First total synthesis of Papilistatin

Article abstract of DOI:10.1039/c0ob01214a

Papilistatin has been isolated recently and found to have good anticancer and antibacterial activity. Papilistatin is a unique phenanthrene-1,10- dicarboxylic acid. The first total synthesis of papilistatin is described here with radical cyclisation as the key step.

Full text of DOI:10.1039/c0ob01214a

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PAPER
First total synthesis of Papilistatin†
Meng Wu, Ling Li, An-Zheng Feng, Bo Su, De-min Liang, Yu-xiu Liu and Qing-min Wang*
Received 20th December 2010, Accepted 25th January 2011
DOI: 10.1039/c0ob01214a
Papilistatin has been isolated recently and found to have good anticancer and antibacterial activity.
Papilistatin is a unique phenanthrene-1,10-dicarboxylic acid. The first total synthesis of papilistatin is
described here with radical cyclisation as the key step.
Introduction
Papilistatin (Fig. 1) was isolated in 2010 by Pettit from a Taiwan
butterfly, and was found to have anticancer and antibacterial
activity.1 Against a panel of six human and the murine P388
leukemia cancer cell lines, papilistatin exhibited cancer cell growth
inhibition with GI50’s of 0.093–3.5 mg mL-1. We have been contin-
uously studying the synthesis and biological activities of phenan-
throindolizidine alkaloids.2 Papilistatin is a unique phenanthrene-
1,10-dicarboxylic acid which is similar to the intermediates
used to construct phenanthroindolizidine alkaloids. Papilistatin’s
relatively simple structure and good biological activities evoked
our interest. In order to explore if it can be used as an alternative
Scheme 1 Retrosynthetic analysis of papilistatin.
to phenanthroindolizidine alkaloids, we developed the first total
synthesis of papilistatin.
MnO26 and m-CPBA.7 However, although we tried many oxidative
coupling reagents (such as VOF3, FeCl3, MnO2, m-CPBA and
PIFA), no oxidative coupling product 5 was formed from 4a. We
believed that the electron-withdrawing methylcarbonyl group at
the benzene ring of diphenylethene 4a made the oxidative coupling
impossible. We then introduced bromine into the compound 2a
to get 2b and then to afford 4b. An intramolecular coupling
reaction of 4b mediated by a palladium catalytic reaction was
tried. But when we used Pd(PPh3)2Cl2 and Pd(OAc)2 as the
palladium catalyst, we also failed to construct the phenanthrene
ring. Then we turned to radical cyclisation with Bu3SnH and
AIBN as reagents which were reported to be used to construct
the phenanthrene ring system efficiently.8 Using this method, we
finally succeeded to get 5 from 4b.
Fig. 1 Structure of papilistatin.
Results and discussion
Our retrosynthetic analysis is shown in Scheme 1. Apparently,
the construction of the phenanthrene ring would be the key
step to synthesize papilistatin. To the best of our knowledge, the
most convenient way to construct the phenanthrene ring system
is intramolecular oxidative coupling of diphenylethene using
oxidative coupling reagents such as Pb(OAc)4,3 VOF3,4 FeCl3,2a,5
2-Methoxycarbonyl-4,5-methylenedioxyphenyl acetic acid
methyl ester 1 was obtained employing piperonal 6 as the starting
material. Condensation of commercially available piperonal 6 and
malonic acid in the presence of piperidine and subsequent catalytic
hydrogenation gave (3,4-methylenedioxy)phenylpropionic acid 8
in 74.8% yield over two steps.9 8 was treated with oxalyl choride in
dichloromethane to give the corresponding acyl chloride, which
formed 5,6-(methylenedioxy)-l-indanone 9 via intramolecular
Friedel-Crafts acylation in the presence of SnCl4 in 95% yield.10
Treating indanone 9 with amyl nitrite in methanol with HC1
afforded the 2-(hydroxyimino)-5,6-(methylenedioxy)-1-indanon
10 in 75% yield.10 Then treating the hydroxyimino ketone 10
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s
Republic of China. E-mail: wang98h@263.net; Fax: +86-22-23499842
† Electronic Supplementary Information (ESI) available: 1H, 13C-NMR
and HRMS spectra for the compouds 1, 3, 4b, 5, papilistatin. See DOI:
10.1039/c0ob01214a.
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Scheme 2 Synthesis of compound 1.
Scheme 3 Synthesis of compound 2.
Scheme 4 Synthesis of papilistatin.
with p-toluenesufonyl chloride in sodium hydroxide solution
afforded 2-carboxy-4,5-methylenedioxyphenylacetic acid 11
via esterification, Beckmann rearrangement and subsequent
hydrolysis in 65% yield.11 Acid 11 reacted with diazomethane to
give 1 in 98% yield (Scheme 2).
2-bromo-6-methoxybenzaldehyde 2b could be easily synthe-
sized from commercially available 2-methoxybenzaldehyde 2a
according to reported literature (Scheme 3).12
With 1 and 2b in hand, we started to conduct reactions following
our synthetic route (Scheme 4). The base-mediated condensation
of aldehydes or ketones with dialkyl succinate to afford alkylidene
succinic monoesters is known as Stobbe condensation. Stobbe
condensation of 1 and 2b in the presence of sodium methoxide in
methanol afforded 3-(2-bromo-6-methoxyphenyl)-2-(2-carboxyl-
4,5-methylenedioxyphenyl)-acrylic acid methyl ester 3 in a yield
of 92% as a 1 : 1 mixture of Z and E isomers (as determined by
1H NMR). Then 3 was treated with diazomethane to afford the
corresponding dimethyl ester 4b (Z/E = 1 : 1) in a yield of 98%.
As we know, the E isomer of 4b is more suitable than the Z
isomer for intramolecular radical cyclisation, therefore we tried to
improve the percentage of the E isomer in 3 and 4b. But we found
the percentage of the E isomer of 3 decreased when potassium
tert-butoxide or sodium hydride was used as the base in Stobbe
condensation. The effort to turn the Z isomers of 3 and 4b to
their corresponding E isomers also failed. The Z and E isomers
of 3 and 4b were very difficult to separate and only a little of
the pure Z isomer of 4b was obtained. Therefore, the mixture 4b
was used for the next step. As we got the pure Z isomer of 4b,
Z and E of 4b can be easily assigned comparing their alkene-H
chemical shift in NMR. According to the reference and chemdraw,
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the chemical shift of alkene-H in E-4b is more down-field than Z-
4b, since in E-4b the ester group is at the cis-position of alkene-H,
which can provide a greater deshielding effect. In the same way,
we could assign the Z and E isomer of 3. The intramolecular
radical cyclisation of 4b (Z/E = 1 : 1) with Bu3SnH and AIBN
proved to be a little complicated, and 3,4-methylenedioxy-8-
methoxyphenanthrene-1,10-dicarboxylic acid dimethyl ester 5 was
separated in a yield of 30%. The main by-product separated was
4a. Treating the Z isomer of 4b in the same condition could
afford 5 only in 10%, which also accounted for the low yield
of the reaction above. Nonetheless, 5 was obtained easily and
then converted to its corresponding dicarboxylic acid papilistatin
through saponification in a yield of 85%.
The resulting mixture was cooled to 0 ◦C and acidified with 2 mol
L-1 hydrochloric acid, then filtered, washed with water and dried
to gi◦ve 3.17 g (92%) of 3 (Z/E = 1 : 1) as a white solid. mp 176–
1
179 C; H NMR (400 MHz, CDCl3): d 7.59 (s, 1 H, C CH),
7.56 (s, 1 H, C CH), 7.55 (s, 1 H, Ar–H), 7.22 (d, J = 8.0 Hz, 1 H,
Ar–H), 7.12–7.17 (m, 2 H, Ar–H), 7.06 (t, J = 8.0 Hz, 1 H, Ar–H),
7.02 (s, 1 H, Ar–H), 6.86 (d, J = 8.0 Hz, 1 H, Ar–H), 6.75 (s, 1 H,
Ar–H), 6.62 (d, J = 8.4 Hz, 1 H, Ar–H), 6.42 (s, 1 H, Ar–H), 6.11
(s, 2 H, OCH2O), 5.97 (s, 2 H, OCH2O), 3.80 (s, 6 H, COOCH3),
3.51 (s, 3 H, OCH3), 3.46 (s, 3 H, OCH3); 13C NMR (100 MHz,
CDCl3) d 171.0, 170.5, 167.1, 166.3, 157.8, 156.9, 147.5, 147.1,
137.8, 137.5, 135.0, 134.2, 133.9, 130.0, 129.4, 126.9, 125.2, 124.4,
124.3, 123.6, 122.0, 112.3, 110.7, 110.6, 109.5, 102.2, 101.9, 56.0,
55.2, 52.2, 51.4. HRMS (ESI): calcd. for C19H15BrO7 [M - H]-
432.9928, found 432.9922.
Conclusion
Papilistatin was first synthesized from easily available materials
1 and 2b under mild conditions in only 4 steps with an overall
yield of 23%. The chemistry described here provides a practical
synthetic method of papilistatin, with which we could also prepare
diversities of papilistatin for biochemical and pharmaceutical
studies.
(Z/E)-3-(2-Bromo-6-methoxyphenyl)-2-(2-methoxycarbonyl-4,5-
methylenedioxyphenyl)-acrylic acid methyl ester (4b)
Compound 3 (3.17 g, 7.30 mmol) was dissolved in dry
◦
dichloromethane (40 mL) and cooled to 0 C and then carefully
treated with diazomethane until the reaction had finished. The
excess diazomethane was decomposed with a few drops of glacial
acetic acid. The resulting mixture was evaporated to afford 3.31 g
(98%) of 4b as a white oil. A little of the Z isomer of 4b could
be obtained through column chromatography (petroleum ether–
Experimental
The melting points were determined with an X-4 binocular
microscope melting-point apparatus (Beijing Tech Instruments
Co, Beijing, China) and were uncorrected. 1H NMR spectra were
obtained by using a Bruker AV 400 spectrometer. Chemical shifts
(d) were given in parts per million (ppm) and were measured
downfield from internal tetramethylsilane.13C NMR spectra were
recorded by using a Bruker AV 400 (100 MHz) and CDCl3, C5D5N
or DMSO-d6 as a solvent. Chemical shifts (d) are reported in
parts per million using the solvent peak. High-resolution mass
spectra were obtained with an FT-ICR MS spectrometer (Ionspec,
7.0 T). All anhydrous solvents were dried and purified by standard
techniques just before use.
1
EtOAc, 8 : 1, v/v). For 4b (Z/E = 1 : 1): H NMR (400 MHz,
CDCl3): d 7.52 (s, 1 H, C CH), 7.48 (s, 1 H, C CH), 7.46 (s, 1
H, Ar–H), 7.20 (d, J = 8.0 Hz, 1 H, Ar–H), 7.12 (t, J = 8.8 Hz, 1
H, Ar–H), 7.11 (d, J = 8.4 Hz, 1 H, Ar–H), 7.02 (t, J = 8.0 Hz, 1
H, Ar–H), 6.98 (s, 1 H, Ar–H), 6.84 (d, J = 8.0 Hz, 1 H, Ar–H),
6.69 (s, 1 H, Ar–H), 6.59 (d, J = 8.4 Hz, 1 H, Ar–H), 6.38 (s, 1
H, Ar–H), 6.06 (s, 2 H, OCH2O), 5.92 (s, 2 H, OCH2O), 3.84 (s,
3 H, COOCH3), 3.79 (s, 6 H, COOCH3), 3.78 (s, 3 H, COOCH3),
3.52 (s, 3 H, OCH3), 3.41 (s, 3 H, OCH3); For the Z isomer of 4b:
1H NMR (400 MHz, CDCl3): d 7.48 (s, 1 H, C CH), 7.20 (d,
J = 8.0 Hz, 1 H, Ar–H), 7.13 (t, J = 8.0 Hz, 1 H, Ar–H), 6.99 (s,
1 H, Ar–H), 6.84 (d, J = 8.0 Hz, 1 H, Ar–H), 6.69 (s, 1 H, Ar–
H), 6.07 (s, 2 H, OCH2O), 3.79 (s, 3 H, COOCH3), 3.78 (s, 3 H,
COOCH3), 3.52 (s, 3 H, OCH3); 13C NMR (100 MHz, CDCl3) d
167.2, 166.0, 156.9, 150.2, 147.0, 137.8, 133.9, 133.7, 130.0, 125.1,
124.3, 124.2, 122.9, 110.4, 109.9, 109.5, 101.9, 55.1, 52.1, 51.8.
HRMS (ESI): calcd. for C20H17BrO7 [M + Na]+ 471.0050, found
471.0052.
2-Methoxycarbonyl-4,5-methylenedioxyphenylacetic acid methyl
ester (1)
Compound 11 (1.81 g, 8.10 mmol) in dry dichloromethane (15 mL)
was cooled to 0 ◦C and then carefully treated with diazomethane
until the reaction had finished. The excess diazomethane was
decomposed with a few drops of glacial acetic acid. The resulting
mixture was evaporated to afford 2.00 g (98%) of 1 as a white solid.
mp 87–88 ◦C; 1H NMR (400 MHz, CDCl3): d 7.49 (s, 1 H, Ph-H),
6.71 (s, 1 H, Ph-H), 6.03 (s, 2 H, OCH2O), 3.93 (s, 2 H, Ph-CH2-),
3.83 (s, 3 H, COOCH3), 3.70 (s, 3 H, COOCH3); 13C NMR (100
MHz, CDCl3) d 172.0, 166.6, 150.8, 146.8, 132,3, 122.7, 112.1,
110.7, 101.9, 51.9, 40.4. HRMS (ESI): calcd. for C12H12O6 [M +
Na]+ 275.0526, found 275.0527.
3,4-Methylenedioxy-8-methoxyphenanthrene-1,10-dicarboxylic
acid dimethyl ester (5)
To a solution of 4b (3.31 g, 7.16 mmol) in toluene (200 mL),
AIBN (0.23 mg, 1.43 mmol) and Bu3SnH (5.00 g, 17.18 mmol)
were added, and the mixture was heated under reflux for 6 h.
The reaction mixture was concentrated by rotary evaporation,
and purified by column chromatography (petroleum ether–EtOAc,
10 : 1, v/v) to give 0.82 g (30%) of 5 as a yellow solid. mp 212–
213 ◦C; 1H NMR (400 MHz, CDCl3): d 8.68 (d, J = 8.0 Hz, 1 H,
H-5), 8.67 (s, 1 H, H-9), 7.71 (s, 1 H, H-2), 7.63 (t, J = 8.0 Hz, 1 H,
H-6), 7.06 (d, J = 8.0 Hz, 1 H, H-7), 6.32 (s, 2 H, OCH2O), 4.04
(s, 3 H, OCH3), 3.92 (s, 3 H, COOCH3), 3.90 (s, 3 H, COOCH3);
13C NMR (100 MHz, CDCl3) d 169.4, 168.8, 156.1, 146.6, 144.9,
(Z/E)-3-(2-Bromo-6-methoxyphenyl)-2-(2-carboxyl-4,5-
methylenedioxyphenyl)-acrylic acid methyl ester (3)
Sodium (0.19 g, 8.10 mmol) was stirred in methanol (80 mL) until
it disappeared. 1 (2.00 g, 7.94 mmol) and 2b (1.73 g, 8.10 mmol)
were added to the solution. The mixture was heated at reflux for
4 h and then rotary evaporated to remove most of the methanol.
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130.4, 129.2, 127.2, 125.4, 124.2, 123.8, 121.2, 119.0, 117.8, 112.1,
107.3, 101.9, 55.7, 52.1, 52.0. HRMS (ESI): calcd. for C20H16O7
[M + Na]+ 391.0788, found 391.0796.
Notes and references
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Papilistatin
Compound 5 (0.82 g, 2.15 mmol) was dissolved in methanol
(35 mL) and dioxane (30 mL) and then 20% potassium hydroxide
(55 mL) was added to the solution. The mixture was warm to 40 ◦C
and stirred for 6 h. The mixture was rotary evaporated to remove
dioxane and methanol, and the resulting mixture was cooled to
0 ◦C and acidified with 2 mol L-1 hydrochloric acid to afford 0.62 g
(85%) of papilistatin as a yellow solid. mp > 300 C; H NMR
(400 MHz, DMSO-d6) d 12.89 (br, 1 H, COOH), 12.85 (br, 1 H,
COOH), 8.65 (d, J = 8.4 Hz, 1 H, H-5), 8.45 (s, 1 H, H-9), 7.74
(t, J = 8.4 Hz, 1 H, H-6), 7.70 (s, 1 H, H-2), 7.30 (d, J = 8.0 Hz,
1 H, H-7), 6.44 (s, 2 H, OCH2O), 4.04 (s, 3 H, OCH3); 1H NMR
(400 MHz, C5D5N) d 9.29 (s, 1 H, H-9), 8.84 (d, J = 8.0 Hz, 1 H,
H-5), 8.21 (s, 1H, H-2), 7.67 (t, J = 8.0 Hz, 1 H, H-6), 7.08 (d,
J = 8.0 Hz, 1 H, H-7), 6.23 (s, 2 H, OCH2O), 3.83 (s, 3 H, OCH3);
13C NMR (100 MHz, C5D5N) d 172.2, 171.7, 156.8, 146.7, 145.8,
131.9, 131.2, 129.6, 129.0, 125.3, 124.7, 122.3, 120.1, 118.8, 112.8,
108.3, 102.8, 56.2. HRMS (ESI): calcd. for C18H12O7 [M - H]-
339.0510, found 339.0501.
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Acknowledgements
We are grateful to the National Key Project for Basic Research
(2010CB126100) and the National Natural Science Foundation of
China (20872072) for generous financial support for our programs.
2542 | Org. Biomol. Chem., 2011, 9, 2539–2542
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