Synthesis of simple 3,4-diarylpyrrole-2,5-dicarboxylic acids and lukianol A by oxidative condensation of 3-arylpyruvic acids with ammonia

Article abstract of DOI:10.1055/s-2007-965876

Several derivatives of 3,4-diaryl- and 3,4-diindolylpyrrole-2,5- dicarboxylic acids including lycogalic acid A and two Halomonas metabolites were synthesized by oxidative dimerization of arylpyruvic acids or arylpyruvates in the presence of ammonia. The r

Full text of DOI:10.1055/s-2007-965876

608
PAPER
Synthesis of Simple 3,4-Diarylpyrrole-2,5-dicarboxylic Acids and Lukianol A
by Oxidative Condensation of 3-Arylpyruvic Acids with Ammonia
S
ynthesis of Sim
l
a
D
iarylpyrro
u
le-2, 5-dicar
d
boxylic
A
cid
i
s
a Hinze, Andreas Kreipl, Andreas Terpin, Wolfgang Steglich*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13 (F), 81377 München, Germany
Fax +49(89)218077756; E-mail: wolfgang.steglich@cup.uni-muenchen.de
Received 6 October 2006
H
H
H
N
I2,
N
N
Abstract: Several derivatives of 3,4-diaryl- and 3,4-diindolylpyr-
role-2,5-dicarboxylic acids including lycogalic acid A and two
Halomonas metabolites were synthesized by oxidative dimerization
of arylpyruvic acids or arylpyruvates in the presence of ammonia.
The reaction can be applied for a short synthesis of lukianol A.
MeOH, NH3
2
(42%)
HO
MeO2C
CO2Me
N
H
CO2Me
4
Key words: biomimetic synthesis, pyrroles, lycogalic acid, 3,4-di-
arylpyrrole-2,5-dicarboxylic acids
Scheme 1
R
R
Lycogalic acid A (1) (Figure 1) has been isolated from the
slime mould Lycogala epidendrum1,2 and from cultures of
Chromobacterium violaceum (chromopyrrolic acid).3 Re-
cently it was demonstrated that 1 is a key intermediate in
the biosynthesis of the indolocarbazole antibiotics stauro-
sporin and rebeccamycin.4 The close relationship between
both types of compounds is also suggested by the co-
occurrence of lycogalic acids with staurosporinone and
arcyriaflavin A (7) in L. epidendrum.1,5 Recently, two
phenyl analogues of lycogalic acid A, designated as
HPPD-1 (3) and HPPD-2 (2) (Figure 1), have been found
in cultures of a marine Halomonas bacterium.6 Both
metabolites show effective antitumor activities.
R
(1) MeOH, NaOMe,
2 (0.5 equiv), 0 °C
then NH4OH
I
(2) CH2N2
MeO2C
MeO2C
CO2Me
N
O
H
5a, R = OMe
5b, R = H
Scheme 2
the bis(4-methoxyphenyl) derivative 5a in 60% yield
(Scheme 2).
In the same fashion, the corresponding diphenyl deriva-
tive 5b was obtained from methyl 3-phenylpyruvate
(Scheme 2). Interestingly, the reaction proceeded more
sluggishly, and the mixture had to be heated under reflux
for four hours to achieve a reasonable yield. Finally, di-
ester 5a could be obtained in one step and with 67% yield
from methyl 3-(4-methoxyphenyl)pyruvate by adding 4 Å
molecular sieves to the refluxing reaction mixture. This
prevented hydrolysis of the ester groups by the water
formed during the pyrrole condensation.
R
R'
H
H
N
N
HO2C
CO2H
HO2C
CO2H
N
N
H
H
2, R = R' = OH
3, R = OH, R' = H
1
Figure 1 Lycogalic acid (1) and its phenyl analogues 2 and 3
Free 3,4-diarylpyrrole-2,5-dicarboxylic acids can be ob-
tained from arylpyruvic acids under anhydrous condi-
tions. This was first demonstrated in the total synthesis of
polycitrin A,7 in which a solution of 3-(4-methoxyphe-
nyl)pyruvic acid in anhydrous tetrahydrofuran at -78 °C
was treated with two equivalents of n-butyllithium fol-
lowed by 0.5 equivalent of iodine. After saturation of the
solution with gaseous ammonia and stirring for 12 hours
with 4 Å molecular sieves or titanium(IV) chloride at am-
bient temperature, 3,4-bis(4-methoxyphenyl)pyrrole-2,5-
dicarboxylic acid8 was obtained in 72% yield. Oxidative
cyclization of a 1:1 mixture of 3-(4-hydroxyphenyl)pyru-
vic acid and 3-phenylpyruvic acid in tetrahydrofuran with
five equivalents of n-butyllithium following the same pro-
cedure afforded a mixture of 25% 2 and 5% 3 (Scheme 3).
None of the symmetrical diphenyl derivative 6 could be
Some time ago we discovered that lycogalic acid A di-
methyl ester (4) is formed by treatment of methyl 3-(in-
dol-3-yl)pyruvate with iodine in methanolic ammonia
(Scheme 1).1a We reasoned that a similar protocol could
be applied for the synthesis of 4,5-diarylpyrrole-2,5-di-
carboxylic acid diesters. In this case, however, partial hy-
drolysis of the ester functions took place, and the crude
product had to be re-esterified with diazomethane. In this
manner methyl 3-(4-hydroxyphenyl)pyruvate afforded
SYNTHESIS 2007, No. 4, pp 0608–0612
x
x
.
x
x
.2
0
0
7
Advanced online publication: 12.01.2007
DOI: 10.1055/s-2007-965876; Art ID: Z21906SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Simple 3,4-Diarylpyrrole-2,5-dicarboxylic Acids
609
H
detected. This can be explained by formation of a reactive
quinone methide intermediate from 3-(4-hydroxyphe-
nyl)pyruvate and iodine, which is able to react with the
enolates of both reaction partners. The higher proportion
of the bis(4-hydroxyphenyl) derivative 2 reflects the
greater reactivity of the (4-hydroxyphenyl)pyruvate trian-
ion as compared to the dianion formed from phenylpyru-
vate. The two dicarboxylic acids 2 and 3 could be easily
separated by HPLC. Their spectroscopic data agreed with
those reported for the Halomonas metabolites HPPD-2
and HPPD-1.6
N
n-BuLi (3 equiv),
2
K3Fe(CN)6
aq NaOH
I2 (0.5 equiv), NH3
1
(36%)
HO
CO2H
H
N
O
O
N
N
H
H
7
Scheme 4
HO
n-BuLi (5 equiv)
THF, –78 °C
HO
HO
I2 (1 equiv)
+
then NH3 (g)
4 Å MS, 20 °C
HO2C
HO2C
HO
NaH, THF, 0 °C
+
O
O
Br
then NH3, 20 °C
4 Å MS
CO2Et
1
:
1
EtO2C
O
EtO2C
CO2Et
O
N
H
OH
OH
8a
9
Scheme 5
+
+
HO2C
CO2H
HO2C
CO2H
HO2C
CO2H
N
H
N
H
N
H
Similarly, half ester 10 was obtained in 34% yield by
reaction of 3-(4-methoxyphenyl)pyruvic acid with its
3-bromo ester derivative 8b (Scheme 6). Decarboxylation
2 (25%)
3 (5%)
6 (0%)
Scheme 3
of compound 10 yielded Fürstner’s intermediate 11,10
a
key compound in previous syntheses of lukianol A
(14).10,11 Usually, 11 is N-alkylated with 4-methoxyphen-
acyl bromide to yield ketone 12, which is then trans-
formed into lukianol A trimethyl ether (13) by cleavage of
the ester group followed by cyclization with Ac2O/
NaOAc.10,11d,e We were able cyclize 12 in one step by ap-
plying Otera’s distannoxane catalyst.12 Lukianol A tri-
methyl ether (13) was thereby obtained in 79% yield,
considering the recovery of 26% of the starting material.
For an alternative approach to lukianol A, see ref. 13.
Treatment of 3-(indol-3-yl)pyruvic acid in the same fash-
ion furnished free lycogalic acid (1) in 36% yield
(Scheme 4), which could be converted into arcyriaflavin
A (7) by oxidation with potassium ferricyanide in alkaline
solution. Under these conditions, both the formation of the
maleimide moiety and the oxidative cyclization to the in-
dolocarbazole system took place. This sequence mimics
the biosynthesis of indolocarbazoles from tryptophan.4
For the synthesis of diester 9 containing two different aryl
substituents, the sodium enolate of ethyl 3-(4-hydroxy-
phenyl)pyruvate was treated with ethyl 3-bromo-3-phe-
nylpyruvate (8a)9 and the resulting 1,4-diketo inter-
mediate cyclized with ammonia in situ (Scheme 5). This
one-pot procedure afforded diester 9 in 14% yield.
In conclusion, we have shown that simple 3,4-diaryl- and
2,4-diindolylpyrrole-2,5-carboxylic acids can be easily
obtained from aryl(indolyl)pyruvic acids and ammonia.
MeO
OMe
RO
OR
O
MeO
MeO
OMe
OMe
d
a
c
CO2Me
O
N
N
+
O
Br
HO2C
CO2Me
R
CO2Me
N
O
O
H
8b
10, R = CO2H
11, R = H
b
OR
OMe
12
13, R = Me
14, R = H
e
Scheme 6 Reagents and conditions: (a) (1) 3-(4-methoxyphenyl)pyruvic acid, NaH, –12 to –5 °C, then 8b, –5 to 25 °C, CH2Cl2, (2) NH3 (gas),
4 Å MS, reflux (34%); (b) copper chromite, quinoline, 200 °C (73%); (c) see ref. 10; (d) Otera’s distannoxane, benzene, water separator charged
with 4 Å MS, reflux, 16 h (79%, calcd for 74% conversion); (e) see ref. 10.
Synthesis 2007, No. 4, 608–612 © Thieme Stuttgart · New York

610
C. Hinze et al.
PAPER
Melting points (uncorrected): Büchi SMP 535 apparatus. IR spec-
tra: PerkinElmer FT-IR Spectrum 1000. Abbreviations: s, strong;
m, medium; w, weak; br, broad. Mass spectra (EI, 70 eV): Finnigan
MAT 90 and Finnigan MAT 95Q. High-resolution mass spectra (EI,
70 eV): Finnigan MAT 95Q. NMR spectra: Bruker ARX 300, Bruk-
er AMX 600, and Varian VXR 400S. The spectra were recorded in
CDCl3 or DMSO-d6 using the residual solvent peak as the internal
standard (CDCl3, dH = 7.26 and dC = 77.1; DMSO-d6, dH = 2.49 and
dC = 39.5). Elemental analyses were carried out by the Microanalyt-
ical Laboratory of the Department Chemie, Universität München.
Flash chromatography (FC): Merck Kieselgel 60 (0.040–0.063
mm). TLC: Aluminum foils, silica gel 60 F254 (Merck). HPLC: Wa-
ters 510 HPLC pump equipped with Waters 996 Photodiode Array
Detector, Waters 717plus Autosampler. Column: Nucleosil 100 RP
18, 5 mm (4 × 250 mm). Solvents for chromatography were distilled
before use.
13C NMR (100 MHz, CDCl3): d = 51.8 (CH3), 55.1 (CH3), 112.9
(CH), 121.1, 125.2, 131.3, 131.9 (CH), 158.6, 160.8.
EI-MS: m/z (%) = 396 (20, [M + H]+), 395 (86, [M]+), 364 (24, [M
– OCH3]+), 363 (100, [M – CH3OH]+), 166 (10).
HRMS: m/z calcd for C22H21NO6: 395.1369; found: 395.1407.
Anal. Calcd for C22H21NO6: C, 66.83; H, 5.35; N, 3.54. Found: C,
67.00; H, 5.46; N, 3.44.
Dimethyl 3,4-Diphenylpyrrole-2,5-dicarboxylate (5b)
The same procedure as for the preparation of 4 was used, starting
from NaOMe in MeOH (30% w/w, 5 mL) and a solution of methyl
3-phenylpyruvate (0.31 g, 1.74 mmol) in MeOH (50 mL). After ad-
dition of I2 (0.22 g, 0.87 mmol) in MeOH (15 mL), the mixture was
stirred for 2 h at r.t., then concd aq NH3 (5 mL) was added and the
solution heated under reflux for 4 h. Re-esterification of the crude
mixture with diazomethane and work-up as usual yielded 5b (0.15
g, 52%) as colorless needles; mp 194–195 °C; Rf = 0.70 (hexanes–
EtOAc, 1:1).
Lycogalic Acid A Dimethyl Ester (4)
A solution of NaOMe in MeOH (30% w/w, 5 mL) was added at
0 °C under argon to a solution of methyl 3-(indol-3-yl)pyruvate
(0.20 g, 0.92 mmol) in anhyd MeOH (40 mL). The mixture was
stirred for 15 min and then treated dropwise with a solution of I2
(0.12 g, 0.46 mmol) in MeOH (20 mL). After warming to r.t., concd
aq ammonia (5 mL) was added and the stirring continued for 30
min. The reaction was completed by heating the solution under re-
flux for 1 h. After addition of EtOAc (100 mL) and neutralization
with 10% aq citric acid, the aq layer was extracted with EtOAc (2 ×
100 mL). The combined organic phases were washed with brine
(100 mL), dried (MgSO4) and concentrated under reduced pressure.
Purification of the residue by FC (hexanes–EtOAc, 1:1) afforded 4
(0.08 g, 42%) as a yellowish resin, which crystallized from MeOH
by addition of H2O. Pale yellow needles, mp 126–127 °C (dec.);
Rf = 0.39 (hexanes–EtOAc, 1:1). The compound was identical with
an authentic sample isolated from L. epidendrum.1
1H NMR (400 MHz, CDCl3): d = 3.73 (s, 6 H, 2 × OCH3), 7.08–7.14
(m, 4 H), 7.16–7.21 (m, 6 H), 9.94 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 51.8 (CH3), 121.3 (C-3), 127.0
(CH-4¢), 127.3 (CH-3¢)*, 130.8 (CH-2¢)*, 131.5 (C-2), 132.9 (C-1¢),
160.8 (* signals may be interchanged).
EI-MS: m/z (%) = 336 (20, [M + H]+), 335 (100, [M]+), 304 (12, [M
– OCH3]+), 303 (54, [M – CH3OH]+), 272 (11, [M + H – 2 ×
CH3OH]+), 270 (5), 245 (12), 244 (19), 217 (15, [M – 2 ×
CO2CH3]+), 216 (15), 214 (11).
HRMS: m/z calcd for C20H17NO4: 335.1158; found: 335.1257.
3,4-Bis(4-hydroxyphenyl)pyrrole-2,5-dicarboxylic Acid (2) and
3-(4-Hydroxyphenyl)-4-phenylpyrrole-2,5-dicarboxylic Acid
(3)
1H NMR (600 MHz, acetone-d6): d = 3.62 (s, 6 H), 6.79 (dd,
n-BuLi (2.5 M solution in hexane, 9.8 mL, 24.4 mmol) was added
at –78 °C to a solution of 3-phenylpyruvic acid (1.00 g, 6.09 mmol)
and 3-(4-hydroxyphenyl)pyruvic acid (1.10 g, 6.09 mmol) in anhyd
THF (200 mL), and the mixture was stirred for 20 min. I2 (1.55 g,
6.09 mmol) dissolved in anhyd THF (20 mL) was then added and
the mixture warmed to r.t. After stirring for 1 h, the solution was sat-
urated with gaseous ammonia in the presence of 4 Å molecular
sieves (2.5 g), and the stirring was continued for 12 h. The turbid so-
lution was made alkaline by addition of 2 N NaOH, washed with
EtOAc (3 × mL), acidified with concd HCl to pH 4, and extracted
with EtOAc (3 × 100 mL). The combined organic extracts were
dried (Na2SO4) and concentrated under reduced pressure. The re-
sulting mixture was separated by preparative HPLC (eluent A:
H2O–MeCN, 9:1; eluent B: MeCN; gradient: start 100% A, 60 min:
100% B; flow rate: 5 mL/min) to yield 3 (100 mg, 5%) and 2 (256
mg, 25%) as yellow-orange solids.
3
3
3
3J = 8.1 Hz, J = 8.1 Hz, 2 H), 6.95 (ddd, J = 8.1, J = 8.1 Hz,
4J = 0.8 Hz, 2 H), 7.16 (d, 3J = 8.1 Hz, 2 H), 7.26 (dd, 3J = 8.1 Hz,
4J = 0.8 Hz, 2 H), 8.00 (br s, 1 H, NH), 9.98 (br s, 2 H, NH).
13C NMR (75 MHz, CDCl3): d = 52.1 (CH3), 108.8, 111.4, 119.7
(CH), 120.5 (CH), 121.9 (CH), 122.9, 125.0 (CH), 125.6, 128.0,
135.9 (CH), 161.4.
FAB-MS: m/z (%) = 414 (48, [M + H]+), 413 (100, [M]+), 382 (7),
350 (22), 295 (5), 257 (5), 144 (5), 130 (5).
FAB-HRMS: m/z calcd for C24H19N3O4: 413.1376; found:
413.1395.
Dimethyl 3,4-Bis(4-methoxyphenyl)pyrrole-2,5-dicarboxylate
(5a)
The same procedure as for the preparation of 4 was used, starting
from NaOMe in MeOH (30% w/w, 2 mL) and a solution of methyl
3-(4-hydroxyphenyl)pyruvate (0.24 g, 1.24 mmol) in MeOH (50
mL). Consecutive treatment with I2 (157 mg, 0.62 mmol) in MeOH
(30 mL) and concd aq NH3 (8 mL) yielded a mixture of 5a and its
hydrolysis products. The residue obtained after the usual work-up
was dissolved in MeOH (40 mL) and treated with a slight excess of
diazomethane in Et2O. After stirring the mixture for 30 min at r.t.,
the excess of diazomethane was destroyed by adding a few drops of
AcOH. The solution was diluted with EtOAc (100 mL), washed
with brine (2 × 75 mL), dried (MgSO4) and filtered. The solvent was
removed under reduced pressure to give the crude product which
was purified by FC (hexanes–EtOAc, 3:1) to yield 5a (125 mg,
60%) as colorless needles; mp 178–179 °C; Rf = 0.67 (hexanes–
EtOAc, 1:1).
2 (HPPD-2)
Mp 93 °C; Rf = 0.21 (toluene–HCO2Et-HCO2H, 10:5:3).
IR (KBr): 3271 (s, br), 2924 (s), 1694 (s), 1614 (m), 1555 (m), 1538
(m), 1514 (m), 1441 (s), 1237 (s), 1173 (s), 1121 (w), 1046 (m),
1024 (s), 992 (s), 824 (w), 787 (w), 764 (w), 737 (m), 540 cm–1 (w).
1H NMR (300 MHz, DMSO-d6): d = 6.53, 6.81 (d each, J = 8.7 Hz,
4 H), 9.20 (br s, 2 H), 11.5 (br s, 1 H), 12.6 (br s, 2 H).
1H NMR (300 MHz, CD3OD): d = 6.61, 6.94 (d each, J = 8.6 Hz, 4
H).
13C NMR (75 MHz, DMSO-d6): d = 114.3 (4 × CH), 122.1 (2 ×),
124.6 (2 ×), 130.4 (2 ×), 132.0 (4 × CH), 156.0 (2 ×), 161.8 (2 ×).
13C NMR (75 MHz, CD3OD): d = 115.3 (4 × CH), 125.1 (2 ×),
127.8 (2 ×), 130.5 (2 ×), 133.4 (4 × CH), 156.5 (2 ×), 167.1 (2 ×).
1H NMR (400 MHz, CDCl3): d = 3.77 (s, 12 H, 4 × OCH3), 6.76,
7.03 (d each, J = 8.8 Hz, 4 H), 9.79 (br s, 1 H, NH).
Synthesis 2007, No. 4, 608–612 © Thieme Stuttgart · New York

PAPER
Synthesis of Simple 3,4-Diarylpyrrole-2,5-dicarboxylic Acids
611
EI-MS: m/z (%) = 339 (3, [M]+), 295 (4), 277 (7), 251 (100), 223
diester, which was purified by preparative HPLC (eluent A: H2O–
(7), 178 (7), 165 (9), 117 (6), 107 (8), 77 (6), 44 (42).
MeCN, 9:1; eluent B: MeCN; gradient: start 100% A, 60 min: 100%
B; flow rate: 5 mL/min) to yield 9 (188 mg, 14%) as a yellow-
orange solid; mp 132 °C; Rf = 0.47 (CH2Cl2–acetone, 20:1).
1H NMR (300 MHz, CDCl3): d = 1.09, 1.14 (t each, J = 7.1 Hz, 3
H), 4.14, 4.17 (q each, J = 7.1 Hz, 2 H), 6.56, 6.91 (d, J = 8.7 Hz, 2
H), 7.02–7.15 (m, 5 H), 9.76 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 14.0 (CH3), 60.9 (2 ×
CH2), 114.8 (2 × CH), 121.4, 121.5, 125.2 126.9 (CH), 127.3 (2 ×
CH), 130.8 (2 × CH), 131.2, 131.4, 132.1 (2 × CH), 133.2, 154.6,
160.5 (2 ×).
HRMS: m/z calcd for C18H13NO6: 339.0743; found: 339.0760.
3 (HPPD-1)
Mp 84 °C; Rf = 0.29 (toluene–HCO2Et-HCO2H, 10:5:3).
IR (KBr): 3414 (br s), 2961 (m), 1690 (s), 1613 (m), 1554 (m), 1485
(m), 1224 (s), 1175 (m), 1127 (m), 992 (m), 918 (w), 843 (m), 789
(m), 763 (w), 700 (m), 634 (w), 556 (w), 532 cm–1 (w).
1H NMR (600 MHz, DMSO-d6): d = 6.52, 6.82 (d each, J = 8.6 Hz,
2 H), 7.03–7.18 (m, 5 H), 9.19 (s, 1 H), 11.6 (s, 1 H), 12.6 (br s, 2 H).
EI-MS: m/z (%) = 380 (23, [M + H]+), 379 (97, [M]+), 334 (19), 333
(77), 261 (28), 260 (32), 233 (33), 232 (21), 220 (17), 194 (14), 191
(15), 176 (9), 106 (10), 105 (100), 91 (23), 85 (11), 83 (17), 77 (27),
51 (10).
(300 MHz, CD3OD): d = 6.56, 6.89 (d each, J = 8.6 Hz, 2 H), 7.10
(m, 2 H), 7.15 (m, 3 H).
13C NMR (151 MHz, DMSO-d6): d = 114.2 (2 × CH), 122.2 (2 ×),
124.3, 126.4 (CH), 127.2 (2 × CH), 130.1, 130.3, 130.9 (2 × CH),
131.9 (2 × CH), 134.3, 156.0, 161.6, 161.7.
Methyl 3-Bromo-3-(4-methoxyphenyl)pyruvate (8b)
To a solution of ethyl 3-(4-methoxyphenyl)pyruvate (3.80 g, 18.0
mmol)15 in anhyd CCl4 (200 mL) was added NBS (2.70 g, 15.0
mmol), and the mixture was irradiated for 20 min with a halogen
lamp (500 W). After cooling to 0 °C, the suspension was filtered
and the orange solution concentrated under reduced pressure. The
crude ester 8b (~5.0 g) was used for the next step without further pu-
rification.
1H NMR (300 MHz, CDCl3): d = 3.68 (s, 3 H), 3.80 (s, 3 H), 6.14
(s, 1 H), 6.82, 7.31 (d each, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 48.8 (CH3), 52.5 (CH), 54.3 (CH3),
113.5 (2 × CH), 123.7, 130.1 (2 × CH), 159.5, 182.4.
(+)-FAB-MS (m-NBA): m/z (%) = 324 (98, [M + H]+), 323 (99,
[M]+), 238 (100).
FAB-HRMS: m/z calcd for C18H13NO5: 323.0794; found: 323.0717.
Lycogalic Acid A (1)
From 3-(indol-3-yl)pyruvic acid (1.00 g, 4.9 mmol), n-BuLi (2.5 M
solution in hexane, 5.9 mL, 14.7 mmol), I2 (0.62 g, 2.45 mmol), and
gaseous NH3 as described in the preceding example. FC (benzene–
HCO2Et–HCO2H, 5:4:1) afforded 1 (0.34 g, 36%) as a beige pow-
der; mp >200 °C. The compound was identical with an authentic
sample isolated from L. epidendrum.1
1H NMR (300 MHz, CD3OD): d = 6.68 (ddd, 3J = 7.9 Hz, 3J = 7.0
3
Hz, 4J = 1 Hz, 2 H), 6.77 (s, 2 H), 6.84 (ddd, 3J = 8.1 Hz, J = 7.0
3,4-Bis(4-methoxyphenyl)pyrrole-2,5-dicarboxylic Acid
Monomethyl Ester (10)
4
3
4
Hz, J = 1 Hz, 2 H), 7.06 (dd, J = 7.9, J = 1 Hz, 2 H), 7.11 (dd,
3J = 8.1 Hz, 4J = 1 Hz, 2 H).
n-BuLi (2.5 M solution in hexane, 20 mL, 50 mmol) was added at
–78 °C to a solution of 3-(4-methoxyphenyl)pyruvic acid (4.85 g,
25 mmol) in anhyd THF (400 mL), and the mixture was stirred for
20 min. A solution of freshly prepared 8b (7.18 g, 25 mmol) in an-
hyd THF (300 mL) was then added dropwise, and, after warming
the mixture to r.t, the stirring was continued for 1 h. The mixture
was then saturated with gaseous NH3 in the presence of 4 Å mol
sieves (5 g) and stirred for 12 h. The turbid solution was made alka-
line by addition of aq 2 N NaOH, washed with EtOAc (3 × 100 mL),
acidified with concd HCl to pH 4, and extracted with EtOAc
(3 × 200 mL). The combined organic extracts were dried (Na2SO4),
concentrated under reduced pressure, and purified by FC to yield 10
(3.20 g, 34%) as colorless crystals; mp 292–295 °C.
1H NMR (300 MHz, CDCl3): d = 3.60 (s, 3 H), 3.70 (s, 6 H), 6.73
(d, J = 8.8 Hz, 4 H), 6.94, 6.96 (d each, J = 8.8 Hz, 2 H), 11.95 (s, 1
H, NH).
13C NMR (75 MHz, CDCl3): d = 52.1 (CH3), 55.7 (2 × CH3), 113.5
(2 × CH), 114.7 (2 ×), 126.5 (4 ×), 126.7, 131.1, 131.6, 132.5 (CH),
132.6 (CH), 158.6, 158.7, 161.2, 162.3.
13C NMR (75 MHz, CD3OD): d = 110.2, 111.7, 119.4 (CH), 121.1
(CH), 121.6 (CH), 125.0, 125.85 (CH), 125.90, 129.4, 137.4 (CH),
165.4.
EI-MS: m/z (%) = 385 (5, [M]+), 368 (40), 267 (31), 175 (36), 148
(79), 147 (21), 140 (18), 133 (14), 130 (100), 117 (31), 90 (12).
FAB-HRMS: m/z calcd for C24H19N3O4: 385.1062; found:
385.1062.
Arcyriaflavin A (7)
To a suspension of 1 (100 mg, 0.26 mmol) in H2O (100 mL) were
added KOH (120 mg), K3Fe(CN)6 (32 mg) and EtOAc (20 mL), and
the mixture was stirred for 13 h at r.t. The dried (MgSO4) organic
phase was then concentrated under reduced pressure and the crude
product purified by preparative TLC (silica gel, CHCl3–MeOH,
20:1). Product 7 was obtained as a pale yellow powder (yield not de-
termined); mp >200 °C. Identical with an authentic sample (UV, 1H
NMR, EI MS, TLC comparison).14
EI-MS: m/z (%) = 382 (22, [M + H]+), 381 (100, [M]+), 363 (30, [M
3-(4-Hydroxyphenyl)-4-phenylpyrrole-2,5-dicarboxylic Acid
Diethyl Ester (9)
– CO]+), 349 (18), 305 (20), 304 (20), 262 (16).
NaH (113 mg, 4.72 mmol) was added at –12 °C to a solution of
ethyl 3-(4-hydroxyphenyl)pyruvate (0.89 g, 4.29 mmol) in anhyd
CH2Cl2 (70 mL). The mixture was allowed to warm to –5 °C, and,
after the H2 evolution had ceased, treated with a solution of freshly
prepared 8a9 (1.16 g, 4.29 mmol) in anhyd CH2Cl2 (60 mL). After
stirring for 20 min at –5 °C, the solution was warmed to r.t. and sat-
urated with gaseous NH3 in the presence of 4 Å molecular sieves (5
g). The mixture was refluxed for 5 h and after keeping overnight at
r.t., filtered and concentrated under reduced pressure. The residue
was dissolved in Et2O (100 mL), washed with 1 M aq KHSO4 (3 ×
50 mL), H2O (50 mL), and brine (50 mL) and dried (MgSO4). Con-
centration of the solution under reduced pressure yielded the crude
Anal. Calcd for C21H19NO6: C, 66.14; H, 5.02; N, 3.67. Found: C,
66.49; H, 5.06; N, 3.64.
Methyl 3,4-Bis(4-methoxyphenyl)pyrrole-2-carboxylate (11)
To a solution of 10 (1.96 g, 5.14 mmol) in freshly distilled quinoline
(40 mL) was added a small portion of Cu chromite, and the mixture
was heated for 10 min at 200 °C. After cooling to r.t., EtOAc (200
mL) was added and the solution washed with sat. aq NaHCO3 (3 ×
100 mL), 2 N HCl (4 × 150 mL), and brine (100 mL), dried
(MgSO4) and concentrated. Purification of the residue by FC (Et2O–
hexanes, 1:1) yielded 11 (1.28 g, 73%) as a yellow oil (Lit.8 mp
Synthesis 2007, No. 4, 608–612 © Thieme Stuttgart · New York

612
C. Hinze et al.
PAPER
169–171 °C). The spectroscopic data agreed with those reported in
the literature.8
102, 461. (b) Howard-Jones, A. R.; Walsh, C. T.
Biochemistry 2005, 44, 15652. (c) Asamizu, S.; Kato, Y.;
Igarashi, Y.; Furumai, T.; Onaka, H. Tetrahedron Lett. 2006,
47, 473. (d) Nishizawa, T.; Grüschow, S.; Jayamaha, D.-H.
E.; Nishizawa-Harada, C.; Sherman, D. H. J. Am. Chem.
Soc. 2006, 128, 724.
Lukianol A Trimethyl Ether (13)
Ketone 12 was prepared from 11 according to the literature.9 Com-
pound 12 (109 mg, 224 mmol), 1-hydroxy-3-(isothiocyan-
ato)tetrabutyldistannoxane12 (228 mg, 224 mmol), and a crystal of
DMAP were dissolved in anhyd benzene (100 mL), and the result-
ing mixture was refluxed for 16 h using a Soxhlet extractor charged
with 4 Å molecular sieves (50 g). Compound 13 (59 mg) was sepa-
rated from starting material 12 (28 mg, 26%) by FC (Et2O–hexanes,
1:1). The yield of 13 was 79%, considering the recovered starting
material. Colorless crystals, mp 206-207 °C (Lit.10 mp 206–
207 °C). The derived spectroscopic data were in good agreement
with those reported in the literature.10
(5) Hosoya, T.; Yamamoto, Y.; Uehara, Y.; Hayashi, M.;
Komiyama, K.; Ishibashi, M. Bioorg. Med. Chem. Lett.
2005, 15, 2776.
(6) Wang, L.; Große, T.; Stevens, H.; Brinkhoff, T.; Simon, M.;
Liang, L.; Bitzer, J.; Bach, G.; Zeeck, A.; Tokuda, H.; Lang,
S. Appl. Microbiol. Biotechnol. 2006, 72, 816.
(7) Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995, 51,
9941.
(8) Friedman, M. J. Org. Chem. 1965, 30, 859.
(9) Okonya, J. F.; Hoffman, R. V.; Johnson, M. C. J. Org. Chem.
2002, 67, 1102.
Acknowledgment
(10) Fürstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995,
60, 6637.
The authors thank the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie for financial support. We thank
Prof. A. Zeeck, Göttingen, for kindly informing us about his work
on the Halomonas metabolites.
(11) (a) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C.
R. Chem. Commun. 1997, 207. (b) Boger, D. L.; Boyce, C.
W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 54. (c) Gupton, J. T.; Krumpe, K. E.; Burnham,
B. S.; Webb, T. M.; Shuford, J. S.; Sikorski, J. A.
Tetrahedron 1999, 55, 14515. (d) Liu, J.-H.; Yang, Q.-C.;
Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65,
3587. (e) Kim, S.; Son, S.; Kang, H. Bull. Korean Chem.
Soc. 2001, 22, 1403. (f) Mathew, P.; Asokan, C. V.
Tetrahedron Lett. 2005, 46, 475.
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Synthesis 2007, No. 4, 608–612 © Thieme Stuttgart · New York