The Total Synthesis of Retrojusticidin B, Justicidin E, and Helioxanthin

Article abstract of DOI:10.1021/acs.joc.5b00866

Making use of a tandem free radical cyclization process mediated by Mn(OAc)₃ as a key operation, the total synthesis of retrojusticidin B, justicidin E, and helioxanthin has been concisely achieved in four or five steps in an overall yield of 4

Full text of DOI:10.1021/acs.joc.5b00866

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Article
The Total Synthesis of Retrojusticidin B, Justicidin E and Helioxanthin
Tzu-Ting Kao, Chun-Cheng Lin, and Kak-Shan Shia
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Jun 2015
Downloaded from http://pubs.acs.org on June 7, 2015
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The Total Synthesis of Retrojusticidin B, Justicidin E and Helioxanthin
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TzuꢀTing Kao,†,‡ ChunꢀCheng Lin,*,† and KakꢀShan Shia*,‡
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†Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30013, R.O.C.
‡ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes,
Miaoli County 35053, Taiwan, R.O.C.
ABSTRACT: Making use of a tandem free radical cyclization process mediated by Mn(OAc)3 as a
key operation, the total synthesis of retrojusticidin B, justicidin E and helioxanthin has been
concisely achieved in four or five steps in an overall yield of 45%, 33% and 44%, respectively, from
a common starting material 5.
INTRODUCTION
Structurally, lignans are a large family of dimeric propyl phenols and could be broadly divided into
eight classes in nature.1 Among them, lignans containing an arylnaphthalene lactone core, as typified
by retrojusticidin B, retrochinensin, justicidin E and helioxanthin (Figure 1), were isolated from a
variety of plant species from different parts,2 including bark, root, leaf, fruit and seed, and belong to
a group noted for various biological activities, such as antitumor,3 antiviral,4 antibacterial,5
cytotoxic,6 HIVꢀ1 reverse transcriptase,7 and phosphodiesterase inhibitory activities.8 Very recently,
helioxanthin was evaluated in vitro to inhibit various steps involved in brain tumor metastasis and
retarded the migration of both melanoma and brain endothelial cell, indicating that natural products
might play a critical role in modern medicine as the horizon of biological knowledge expands.9
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O
O
O
O
MeO
MeO
O
O
O
O
O
O
O
O
O
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O
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O
OMe
O
O
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O
OMe
O
O
Retrojusticidin B
Retrochinensin
Justicidin E
Helioxanthin
Figure 1. Natural arylnaphthalene lignans.
Thus, developing various synthetic methods to synthesize naturally occurring compounds in a
more efficient manner becomes more and more important, particularly considering that the
extinction of terrestrial and marine species is so rapid. As documented, arylnaphthalene lignans
had been known to be synthesized by many different approaches, by which the desired
arylnaphthalene lactone cores were mainly constructed via DielsꢀAlder reaction,10 Auꢀcatalyzed
annulation,11 Pdꢀ, or Agꢀcatalyzed [2+2+2] cocyclization,12 dehydroꢀDielsꢀAlder reaction,13 and
benzannulation.4b,14 In continuation of our studies on the synthesis of natural and unnatural
lignan for new drug screening, we have developed several efficient cyclization processes to have
facile access to linear [6,6,5] or [5,6,5] tricyclic systems (Scheme 1).15ꢀ17
These protocols are currently extended to the synthesis of various natural products containing
either cyclopenta[b]naphthalene or benzo[b]fluorene skeletons, such as stealthins and
kinamycins.18 In addition, it was discovered that instead of using αꢀcyano ketones as substrates,
Scheme 1. Tandem Cyclization via a Free Radical Catalytic Process under Conditions (a), (b) or (c)
O
O
CN
X
X
CN
(a) TBAI/TBHP
(b) CuI/O2
(c) Mn(OAc)3
n
n
R
R
n = 0,1; x = C, O, S; R = silyl, aryl, ester, ketone,
amide, phosphonate, halogen
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the corresponding αꢀcyano esters, as typified by compound 2 in the model study in Scheme 2,
could also undergo the same free radical cyclization cascade to afford synthetically useful
arylnaphthalene lactone skeletons (e.g. 3 in Scheme 2).15ꢀ17,19 In general, αꢀcyano ketone system
(Scheme 1) is more reactive than αꢀcyano esters for the cyclization process. Herein, we wish to
report that making use of this newly developed methodology as a key operation, the synthesis of
retrojusticidin B, justicidin E and helioxanthin, respectively, has been experimentally realized.
Compared to above conventional methods in synthesizing the arylnaphthalene natural
products,10ꢀ14,4b the advantage of the present free radical cascade method exhibits higher yields,
shorter synthetic routes and more economy. Results are presented as follows.
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RESULTS AND DISCUSSION
According to Scheme 2, the project began with synthesizing phenylnaphthalene lactone 4 as a model
study. Esterification of 3ꢀphenylꢀ2ꢀpropynꢀ1ꢀol and cyanoacetic acid in the presence of EDCI and
DMAP gave rise to αꢀcyano ester 1 in almost quantitative yield (97%). Compound 1 was subjected
to a modified Knoevenagel condensation, by which Hantzsch ester was added in one pot to reduce
the aldol condensation product formed in situ, to afford intermediate 2 in 81% yield. αꢀCyano ester 2
was transformed into αꢀcyano lactone 3 in 75% yield under a tandem radical annulation process
mediated by manganese (III) acetate.17 Finally, compound 3 was reduced with SmI2 followed by
DDQ oxidation to furnish the desired product 4 in 84% yield over two steps.20 Alternatively,
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reductive decyanation could be fulfilled via lithium naphthalenide (LN),21 but yields were much
lower.
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Scheme 2. Synthesis of Phenylnaphthalene Lactone
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O
O
CN
benzaldehyde, L-proline
Hantzsch ester
cyanoacetic acid
O
CN
OH
EDCI, DMAP
O
EtOH, rt, 16 h, 81%
DCM, rt, 3 h, 97%
2
1
O
O
CN
O
O
O
O
SmI2 (0.1 M in THF)
0 °C, 1 h
Mn(OAc)3
PhH, 90 °C, 16 h, 75%
DDQ
PhH reflux, 10 h
84% for two steps
3
4
Encouraged by the success of the model study, the synthesis of retrojusticidin B was then
attempted following the similar approach starting from alkynol 5, commercially available or
readily prepared according to the procedure reported in the literature.11 As illustrated in Scheme
3, compound 5 was subjected to esterification to furnish cyano ester 6 in almost quantitative
yield (98%), which in turn underwent Knoevenagel condensation in the presence of Hantzsch
ester to afford the key intermediate 7 in 85% yield. Compound 7 was converted to a pair of
o
separable regioisomers 8 (67%) and 9 (22%) with Mn(OAc)3 in a sealed pressure vessel at 90 C
for 16 h. The desired retrojusticidin B was unexpectedly achieved in 80% yield when
decyanation of isomer 8 was carried out with SmI2 in the presence of triethylamine under air.22
The mechanistic insight of the rapid aromatization under these reaction conditions is not fully
understood, and worth further studies. By this synthetic strategy, retrojusticidin B was
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accomplished in four steps in an overall yield of 45%.
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Scheme 3. Synthesis of Retrojusticidin B
8
9
O
CN
OH
O
3,4-dimethoxybenzaldehyde
L-proline, Hantzsch ester
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cyanoacetic acid
EDCI, DMAP
EtOH, rt, 12 h, 85%
DCM, rt, 3 h, 98%
6
O
5
O
O
O
O
CN
R1
R2
O
O
CN
O
R3
Mn(OAc)3
PhH, 90 °C, 16 h, 89%
OMe
OMe
O
O
O
7
O
8
9
R
R
1 = R2 = OMe, R3 = H, 67%
1 = H, R2 = R3 = OMe, 22%
O
MeO
MeO
O
SmI2 (0.1 M in THF)
0 °C, 1h
then Et3N under air
30 min, 80%
O
O
Retrojusticidin B
A similar approach was further extended to synthesize justicidin E and helioxanthin starting from
the common intermediate αꢀcyano ester 6. As depicted in Scheme 4, compound 6 was first
coupled with piperonal to afford the key intermediate 10 in moderate yield (78%), which in turn
underwent Mn(III)ꢀmediated oxidative cyclization to give a pair of inseparable regioisomers 11
and 12 in a ratio of 3:1 in 71% yield. The mixture of compounds 11 and 12 was then reduced
with SmI2 and triethylamine under air to afford justicidin E and helioxanthin, respectively, in
59% and 20%, which were readily purified by HPLC. By this approach, justicidin E was
achieved in four steps in an overall yield of 33% starting from compound 5. Indeed, helioxanthin
could be obtained exclusively via a more efficient synthetic design as illustrated in Scheme 5.
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Scheme 4. Synthesis of Justicidin E and Helioxanthin
4
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6
O
CN
7
8
9
O
piperonal, L-proline
Hantzsch ester
Mn(OAc)3
O
O
6
EtOH, 60 °C, 6 h, 78%
PhH, 90 °C, 16 h, 71%
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O
O
10
O
O
O
CN
R1
R2
O
O
O
SmI2 (0.1 M in THF)
0 °C, 1 h
O
O
O
O
R3
+
then Et3N under air
30 min, 79%
O
O
O
O
O
O
Justicidin E
Helioxanthin
(20%)
(59%)
11 R1-R2 = OCH2O, R3 = H
1 = H, R2-R3 = OCH2O
12
R
Instead of piperonal, 6ꢀbromopiperonal was employed to couple with compound 6 to furnish
compound 13 (83%), which could undergo cyclization regioselectively. Bromo lactone 14 (68%)
thus obtained was further reduced with SmI2 (85%) followed by hydrogenolysis (92%) to achieve
helioxanthin in five steps in an overall yield of 44% starting from compound 5. The
spectroscopic data of synthetic retrojusticidin B, justicidin E and helioxanthin were found to be
in good agreement with those reported in the literature.10ꢀ14
Scheme 5. Synthesis of Helioxanthin
Br
O
O
CN
CN
6-bromopiperonal
O
O
Mn(OAc)3
L-proline, Hantzsch ester
O
O
6
O
PhH, 90 °C, 16 h, 68%
EtOH, 60 °C, 6 h, 83%
O
O
Br
O
13
14
O
O
O
O
Br
O
SmI2 (0.1 M in THF)
0 °C, 1 h
O
O
O
H2, 5% Pd/C
O
1,4-dioxane, 16 h, 92%
then Et3N under air
30 min, 85%
O
O
O
15
O
O
Helioxanthin
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CONCLUSION
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In conclusion, it is envisioned that the newly developed approach mediated by Mn(III) oxidative
cyclization of αꢀcyano ester systems can be extended to the synthesis of many structurally
diverse arylnaphthelene lactones concisely, which could be used to synthesize natural or
unnatural lignans for new drug screening by appropriate structural modifications of the starting
material. It is believed that the above tandem cyclization protocol is a valuable and significant
addition to synthetic organic chemistry.
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EXPERIMENTAL SECTION
General Experimental Procedure. All reactions were performed under air unless otherwise stated.
All solvents and reagents were employed as received without further purification. Analytical thin
layer chromatography was performed on SiO2 60 Fꢀ254 plates and flash column chromatography
was carried out using SiO2 60 (particle size 0.040–0.055 mm, 230–400 mesh). Visualization was
performed under UV irradiation at 254 nm followed by staining with aqueous potassium
permanganate [KMnO4 (3 g) and K2CO3 (20 g) in 300 mL of H2O containing 5 mL of an aqueous
solution of NaOH (5%, w/v)] and charring by heat gun. Infrared spectra (IR) were recorded on a
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FTꢀIR spectrometer and expressed in cmꢀ1. H NMR spectra were recorded at 400 MHz and 13C
NMR spectra at 100 MHz. Chloroformꢀd were used as the solvent and TMS (δ = 0.00 ppm) as an
internal standard. Chemical shifts are reported as δ values in ppm as referenced to TMS.
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Multiplicities are recorded as s (singlet), d (doublet), q (quartet), dd (doublet of doublets), m
(multiplet), br (broad). Coupling constants (J) are expressed in Hz. HRMS was obtained on a triple
quadrupole mass analysis using electrospray ionization (ESI) source, and spectral data were recorded
as m/z values. Melting points were measured using an electrothermal instrument.
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3ꢀPhenylpropꢀ2ꢀynyl 2ꢀcyanoacetate (1). A mixture of 3ꢀphenylꢀ2ꢀpropynꢀ1ꢀol (6.0 g, 45.4 mmol),
cyanoacetic acid (7.6 g, 90.8 mmol), EDCI (13.0 g, 68.0 mmol) and DMAP (831.4 mg, 6.8 mmol) in
CH2Cl2 (80.0 mL) was stirred at room temperature for 3 h. After reaction was complete, the mixture
was washed with water, and the aqueous layer was separated and extracted with CH2Cl2 (2 × 50 mL).
Organic layers were combined and dried with MgSO4, filtered, and concentrated under reduced
pressure to give the crude residue, which was purified by flash chromatography on silica gel
(EtOAc/nꢀhexane, 1:6) to afford compound 1 (8.7 g, 97%) as a yellow liquid; 1H NMR (CDCl3, 400
MHz) δ: 7.77 (d, J = 1.6 Hz, 2H), 7.42–7.28 (m, 3H), 5.01 (s, 2H), 3.52 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ: 162.4, 131.9, 129.1, 128.3, 121.5, 112.6, 87.7, 81.2, 54.9, 24.6; IR (CH2Cl2 cast): 2929,
2360, 2245, 1755, 1490, 1173 cmꢀ1; HRMS (ESI, m/z): calcd for C12H9NO2: 199.0623 [M]+, found:
199.0633.
3ꢀPhenylpropꢀ2ꢀynyl 2ꢀcyanoꢀ3ꢀphenylpropanoate (2). To a solution of compound 1 (4.0 g,
20.0 mmol) in ethanol (200.0 mL) at room temperature was sequentially added benzaldehyde (2.5
g, 24.1 mmol), Lꢀproline (460.0 mg, 4.0 mmol) and Hantzsch ester (5.0 g, 20.0 mmol) in one
portion. The reaction mixture was stirred at room temperature for 16 h and concentrated under
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reduced pressure to give the crude residue, which was purified by flash chromatography on silica
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gel (EtOAc/nꢀhexane, 1:10) to afford compound 2 (4.6 g, 81%) as a yellow liquid. H NMR
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(CDCl3, 400 MHz) δ: 7.45–7.46 (m, 2H), 7.37–7.28 (m, 8H), 5.07 (d, J = 15.6 Hz, 1H), 4.98 (d, J
= 15.6 Hz, 1H), 3.81 (dd, J = 8.8, 6.0 Hz, 1H), 3.32 (dd, J = 14.0, 6.0 Hz, 1H), 3.24 (dd, J = 14.0,
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8.8 Hz, 1H); C NMR (CDCl3, 100 MHz) δ: 164.9, 134.9, 131.9, 129.1, 129.0, 128.9, 128.4,
127.9, 121.6, 115.7, 87.7, 81.4, 54.9, 39.6, 35.7; IR (CH2Cl2 cast): 3490, 3032, 2936, 2251, 1751,
1490, 1190 cmꢀ1; HRMS (ESI, m/z): calcd for C19H15NO2: 289.1103 [M]+, found: 289.1102.
3ꢀOxoꢀ9ꢀphenylꢀ1,3,3α,4ꢀtetrahydronaphtho[2,3ꢀc]furanꢀ3αꢀcarbonitrile (3). A mixture of
compound 2 (1.0 g, 3.4 mmol) and Mn(OAc)3 (1.8 g, 6.8 mmol) in benzene (34.0 mL) was stirred
o
in a sealed pressure vessel at 90 C for 16 h. After reaction was complete, the mixture was
filtered through a pad of celite followed by washing with CH2Cl2 (3 × 30 mL). The filtrate was
concentrated under reduced pressure to give the crude residue, which was subjected to
purification by flash chromatography on silica gel (EtOAc/nꢀhexane, 1:8) to afford compound 3
o
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(975.8 mg, 75 %) as a white solid. mp 138–139 C; H NMR (CDCl3, 400 MHz) δ: 7.47–7.43 (m,
3H), 7.38–7.36 (m, 2H), 7.34–7.21 (m, 3H), 7.05 (d, J = 7.2 Hz, 1H), 5.33 (d, J = 13.6 Hz, 1H),
4.80 (d, J = 13.6 Hz, 1H), 3.48 (d, J = 15.6 Hz, 1H), 3.23 (d, J = 15.6 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ: 168.8, 138.1, 134.4, 133.1, 130.1, 129.5, 129.4, 128.9, 128.8, 128.6, 128.3, 127.8,
124.2, 115.0, 70.0, 40.4, 34.4; IR (CH2Cl2 cast): 3062, 2360, 2235, 1786, 1444, 1155 cmꢀ1;
HRMS (ESI, m/z): calcd for C19H13NO2: 287.0946 [M]+, found: 287.0945.
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4ꢀPhenylnaphtho[2,3ꢀc]furanꢀ1(3H)ꢀone (4). Compound 3 (160.0 mg, 0.5 mmol) was dissolved
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7
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in a solution of SmI2 (0.1 M) in THF (33.4 mL, 3.3 mmol) at 0 C under argon. After stirring for
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1 h at 0 C, reaction was allowed to warm up to room temperature and quenched with saturated
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aqueous NH4Cl (5 mL). The aqueous layer was separated and extracted with EtOAc (3 × 20 mL).
The combined organic layer was dried with MgSO4, filtered, and concentrated under reduced
pressure to give the residue, which without purification was dissolved in benzene (5.0 mL) and
treated with DDQ (249.7 mg, 1.0 mmol). The reaction mixture was heated up to reflux for 10 h,
and then cooled down and filtered through a pad of celite followed by washing with CH2Cl2 (3 ×
30 mL). The organic layer was concentrated under reduced pressure to give the crude residue,
which was subjected to purification by flash chromatography on silica gel (EtOAc/nꢀhexane, 1:8)
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to afford compound 4 (120.1 mg, 84 %) as a white solid. mp 161–162 C; H NMR (CDCl3, 400
MHz) δ: 8.53 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.63–7.49 (m, 5H), 7.39
13
(d, J = 7.2 Hz, 2H), 5.28 (s, 2H); C NMR (CDCl3, 100 MHz) δ: 171.2, 138.4, 135.7, 134.8,
134.1, 133.6, 130.1, 129.3, 129.1, 129.0, 128.4, 126.7, 126.4, 125.8, 122.9, 69.5; IR (CH2Cl2
cast): 3061, 2924, 1763, 1632, 1024 cmꢀ1; HRMS (ESI, m/z): calcd for C18H12O2: 260.0837 [M]+,
found: 260.0837.
3ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)propꢀ2ꢀynyl
2ꢀcyanoacetate
(6).
A
mixture
of
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mmol), EDCI (10.0 g, 52.1 mmol) and DMAP (500.0 mg, 4.1 mmol) in CH2Cl2 (60.0 mL) was
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stirred at room temperature for 3 h. After reaction was complete, the mixture was washed with
water, and the aqueous layer was separated and extracted with CH2Cl2 (2 × 50 mL). Organic
layers were combined and dried with MgSO4, filtered, and concentrated under reduced pressure
to give the crude residue, which was purified by flash chromatography on silica gel
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(EtOAc/nꢀhexane, 1:6) to afford compound 6 (6.7 g, 98%) as a yellow solid. mp 109–110 C; H
NMR (CDCl3, 400 MHz) δ: 6.98 (dd, J = 8.0, 1.6 Hz, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.75 (d, J =
8.0 Hz, 1H), 5.98 (s, 2H), 5.00 (s, 2H), 3.54 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 162.4, 148.5,
147.4, 126.8, 114.6, 112.6, 111.7, 108.4, 101.4, 87.6, 79.7, 55.0, 24.6; IR (CH2Cl2 cast): 2929,
2360, 2232, 1753, 1489, 1215 cmꢀ1; HRMS (ESI, m/z): calcd for C13H9NO4: 243.0532 [M]+,
found: 243.0533.
3ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)propꢀ2ꢀynyl 2ꢀcyanoꢀ3ꢀ(3,4ꢀdimethoxyphenyl)propanoate (7). To
a solution of compound 6 (1.5 g, 6.1 mmol) in ethanol (50.0 mL) at room temperature was
sequentially added 3,4ꢀdimethoxybenzaldehyde (1.2 g, 7.3 mmol), Lꢀproline (140.0 mg, 1.2
mmol) and Hantzsch ester (1.5 g, 6.1 mmol) in one portion. The reaction mixture was stirred at
room temperature for 12 h and concentrated under reduced pressure to give the crude residue,
and which was purified by flash chromatography on silica gel (EtOAc/nꢀhexane, 1:3) to afford
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compound 7 (2.0 g, 85%) as a white solid. mp 100–101 C; H NMR (CDCl3, 400 MHz) δ: 6.98
(dd, J = 8.0, 1.6 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.85–6.75 (m, 4H), 5.99 (s, 2H), 4.99 (d, J =
15.6 Hz, 1H), 4.95 (d, J = 15.6 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.78 (dd, J = 8.4, 5.6 Hz, 1H),
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3.26 (dd, J = 14.0, 5.6 Hz, 1H), 3.18 (dd, J = 14.0, 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ:
165.0, 149.0, 148.6, 148.5, 147.4, 127.3, 126.8, 121.3, 115.8, 114.7, 112.0, 111.8, 111.3, 108.4,
101.4, 87.6, 79.8, 55.8, 55.7, 54.9, 39.8, 35.4; IR (CH2Cl2 cast): 2937, 2360, 2232, 1750, 1517,
1034 cmꢀ1; HRMS (ESI, m/z): calcd for C22H19NO6: 393.1212 [M]+, found: 393.1213.
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9ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ6,7ꢀdimethoxyꢀ3ꢀoxoꢀ1,3,3α,4ꢀtetrahydronaphtho[2,3ꢀc]furanꢀ3
αꢀcarbonitrile (8). A mixture of compound 7 (1.4 g, 3.5 mmol) and Mn(OAc)3 (2.8 g, 10.6 mmol)
o
in benzene (40.0 mL) was stirred in a sealed pressure vessel was stirred at 90 C for 16 h. After
reaction was complete, the mixture was filtered through a pad of celite followed by washing with
CH2Cl2 (3 × 30 mL). The filtrate was concentrated under reduced pressure to give the crude
residue, which was subjected to purification by flash chromatography on silica gel
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(EtOAc/nꢀhexane, 1:2) to afford compound 8 (921.5 mg, 67 %) as a white solid. mp 130–131 C;
1H NMR (CDCl3, 400 MHz) δ: 6.91–6.88 (m, 2H), 6.75–6.65 (m, 2H), 6.61 (s, 1H), 6.06–6.03 (m,
2H), 5.31 (d, J = 13.6 Hz, 1H), 4.82 (d, J = 13.6 Hz, 1H), 3.95 (s, 3H), 3.73 (s, 3H), 3.35 (d, J =
15.2 Hz, 1H), 3.17 (d, J = 15.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 169.0, 149.5, 148.3,
148.0, 137.4, 128.1, 125.6, 123.3, 123.1, 122.8, 121.4, 115.3, 111.9, 111.2, 109.7, 108.5, 101.4,
70.1, 56.0 (2C), 40.7, 34.1; IR (CH2Cl2 cast): 2937, 2234, 1791, 1514, 1257 cmꢀ1; HRMS (ESI,
m/z): calcd for C22H17NO6: 391.1056 [M]+, found: 391.1056.
9ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ7,8ꢀdimethoxyꢀ3ꢀoxoꢀ1,3,3α,4ꢀtetrahydronaphtho[2,3ꢀc]furanꢀ3
o
αꢀcarbonitrile (9). Yield: 22%; pale yellow solid. mp 237–238 C; 1H NMR (CDCl3, 400 MHz) δ:
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7.09 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.69–6.51 (m, 2H),
6.00–5.98 (m, 2H), 5.26 (d, J = 14.0 Hz, 1H), 4.82 (d, J = 14.0 Hz, 1H), 3.84 (s, 3H), 3.35 (d, J =
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14.8 Hz, 1H), 3.31 (s, 3H), 3.07 (d, J = 14.8 Hz, 1H); C NMR (CDCl3, 100 MHz) δ: 168.9,
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153.6, 147.6, 136.1, 130.7, 126.4, 124.0, 123.2, 120.7, 114.9, 112.6, 107.8, 101.3, 70.1, 61.0,
55.8, 40.8, 35.5; IR (CH2Cl2 cast): 2922, 2356, 2238, 1792, 1479, 1257 cmꢀ1; HRMS (ESI, m/z):
calcd for C22H17NO6: 391.1056 [M]+, found: 391.1054.
Retrojusticidin B. The compound 8 (120.0 mg, 0.3 mmol) was dissolved in a solution of SmI2
o
(0.1M) in THF (18.0 mL, 1.8 mmol) at 0 C under argon. After stirring for 1 h at 0 oC, Et3N (0.08
mL, 0.6 mmol) was added at the same temperature by syringe under air. The reaction mixture
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was stirred for another 30 min at 0 C and then saturated aqueous NH4Cl solution (3 mL) was
added and diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layer
was dried with MgSO4, filtered, and concentrated under reduced pressure to give the residue,
which was subjected to purification by flash chromatography on silica gel (EtOAc/nꢀhexane, 1:2)
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to afford retrojusticidin B (87.4 mg, 80 %) as a yellow solid. H NMR (CDCl3, 400 MHz) δ: 8.28
(s, 1H), 7.28 (s, 1H), 7.08 (s, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 1.2 Hz, 1H), 6.82 (d, J =
2.0 Hz, 1H), 6.10 (d, J = 1.2 Hz, 1H), 6.06 (d, J = 1.2 Hz, 1H), 5.20 (s, 2H), 4.04 (s, 3H), 3.85 (s,
3H). 13C NMR (CDCl3, 100 MHz) δ: 171.6, 152.0, 150.1, 148.3, 147.6, 137.9, 131.9, 131.6, 129.8,
129.7, 124.1, 122.7, 121.3, 109.5, 109.0, 107.6, 104.0, 101.4, 69.5, 56.0, 55.9.
3ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)propꢀ2ꢀynyl
3ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ2ꢀcyanopropanoate
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(10). To a solution of compound 6 (7.2 g, 29.6 mmol) in ethanol (200.0 mL) at room temperature
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was sequentially added piperonal (5.3 g, 35.5 mmol), Lꢀproline (680.0 mg, 5.9 mmol) and
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Hantzsch ester (7.4 g, 29.6 mmol) in one portion. The reaction mixture was stirred at 60 C for 6
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h and concentrated under reduced pressure to give the crude residue, which was purified by flash
chromatography on silica gel (EtOAc/nꢀhexane, 1:4) to afford compound 10 (8.7 g, 78%) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ: 6.98 (dd, J = 8.0, 1.6 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H),
6.77–6.73 (m, 4H), 5.98 (s, 2H), 5.93 (s, 2H), 4.99 (d, J = 15.6 Hz, 1H), 4.95 (d, J = 15.6 Hz, 1H),
3.75 (dd, J = 8.0, 5.6 Hz, 1H), 3.22 (dd, J = 14.0, 5.6 Hz, 1H), 3.15 (dd, J = 14.0, 8.0 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ: 164.9, 148.5, 147.9, 147.4, 147.2, 128.5, 126.9, 122.4, 115.7,
114.8, 111.8, 109.3, 108.6, 108.4, 101.4, 101.1, 87.6, 79.8, 54.9, 39.8, 35.5; IR (CH2Cl2 cast):
2901, 2232, 1750, 1490, 1038 cmꢀ1; HRMS (ESI, m/z): calcd for C21H15NO6: 377.0899 [M]+,
found: 377.0898.
9ꢀ(1,3ꢀBenzodioxolꢀ5ꢀyl)ꢀ6ꢀoxoꢀ5,8ꢀdihydrofuro[3',4':6,7]naphtho[2,3ꢀd][1,3]dioxoleꢀ5α(6H)ꢀ
carbonitrile
(11)
and
10ꢀ(1,3ꢀBenzodioxolꢀ5ꢀyl)ꢀ7ꢀoxoꢀ6,9ꢀdihydrofuro[3',4':6,7]naphtho[1,2ꢀd][1,3]dioxoleꢀ6α(7H
)ꢀcarbonitrile (12). A mixture of compound 10 (300.0 mg, 0.8 mmol) and Mn(OAc)3 (639.0 mg,
o
2.3 mmol) in benzene (10.0 mL) was stirred in a sealed pressure vessel at 90 C for 16 h. After
reaction was complete, the mixture was filtered through a pad of celite followed by washing with
CH2Cl2 (3 × 20 mL). The filtrate was concentrated under reduced pressure to give the crude
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residue, which was subjected to purification by flash chromatography on silica gel
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(EtOAc/nꢀhexane, 1:2) to afford compound 11:12 = 3/1 (213.0 mg, 71 %) as a yellow solid. H
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NMR (CDCl3, 400 MHz) δ: 6.89–6.83 (m, 4H), 6.78–6.57 (m, 6H), 6.03–5.97 (m, 7H), 5.80–5.76
(m, 1H), 5.33–5.26 (m, 2H), 4.85 (d, J = 13.6 Hz, 1H), 4.79 (d, J = 13.6 Hz, 1H), 3.87 (d, J =
14.6 Hz, 1H), 3.30 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 15.6 Hz, 1H), 3.06 (d, J = 14.6 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ: 168.8, 168.7, 148.5, 147.9, 147.4, 145.2, 137.4, 134.2, 128.0, 127.1,
125.1, 124.5, 123.4, 123.2, 122.7, 121.9, 121.8, 115.1, 114.8, 109.4, 108.6, 108.5, 108.3, 101.6,
101.5, 101.4, 101.2, 77.2, 69.9, 40.9, 40.6, 34.8, 34.5; IR (CH2Cl2 cast): 2905, 2360, 2238, 1790,
1761, 1488, 1234 cmꢀ1; HRMS (ESI, m/z): calcd for C21H13NO6: 375.0743 [M]+, found: 375.0742.
Justicidin E and Helioxanthin. Compound 11 and 12 (120.0 mg, 0.3 mmol) was dissolved in a
solution of SmI2 (0.1M) in THF (19.2 mL, 1.9 mmol) at 0 oC under argon. After stirring for 1 h at
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0 C, Et3N (0.08 mL, 0.6 mmol) was added at the same temperature by syringe under air. The
reaction mixture was stirred for another 30 min at 0 oC and then saturated aqueous NH4Cl (3 mL)
was added and diluted with water and extracted with EtOAc (3 × 20 mL). The organic layer was
concentrated under reduced pressure to give the crude residue, which was subjected to
purification by HPLC with 250×10 mm Hypersil GOLD 5µ semiꢀprep column (H2O/MeOH, 1:9);
flow rate = 0.5 mLminꢀ1 to afford justicidin E (61.8 mg, 59 %) as a white solid and helioxanthin
(20.6 mg, 20%) as a white solid.
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Justicidin E. H NMR (CDCl3, 400 MHz) δ: 8.27 (s, 1H), 7.31 (s, 1H), 7.10 (s, 1H), 6.98 (d, J =
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7.2 Hz, 1H), 6.80–6.78 (m, 2H), 6.10–6.08 (m, 4H), 5.23 (d, J = 14.8 Hz, 1H), 5.18 (d, J = 14.8
Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ: 171.5, 150.5, 148.4, 148.2, 147.7, 138.4, 133.4, 132.6,
131.3, 129.6, 124.7, 122.7, 121.6, 109.6, 109.0, 105.3, 102.1, 101.9, 101.4, 69.4.
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3ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)propꢀ2ꢀynyl
3ꢀ(6ꢀbromobenzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ2ꢀcyanopropanoate (13). To a solution of compound 6 (4.6 g,
18.9 mmol) in ethanol (200.0 mL) at room temperature was sequentially added 6ꢀbromopiperonal
(5.0 g, 21.8 mmol), Lꢀproline (435.0 mg, 3.7 mmol) and Hantzsch ester (4.8 g, 18.9 mmol) in one
portion. The reaction mixture was stirred at 60 oC for 6 h and concentrated under reduced pressure to
give the crude residue, which was purified by flash chromatography on silica gel (EtOAc/nꢀhexane,
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1:10) to afford compound 13 (7.1 g, 83%) as a white solid. mp 130–131 C; H NMR (CDCl3, 400
MHz) δ: 7.02 (s, 1H), 6.99 (dd, J = 8.0, 1.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.84 (s, 1H), 6.76 (d, J
= 8.0 Hz, 1H), 5.99 (s, 2H), 5.97 (d, J = 1.2 Hz, 1H), 5.96 (d, J = 1.2 Hz, 1H), 5.01 (s, 2H), 3.95 (dd,
J = 9.2, 6.4 Hz, 1H), 3.44 (dd, J = 14.0, 6.4 Hz, 1H), 3.15 (dd, J = 14.0, 9.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ: 164.7, 148.5, 148.3, 147.6, 147.4, 127.3, 126.9, 115.4, 114.8, 114.7, 113.0,
111.9, 111.2, 108.4, 102.0, 101.4, 87.7, 79.8, 55.1, 37.4, 36.1; IR (CH2Cl2 cast): 2231, 1749, 1480,
1037 cmꢀ1; HRMS (ESI, m/z): calcd for C21H14BrNO6: 455.0004 [M]+, found: 455.0005.
10ꢀ(1,3ꢀBenzodioxolꢀ5ꢀyl)ꢀ5ꢀbromoꢀ7ꢀoxoꢀ6,9ꢀdihydrofuro[3',4':6,7]naphtho[1,2ꢀd][1,3]diox
oleꢀ6α(7H)ꢀcarbonitrile (14). A mixture of compound 13 (300.0 mg, 0.6 mmol) and Mn(OAc)3
(530.0 mg, 1.9 mmol) in benzene (10.0 mL) was stirred in a sealed pressure vessel at 90 oC for 16
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h. After reaction was complete, the mixture was filtered through a pad of celite followed by
washing with CH2Cl2 (3 × 20 mL). The filtrate was concentrated under reduced pressure to give
the crude residue, which was subjected to purification by flash chromatography on silica gel
(EtOAc/nꢀhexane, 1:2) to afford compound 14 (185.5 mg, 68 %) as a yellow solid. mp 217–218
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oC; H NMR (CDCl3, 400 MHz) δ: 7.04 (s, 1H), 6.86–6.84 (br, 1H), 6.64–6.62 (m, 2H),
6.05–6.02 (m, 2H), 5.83–5.80 (m, 2H), 5.32 (d, J = 13.8 Hz, 1H), 4.85 (d, J = 13.8 Hz, 1H), 3.95
(d, J = 15.8 Hz, 1H), 2.83 (d, J = 15.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 168.3, 148.9,
148.5, 145.2, 134.1, 127.9, 122.7, 122.0, 116.6, 115.4, 114.5, 113.2, 108.2, 101.9, 101.5, 69.7,
40.7, 34.6; IR (CH2Cl2 cast): 2234, 1793, 1447, 1020 cmꢀ1; HRMS (ESI, m/z): calcd for
C21H12BrNO6: 452.9848 [M]+, found: 452.9845.
10ꢀ(1,3ꢀBenzodioxolꢀ5ꢀyl)ꢀ5ꢀbromofuro[3',4':6,7]naphtho[1,2ꢀd][1,3]dioxolꢀ7(9H)ꢀone (15).
The compound 14 (100.0 mg, 0.2 mmol) was dissolved in a solution of SmI2 (0.1M) in THF
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(13.0 mL, 1.3 mmol) at 0 C under argon. After stirring for 1 h at 0 oC, Et3N (0.08 mL, 0.6 mmol)
was added at the same temperature by syringe under air. The reaction mixture was stirred for
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another 30 min at 0 C and then saturated aqueous NH4Cl (3 mL) was added and diluted with
water and extracted with EtOAc (3 × 20 mL). The organic layer was concentrated under reduced
pressure to give the crude residue, which was subjected to purification by flash chromatography
on silica gel (EtOAc/nꢀhexane, 1:2) to afford compound 15 (72.4 mg, 85 %) as a yellow solid.
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mp 261–262 C; H NMR (CDCl3, 400 MHz) δ: 8.88 (s, 1H), 7.64 (s, 1H), 6.88 (d, J = 8.4 Hz,
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1H), 6.78–6.75 (m, 2H), 6.06 (d, J = 11.2 Hz, 2H), 5.95 (d, J = 9.8 Hz, 2H), 5.24 (d, J = 15.4 Hz,
1H), 5.17 (d, J = 15.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 170.8, 147.6, 147.4, 146.6, 141.8,
140.5, 129.9, 129.8, 128.9, 127.2, 122.3, 122.2, 117.3, 116.2, 109.5, 108.1, 102.0, 101.3, 69.4; IR
(CH2Cl2 cast): 1767, 1487, 1239, 1037 cmꢀ1; HRMS (ESI, m/z): calcd for C20H11BrO6: 425.9739
[M]+, found: 425.9739.
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Helioxanthin. To a solution of compound 15 (72.4 mg, 0.17 mmol) in 1,4ꢀdioxane (10.0 mL)
was added 5% Pd/C (20 mg) at room temperature and stirred for 16 h under an atmosphere of H2
(balloon). The reaction mixture was filtered through a pad of Celite and concerted under reduced
pressure. The residue was purified by flash chromatography on silica gel (EtOAc/nꢀhexane, 1:2)
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to afford helioxanthin (54.4 mg, 92%). H NMR (CDCl3, 400 MHz) δ: 8.43 (s, 1H), 7.71 (d, J =
8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.82–6.79 (m, 2H), 6.06 (dd, J =
13
11.6, 1.2 Hz, 2H), 5.96 (dd, J = 9.2, 1.2 Hz, 2H), 5.23 (q, J = 15.2 Hz, 2H). C NMR (CDCl3,
100 MHz) δ: 171.1, 147.4, 146.9, 141.7, 139.7, 130.7, 130.4, 129.1, 127.4, 125.4, 122.3, 121.5,
121.1, 111.8, 109.6, 107.9, 101.5, 101.2, 69.5.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of novel compounds and synthetic natural products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail: cclin66@mx.nthu.edu.tw
*Eꢀmail: ksshia@nhri.org.tw.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Health Research Institutes and Ministry of Science and Technology
of Taiwan (MOSTꢀ103ꢀ2113ꢀMꢀ400ꢀ002ꢀMY3) for financial support.
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