 g, 99%) as white solids.
mp = 109.3-110.6 oC. 1H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 7.00 (s,
1H), 5.99 (s, 1H), 4.18-4.15 (m, 2H), 4.06-4.03 (m, 2H), 3.88 (s, 3H), 3.86
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 150.2, 148.5, 128.3, 115.4, 113.4,
110.2, 102.6, 65.4, 56.2, 56.0. FT-IR (ATR): 1666, 1584, 1503, 1384, 1268,
1217, 1189, 1153, 1040, 1014, 978, 864, 811, 736 cm-1. ESI-MS: m/z calcd
for C11H14BrO4 [M+H]+ 289.01, found 289.10. The spectroscopic data were
in agreement with that reported in the literature.[21]
7-Oxo-5,7-dihydro-[1,3]dioxolo[4,5-f]isobenzofuran-5-carbonitrile
(7b): To
a solution of 6-formyl-N,N-dimethylbenzo[d][1,3]dioxole-5-
carboxamide 6b (500 mg, 2.26 mmol) in CH2Cl2 (4.52 mL) was added KCN
(44.3 mg, 0.68 mmol) and 18-crown-6 (180 mg, 0.68 mmol) under an
atmosphere of nitrogen. The reaction mixture was cooled to 0 oC and
TMSCN (448 mg, 4.52 mmol) was added dropwise and reacted at room
temperature for 12 h. The solvent was removed under reduced pressure
and the residue taken up in AcOH (4.52 mL) and the mixture stirred
overnight at room temperature. The solvent was removed under reduced
pressure. The residue was purified by column chromatography (only ethyl
acetate) on silica gel to afford 7b (403.8 g, 88%) as white solids. mp =
2-Formyl-4,5-dimethoxy-N,N-dimethylbenzamide (6a): A solution of 2-
(2-bromo-4,5-dimethoxyphenyl)-1,3-dioxolane 5a (5.0 g, 17.4 mmol) in
THF (174 mL) was cooled to -78 oC under an atmosphere of argon and n-
BuLi (20.8 mL, 20.8 mmol of a 1.0 M solution) was added slowly. The
solution turned yellow and was stirred for a further 5 min. N,N-
Dimethylcarbamoyl chloride (2.25 g, 20.9 mmol) was added and the
mixture warmed to 0 oC. The reaction was quenched by the addition of 8.7
mL of a 2N HCl solution. The resulting clear colorless solution was stirred
for 30 min at 0 oC to complete deprotection of the acetal group. The
solution was extracted using EtOAc, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography (hexane:ethyl acetate, 4:1) on silica gel to afford 6a (3.26
g, 79%) as white solids. mp = 125.2-126.6 oC. 1H NMR (400 MHz, CDCl3)
δ 9.86 (s, 1H), 7.39 (s, 1H), 6.80 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.13
(s, 3H), 2.81 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 188.9, 168.9, 154.0,
149.6, 134.4, 125.9, 109.8, 109.2, 56.4, 56.2, 38.9, 34.9. FT-IR (ATR):
1616, 1498, 1387, 1276, 1215, 1145, 1090, 989, 941, 869, 766 cm-1. EI-
HRMS: m/z calcd for C12H15NO4 [M]+ 237.1001, found 237.1001.
o
1
134.2-135.4 C. H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.03 (s, 1H),
6.21 (s, 2H), 5.96 (d, J = 0.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.1,
154.9, 151.1, 138.2, 118.5, 113.9, 104.8, 103.5, 102.3, 65.2. FT-IR (ATR):
1758, 1465, 1304, 1258, 1216, 1088, 1027, 1014, 930, 882, 809, 764 cm-
1. EI-HRMS: m/z calcd for C10H5NO4 [M]+ 203.0219, found 203.0216.
4,9-Dihydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one
(8aa):
1,3-Dihydro-5,6-dimethoxy-3-oxo-1-isobenzofurancarbonitrile 7a (438 mg,
2.0 mmol) was dissolved in distilled THF (50 mL, 0.04 M). Lithium
bis(trimethylsilyl)amide 1.0 M solution (6.2 mL, 6.2 mmol) was added and
the bright yellow mixture stirred for 0.5 h. -Crotonolactone (202 mg, 2.4
mmol) was added and then slowly warmed to -30 oC. The solution turned
a bright yellow turbid solution as it was stirred for 5 min until TLC showed
disappearance of 7a. The reaction was quenched with the acetic acid (343
uL, 6.0 mmol) and stirred for 2 h. After the usual aqueous extractive work-
up with EtOAc and purified by column chromatography (hexane:ethyl
acetate, 1:1) as light yellow solid (491.4 mg, 89%). mp = 244.1-245.8 oC.
1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.59 (s, 1H), 7.55 (s, 1H),
7.48 (s, 1H), 5.32 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 170.9, 151.6, 149.4, 146.2, 137.9, 126.2, 121.1, 120.4, 104.5,
102.7, 101.6, 68.0, 56.0, 55.9. FT-IR (ATR): 1720, 1693, 1616, 1491, 1308,
1257, 1202, 1159, 1066, 1015, 970, 905, 790 cm-1. EI-HRMS: m/z calcd
for C14H12O6 [M]+ 276.0634, found 276.0632.
1,3-Dihydro-5,6-dimethoxy-3-oxo-1-isobenzofurancarbonitrile (7a):
To a solution of 2-formyl-4,5-dimethoxy-N,N-dimethylbenzamide 6a (2 g,
8.44 mmol) in CH2Cl2 (16.9 mL) was added KCN (165 mg, 2.53 mmol) and
18-crown-6 (669 mg, 2.53 mmol) under an atmosphere of nitrogen. The
reaction mixture was cooled to 0 oC and TMSCN (1.67 g, 16.9 mmol) was
added dropwise and reacted at room temperature for 12 h. The solvent
was removed under reduced pressure and the residue taken up in AcOH
(16.9 mL) and the mixture stirred overnight at room temperature. The
solvent was removed under reduced pressure. The residue was purified
by column chromatography (only ethyl acetate) on silica gel to afford 7a
o
1
(1.72 g, 93%) as white solids. mp = 226.9-227.7 C. H NMR (400 MHz,
CDCl3) δ 7.33 (s, 1H), 7.06 (s, 1H), 5.97 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 167.8, 156.0, 152.2, 136.2, 116.6, 114.1,
106.5, 103.6, 65.2, 56.8, 56.5. FT-IR (ATR): 1761, 1598, 1504, 1446, 1313,
1255, 1232, 1118, 1045, 1024, 989, 862, 763 cm-1. ESI-MS: m/z calcd for
C11H10NO4 [M+H]+ 220.06, found 220.30. The spectroscopic data were in
agreement with that reported in the literature.[17]
tert-Butyl (9-hydroxy-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-
c]furan-4-yl) carbonate (8ab): The title compound was prepared
according to the general procedure described above by the reaction
between 1,3-dihydro-5,6-dimethoxy-3-oxo-1-isobenzofurancarbonitrile 7a
(438 mg, 2.0 mmol) with di-tert-butyl dicarbonate (310 uL, 2.0 mmol) as an
electrophile, and purified by column chromatography (hexane:ethyl
acetate, 1:1) as light yellow solid (624.4 mg, 83%). mp = 153.7-154.6 oC.
1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.58 (s, 1H), 7.17 (s, 1H), 5.37
5-Bromo-6-(1,3-dioxolan-2-yl)benzo[1,3]dioxole (5b): To a solution of
6-bromopiperonal (4b) (5.0 g, 21.9 mmol) in benzene (220 mL) were
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10.1002/ejoc.201601611
European Journal of Organic Chemistry
FULL PAPER
(s, 2H), 4.04 (s, 6H), 1.60 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 172.7,
153.0, 151.3, 150.7, 149.8, 131.6, 128.3, 127.7, 119.8, 103.2, 102.1, 100.1,
84.6, 68.8, 56.1, 56.0. FT-IR (ATR): 1748, 1733, 1487, 1248, 1144, 1128,
1064, 1002, 856, 776 cm-1. EI-HRMS: m/z calcd for C19H20O8 [M]+
376.1158, found 376.1158.
9-Hydroxy-8-oxo-6,8-dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-
5-yl methanes-ulfonate (8bb): The title compound was prepared
according to the general procedure described above by the reaction
between 7-oxo-5,7-dihydro-[1,3]dioxolo[4,5-f]isobenzofuran-5-carbonitrile
7b (406 mg, 2.0 mmol) with di-tert-butyl dicarbonate (310 uL, 2.0 mmol) as
an electrophile, and purified by column chromatography (hexane:ethyl
acetate, 1:1) as light yellow solid (513.8 mg, 76%). mp = 207.3-207.9 oC.
1H NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.48 (s, 1H), 6.27 (s, 2H),
5.46 (s, 2H), 3.66 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 168.8, 152.0,
151.3, 148.0, 132.5, 130.0, 122.6, 104.8, 102.5, 99.8, 98.6, 67.1, 38.3,
29.0. FT-IR (ATR): 3390, 1737, 1463, 1351, 1296, 1170, 1116, 1033, 959,
899, 815 cm-1. EI-HRMS: m/z calcd for C14H10O8S [M]+ 338.0096, found
338.0096.
9-Hydroxy-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl
methanesulfo-nate (8ac): The title compound was prepared according to
the general procedure described above by the reaction between 1,3-
dihydro-5,6-dimethoxy-3-oxo-1-isobenzofurancarbonitrile 7a (438 mg, 2.0
mmol) with methanesulfonyl chloride (158 uL, 2.0 mmol) as an electrophile,
and purified by column chromatography (hexane:ethyl acetate, 1:1) as
light yellow solid (587.7 mg, 83%). mp = 173.6-174.3 oC. 1H NMR (400
MHz, CDCl3) δ 8.59 (s, 1H), 7.61 (s, 1H), 7.35 (s, 1H), 5.57 (s, 2H), 4.07
(s, 3H), 4.06 (s, 3H), 3.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 172.4,
153.5, 152.4, 150.1, 130.2, 129.0, 120.2, 103.7, 102.2, 100.8, 69.4, 56.2,
56.2, 38.6, 29.7. FT-IR (ATR): 1732, 1494, 1359, 1257, 1300, 1163, 1075,
1075, 910, 809 cm-1. EI-HRMS: m/z calcd for C15H14O8S [M]+ 354.0410,
found 354.0409.
9-((tert-Butoxycarbonyl)oxy)-6,7-dimethoxy-3-oxo-1,3-
dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate (9): To a
solution of 8ab (250 mg, 0.66 mmol) in CH2Cl2 (13.3 mL, 0.05 M) was
o
added pyridine (78.9 mg, 1.0 mmol) and the solution was cooled to 0 C.
Trifluoromethanesulfonic anhydride (225 mg, 0.80 mmol) was added
dropwise and the mixture was warmed to room temperature. The reaction
was complete within 2 h as shown by TLC. The mixture was diluted with
Et2O, quenched with 1N HCl solution and washed successively with
saturated NaHCO3 solution and brine. After drying (Na2SO4) the solvent
was removed under reduced pressure and the residue was purified by
column chromatography (hexane:ethyl acetate, 3:1) to afford the product
9 as light yellow solid (332 mg, 98%). mp = 135.7-135.4 oC. 1H NMR (400
MHz, CDCl3) δ 7.47 (s, 1H), 7.24 (s, 1H), 5.36 (s, 2H), 4.07 (s, 3H), 4.06
(s, 3H), 1.62 (s, 9H) 13C NMR (100 MHz, CDCl3) δ 166.4, 153.4, 152.0,
149.9, 138.6, 138.3, 130.3, 128.3, 123.9, 120.3, 117.1, 114.4, 101.0, 99.8,
85.6, 67.0, 56.3, 56.1. FT-IR (ATR): 1759, 1416, 1244, 1196, 1133, 1111,
1029, 997, 856, 819 cm-1. EI-HRMS: m/z calcd for C20H19F3O10S [M]+
508.0651, found 508.0652.
9-Hydroxy-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl
4-methylbenze-nesulfonate (8ad): The title compound was prepared
according to the general procedure described above by the reaction
between 1,3-dihydro-5,6-dimethoxy-3-oxo-1-isobenzofurancarbonitrile 7a
(438 mg, 2.0 mmol) with p-toluenesulfonyl chloride (381 mg, 2.0 mmol) as
an electrophile, and purified by column chromatography (hexane:ethyl
acetate, 1:1) as light yellow solid (266.6 mg, 31%). mp = 203.8-204.9 oC.
1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.78 (d, J = 6.8 Hz, 2H), 7.52
(s, 1H), 7.32 (d, J = 6.8 Hz, 2H), 6.84 (s, 1H), 5.39 (s, 2H), 4.02 (s, 3H),
3.37 (s, 3H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 172.5, 152.8,
152.1, 149.7, 146.2, 132.8, 130.3, 130.3, 130.2, 128.9, 128.4, 119.9, 103.7,
101.9, 100.9, 69.4, 56.1, 55.7, 21.7. FT-IR (ATR): 3381, 1742, 1598, 1363,
1344, 1178, 1060, 1039, 1021, 963, 778, 766 cm-1. EI-HRMS: m/z calcd
for C21H18O8S [M]+ 430.0722, found 430.0724.
Diphyllin (10): To a solution of 9 (50.0 mg, 0.098 mmol), Pd(OAc)2 (2.2
mg, 0.010 mmol), PCy3 (5.6 mg, 0.020 mmol), Cs2CO3 (95.8 mg, 0.29
mmol) in 25% aqueous 1,4-dioxane (0.94 mL, 0.1 M) was added
potassium 1,3-benzodioxol-5-yltrifluoroborate (29.8 mg, 0.15 mmol). The
mixture was stirred at 120 oC for 17 h. The mixture was quenched with
saturated NH4Cl solution, extracted with EtOAc, and washed with brine.
After drying (Na2SO4) the solvent was removed under reduced pressure
and the residue was purified by column chromatography (hexane:ethyl
acetate, 2:1) to afford the product 10 as white solid (36.3 mg, 97%). mp =
9-Hydroxy-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl
4-nitrobenzen-esulfonate (8ae): The title compound was prepared
according to the general procedure described above by the reaction
between 1,3-dihydro-5,6-dimethoxy-3-oxo-1-isobenzofurancarbonitrile 7a
(438 mg, 2.0 mmol) with p-nitrosulfonyl chloride (443 mg, 2.0 mmol) as an
electrophile, and purified by column chromatography (hexane:ethyl
acetate, 1:1) as light yellow solid (239.7 mg, 26%). mp = 181.3-182.1 oC.
1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.40 (d, J = 8.8 Hz, 2H), 8.16
(d, J = 8.8 Hz, 2H), 7.55 (s, 1H), 6.84 (s, 1H), 5.51 (s, 2H), 4.02 (s, 3H),
3.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 172.3, 153.2, 152.6, 151.3,
150.5, 141.3, 130.2, 129.8, 129.6, 128.5, 124.7, 120.2, 103.8, 102,2, 100.3,
69.2, 56.2, 55.8. FT-IR (ATR): 1683, 1531, 1257, 1208, 1191, 903, 856,
796, 787 cm-1. FAB-HRMS: m/z calcd for C20H17NO10S [M+H]+ 462.0489,
found 462.0489.
o
267.1-268.5 C. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.62 (s,
1H), 7.01 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.75
(dd, J = 1.6, 8.0 Hz, 1H), 6.11 (s, 2H), 5.35 (s, 2H), 3.94 (s, 3H), 3.65 (s,
3H). 13C NMR (100 MHz, DMSO-d6) δ 169.6, 150.4, 149.7, 146.8, 146.6,
144.8, 129.5, 129.4, 128.7, 123.7, 123.2, 121.6, 118.6, 111.0, 107.8, 105.4,
101.0, 100.7, 66.6, 55.6, 55.1. FT-IR (ATR): 3176, 1707, 1615, 1489, 1432,
1358, 1209, 1168, 1035, 1001 cm-1. ESI-MS: m/z calcd for C21H17O7
[M+H]+ 381.10, found 381.20. The spectroscopic data were in agreement
with that reported in the literature.[23]
4,9-Dihydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one
(8af):
The title compound was prepared according to the general procedure
described above by the reaction between 1,3-dihydro-5,6-dimethoxy-3-
oxo-1-isobenzofurancarbonitrile 7a (438 mg, 2.0 mmol) with iodomethane
(185 uL, 2.0 mmol) as an electrophile, and purified by column
chromatography (only chloroform to hexane:ethyl acetate, 1:1) as light
yellow solid (69.6 mg, 12%). mp = 135.6-136.2 oC. 1H NMR (400 MHz,
DMSO-d6) δ 7.58 (s, 1H), 7.37 (s, 1H), 5.61 (s, 2H), 3.97 (s, 3H), 3.93 (s,
3H), 3.91 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 170.0, 151.7, 149.1,
148.0, 140.1, 127.1, 123.6, 120.5, 103.9, 102.3, 100.8, 67.5, 59.2, 55.6,
55.5. FT-IR (ATR): 1731, 1607, 1462, 1414, 1356, 1258, 1201, 1130, 1071,
1004, 909, 862, 772 cm-1. EI-HRMS: m/z calcd for C15H14O6 [M]+ 290.0790,
found 290.0791.
9-(3,4-Dimethoxyphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-
c]furan-1(3H)-one (11): To a solution of 9 (47.8 mg, 0.094 mmol),
Pd(OAc)2 (2.1 mg, 0.009 mmol), PCy3 (5.3 mg, 0.019 mmol), Cs2CO3 (91.9
mg, 0.28 mmol) in 25% aqueous 1,4-dioxane (0.94 mL, 0.1 M) was added
potassium 1,3-benzodioxol-5-yltrifluoroborate (29.8 mg, 0.15 mmol). The
mixture was stirred at 120 oC for 17 h. The mixture was quenched with
saturated NH4Cl solution, extracted with EtOAc, and washed with brine.
After drying (Na2SO4) the solvent was removed under reduced pressure
and the residue was purified by column chromatography (hexane:ethyl
acetate, 2:1) to afford the product 11 as white solid (33.9 mg, 91%). mp =
o
269.5-271.4 C. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.63 (s,
tert-Butyl
(9-hydroxy-8-oxo-6,8-dihydrofuro[3',4':6,7]naphtho[2,3-
1H), 7.05 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.89 (d, J = 1.6 Hz, 1H), 6.85
(dd, J = 1.6, 8.0 Hz, 1H), 5.36 (s, 2H), 3.94 (s, 3H), 3.84 (s, 3H), 3.72 (s,
3H), 3.64 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.6, 150.4, 149.6,
148.1, 148.0, 144.7, 130.0, 129.4, 127.3, 123.3, 122.8, 121.7, 118.5, 114.4,
111.0, 105.6, 100.7, 66.5, 55.6, 55.5, 55.3, 55.1. FT-IR (ATR): 2930, 1718,
1612, 1509, 1488, 1431, 1355, 1258, 1210, 1162, 1008 cm-1. ESI-MS: m/z
calcd for C22H21O7 [M+H]+ 397.13, found 397.00. The spectroscopic data
were in agreement with that reported in the literature.[24]
d][1,3]dioxol-5-yl) carbonate (8ba): The title compound was prepared
according to the general procedure described above by the reaction
between 7-oxo-5,7-dihydro-[1,3]dioxolo[4,5-f]isobenzofuran-5-carbonitrile
7b (406 mg, 2.0 mmol) with di-tert-butyl dicarbonate (310 uL, 2.0 mmol) as
an electrophile, and purified by column chromatography (hexane:ethyl
acetate, 1:1) as light yellow solid (576.1 mg, 80%). mp = 266.1-267.1 oC.
1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.59 (s, 1H), 7.23 (s, 1H), 6.13
(s, 2H), 5.34 (s, 2H), 1.59 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 172.6,
151.6, 151.5, 150.8, 148.2, 132.1, 130.1, 128.4, 121.3, 103.7, 102.1, 100.1,
98.2, 84.6, 68.3, 27.6. FT-IR (ATR): 1722, 1465, 1243, 1130, 1118, 1033,
932, 862, 847 cm-1. EI-HRMS: m/z calcd for C18H16O8 [M]+ 360.0845, found
360.0847.
Justicidin A (12): To a solution of 10 (10.2 mg, 0.027 mmol) in acetone
(0.27 mL, 0.1 M) was added K2CO3 (7.4 mg, 0.054 mmol) and the solution
was cooled to 0 oC. Iodomethane (5.7 mg, 0.040 mmol) was added
dropwise and the mixture was warmed to room temperature. The reaction
was complete within 2 h as shown by TLC. The mixture was quenched
with saturated NH4Cl solution, extracted with EtOAc, and washed with
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601611
European Journal of Organic Chemistry
FULL PAPER
brine. After drying (Na2SO4) the solvent was removed under reduced
pressure and the residue was purified by column chromatography
(hexane:ethyl acetate, 3:1) to afford the product 12 as white solid (9.3 mg,
88%). mp = 254.0-254.5 oC. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (s, 1H),
7.03 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.75 (dd, J
= 1.6, 8.0 Hz, 1H), 6.12 (s, 2H), 5.71 (s, 2H), 4.14 (s, 3H), 3.95 (s, 3H),
3.65 (s, 3H), 13C NMR (100 MHz, DMSO-d6) δ 169.5, 151.7, 150.4, 147.7,
147.4, 147.2, 133.0, 129.9, 128.9, 125.3, 124.2, 124.0, 119.5, 111.3, 108.4,
106.0, 101.5, 101.0, 67.2, 59.5, 56.1, 55.6 FT-IR (ATR): 1748, 1478, 1434,
1355, 1261, 1212, 1168, 1151, 1084, 1030, 1012, 769 cm-1. ESI-MS: m/z
calcd for C22H19O7 [M+H]+ 395.12, found 395.20. The spectroscopic data
were in agreement with that reported in the literature.[25]
acetate, 2:1) to afford the product 16 as white solid (29.8 mg, 90%). mp =
283.9-284.6 oC. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.11 (d, J
= 7.6 Hz, 1H), 6.91 (s, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 2.0, 7.6
Hz, 1H), 6.22 (s, 2H), 5.41 (s, 2H), 3.90 (s, 3H), 3.77 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 169.4, 148.7, 148.3, 148.2, 148.1, 145.2, 131.1,
130.4, 127.5, 124.6, 122.5, 122.4, 119.1, 114.3, 111.2, 102.5, 101.9, 98.0,
66.5, 55.5, 55.4. FT-IR (ATR): 1745, 1460, 1335, 1239, 1216, 1125, 1015,
987, 934, 762 cm-1. ESI-MS: m/z calcd for C21H17O7 [M+H]+ 381.10, found
381.20. The spectroscopic data were in agreement with that reported in
the literature.[25]
Taiwanin E methyl ether (17): To a solution of 15 (6.9 mg, 0.019 mmol)
in acetone (0.19 mL, 0.1 M) was added K2CO3 (5.2 mg, 0.038 mmol) and
the solution was cooled to 0 oC. Iodomethane (4.0 mg, 0.028 mmol) was
added dropwise and the mixture was warmed to room temperature. The
reaction was complete within 2 h as shown by TLC. The mixture was
quenched with saturated NH4Cl solution, extracted with EtOAc, and
washed with brine. After drying (Na2SO4) the solvent was removed under
reduced pressure and the residue was purified by column chromatography
(hexane:ethyl acetate, 3:1) to afford the product 17 as white solid (6.3 mg,
88%). mp = 195.8-196.6 oC. 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H),
7.06 (s, 1H), 6.94 (s, J = 7.6 Hz, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.75 (dd, J
= 1.6, 8.0 Hz, 1H), 6.08 (s, 2H), 6.06 (dd, J = 1.6, 10.0 Hz, 2H), 5.51 (s,
2H), 4.09 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.4, 149.9, 148.9, 148.4,
147.5, 135.0, 132.3, 128.4, 127.9, 127.7, 125.7, 123.6, 119.7, 110.7, 108.2,
104.0, 101.8, 101.2, 98.5, 66.5, 60.0. FT-IR (ATR): 1723, 1458, 1437,
1348, 1240, 1220, 1137, 1119, 1029, 925 cm-1. ESI-MS: m/z calcd for
C21H15O7 [M+H]+ 379.08, found 379.00. The spectroscopic data were in
agreement with that reported in the literature.[27]
Cilinaphthalide B (13): To a solution of 11 (11.3 mg, 0.029 mmol) in
acetone (0.29 mL, 0.1 M) was added K2CO3 (7.9 mg, 0.057 mmol) and the
solution was cooled to 0 oC. Iodomethane (6.1 mg, 0.043 mmol) was
added dropwise and the mixture was warmed to room temperature. The
reaction was complete within 2 h as shown by TLC. The mixture was
quenched with saturated NH4Cl solution, extracted with EtOAc, and
washed with brine. After drying (Na2SO4) the solvent was removed under
reduced pressure and the residue was purified by column chromatography
(hexane:ethyl acetate, 3:1) to afford the product 13 as white solid (10.5 mg,
90%). mp = 197.4-198.8 oC. 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H),
7.09 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 2.0, 8.4 Hz, 1H), 6.88
(d, J = 1.6 Hz, 1H), 5.55 (s, 2H), 4.14 (s, 3H), 4.08 (s, 3H), 3.99 (s, 3H),
3.87 (s, 3H), 3.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.6, 151.60,
150.29, 148.75, 148.49, 147.71, 134.80, 131.67, 130.65, 127.29, 126.03,
124.69, 122.73, 119.14, 113.60, 110.78, 106.33, 100.54, 66.57, 59.72,
56.14, 55.95, 55.79. FT-IR (ATR): 2926, 1755, 1505, 1343, 1258, 1243,
1211, 1172, 1093, 1008, 857, 759 cm-1. ESI-MS: m/z calcd for C23H23O7
[M+H]+ 411.15, found 411.00. The spectroscopic data were in agreement
with that reported in the literature.[26]
Chinensinaphthol methyl ether (18): To a solution of 16 (12.1 mg, 0.032
mmol) in acetone (0.32 mL, 0.1 M) was added K2CO3 (8.8 mg, 0.064 mmol)
o
and the solution was cooled to 0 C. Iodomethane (6.8 mg, 0.045 mmol)
9-((tert-Butoxycarbonyl)oxy)-6-oxo-6,8-dihydrofuro[3',4':6,7]
was added dropwise and the mixture was warmed to room temperature.
The reaction was complete within 2 h as shown by TLC. The mixture was
quenched with saturated NH4Cl solution, extracted with EtOAc, and
washed with brine. After drying (Na2SO4) the solvent was removed under
reduced pressure and the residue was purified by column chromatography
(hexane:ethyl acetate, 3:1) to afford the product 18 as white solid (11.4 mg,
90%). mp = 198.8-200.1 oC. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H),
7.07 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 2.0, 8.0 Hz, 1H), 6.83
(d, J = 1.6 Hz, 1H), 6.08 (s, 2H), 5.51 (s, 2H), 4.09 (s, 3H), 3.97 (s, 3H),
3.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ . FT-IR (ATR): 1723, 1688,
1456, 1345, 1240, 1209, 1129, 1029, 933 cm-1. ESI-MS: m/z calcd for
C22H19O7 [M+H]+ 395.12, found 395.20. The spectroscopic data were in
agreement with that reported in the literature.[28]
naphtho[2,3-d][1,3]dioxol-5-yl trifluoromethanesulfonate (14): To a
solution of 8ba (651 mg, 1.81 mmol) in CH2Cl2 (36.2 mL, 0.05 M) was
added pyridine (215 mg, 2.72 mmol) and the solution was cooled to 0 oC.
Trifluoromethanesulfonic anhydride (613 mg, 2.17 mmol) was added
dropwise and the mixture was warmed to room temperature. The reaction
was complete within 2 h as shown by TLC. The mixture was diluted with
Et2O, quenched with 1N HCl solution and washed successively with
saturated NaHCO3 solution and brine. After drying (Na2SO4) the solvent
was removed under reduced pressure and the residue was purified by
column chromatography (hexane:ethyl acetate, 3:1) to afford the product
o
1
14 as light yellow solid (891 mg, quant.). mp = 136.3-137.8 C. H NMR
(400 MHz, CDCl3) δ 7.46 (s, 1H), 7.33 (s, 1H), 6.21 (s, 2H), 5.34 (s, 2H),
1.61 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 166.2, 151.8, 150.6, 149.9,
139.1, 138.9, 131.1, 130.1, 125.6, 115.0, 102.8, 98.9, 98.1, 85.7, 66.9,
27.6. FT-IR (ATR): 1753, 1496, 1434, 1267, 1198, 1095, 998, 763 cm-1.
EI-HRMS: m/z calcd for C19H15F3O10S [M]+ 492.0338, found 492.0340.
6,7,9-Trimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl
methanesulfonate (19): To a solution of 8ac (12.7 mg, 0.036 mmol) in
acetone (0.36 mL, 0.1 M) was added K2CO3 (9.6 mg, 0.069 mmol) and the
solution was cooled to 0 oC. Iodomethane (7.7 mg, 0.054 mmol) was
added dropwise and the mixture was warmed to room temperature. The
reaction was complete within 2 h as shown by TLC. The mixture was
quenched with saturated NH4Cl solution, extracted with EtOAc, and
washed with brine. After drying (Na2SO4) the solvent was removed under
reduced pressure and the residue was purified by column chromatography
(hexane:ethyl acetate, 3:1) to afford the product 19 as light yellow solid
(13.0 mg, 99%). mp = 249.1-249.9 oC. 1H NMR (400 MHz, CDCl3) δ 7.54
(s, 1H), 7.37 (s, 1H), 5.50 (s, 2H), 4.38 (s, 3H), 4.06 (s, 3H), 4.05 (s, 3H),
3.67 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.9, 155.2, 153.4, 150.5,
133.0, 131.4, 128.5, 125.0, 110.0, 102.8, 100.5, 67.3, 63.9, 56.2, 39.0. FT-
IR (ATR): 2921, 1751, 1429, 1319, 1265, 1167, 1156, 1032, 989, 946, 860,
801 cm-1. EI-HRMS: m/z calcd for C16H16O8S [M]+ 368.0566, found
368.0567.
Taiwanin E (15): To a solution of 14 (35.3 mg, 0.072 mmol), Pd(OAc)2
(1.6 mg, 0.007 mmol), PCy3 (4.0 mg, 0.014 mmol), Cs2CO3 (70.4 mg, 0.22
mmol) in 25% aqueous 1,4-dioxane (0.72 mL, 0.1 M) was added
potassium 1,3-benzodioxol-5-yltrifluoroborate (24.6 mg, 0.11 mmol). The
mixture was stirred at 120 oC for 17 h. The mixture was quenched with
saturated NH4Cl solution, extracted with EtOAc, and washed with brine.
After drying (Na2SO4) the solvent was removed under reduced pressure
and the residue was purified by column chromatography (hexane:ethyl
acetate, 2:1) to afford the product 15 as white solid (23.3 mg, 89%). mp =
>350 oC. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.61 (s, 1H), 7.00
(d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.81 (d, J = 1.6 Hz, 1H), 6.69 (dd, J = 1.6,
8.0 Hz, 1H), 6.16 (d, J = 2.0 Hz, 2H), 6.11 (d, J = 11.6 Hz, 2H), 5.35 (s,
2H). 13C NMR (100 MHz, DMSO-d6) δ 169.4, 148.7, 148.3, 146.8, 146.6,
145.4, 131.1, 129.9, 128.8, 124.6, 123.7, 122.3, 119.2, 110.9, 107.8, 102.4,
102.0, 101.0, 98.1, 66.6. FT-IR (ATR): 1712, 1457, 1350, 1240, 1215,
1139, 1034, 997, 931, 790 cm-1. ESI-MS: m/z calcd for C20H13O7 [M+H]+
365.07, found 364.90. The spectroscopic data were in agreement with that
reported in the literature.[23]
9-Methoxy-8-oxo-6,8-dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-
5-yl methane-sulfonate (20): To a solution of 8bb (27.8 mg, 0.082 mmol)
in acetone (0.82 mL, 0.1 M) was added K2CO3 (22.6 mg, 0.16 mmol) and
the solution was cooled to 0 oC. Iodomethane (17.5 mg, 0.12 mmol) was
added dropwise and the mixture was warmed to room temperature. The
reaction was complete within 2 h as shown by TLC. The mixture was
quenched with saturated NH4Cl solution, extracted with EtOAc, and
washed with brine. After drying (Na2SO4) the solvent was removed under
reduced pressure and the residue was purified by column chromatography
(hexane:ethyl acetate, 3:1) to afford the product 20 as light yellow solid
(28.9 mg, quant.). mp = 197.4-198.2 oC. 1H NMR (400 MHz, CDCl3) δ 7.67
(s, 1H), 7.34 (s, 1H), 6.16 (s, 2H), 5.50 (s, 2H), 4.32 (s, 3H), 3.37 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 167.8, 155.4, 151.8, 149.1, 133.6, 132.0,
Chinensinaphthol (16): To a solution of 14 (42.8 mg, 0.087 mmol),
Pd(OAc)2 (2.0 mg, 0.009 mmol), PCy3 (4.9 mg, 0.017 mmol), Cs2CO3 (85.0
mg, 0.26 mmol) in 25% aqueous 1,4-dioxane (0.87 mL, 0.1 M) was added
potassium 1,3-benzodioxol-5-yltrifluoroborate (31.8 mg, 0.13 mmol). The
mixture was stirred at 120 oC for 17 h. The mixture was quenched with
saturated NH4Cl solution, extracted with EtOAc, and washed with brine.
After drying (Na2SO4) the solvent was removed under reduced pressure
and the residue was purified by column chromatography (hexane:ethyl
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10.1002/ejoc.201601611
European Journal of Organic Chemistry
FULL PAPER
130.2, 126.7, 110.9, 102.3, 100.8, 98.3, 67.4, 63.9, 38.8. FT-IR (ATR):
2924, 1752, 1615, 1458, 1318, 1259, 1170, 1129, 1037, 968, 948, 813 cm-
1. EI-HRMS: m/z calcd for C15H12O8S [M]+ 352.0253, found 352.0254.
Feng, C.-H. Liu, M. Li, Y.-X. Li, M. Y. Geng, J. Ding, Invest. New Drugs
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H. C. Lin, C. N. Lin, Arch. Pharm. (Weinheim) 2004, 337, 207212.
D. Janmanchi, Y. P. Tseng, K.-C. Wang, R. L. Huang, C. H. Lin, S. F.
Yeh, Bioorg. Med. Chem. 2010, 18, 12131226.
Justicidin C (21): To a solution of 19 (5.2 mg, 0.014 mmol), Pd(OAc)2 (0.3
mg, 0.001 mmol), RuPhos (1.4 mg, 0.003 mmol), Cs2CO3 (31.9 mg, 0.042
mmol) in THF/t-BuOH 1:1 (0.14 mL, 0.1 M) was added potassium 1,3-
benzodioxol-5-yltrifluoroborate (4.8 mg, 0.021 mmol). The mixture was
stirred at 85 oC for 17 h. The mixture was quenched with saturated NH4Cl
solution, extracted with EtOAc, and washed with brine. After drying
(Na2SO4) the solvent was removed under reduced pressure and the
residue was purified by column chromatography (hexane:ethyl acetate, 3:1)
to afford the product 21 as white solid (8.7 mg, 93%). mp = 260.7-262.2
[3]
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1
oC. H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.99 (s, 1H), 6.97 (dd, J =
D. Delorme, Y. Ducharme, C. Brideau, C.-C. Chan, N. Chauret, S.
Desmarais, D. Dube, J.-P. Falgueyret, R. Fortin, J. Guay, P. Hamel, T.
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0.4, 7.6 Hz, 1H), 6.80 (m, 2H), 6.08 (dd, J = 1.2, 13.2 Hz, 2H), 5.14 (s, 2H),
4.38 (s, 3H), 4.07 (s, 3H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.3,
155.5, 152.4, 149.8, 148.3, 147.5, 139.0, 133.5, 129.7, 126.4, 123.7, 122.9,
109.8, 109.4, 109.0, 104.2, 102.3, 101.4, 68.8, 63.5, 56.1, 55.9. FT-IR
(ATR): 2916, 1747, 1706, 1505, 1431, 1346, 1260, 1226, 1212, 1159, 1037,
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395.00. The spectroscopic data were in agreement with that reported in
the literature.[29]
[7]
Justicidin D (22): To a solution of 20 (11.2 mg, 0.032 mmol), Pd(OAc)2
(0.7 mg, 0.003 mmol), RuPhos (2.8 mg, 0.006 mmol), Cs2CO3 (31.3 mg,
0.096 mmol) in THF/t-BuOH 1:1 (0.32 mL, 0.1 M) was added potassium
1,3-benzodioxol-5-yltrifluoroborate (10.9 mg, 0.048 mmol). The mixture
[8]
[9]
o
was stirred at 85 C for 17 h. The mixture was quenched with saturated
NH4Cl solution, extracted with EtOAc, and washed with brine. After drying
(Na2SO4) the solvent was removed under reduced pressure and the
residue was purified by column chromatography (hexane:ethyl acetate,
3:1) to afford the product 22 as white solid (11.0 mg, 91%). mp = 251.1-
252.9 oC. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.00 (s, 1H), 6.76 (m,
2H), 6.08 (m, 4H), 5.12 (dd, J = 15.2, 20.0 Hz, 2H), 4.33 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 169.1, 155.7, 150.8, 148.3, 148.2, 147.6, 139.4, 135.2,
129.6, 127.3, 125.3, 122.9, 110.1, 109.9, 109.0, 102.1, 101.8, 101.4, 100.3,
68.8, 63.5. FT-IR (ATR): 2920, 1759, 1603, 1501, 1459, 1376, 1244, 1220,
1114, 1025, 933 cm-1. ESI-MS: m/z calcd for C21H15O7 [M+H]+ 379.08,
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Acknowledgements
This work was supported by the Korea Institute of Science and
Technology (KIST) institutional program (Project No. 2Z04930).
This research was also conducted under the industrial
infrastructure program for fundamental technologies (N0000885)
which is funded by the Ministry of Trade, Industry & Energy
(MOTIE, Korea).
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Keywords: Total synthesis • Arylnaphthalene lactone •
HauserKraus annulation • SuzukiMiyaura cross-coupling
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European Journal of Organic Chemistry
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Entry for the Table of Contents
FULL PAPER
Total Synthesis
Taejung Kim, Kyu Hyuk Jeong, Ki Sung
Kang, Masaya Nakata, Jungyeob Ham*
Page No. – Page No.
An Optimized and General Synthetic
Strategy to Prepare Arylnaphthalene
Lactone Natural Products from
Cyanophthalides
In this study, a novel and simple method for the preparation of various
arylnaphthalene lactone natural products was developed and used to synthesize nine
arylnaphthalene lactone natural products. The syntheses proceeded via
HauserKraus annulation of cyanophthalides and SuzukiMiyaura cross-coupling of
arylnaphthalene lactones having a sulfonate group with the corresponding potassium
aryltrifluoroborates.
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